ITEM 1. BUSINESS
Overview
Theravance Biopharma, Inc. ("Theravance Biopharma") is a diversified biopharmaceutical company with the core purpose of creating
medicines that help improve the lives of patients suffering from serious illness.
Our
pipeline of internally discovered product candidates includes potential best-in-class medicines to address the unmet needs of patients being treated for serious conditions primarily
in the acute care setting. VIBATIV® (telavancin), our first commercial product, is a once-daily dual-mechanism antibiotic approved in the U.S., Europe and certain other countries for
certain difficult-to-treat infections. Revefenacin (TD-4208) is a long-acting muscarinic antagonist ("LAMA") being developed as a potential once-daily, nebulized treatment for chronic obstructive
pulmonary disease ("COPD"). Our neprilysin ("NEP") inhibitor program is designed to develop selective NEP inhibitors for the treatment of a range of major cardiovascular and renal diseases, including
acute and chronic heart failure, hypertension and chronic kidney diseases such as diabetic nephropathy. Our research efforts are focused in the areas of inflammation and immunology, with the goal of
designing medicines that provide targeted drug delivery to tissues in the lung and gastrointestinal tract in order to maximize patient benefit and minimize risk. The first program to emerge from this
research is designed to develop intestinally restricted pan-Janus kinase ("JAK") inhibitors for the treatment of a range of inflammatory intestinal diseases.
In
addition, we have an economic interest in future payments that may be made by Glaxo Group Limited or one of its affiliates ("GSK") pursuant to its agreements with
Innoviva, Inc. ("Innoviva") (known as Theravance, Inc. prior to January 7, 2016) relating to certain drug development programs, including the combination of fluticasone furoate,
umeclidinium, and vilanterol (the "Closed Triple"), currently in development for the treatment of COPD and asthma.
2016 Highlights
In 2016, we accomplished a number of key corporate goals directed towards creating medicines to help improve the lives of patients. We reported
positive Phase 1 clinical results for two potentially best-in-class programs: our intestinally restricted JAK inhibitor program for inflammatory intestinal diseases and our NEP inhibitor
program for cardiovascular and renal diseases and progressed candidates from pre-clinical development into early clinical development in our JAK inhibitor program. We completed enrollment in each of
our three studies in the Phase 3 program for revefenacin (TD-4208) in COPD. Of these, we reported positive results from two replicate efficacy studies while the long term safety study remains
ongoing. We progressed two other key programs in Phase 2 clinical development: our highly selective 5-HT4 receptor agonist velusetrag (TD-5108) in gastroparesis, for which we received Fast
Track designation from the Food and Drug Administration
("FDA") for the treatment of symptoms associated with idiopathic and diabetic gastroparesis, and our norepinephrine and serotonin reuptake inhibitor (NSRI) TD-9855 in neurogenic orthostatic
hypotension ("nOH"). We entered into a global license, development and commercialization agreement with Millennium Pharmaceuticals, Inc., a subsidiary of Takeda Pharmaceutical Company Limited
(together, "Takeda") for TD-8954, a selective 5-HT4 receptor agonist for the treatment of enteral feeding intolerance and other gastrointestinal motility disorders. We also continued to execute our
commercial strategy for VIBATIV including the progression of the Telavancin Observational Use Registry (TOUR
TM
), a patient registry study designed to assess how VIBATIV is being used in
real-world clinical settings, and the Phase 3 bacteremia study designed to expand the product's existing label. Finally, we strengthened our balance sheet through public offerings, the proceeds
of which are intended for general corporate purposes including the support of key programs and objectives.
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Our Programs
The table below summarizes the status of our approved product and our most advanced product candidates in development. Our research and
development activities are concentrated primarily on four therapeutic areasinfectious disease, respiratory, gastrointestinal disease and cardiovascular and renal diseaseand
our commercial infrastructure is focused primarily on the acute care setting. The table also includes the status of the respiratory programs in which we have an economic interest and are being
developed by GSK pursuant to agreements between Innoviva and GSK ("GSK-Partnered Respiratory Programs"). These programs consist of the Closed Triple program, the Inhaled Bifunctional Muscarinic
Antagonist-Beta2 Agonist ("MABA") program and other future products that may be combined with Closed Triple or MABA. We have an economic interest in these programs through our interest in Theravance
Respiratory Company, LLC ("TRC"), a limited liability company managed by Innoviva. The status of all GSK programs referenced in this Annual Report on Form 10-K solely reflects publicly
available information.
-
*
-
R-Pharm
is conducting a Phase 3 clinical study of TD-1792 in complicated skin and soft tissues infections (cSSSI), caused by gram-positive bacteria with
clinical sites in the Russian Federation and the country of Georgia. Not currently under development in the United States.
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-
**
-
The
information regarding the Closed Triple and the MABA programs are based solely upon publicly available information and may not reflect the most recent
developments under the programs.
Glossary of Defined Terms used in Table Above:
CNS:
Central Nervous System;
COPD:
Chronic Obstructive Pulmonary Disease;
cSSSI:
Complicated Skin and Skin Structure Infections;
FDC:
Fixed Dose Combination;
FF:
Fluticasone Furoate;
GI:
Gastrointestinal;
HABP/VABP:
Hospital-Acquired and Ventilator-Associated Bacterial Pneumonia;
HCV:
Hepatitis C Virus;
ICS:
Inhaled Corticosteriod;
MABA:
Bifunctional Muscarinic Antagonist-Beta
2
Agonist;
MRSA:
Methicillin-Resistant Staphylococcus Aureus;
nOH:
Neurogenic Orthostatic Hypotension;
OIC:
Opioid Induced Constipation;
UMEC:
Umeclidinium;
VI:
Vilanterol;
Status:
The most advanced stage of clinical development that has been completed or is in process;
Phase 1:
initial clinical safety testing into patients or healthy human volunteers, or studies directed toward understanding the mechanisms of
action of the drug;
Phase 2:
further clinical safety testing and preliminary efficacy testing in a limited patient population;
Phase 3:
evaluation of clinical efficacy and safety within an expanded patient population;
Filed:
a marketing application has been submitted to a regulatory authority; and
Approved:
approved for marketing.
Program Highlights
VIBATIV® (telavancin)
VIBATIV is a bactericidal, once-daily injectable antibiotic to treat patients with serious, life-threatening infections due to
Staphylococcus
aureus
and other Gram-positive bacteria, including methicillin-resistant ("MRSA") strains. VIBATIV is approved in the U.S. for the
treatment of adult patients with complicated skin and skin structure infections ("cSSSI") caused by susceptible Gram-positive bacteria and for the treatment of adult patients with hospital-acquired
and ventilator-associated bacterial pneumonia ("HABP"/ "VABP") caused by susceptible isolates of
Staphylococcus aureus
when alternative treatments are
not suitable. VIBATIV is indicated in the European Union ("EU") for the treatment of adults with nosocomial pneumonia, including ventilator-associated
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pneumonia,
known or suspected to be caused by MRSA when other alternatives are not suitable. VIBATIV is also indicated in Canada and Russia for cSSSI and HABP and VABP caused by Gram-positive
bacteria, including MRSA.
Our
focused acute care sales force currently markets VIBATIV in the U.S., and we maintain an independent sales, marketing, and medical affairs team. Outside of the U.S., our strategy is
to market VIBATIV through a network of partners. To date, we have secured partners for VIBATIV in the following geographiesCanada, Middle East and North Africa, Israel, Russia, China and
India. In August 2016, we and Clinigen Group ("Clinigen") reached a mutual decision for Clinigen to return commercial rights to market and distribute VIBATIV in the EU to Theravance Biopharma. On
November 4, 2016, the European Commission approved the transfer of the centralized marketing authorization for VIBATIV from Clinigen to our wholly-owned Irish subsidiary, Theravance Biopharma
Ireland Limited. We are in discussion with potential collaborators with the goal of establishing a new strategic commercial partnership in the EU.
Supplemental New Drug Application (sNDA) for Concurrent Staphylococcus aureus Bacteremia
In May 2016, we announced approval of our sNDA by the FDA allowing for the addition of new clinical data to the VIBATIV label concerning
concurrent bacteremia in cases of HABP/VABP and cSSSI. The sNDA submission was based on the combined data from our previously conducted pivotal trials of VIBATIV in its two approved
indicationscSSSI (ATLAS I and ATLAS II) and HABP/VABP (ATTAIN I and ATTAIN II). The trials were large, multi-center, multi-national, double-blind, randomized Phase 3
clinical studies enrolling and treating 3,370 adult patients, including a portion of patients with concurrent bacteremia. Importantly, these studies involved two of the largest cohorts of patients
ever studied in these diseases and included one of the largest cohorts of patients with MRSA infections studied to date. Separately, we are conducting a Phase 3 registrational study in patients
with
Staphylococcus aureus
bacteremia.
Phase 3 Registrational Study in Staphylococcus aureus Bacteremia
As part of our effort to explore additional settings in which VIBATIV may offer patients therapeutic benefit, in February 2015, we initiated a
Phase 3 registrational study for the treatment of patients with
Staphylococcus aureus
bacteremia. The 250-patient registrational study is a
multi-center, randomized, open-label study designed to evaluate the non-inferiority of telavancin in treating
Staphylococcus aureus
bacteremia as
compared to standard therapy. Key secondary outcome measures of the study include an assessment of the duration of bacteremia post-randomization and the incidence of development of metastatic
complications, as compared to standard therapy. We expect to complete the study in 2018.
Telavancin Observational Use Registry ("TOUR
TM
") Study
Initiated in February 2015, the 1,000-patient TOUR
TM
study is designed to assess the manner in which VIBATIV is used by healthcare
practitioners to treat patients. By broadly collecting and examining data related to VIBATIV treatment patterns, as well as clinical and safety outcomes in the real world, we aim to create an
expansive knowledge base to guide future development and optimal use of the drug. In February 2017, we announced that enrollment in the TOUR
TM
study was complete.
In
October 2016, we announced interim data from the TOUR
TM
study. An initial review of data from the first 200 patients enrolled in TOUR demonstrate clinical response rates
of 74% in a range of difficult-to-treat infection types including HABP/VABP, cSSSI, bone and joint infections and bacteremia. Results show 17% of the first 200 patients were considered non-evaluable
with 9% deemed to have failed treatment. Clinical response was defined as cure or improvement leading to step-down oral therapy.
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In
January 2017, we announced interim data from the TOUR
TM
study, focused on a subset of registry patients with diagnoses of bacteremia or infective endocarditis. Data
demonstrated positive clinical responses in 64% of patients, with 7% of patients failing treatment and 29% considered non-evaluable. Positive clinical response was defined as cure or improvement
leading to step-down oral therapy.
Long-Acting Muscarinic AntagonistRevefenacin (TD-4208)
Revefenacin is an investigational long acting muscarinic antagonist ("LAMA") in development for the treatment of COPD. We believe that
revefenacin may become a valuable addition to the COPD treatment regimen and that it represents a significant commercial opportunity. Our market research indicates there is an enduring population of
COPD patients in the U.S. that either need or prefer nebulized delivery for maintenance therapy. LAMAs are a cornerstone of maintenance therapy for COPD, but existing LAMAs are only available in
handheld devices that may not be suitable for every patient. Revefenacin has the potential to be a best-in-class once-daily single-agent product for COPD patients who require, or prefer, nebulized
therapy. The therapeutic profile of revefenacin,
together with its physical characteristics, suggest that this LAMA could serve as a foundation for combination products and for delivery in metered dose inhaler and dry powder inhaler products.
Mylan Collaboration
In January 2015, Mylan Ireland Limited ("Mylan") and we established a strategic collaboration for the development and, subject to regulatory
approval, commercialization of revefenacin. Partnering with a world leader in nebulized respiratory therapies enables us to expand the breadth of our revefenacin development program and extend our
commercial reach beyond the acute care setting where we currently market VIBATIV. Funding of the Phase 3 development program by Mylan strengthens our capital position and enhances our financial
flexibility to advance other high-value pipeline assets alongside revefenacin.
Under
the terms of the Mylan Development and Commercialization Agreement (the "Mylan Agreement"), Mylan and we are co-developing nebulized revefenacin for COPD and other respiratory
diseases. We are leading the U.S. Phase 3 development program and Mylan is responsible for reimbursement of our costs related to the registrational program up until the approval of the first
new drug application, after which costs will be shared. If a product developed under the collaboration is approved in the U.S., Mylan will lead commercialization and we will retain the right to
co-promote the product in the U.S. under a profit-sharing arrangement (65% Mylan/35% Theravance Biopharma). Outside the U.S. (excluding China), Mylan will be responsible for development and
commercialization and will pay us a tiered royalty on net sales at percentage royalty rates ranging from low double-digits to mid-teens.
Under
the Mylan Agreement, Mylan paid us an initial payment of $15.0 million in cash in the second quarter of 2015. Also, pursuant to an ordinary share purchase agreement entered
into on January 30, 2015, Mylan Inc., the indirect parent corporation of Mylan, made a $30.0 million equity investment in us, buying 1,585,790 ordinary shares from us in early
February 2015 in a private placement transaction at a price of approximately $18.918 per share, which represented a 10% premium over the volume weighted average price per share of our ordinary shares
for the five trading days ending on January 30, 2015. In February 2016, we earned a $15.0 million development milestone payment for achieving 50% enrollment in the Phase 3
twelve-month safety study. As of December 31, 2016, we are eligible to receive from Mylan additional potential development, regulatory and sales milestone payments totaling up to
$205.0 million in the aggregate, with $160.0 million associated with revefenacin monotherapy and $45.0 million for future potential combination products. Of the
$160.0 million associated with monotherapy, $150.0 million relates to commercialization and
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$10.0 million
relates to regulatory actions in the EU. We do not expect to earn any milestone payments from Mylan in 2017.
We
retain worldwide rights to revefenacin delivered through other dosage forms, such as a metered dose inhaler or dry powder inhaler ("MDI"/"DPI"), while Mylan has certain rights of
first negotiation with respect to our development and commercialization of revefenacin delivered other than via a nebulized inhalation product.
Phase 3 Study in COPD
In September 2015, we announced, with our partner Mylan, the initiation of the Phase 3 development program for revefenacin for the
treatment of COPD. The Phase 3 development program, designed to support the registration of the product in the U.S., includes two replicate three-month efficacy studies and a single
twelve-month safety study. The two efficacy studies examined 2 doses (88 mcg and 175 mcg) of revefenacin inhalation solution administered once-daily via nebulizer in patients with moderate to severe
COPD. The Phase 3 efficacy studies were replicate, randomized, double-blind, placebo-controlled, parallel-group trials designed to provide pivotal efficacy and safety data for once-daily
revefenacin over a dosing period of 12 weeks, with a primary endpoint of trough forced expiratory volume in one second (FEV1) on day 85. The Phase 3 safety study is an open-label, active
comparator study of 12 months duration. In February 2016, we announced the achievement of 50% enrollment in all three of the Phase 3 clinical studies for revefenacin. The achievement of
50% enrollment in the twelve-month safety study triggered a $15.0 million milestone payment to us by Mylan.
In
October 2016, we announced positive top line results from the two replicate Phase 3 efficacy studies of revefenacin in more than 1,250 moderate to very severe COPD patients.
Both Phase 3 efficacy studies met their primary endpoints, demonstrating statistically significant improvements over placebo in trough forced expiratory volume in one second (FEV1) after
12 weeks of dosing for each of the revefenacin doses studied (88 mcg once daily and 175 mcg once daily). The studies also demonstrated that the 88 mcg and 175 mcg doses of revefenacin were
generally well-tolerated, with comparable rates of adverse events and serious adverse events across all treatment groups (active and placebo). In addition to the two efficacy studies, the safety study
has enrolled more than 1,050 patients and is expected to be completed in mid-2017. Together, the three studies enrolled approximately 2,300 patients. Should results from the safety study be
supportive, we expect to file a new drug application for revefenacin with the FDA by the end of 2017.
Velusetrag (TD-5108)
Velusetrag is an oral, investigational medicine developed for gastrointestinal motility disorders. It is a highly selective agonist with high
intrinsic activity at the human 5-HT4 receptor. Velusetrag is being developed in collaboration with Alfa Wassermann S.p.A. ("Alfa Wassermann") in a two-part Phase 2 program to test the
efficacy, safety and tolerability of velusetrag in the treatment of patients with gastroparesis. Positive top-line results from the initial Phase 2 proof-of-concept study under this
partnership, which evaluated gastric emptying, safety and tolerability of multiple doses of velusetrag, were announced in April 2014. In March 2015, we initiated a Phase 2b study of velusetrag
for the treatment of patients with gastroparesis. The 200-patient study is a multi-center, double-blind, randomized, placebo-controlled, parallel-group trial which will explore the efficacy and safety
of multiple doses of velusetrag in patients with diabetic or idiopathic gastroparesis. The twelve-week study will test three doses: 5, 15, and 30 mg administered once-daily. The primary endpoint will
be the effect of velusetrag on symptoms in subjects with gastroparesis. The study will also evaluate the effect of velusetrag on gastric emptying, and the psychometric properties of the Gastroparesis
Rating Scale, a daily patient-reported outcome measure. In February 2017, we announced the completion of enrollment in the study. We currently expect results from the Phase 2b study in
mid-2017. Pursuant to our
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agreement
with Alfa Wassermann, the first Phase 2 study was, and the majority of the Phase 2b study is, funded by Alfa Wassermann.
In
December 2016, the FDA granted Fast Track designation to velusetrag for the treatment of symptoms associated with idiopathic and diabetic gastroparesis. The FDA's Fast Track program
was established to facilitate the development and expedite the review of drugs with the potential to treat serious conditions and address an unmet medical need.
TD-9855
TD-9855 is an investigational norepinephrine and serotonin reuptake inhibitor (NSRI). TD-9855 completed a Phase 2 study in patients with
fibromyalgia, demonstrating statistically significant and clinically meaningful improvements in pain and core symptoms at the highest dose tested compared to placebo. We are assessing the potential
use of TD-9855 in neurogenic orthostatic
hypotension (nOH), and in May 2016, we initiated a Phase 2a study of TD-9855 in this indication. The 30 patient study is a randomized, two-part, single- and double-blind trial conducted in male
and female subjects with nOH to evaluate the effect of TD-9855 in improving symptoms of nOH. The Phase 2a study is designed to evaluate postural changes in blood pressure, symptom reduction, and
safety and tolerability. In February 2017, we announced our plan to amend the protocol of the Phase 2a study to allow patients who respond to continue beyond a single dose. We currently expect
to complete the extended Phase 2a study by the end of 2017.
Oral Peripherally-Acting Mu Opioid Receptor AntagonistAxelopran (TD-1211)
OIC Program
Axelopran is an investigational, once-daily, oral peripherally-active mu opioid receptor antagonist for opioid- induced constipation ("OIC").
The axelopran Phase 2 program demonstrated a clinically meaningful treatment effect in OIC patients compared to placebo. The goal for this program is to demonstrate the ability to normalize
bowel function without impacting analgesia and improve a variety of GI symptoms associated with constipation, which could provide axelopran with a competitive advantage in the OIC market if
demonstrated in Phase 3 studies and approved by regulatory authorities. We have developed a patient reported outcomes tool designed to measure patient symptoms which would be used in a
Phase 3 registrational program and potentially generate data that could differentiate the product from the competition.
Fixed Dose Combination
In December 2014, we completed a Phase 1 study to determine the relative bioavailability of OxyContin® (oxycodone) and
axelopran after oral administration as a fixed dose combination ("FDC") relative to the individual components administered together. The study examined a spray-coat application of axelopran to an
opioid, OxyContin, to determine the effect of axelopran on OxyContin exposure. The study compared exposure of OxyContin alone, axelopran alone, OxyContin and axelopran administered as two separate
tablets, and OxyContin spray-coated with axelopran in a FDC. Study results demonstrated that axelopran does not significantly alter systemic exposure to OxyContin when delivered as a FDC relative to
when co-administered as individual tablets.
A FDC of axelopran and an opioid could present an important market opportunity, as it has the potential to provide pain relief without constipation in a single abuse-deterrent pill for patients using
opioids on a chronic basis.
NS5A InhibitorTD-6450
TD-6450 is a multivalent NS5A inhibitor. TD-6450 has successfully completed Phase 1 studies in both healthy volunteers and hepatitis C
virus ("HCV") patients. In September 2015, we entered into a licensing agreement with Trek Therapeutics, PBC ("TREKtx") (the "TREKtx Agreement") granting
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TREKtx
an exclusive worldwide license for the development, manufacturing, use, marketing and sale of TD-6450 as a component in combination HCV products (the "HCV Products"). Pursuant to the TREKtx
Agreement, we received an upfront payment of $8.0 million in the form of TREKtx's Series A preferred stock and will be eligible to receive future royalties based on net sales of the HCV
Products. In October 2015, TREKtx initiated an open-label Phase 2a clinical trial to evaluate faldaprevir ("FDV"), an HCV protease inhibitor, combined with TD-6450 and ribavirin ("RBV") in
patients infected with HCV genotype 4. In September 2016, TREKtx announced interim data from the study that showed the sustained viral response (SVR) rate four weeks after the completion of
treatment (SVR4) was 100% (16 of 16) in treatment naïve patients with chronic genotype 4 HCV who received 120 mg of FDV and RBV in combination with 60 mg or 120 mg of
TD-6450 for 12 weeks. In February 2017, TREKtx announced that 100% of these patients (16 of 16) had maintained SVR at twelve weeks after the completion of treatment (SVR12) as well. TREKtx is
conducting a second Phase 2a study of FDV and TD-6450, with and without RBV in patients with HCV genotype 1b. In the ongoing study, TREKtx reported that 14 out of 15 patients in the
study arm containing RBV achieved SVR4.
Neprilysin (NEP) Inhibitor Program (TD-0714 and TD-1439)
Neprilysin ("NEP") is an enzyme that degrades natriuretic peptides. These peptides play a protective role in controlling blood pressure and
preventing cardiovascular tissue remodeling. Inhibiting NEP may result in clinical benefit for patients, including diuresis, control of blood pressure, and reversing maladaptive changes in the heart
and vascular tissue in patients with
congestive heart failure. Our primary objective is to develop a NEP inhibitor that could be used across a broad population of patients with cardiovascular and renal diseases, including acute and
chronic heart failure and chronic kidney disease, including diabetic nephropathy. We aim to create a platform for multiple combination products with our NEP inhibitor with features that are
differentiated from currently available products. Specifically, we intend to develop compounds that are non-renally cleared, dosed once-daily, dosed alone or in combination with other medicines and
that may be dosed orally or intravenously.
TD-0714
Phase 1 Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) Studies
In March 2016, we completed a Phase 1 randomized, double-blind, placebo-controlled, single ascending dose ("SAD") study in healthy
volunteers of our most advanced NEP inhibitor compound, TD-0714. The study was designed to assess the safety, tolerability and pharmacokinetics of TD-0714, as well as measure biomarker evidence of
target engagement and the amount of the drug that is eliminated via the kidneys. Results from the SAD study of TD-0714 demonstrate that the compound achieved maximal and sustained levels of target
engagement for 24 hours after a single-dose, supporting the drug's potential for once-daily dosing. Target engagement was measured by dose-related increases in the levels of cyclic GMP (cGMP, a
well-precedented biomarker of NEP engagement). TD-0714 also demonstrated very low levels of renal elimination, as evidenced by intravenous microtracer testing technology, and a favorable tolerability
profile. These results met our target product profile and provide confidence for future efficacy studies of TD-0714 in a broad range of cardiovascular and renal diseases, including in patients with
compromised renal function.
In
October 2016, we completed a Phase 1 randomized, double-blind, placebo-controlled, multiple ascending dose ("MAD") study in healthy volunteers of TD-0714. The findings from the
MAD study were consistent with the Phase 1 randomized, double-blind, placebo-controlled, SAD study in healthy volunteers we completed in March 2016, demonstrating sustained target engagement,
low levels of renal elimination, and a favorable tolerability profile. Findings from the studies support clinical progression of TD-0714, which potential studies are being evaluated in the context of
our overall NEPi program.
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TD-1439
In September 2016, we progressed a second NEP inhibitor compound, TD-1439, which is structurally distinct from TD-0714, into Phase 1
randomized, double-blind, placebo-controlled, SAD and MAD studies in healthy volunteers. In February 2017, we announced favorable results from the Phase 1 SAD study. In this study, TD-1439
demonstrated characteristics consistent with our target product profile, including sustained 24-hour target engagement, low levels of renal elimination and a favorable tolerability profile. We expect
to complete the Phase 1 MAD study in the first half of 2017.
We
are currently evaluating next steps for the compounds in our NEPi clinical program, including compound and formulation selection, potential combinations, study population, and timing.
Intestinally Restricted Pan-Janus Kinase (JAK) Inhibitor Program (TD-1473 and TD-3504)
JAK inhibitors function by inhibiting the activity of one or more of the Janus kinase family of enzymes (JAK1, JAK2, JAK3, TYK2) that play a key
role in cytokine signaling. Inhibiting these JAK enzymes interferes with the JAK/STAT signaling pathway and, in turn, modulates the activity of a wide range of pro-inflammatory cytokines. JAK
inhibitors are currently approved for the treatment of rheumatoid arthritis and myelofibrosis and have demonstrated therapeutic benefit for patients with ulcerative colitis. However, these
products are known to have side effects based on their systemic exposure. Our goal is to develop an orally administered, intestinally restricted pan-JAK inhibitor specifically designed to distribute
adequately and predominantly to the tissues of the intestinal tract, treating inflammation in those tissues while minimizing systemic exposure. We are focused on utilizing targeted JAK inhibitors for
potential treatment of a range of inflammatory intestinal diseases including ulcerative colitis.
TD-1473
Phase 1 Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) Studies
In June 2016, we completed a Phase 1 clinical study of TD-1473, an internally-discovered JAK inhibitor that has demonstrated a high
affinity for each of the JAK family of enzymes. The primary objective of the study was to evaluate the safety and tolerability of single ascending and multiple ascending doses of TD-1473 in healthy
volunteers. A key secondary objective of the trial was to characterize the pharmacokinetics of TD-1473, including the determination of the amount of TD-1473 that entered systemic circulation following
oral administration. Data from the study demonstrated TD-1473 to be generally well tolerated. Study results also demonstrated that systemic exposures of TD-1473 were low relative to that reported for
tofacitinib, a JAK inhibitor currently in development for ulcerative colitis. At steady state, the plasma exposures of TD-1473 were significantly lower than the plasma exposure of tofacitinib.
Furthermore,
subjects exhibited high stool concentrations of TD-1473, which were comparable to concentrations associated with efficacy in preclinical colitis models. Preclinical studies
also demonstrated penetration of TD-1473 into the intestinal wall and membrane. The data generated from the study met our target pharmacokinetic profile and support clinical progression of the
compound.
Previously
announced findings from a preclinical model of colitis evaluating TD-1473 and tofacitinib demonstrated that both compounds significantly reduced disease activity scores.
However, at doses providing similar preclinical efficacy, the systemic exposure of TD-1473 was much lower than that of tofacitinib and TD-1473 did not reduce systemic immune cell counts, in contrast
to tofacitinib. Based on these preclinical findings, we believe that TD-1473 represents a potential breakthrough approach to treating ulcerative colitis without the risk generally associated
with systemically active therapies.
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Phase 1b Study
In October 2016, we announced dosing of the first patient in a Phase 1b clinical study of TD-1473 in patients with moderate to
severe ulcerative colitis. The multi-center, randomized, double-blind, multi-dose, placebo-controlled study is designed to enroll 40 patients randomized to receive one of three doses of TD-1473
or placebo administered for 28 days in sequential fashion. The primary objectives of the study will include evaluation of the safety and tolerability of TD-1473 administered for 28 days,
as well as assessment of the compound's plasma exposure following administration. A key secondary objective of the study will be the evaluation of the effect of TD-1473 on levels of a range of
key ulcerative colitis biomarkers, including C-reactive protein and fecal calprotectin. Additionally, investigators are expected to evaluate a number of exploratory objectives, including
changes in partial Mayo score and improvement in disease activity through endoscopic and histologic assessments. We expect data from the Phase 1b study in mid-2017. Also in October 2016, we
announced that we had successfully completed the TD-1473 13-week toxicology studies, clearing the compound to progress to longer term clinical studies.
TD-3504
In September 2016, we announced plans to progress a second compound, TD-3504, from our JAK inhibitor program. TD-3504 is an innovative prodrug
of tofacitinib, an investigational JAK inhibitor in development for ulcerative colitis. TD-3504 is chemically distinct from TD-1473 and is designed to release active tofacitinib into the
intestinal tract. In preclinical studies, TD-3504 demonstrated rapid formation of tofacitinib in the intestinal tract, reduction in disease activity score comparable to tofacitinib, and low systemic
exposure in contrast to tofacitinib. We plan to initiate a Phase 1 study of TD-3504 in healthy volunteers and ulcerative colitis patients in the first half of 2017.
Selective 5-HT4 Agonist (TD-8954)
Takeda Collaborative Arrangement
In June 2016, we entered into a License and Collaboration Agreement with Millennium Pharmaceuticals, Inc., a Delaware corporation
("Millennium") (the "Takeda Agreement"), in order to establish a collaboration for the development and commercialization of TD-8954, a selective 5-HT4 receptor agonist. Prior to the Takeda Agreement,
we developed TD-8954 for potential use in the treatment of gastrointestinal motility disorders, including short-term intravenous use for enteral feeding intolerance ("EFI") to achieve early
nutritional adequacy in critically ill patients at high nutritional risk, an indication for which the compound received FDA Fast Track designation. Millennium is an indirect wholly-owned subsidiary of
Takeda Pharmaceutical Company Limited (TSE: 4502), a publicly-traded Japanese corporation listed on the Tokyo Stock Exchange (collectively with Millennium, "Takeda"). Under the terms of the Takeda
Agreement, Takeda will be responsible for worldwide development and commercialization of TD-8954. We received an upfront cash payment of $15.0 million and will be eligible to receive
success-based development, regulatory and sales milestone payments by Takeda. The first $110.0 million of potential milestones are associated with the development, regulatory and commercial
launch milestones for EFI or other intravenously dosed indications. We will also be eligible to receive a tiered royalty on worldwide net sales by Takeda at percentage royalty rates ranging from low
double-digits to mid-teens.
Other Programs
Economic Interest in GSK-Partnered Respiratory Programs
We are entitled to receive an 85% economic interest in any future payments that may be made by GSK (pursuant to its agreements with Innoviva)
relating to certain of the respiratory programs (the "GSK-Partnered Respiratory Programs") that Innoviva partnered with GSK and assigned to Theravance
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Respiratory
Company, LLC ("TRC") in connection with Innoviva's separation of its biopharmaceutical operations into its then wholly-owned subsidiary Theravance Biopharma (the "Spin-Off"). The
GSK-Partnered Respiratory Programs consist primarily of the Closed Triple program and the Inhaled Bifunctional Muscarinic Antagonist-Beta2 Agonist ("MABA") program, each of which are described in more
detail below. We are entitled to this economic interest through our equity ownership in TRC. Our economic interest will not include any payments associated with RELVAR®
ELLIPTA®/BREO® ELLIPTA®, ANORO® ELLIPTA® or vilanterol monotherapy. The following information regarding the Closed Triple and the MABA
program is based solely upon publicly available information and may not reflect the most recent developments under the programs.
"Closed Triple" or FF/UMEC/VI (fluticasone furoate/umeclidinium bromide/vilanterol)
The Closed Triple program seeks to provide the activity of an inhaled corticosteroid (FF) plus two bronchodilators (UMEC, a LAMA, and VI, a
long-acting beta2 agonist, or LABA) in a single delivery device administered once-daily. If the Closed Triple is successfully developed and commercialized, we are entitled to receive an 85% economic
interest in the royalties
payable by GSK to TRC on worldwide net sales, which royalties are upward-tiering from 6.5% to 10%. Previously, Innoviva and GSK announced the initiation of two global pivotal Phase 3 studies of
the Closed Triple. The IMPACT study, which will enroll approximately 10,000 COPD patients, was initiated in July 2014. The IMPACT study will assess whether the Closed Triple can reduce the rate of
moderate and severe exacerbations compared with two approved once-daily COPD treatments, RELVAR® ELLIPTA®/BREO® ELLIPTA® (FF/VI), an ICS/LABA
combination, and ANORO® ELLIPTA® (UMEC/VI), a LAMA/LABA combination. The IMPACT study is ongoing and is expected to read out in 2017. The FULFIL study, which enrolled
approximately 1,800 COPD patients was initiated in February 2015. In June 2016, GSK and Innoviva disclosed positive top-line results from the FULFIL study, in which data demonstrated superiority of
the Closed Triple as compared to twice-daily SYMBICORT® TURBOHALER® (budesonide/formoterol) in improving lung function and health-related quality of life in COPD patients. In
November 2016, GSK and Innoviva announced the filing of a New Drug Application ("NDA") in the U.S. for the Closed Triple for patients with COPD. In December 2016, GSK and Innoviva announced the filing
of a Marketing Authorization Application ("MAA") in the EU for the Closed Triple for patients with COPD. In December 2016, GSK and Innoviva announced the initiation of the Phase 3 (CAPTAIN)
study of the Closed Triple in patients with asthma. The CAPTAIN study is expected to read out in 2018.
Inhaled Bifunctional Muscarinic Antagonist-Beta2 Agonist (MABA)
GSK961081 ('081), also known as batefenterol, is an investigational, single-molecule bifunctional bronchodilator with both muscarinic antagonist
and beta2 receptor agonist activity that was discovered by us when we were part of Innoviva.
If
a single-agent MABA medicine containing '081 is successfully developed and commercialized, we are entitled to receive an 85% economic interest in the royalties payable by GSK to TRC
on worldwide net sales, which royalties range between 10% and 20% of annual global net sales up to $3.5 billion, and 7.5% for all annual global net sales above $3.5 billion. If a MABA
medicine containing '081 is commercialized only as a combination product, such as '081/FF, the royalty rate is 70% of the rate applicable to sales of the single-agent MABA medicine. If a MABA medicine
containing '081 is successfully developed and commercialized in multiple regions of the world, TRC is eligible to receive contingent milestone payments from GSK. The agreements allow for total
milestones of up to $125.0 million for a single-agent medicine and an incremental $125.0 million for a combination medicine. Of these amounts, $112.0 million in potential
milestones remain for a single-agent medicine, and $122.0 million remain for a combination medicine. In each case, we would be entitled to receive an 85% economic interest in any such payments.
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Theravance Respiratory Company, LLC
Prior to the June 1, 2014 separation of its biopharmaceutical operations into its then wholly-owned subsidiary Theravance Biopharma (the
"Spin-Off"), Innoviva assigned to TRC its strategic alliance agreement with GSK and all of its rights and obligations under its LABA collaboration agreement with GSK other than with respect to
RELVAR® ELLIPTA®/BREO® ELLIPTA®, ANORO® ELLIPTA® and vilanterol monotherapy. Our equity interest in TRC is the mechanism by
which we are entitled to the 85% economic interest in any future payments made by GSK under the strategic alliance agreement and under the portion of the collaboration agreement assigned to TRC. The
drug programs assigned to TRC include the Closed Triple and the MABA program, as monotherapy and in combination with other therapeutically active components, such as an inhaled corticosteroid ("ICS"),
as well as any other product or combination of products that may be discovered and developed in the future under these GSK agreements.
Our Strategy
Our mission is to create value from a diverse and distinctive portfolio of assets: an approved product, a pipeline with assets at all stages of
development, and a productive research platform designed for long-term growth. With our successful drug discovery and development track record, commercial infrastructure, experienced management team
and efficient corporate structure, we believe that we are well positioned to create value for our shareholders and make a difference in the lives of patients.
We
follow these core guiding principles in our mission to drive value creation:
-
-
Focus on insight and innovation;
-
-
Outsource non-core activities;
-
-
Create and foster an integrated environment; and
-
-
Aggressively manage uncertainty.
Our
research and development activities are concentrated primarily on four therapeutic areasinfectious disease, respiratory, gastrointestinal disease and cardiovascular and
renal diseaseand we have established a commercial infrastructure focused primarily on the acute care setting. We manage our pipeline with the goal of optimizing program value and
allocation of resources. We employ multiple strategies for commercialization of our products. Our approach may involve retaining product rights and marketing a product independently in the U.S.,
predominantly in the acute care setting, or we may partner a product to extend our commercial reach beyond the acute care setting, to expand our geographic reach, and/or to manage the financial risk
associated with the program. Alternatively, we may monetize or divest an asset that we designate as outside our core business, where we believe the program is optimized by leveraging partner
capabilities and removing or limiting our research and development costs.
Manufacturing
We rely primarily on a network of third-party manufacturers, including contract manufacturing organizations, to produce our active
pharmaceutical ingredient ("API") and our drug product. We believe that we have in-house expertise to manage this network of third-party manufacturers and we believe that we will be able to continue
to negotiate third-party manufacturing arrangements on commercially reasonable terms and that it will not be necessary for us to obtain internal manufacturing capacity in order to develop or
commercialize our products. However, if we are unable to obtain contract manufacturing or obtain such manufacturing on commercially reasonable terms, or if
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manufacturing
is interrupted at one of our suppliers, whether due to regulatory or other reasons, we may not be able to develop or commercialize our products as planned.
We
have a single source of supply of API for telavancin and another, separate single source of supply of VIBATIV drug product. If, for any reason, either single-source third-party
manufacturer of telavancin API or of VIBATIV drug product is unable or unwilling to perform, or if the performance of either does not meet regulatory requirements, including maintaining current Good
Manufacturing Practice ("cGMP") compliance, we may not be able to locate alternative manufacturers, enter into acceptable agreements with them or obtain sufficient quantities of API or drug product in
a timely manner. Any inability to acquire sufficient quantities of API or drug product in a timely manner from current or future sources would adversely affect the commercialization of VIBATIV.
Government Regulation
The development and commercialization of VIBATIV and our product candidates by us and our collaboration partners and our ongoing research are
subject to extensive regulation by governmental authorities in the United States and other countries. Before marketing in the United States, any medicine must undergo rigorous preclinical studies and
clinical studies and an extensive regulatory approval process implemented by the FDA under the Federal Food, Drug, and Cosmetic Act. Outside the United States, the ability to market a product depends
upon receiving a marketing authorization from the appropriate regulatory authorities. The requirements governing the conduct of clinical studies, marketing authorization, pricing and reimbursement
vary widely from country to country. In any country, however, the commercialization of medicines is permitted only if the appropriate regulatory authority is satisfied that we have presented adequate
evidence of the safety, quality and efficacy of our medicines.
Before
commencing clinical studies in humans in the United States, we must submit to the FDA an investigational new drug application ("IND") that includes, among other things, the
general investigational plan and protocols for specific human studies, and the results of preclinical studies. An IND will go into effect 30 days following its receipt by the FDA unless the FDA
issues a clinical hold. Once clinical studies have begun under the IND, they are usually conducted in three phases and under FDA oversight. These phases generally include the following:
Phase 1.
The product candidate is introduced into patients or healthy human volunteers and is tested for safety, dose
tolerance and
pharmacokinetics.
Phase 2.
The product candidate is introduced into a limited patient population to assess the efficacy of
the drug in specific, targeted indications, assess dosage tolerance and optimal dosage, and identify possible adverse effects and safety risks.
Phase 3.
If a compound is found to be potentially effective and to have an acceptable safety profile in Phase 2
evaluations, the
clinical study will be expanded to further demonstrate clinical efficacy, optimal dosage and safety within an expanded patient population.
The
results of product development, preclinical studies and clinical studies must be submitted to the FDA as part of a NDA. The NDA also must contain extensive manufacturing information.
The Prescription Drug User Fee Act ("PDUFA") establishes timeframes for FDA review of NDAs, with a performance goal of reviewing and acting on 90 percent of priority new molecular entity
("NME") NDA submissions within 6 months of the 60-day filing date, and to review and act on 90 percent of standard NME NDA submissions within 10 months of the 60-day filing date.
The 2007 Food and Drug Administration Amendments Act gave the FDA authority to require implementation of a formal Risk Evaluation and Management Strategy to ensure that the benefits of a product
outweigh its risks. At the end of the review period, the FDA communicates either approval of the NDA or a complete response listing the application's deficiencies.
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Once
approved, the FDA may withdraw the product approval if compliance with post-marketing regulatory standards is not maintained or if safety or quality issues are identified after the
product reaches the marketplace. In addition, the FDA may require post-marketing studies, sometimes referred to as Phase 4 studies, to monitor the safety and effectiveness of approved products,
and may limit further marketing of the product based on the results of these post-marketing studies. The FDA has broad post-market regulatory and enforcement powers, including the ability to suspend
or delay issuance of approvals, seize products, withdraw approvals, enjoin violations, and initiate criminal prosecution.
If
regulatory approval for a medicine is obtained, the clearance to market the product will be limited to those diseases and conditions approved by FDA and for which the medicine was
shown to be effective, as demonstrated through clinical studies and specified in the medicine's labeling. Even if this regulatory approval is obtained, a marketed medicine, its manufacturer and its
manufacturing facilities are subject to continual review and periodic inspections by the FDA. The FDA ensures the quality of approved medicines by carefully monitoring manufacturers' compliance with
its cGMP regulations. The cGMP regulations for drugs contain minimum requirements for the methods, facilities, and controls used in manufacturing, processing, and packaging of a medicine. The
regulations are intended to make sure that a medicine is safe for use, and that it has the ingredients and strength it claims to have. Discovery
of previously unknown problems with a medicine, manufacturer or facility may result in restrictions on the medicine or manufacturer, including costly recalls or withdrawal of the medicine from the
market.
We
and our collaboration partners are also subject to various laws and regulations regarding laboratory practices, the experimental use of animals and the use and disposal of hazardous
or potentially hazardous substances in connection with our research. In each of these areas, as above, the FDA and other regulatory authorities have broad regulatory and enforcement powers, including
the ability to suspend or delay issuance of approvals, seize products, withdraw approvals, enjoin violations, and initiate criminal prosecution, any one or more of which could have a material adverse
effect upon our business, financial condition and results of operations.
Outside
the United States our ability to market our products will also depend on receiving marketing authorizations from the appropriate regulatory authorities. Risks similar to those
associated with FDA approval described above exist with the regulatory approval processes in other countries.
United States Healthcare Reform
The Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (together the "Healthcare
Reform Act"), substantially changed the way healthcare is financed by both governmental and private insurers, and impacts pricing and reimbursement with respect to our VIBATIV business, and any
potential additional commercial operations. Moreover, legislative changes to the Healthcare Reform Act remain possible and appear likely in the 115th United States Congress and under the Trump
Administration. We expect that the Healthcare Reform Act, as currently enacted or as it may be amended in the future, and other healthcare reform measures that may be adopted in the future, could have
a material adverse effect on our industry generally and on our ability to maintain or increase sales of our existing products or to successfully commercialize our product candidates, if approved. For
more information, see the risk factor under the heading "
Changes in healthcare law and implementing regulations, including government restrictions on pricing and reimbursement,
as well as healthcare policy and other healthcare payor cost-containment initiatives, may negatively impact our ability to generate revenues"
of this Annual Report on
Form 10-K.
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Pharmaceutical Pricing and Reimbursement
We participate in and have certain price reporting obligations under the Medicaid Drug Rebate program. Our participation in the Medicaid Drug
Rebate program is described in greater detail under the risk factor "
If we fail to comply with our reporting and payment obligations under the Medicaid Drug Rebate program or
other governmental pricing programs, we could be subject to additional reimbursement requirements, penalties, sanctions and fines, which could have a material adverse effect on our business, financial
condition, results of operations and growth prospects"
of this Annual Report on Form 10-K.
Our
ability to commercialize our products successfully, and to attract commercialization partners for our products, depends in significant part on the availability of adequate financial
coverage and reimbursement from third party payors, including, in the United States, governmental payors such as the Medicare and Medicaid programs, managed care organizations, and private health
insurers. The reimbursement environment is described in greater detail under the risk factor
"Changes in healthcare law and implementing regulations, including government
restrictions on pricing and reimbursement, as well as healthcare policy and other healthcare payor cost-containment initiatives, may negatively impact our ability to generate
revenues"
of this Annual Report on Form 10-K.
Fraud and Abuse Laws
Our interactions and arrangements with customers and third-party payors are subject to applicable fraud and abuse laws. These laws and the
related risks are described in greater detail under the risk factor "
Our relationships with customers and third-party payors are subject to applicable anti-kickback, fraud and
abuse, transparency and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, exclusion, contractual damages, reputational harm and diminished profits
and future earnings
" of this Annual Report on Form 10-K.
Data Privacy and Protection
We are subject to laws and regulations that address privacy and data security. In the U.S., numerous federal and state laws and regulations,
including state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws (e.g., Section 5 of
the FTC Act), govern the collection, use, disclosure, and protection of health-related and other personal information. These laws and related risks are described in greater detail under the risk
factor "
If we fail to comply with data protection laws and regulations, we could be subject to government enforcement actions (which could include civil or criminal penalties),
private litigation and/or adverse publicity, which could negatively affect our operating results and business
" of this Annual Report on Form 10-K.
Patents and Proprietary Rights
We will be able to protect our technology from unauthorized use by third parties only to the extent that our technology is covered by valid and
enforceable patents or is effectively maintained as trade secrets. Our success in the future will depend in part on obtaining patent protection for our product candidates. Accordingly, patents and
other proprietary rights are essential elements of our business. Our policy is to seek in the United States and selected foreign countries patent protection for novel technologies and compositions of
matter that are commercially important to the development of our business. For proprietary know-how that is not patentable, processes for which patents are difficult to enforce and any other elements
of our drug discovery process that involve proprietary know-how and technology that is not covered by patent applications, we rely on trade secret protection and confidentiality agreements to protect
our interests. We require all of our employees, consultants and advisors to enter into confidentiality agreements. Where it is necessary to share our proprietary information or data with outside
parties, our policy is to make available only that information and data
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required
to accomplish the desired purpose and only pursuant to a duty of confidentiality on the part of those parties.
As
of December 31, 2016, we or one of our wholly-owned subsidiaries owned 434 issued United States patents and 1,681 granted foreign patents, as well as additional pending United
States patent applications and foreign patent applications. The claims in these various patents and patent applications are directed to compositions of matter, including claims covering product
candidates, lead compounds and key intermediates, pharmaceutical compositions, methods of use and processes for making our compounds along with methods of design, synthesis, selection and use relevant
to multivalency in general and to our research and development programs in particular. In particular, our wholly-owned subsidiary Theravance Biopharma Antibiotics IP, LLC owns the following
U.S. patents which are listed in the FDA
Approved Drug Products with Therapeutic Equivalence Evaluations
(Orange Book) for telavancin: U.S. Patent
No. 6,635,618 B2, expiring on September 11, 2023; U.S. Patent No. 6,858,584 B2, expiring on August 24, 2022; U.S. Patent No. 6,872,701 B2, expiring on
June 5, 2021; U.S. Patent
No. 7,008,923 B2, expiring on May 6, 2021; U.S. Patent No. 7,208,471 B2, expiring on May 1, 2021; U.S. Patent No. 7,351,691 B2, expiring on May 1, 2021; U.S.
Patent No. 7,531,623 B2, expiring on January 1, 2027; U.S. Patent No. 7,544,364 B2, expiring on May 1, 2021; U.S. Patent No. 7,700,550 B2, expiring on May 1,
2021; U.S. Patent No. 8,101,575 B2, expiring on May 1, 2021; and U.S. Patent No. 8,158,580 B2, expiring on May 1, 2021. Thus, the last-to-expire patent currently listed in
the Orange Book for telavancin expires on January 1, 2027.
United
States issued patents and foreign patents generally expire 20 years after filing. The patent rights relating to VIBATIV (telavancin) currently consist of United States
patents that expire between 2019 and 2027, additional pending United States patent applications and counterpart patents and patent applications in a number of jurisdictions, including Europe.
Additionally, our patent rights relating to revefenacin, velusetrag and TD-9855 currently include issued United States composition of matter patents that expire in 2025, 2025 and 2030, respectively
(not including any patent term extensions that may be available under the Drug Price Competition and Patent Term Restoration Act of 1984), as well as additional issued United States patents, pending
United States patent applications and counterpart patents and patent applications in a number of jurisdictions. Nevertheless, issued patents can be challenged, narrowed, invalidated or circumvented,
which could limit our ability to stop competitors from marketing similar products and threaten our ability to commercialize our product candidates. Our patent position, similar to other companies in
our industry, is generally uncertain and involves complex legal and factual questions. To maintain our proprietary position we will need to obtain effective claims and enforce these claims once
granted. It is possible that, before any of our products can be commercialized, any related patent may expire or remain in force only for a short period following commercialization, thereby reducing
any advantage of the patent. Also, we do not know whether any of our patent applications will result in any issued patents or, if issued, whether the scope of the issued claims will be sufficient to
protect our proprietary position.
We
are party to a license agreement with Janssen Pharmaceuticals ("Janssen") pursuant to which we have licensed rights under certain patents owned by Janssen covering an excipient used
in the formulation of telavancin. Pursuant to the terms of this license agreement, we are obligated to pay royalties to Janssen based on any commercial sales of VIBATIV (telavancin). The license is
terminable by us upon prior written notice to Janssen or upon an uncured breach or a liquidation event of one of the parties.
Competition
Our marketed product and our research and development programs target four therapeutic areasinfectious disease, respiratory,
gastrointestinal disease and cardiovascular and renal diseaseand our commercial infrastructure is focused primarily on the acute care setting. We expect that any
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medicines
that we commercialize with our collaborative partners or on our own will compete with existing and future market-leading medicines.
Many
of our competitors have substantially greater financial, technical and personnel resources than we have. In addition, many of these competitors have significantly greater commercial
infrastructures than we have. Our ability to compete successfully will depend largely on our ability to leverage our experience in drug discovery, development and commercialization
to:
-
-
discover and develop medicines that are superior to other products in the market;
-
-
attract qualified scientific, product development and commercial personnel;
-
-
obtain patent and/or other proprietary protection for our medicines and technologies;
-
-
obtain required regulatory approvals;
-
-
commercialize approved products; and
-
-
successfully collaborate with pharmaceutical companies in the discovery, development and commercialization of new medicines.
VIBATIV (telavancin).
VIBATIV competes with vancomycin, linezolid and daptomycin, generic drugs that are manufactured by a variety of
companies, as
well as other drugs marketed to treat complicated skin and skin structure infections and hospital acquired and ventilator associated bacterial pneumonia caused by Gram-positive bacteria. In
particular, daptomycin has recently become available as a generic product and we believe the outpatient setting has been particularly impacted by its availability. Currently marketed products include
but are not limited to Sivextro
®
(tedizolid) marketed by Merck & Co., Inc.;
Teflaro
®
(ceftaroline) and Dalvance (dalbavancin) marketed by Allergan; and Orbactiv (oritavancin) marketed by The
Medicines Company. To compete effectively with these medicines, and in particular with the relatively inexpensive generic options of vancomycin, linezolid and daptomycin, we will need to demonstrate
to physicians that, based on experience, clinical data, side effect profiles and other factors, VIBATIV is a preferred injectable
Staphyloccocus aureus
treatment for patients not likely to respond to other
Staphyloccocus aureus
therapies.
Revefenacin (TD-4208) long-acting muscarinic antagonist (LAMA).
If successfully developed and approved as the first once-daily
nebulized LAMA,
revefenacin would be expected to compete predominantly with short-acting nebulized bronchodilators used 3 to 4 times per day and has the potential to be a first line prescription or complement to
single agent nebulized long-acting beta agonist (LABA) products used two times per day.
"Closed Triple" or FF/UMEC/VI (fluticasone furoate/umeclidinium bromide/vilanterol) and Inhaled Bifunctional Muscarinic Antagonist-Beta2 Agonist
(MABA).
If GSK successfully develops and brings to market an approved Closed Triple product, such product might compete with a number of other closed triple
products that are currently under development. We believe that Chiesi Farmaceutici, AstraZeneca and Novartis all have closed triple products in late stage development for COPD and/or asthma. If GSK
successfully develops and brings to market an approved MABA product, such product might compete with other MABA products that are currently under development such as AstraZeneca's AZD-8871, which is
currently in Phase II studies for COPD, or dual LABA-LAMA combination products.
Research and Development
We spent $141.7 million, $129.2 million, and $168.5 million on research and development, net of reimbursements from
collaboration partners, for the years ended December 31,
2016, 2015, and 2014, respectively. Additional information regarding these expenditures is included in Note 1, "Description of Operations and Summary of Significant Accounting Policies," to our
consolidated financial statements in this Annual Report on Form 10-K.
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Employees
As of December 31, 2016, we had 316 permanent employees, of which 185 were engaged in research and development activities. Of our 316
employees, 310 were located in the U.S. and six were located in Ireland. We consider our employee relations to be good.
Financial Information About Geographic Areas
Information on our total revenues attributed to geographic areas and customers who represented at least 10% of our total revenues is included in
Note 3, "Segment Information," to our consolidated financial statements in this Annual Report on Form 10-K.
Corporation Information
Theravance Biopharma was incorporated in the Cayman Islands in July 2013 under the name Theravance Biopharma, Inc. Theravance Biopharma
began operating as an independent, publicly-traded company on June 2, 2014 following a spin-off from Innoviva, Inc. Our corporate address in the Cayman Islands is and principal executive
office is P.O. Box 309, Ugland House, Grand Cayman, KY1-1104, Cayman Islands and the address of our wholly-owned U.S. operating subsidiary Theravance Biopharma US, Inc. is 901
Gateway Boulevard, South San Francisco, California 94080. While Theravance Biopharma is incorporated under Cayman Island law, the Company became an Irish tax resident effective July 1, 2015.
The address of our wholly-owned Irish operating subsidiary, Theravance Biopharma Ireland Limited, is Fitzwilliam Hall, Fitzwilliam Place, Dublin 2 Ireland.
Available Information
Our Internet address is
www.theravance.com
. Our investor relations website is located at
http://investor.theravance.com
. We make available free of charge on our investor relations website under "SEC Filings" our Annual Reports on
Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, our directors' and officers' Section 16 Reports and any amendments to those reports as soon as
reasonably practicable after filing or furnishing such materials to the U.S. Securities and Exchange Commission ("SEC"). The information found on our website is not part of this or any other report
that we file with or furnish to the SEC. Theravance Biopharma and the Theravance Biopharma logo are registered trademarks of the Theravance Biopharma group of companies. Trademarks, tradenames or
service marks of other companies appearing in this report are the property of their respective owners.
ITEM 1A. RISK FACTORS
RISKS RELATING TO THE COMPANY
The risks described below and elsewhere in this Annual Report on Form 10-K and in our other public filings with the SEC are not the only
risks facing the Company. Additional risks and uncertainties not currently known to us or that we currently deem to be immaterial also may materially adversely affect our business, financial condition
and/or operating results.
We anticipate that we will incur losses for the foreseeable future. We may never achieve or sustain
profitability.
First as part of Innoviva, Inc. (known as Theravance, Inc. prior to January 7, 2016), and since June 2, 2014 as
Theravance Biopharma, we have been engaged in discovery and development of compounds and product candidates since mid-1997. We may never generate sufficient revenue from the sale of medicines,
royalties on sales by our partners or from our interest in Theravance Respiratory Company, LLC ("TRC") to achieve profitability. During the years ended December 31, 2016, 2015 and 2014,
we recognized losses of $190.7 million, $182.2 million and $237.0 million, respectively, which are
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reflected
in the Shareholders' Equity on our consolidated balance sheets. We reflect cumulative net loss incurred after June 2, 2014, the effective date of the Spin-Off, as accumulated deficit
on our consolidated balance sheets. We expect to continue to incur net losses at least over the next several years as we continue our drug discovery and development efforts and incur significant
preclinical and clinical development costs related to our current product candidates and commercialization and development costs relating to VIBATIV® (telavancin) and, in anticipation of
potential approval, revefenacin. In particular, to the extent we advance our product candidates into and through additional clinical studies without a partner, we will incur substantial expenses. We
are also making additional investments in telavancin, our antibiotic that has been approved for certain difficult-to-treat
infections. For example, in February 2015 we initiated a Phase 3 registrational study of telavancin for bacteremia and a patient registry study. We are incurring all of the costs and expenses
associated with the commercialization of VIBATIV in the U.S., including the maintenance of an independent sales and marketing organization with appropriate technical expertise, supporting
infrastructure and distribution capabilities, expanded medical affairs presence, manufacturing and third-party vendor logistics and consultant support, and post-marketing studies. We are also making
additional investments in revefenacin in anticipation of potential approval. Our commitment of resources to VIBATIV, to the continued development of our existing product candidates and to our
discovery programs will require significant additional funding. Our operating expenses also will increase if, among other things:
-
-
our earlier stage potential products move into later-stage clinical development, which is generally more expensive than early stage
development;
-
-
additional preclinical product candidates are selected for clinical development;
-
-
we pursue clinical development of our potential or current products in new indications;
-
-
we increase the number of patents we are prosecuting or otherwise expend additional resources on patent prosecution or defense; or
-
-
we acquire or in-license additional technologies, product candidates, products or businesses.
Other
than revenues from sales of VIBATIV, our only approved medicine and potential payments under collaboration agreements, we do not expect to generate revenues from our programs for
the foreseeable future. Since we or our collaborators or licensees may not successfully develop additional products, obtain required regulatory approvals, manufacture products at an acceptable cost or
with
appropriate quality, or successfully market and sell such products with desired margins, our expenses may continue to exceed any revenues we may receive.
In
the absence of substantial licensing payments, contingent payments or other revenues from third-party collaborators, royalties on sales of products licensed under our intellectual
property rights, future revenues from VIBATIV and product candidates in development that receive regulatory approval or other sources of revenues, we will continue to incur operating losses and will
require additional capital to execute our business strategy. The likelihood of reaching, and the time required to reach, and then to sustain, profitability are highly uncertain. As a result, we expect
to continue to incur substantial losses for the foreseeable future. We are uncertain when or if we will ever be able to achieve or sustain profitability. Failure to become and remain profitable would
adversely affect the price of our securities and our ability to raise capital and continue operations.
If additional capital is not available, we may have to curtail or cease operations or we could be forced to
share our rights to commercialize our product candidates with third parties on terms that may not be favorable to us.
Based on our current operating plans and financial forecasts, we believe that our cash, cash equivalents and marketable securities will be
sufficient to meet our anticipated operating needs for at least the next twelve months. If our current operating plans or financial forecasts change, we may
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require
or seek additional funding sooner in the form of public or private equity or equity-linked offerings, debt financings or additional collaborations and licensing arrangements. For example, if
we choose to progress any additional product candidates into later-stage development on our own, our capital needs would increase substantially. We also are making significant investments in
telavancin, our approved antibiotic, which increases our operating expenses. For example, in 2015 we initiated a Phase 3 registrational study of telavancin for bacteremia and our Telavancin
Observational Use Registry ("TOUR"), a patient registry study. In addition, we maintain an independent sales and marketing organization and medical affairs team focused on the acute care setting and
VIBATIV. We are also making additional investments in revefenacin in anticipation of potential approval. In 2016, we increased our anticipated operating loss, primarily because of accelerated
enrollment in TOUR, increased investment in our neprilysin ("NEP") inhibitor program and increased funding for the development of our intestinally restricted pan-Janus kinase ("JAK") inhibitors.
We
may need to raise additional capital in the future to, among other things:
-
-
fund our discovery efforts and research and development programs;
-
-
fund our commercialization strategies for VIBATIV and any additional approved products;
-
-
progress mid-to-late stage product candidates into later-stage development, if warranted;
-
-
respond to competitive pressures; and
-
-
acquire complementary businesses or technologies.
Our
future capital needs depend on many factors, including:
-
-
the scope, duration and expenditures associated with our discovery efforts and research and development programs;
-
-
continued scientific progress in these programs;
-
-
the extent to which we encounter technical obstacles in our research and development programs;
-
-
the outcome of potential licensing or partnering transactions, if any;
-
-
competing technological developments;
-
-
the extent of our proprietary patent position in telavancin and our product candidates;
-
-
our facilities expenses, which will vary depending on the time and terms of any facility lease or sublease we may enter into, and other
operating expenses;
-
-
the scope and extent of the expansion of our sales and marketing efforts;
-
-
potential litigation and other contingencies; and
-
-
the regulatory approval process for our product candidates.
We
may seek to raise additional capital or obtain future funding through public or private equity offerings, debt financings or additional collaborations and licensing arrangements. We
may not be able to obtain additional financing on terms favorable to us, if at all. General market conditions may make it difficult for us to seek financing from the capital markets. We may be
required to relinquish rights to our technologies, product candidates or territories, or grant licenses on terms that are not favorable to us, in order to raise additional funds through collaborations
or licensing arrangements. We may sequence pre-clinical and clinical studies as opposed to conducting them concomitantly in order to conserve resources, or delay, reduce or eliminate one or more of
our research or development programs and reduce overall overhead expenses. If we are unable to raise additional capital or obtain future funding in sufficient amounts or on terms acceptable to us, we
may have to make reductions in our workforce and may be prevented from continuing our discovery, development and
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commercialization
efforts and exploiting other corporate opportunities. This would likely harm our business, prospects and financial condition and cause the price of our securities to fall.
We may seek to obtain future financing through the issuance of debt or equity, which may have an adverse
effect on our shareholders or may otherwise adversely affect our business.
If we raise funds through the issuance of additional debt, including convertible debt or equity, any debt securities or preferred shares issued
will have rights, preferences and privileges senior to those of holders of our ordinary shares in the event of liquidation. The terms of our existing convertible senior notes do not restrict our
ability to issue additional debt. In such event, there is a possibility that once all senior claims are settled, there may be no assets remaining to pay out to the holders of ordinary shares. In
addition, if we raise funds through the issuance of additional equity, whether through private placements or public offerings, such an issuance would dilute ownership of our current shareholders that
do not participate in the issuance. For example, since our Spin-Off in June 2014, we have raised an aggregate of $583.9 million through the sale of approximately 17.5 million shares and
$230.0 million aggregate principal amount of 3.250% convertible senior notes due 2023 in a combination of private sale, public offerings and pursuant to our at-the-market offering program. If
we are unable to obtain any needed additional funding, we may be required to reduce the scope of, delay, or eliminate some or all of, our planned research, development and commercialization activities
or to license to third parties the rights to develop and/or commercialize products or technologies that we would otherwise seek to develop and/or commercialize ourselves or on terms that are less
attractive than they might otherwise be, any of which could materially harm our business.
Furthermore,
the terms of any additional debt securities we may issue in the future may impose restrictions on our operations, which may include limiting our ability to incur additional
indebtedness, pay dividends on or repurchase our share capital, or make certain acquisitions or investments. In addition, we may be subject to covenants requiring us to satisfy certain financial tests
and ratios, and our ability to satisfy such covenants may be affected by events outside of our control.
Servicing our convertible senior notes requires a significant amount of cash, and we may not have sufficient
cash flow from our business to pay our debt. Additionally, holders may require us to repurchase our convertible senior notes under certain circumstances, and we may not have sufficient cash to do so.
Our ability to make interest or principal payments when due or to refinance the Notes depends on our future performance, which is subject to
economic, financial, competitive and other factors beyond our control. Our business may not generate cash flow from operations sufficient to satisfy our obligations under the Notes and any future
indebtedness we may incur and to make necessary capital expenditures. We may be required to adopt one or more alternatives, such as reducing or delaying investments or capital expenditures, selling
assets, refinancing or obtaining additional equity capital on terms that may be onerous or highly dilutive. Our ability to refinance the Notes or future indebtedness will depend on the capital markets
and our financial condition at such time. We may not be able to engage in any of these activities on desirable terms or at all, which could result in a default on the Notes or future indebtedness.
Additionally,
holders of the Notes may have the right to require us to repurchase the Notes upon the occurrence of a "fundamental change" such as a change of control of our Company or
the termination of trading of our ordinary shares, as defined in the indenture, as amended, governing the Notes. We may not have sufficient funds to repurchase the Notes in cash or have the ability to
arrange necessary financing on acceptable terms. Our failure to repurchase the Notes when required would result in an event of default with respect to the Notes. Any acceleration of the repayment of
the Notes or future indebtedness after any applicable notice or grace periods could have a material adverse effect on our business, results of operations and financial condition.
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If we are unable to enter into future collaboration arrangements or if any such collaborations with third
parties are unsuccessful, we will be unable to fully develop and commercialize all of our product candidates and our business will be adversely affected.
We have collaborations with a number of third parties including Mylan for the development and commercialization of a nebulized formulation of
revefenacin (TD-4208), our LAMA compound, Alfa Wassermann S.p.A. ("Alfa Wassermann") for velusetrag, Millennium Pharmaceuticals, Inc., an indirect wholly-owned subsidiary of
Takeda Pharmaceutical Company Limited (collectively with Millennium, "Takeda") for the development and commercialization of a selective 5-HT4 receptor agonist (TD-8954) and other companies for
regional development and commercialization of VIBATIV. Also, through our interest in TRC we may participate economically in Innoviva's collaborations with GSK with respect to the GSK-Partnered
Respiratory Programs and we received non-marketable equity securities in connection with our September 2015 licensing agreement with Trek Therapeutics, PBC. Additional collaborations will likely be
needed to fund later-stage development of certain programs that have not been licensed to a collaborator, such as our NEP inhibitor program and axelopran (TD-1211) for opioid-induced constipation and
to commercialize the product candidates in our programs if approved by the necessary regulatory authorities. We may also seek collaboration arrangements with additional third parties to pursue the
future commercialization of VIBATIV. Collaborations with third parties regarding our programs may require us to relinquish material rights, including revenue from commercialization of our medicines,
or to assume material ongoing development obligations that we would have to fund. These collaboration arrangements are complex and time-consuming to negotiate, and if we are unable to reach agreements
with third-party collaborators, we may fail to meet our business objectives and our financial condition may be adversely affected. We face significant competition in seeking third-party collaborators.
We may be unable to find third parties to pursue product collaborations on a timely basis or on acceptable terms. Furthermore, for any collaboration, we may not be able to control the amount of time
and resources that our partners devote to our product candidates and our partners may choose to prioritize alternative programs or otherwise be unsuccessful in their efforts with respect to our
products or product candidates. Our inability to successfully collaborate with third parties would increase our development costs and may cause us to choose not to continue development of certain
product candidates, would limit the likelihood of successful commercialization of some of our product candidates and could cause the price of our securities to fall.
We do not control TRC and, in particular, have no control over or access to non-public information about the
GSK-Partnered Respiratory Programs.
Innoviva has assigned to TRC its strategic alliance agreement with GSK and all of its rights and obligations under its LABA collaboration
agreement other than with respect to RELVAR® ELLIPTA®/BREO® ELLIPTA®, ANORO® ELLIPTA® and vilanterol monotherapy. Our equity
interest in TRC entitles us to an 85% economic interest in any future payments made by GSK under the strategic alliance agreement and under the portion of the collaboration agreement assigned to TRC
(the "GSK Agreements"). Our equity interest covers various drug programs including the Closed Triple combination of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) (ICS/LAMA/LABA)
and
the MABA program, as monotherapy and in combination with other therapeutically active components, such as an inhaled corticosteroid ("ICS"), and any other product or combination of products that may
be discovered and developed in the future under the GSK Agreements. Our economic interest does not include any payments by GSK associated with RELVAR®
ELLIPTA®/BREO® ELLIPTA®, ANORO® ELLIPTA® or vilanterol monotherapy. Innoviva controls TRC and, except for certain limited consent rights, we
have no right to participate in the business and affairs of TRC. Innoviva has the exclusive right to appoint TRC's manager who, among other things, is responsible for the day-to-day management of the
GSK-Partnered Respiratory Programs and exercises the rights relating to the GSK-Partnered Respiratory Programs. As a result, we have no rights to participate in, or access to non-public information
about, the development and commercialization of
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the
GSK-Partnered Respiratory Programs and no right to enforce rights under the GSK Agreements assigned to TRC. Moreover, we have many of the same risks with respect to our and TRC's dependence on GSK
as we have with respect to our dependence on our own partners.
If the GSK-Partnered Respiratory Programs in which we have a substantial economic interest, including the
Closed Triple program and MABA program, encounter delays, do not demonstrate safety and efficacy, are terminated, or if there are any adverse developments or perceived adverse developments with
respect to these programs, our business will be harmed, and the price of our securities could fall.
We have no access to confidential information regarding the progress of, or plans for, the GSK-Partnered Respiratory Programs, including the
Closed Triple program and the MABA program, and we have little, if any, ability to influence the progress of those programs because our interest in these programs is only through our economic interest
in TRC, which is controlled by Innoviva. However, if any of the GSK-Partnered Respiratory Programs in which we have a substantial economic interest, including the Closed Triple program and MABA
program, encounter delays, do not demonstrate safety and efficacy, are terminated, or if there are any adverse developments or perceived adverse developments with respect to such programs, our
business will be harmed, and the price of our securities could fall. Examples of such adverse developments include, but are not limited to:
-
-
GSK deciding to delay or halt development of any of the GSK-Partnered Respiratory Programs in which we have a substantial economic interest,
including the Closed Triple or GSK961081 ('081), the lead compound in the MABA program;
-
-
the U.S. Food and Drug Administration ("FDA") and/or other regulatory authorities determining that any of the studies under these programs do
not demonstrate adequate safety or efficacy, or that additional non-clinical or clinical studies are required with respect to such programs;
-
-
safety, efficacy or other concerns arising from clinical or non-clinical studies in these programs;
-
-
any particular FDA requirements or changes in FDA policy or guidance regarding these programs; or
-
-
the emergence of new closed triple or other alternative therapies or any developments regarding these potentially competitive therapies,
comparative price or efficacy of such potentially competitive therapies.
VIBATIV may not be broadly accepted by physicians, patients, third-party payors, or the medical community in
general, which would have a material, adverse effect on our business.
The commercial success of VIBATIV depends upon its acceptance by physicians, patients, third-party payors and the medical community in general.
VIBATIV may not be sufficiently accepted by these parties. VIBATIV competes with vancomycin (which accounts for a substantial majority of patient treatment days), linezolid and daptomycin, all
relatively inexpensive generic drugs that are manufactured by a variety of companies, and a number of existing antibacterials manufactured and marketed by major pharmaceutical companies and others,
and may compete against new antibacterials that are not yet on the market. If we are unable to demonstrate to physicians that, based on experience, clinical data, side effect profiles and other
factors, VIBATIV is a preferred injectable treatment for treating the infections for which it is indicated, we may never generate significant revenue or profits from VIBATIV. In that case we may in
the future reassess the VIBATIV business and respond in a number of ways which could include, for example, materially reducing our spending on commercialization and development efforts or other
actions, any of which could cause the price of our securities to fall. Responding to ongoing challenges in the branded antibiotics market, we scaled back the size of our sales force in early 2017 and
are allocating our resources with a focus on promotionally
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sensitive
territories. In addition, if we fail to meet expectations about our net sales of VIBATIV and our VIBATIV commercialization strategy, the price of our securities could fall. For example, we
reduced our projected U.S. net sales target for VIBATIV for 2015 more than once.
The
degree of market acceptance of VIBATIV, the rate of our VIBATIV sales and our ability to generate revenues through sales of VIBATIV depends on a number of factors, including, but not
limited to:
-
-
the experiences of physicians, patients and payors with the use of VIBATIV;
-
-
the occurrence of unexpected serious adverse reactions in relation to VIBATIV;
-
-
the market price of VIBATIV relative to competing therapies, including generic therapies;
-
-
the timing, frequency and impact of price changes or changes to pricing programs;
-
-
our customer mix;
-
-
any adverse developments or perceived adverse developments with respect to Pfizer, Inc. which may adversely impact our single source of
supply for VIBATIV drug product;
-
-
any developments with, or comments by, the FDA or other regulatory agencies with respect to the manufacture, use or sale of VIBATIV;
-
-
our ability to complete our ongoing Phase 3 registrational study for use of telavancin in the treatment of patients with
Staphylococcus
aureus
bacteremia, the timing of any such completion, and the results of this study;
-
-
our ability to remove VIBATIV from the List of "Antineoplastic and Other Hazardous Drugs in Healthcare Settings" published by the National
Institute of Occupational Safety and Hazards (NIOSH);
-
-
the advantages and disadvantages of VIBATIV compared to alternative therapies;
-
-
our ability to find an EU commercialization partner for VIBATIV, which we have not had since August 2016 when we and Clinigen reached a mutual
decision that Clinigen will return VIBATIV EU commercial rights to us;
-
-
our ability to educate the medical community about the appropriate circumstances for use of VIBATIV;
-
-
the acceptance of VIBATIV onto formulary by hospitals and healthcare systems;
-
-
our ability to attract, train and retain appropriate numbers of sales and marketing personnel in the U.S.;
-
-
our ability to attract, train and retain medical science liaisons in the U.S. supporting physician education on the proper usage of VIBATIV;
-
-
the effectiveness of sales personnel in obtaining access to and educating adequate numbers of physicians about prescribing VIBATIV in
appropriate clinical situations;
-
-
the lack of complementary products offered by our sales personnel, which may put us at a competitive disadvantage relative to companies with
more extensive product lines; and
-
-
the reimbursement policies of government and third-party payors, including the amount of chargebacks and government rebates.
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We market, sell and distribute VIBATIV in the U.S. without a partner and we may bear similar costs with
respect to additional products in the future, which subjects us to certain risks.
We evaluate commercial strategy on a product by product basis either to engage pharmaceutical or other healthcare companies with an existing
sales and marketing organization and distribution system to market, sell and distribute our products or to commercialize a product ourselves. However, we may not be able to establish these sales and
distribution relationships on acceptable terms, or at all, or may encounter difficulties in commercializing a product ourselves. For any of our product candidates that receive regulatory approval in
the future and are not covered by our current collaboration agreements, we will need a partner in order to commercialize such products unless we establish independent sales, marketing and distribution
capabilities with appropriate technical expertise and supporting infrastructure.
VIBATIV
was returned to us by Astellas Pharma Inc. ("Astellas"), our former VIBATIV collaboration partner, in January 2012, and Astellas is entitled to a ten-year, 1% royalty on
future net sales of VIBATIV. On August 14, 2013, we (at the time with Innoviva) announced the reintroduction of VIBATIV to the U.S. market with the commencement of shipments into the wholesaler
channel and we now maintain a VIBATIV sales force in the U.S. The risks of commercializing VIBATIV in the U.S. without a partner and commercializing any future products that we may choose to
commercialize without a partner include:
-
-
costs and expenses associated with creating and maintaining an independent sales and marketing organization with appropriate technical
expertise and supporting infrastructure and distribution capability, including third- party vendor logistics and consultant support, which costs and expenses could, depending on the scope and method
of the marketing effort, exceed any product revenue from VIBATIV or any future products for several years;
-
-
our unproven ability to retain effective sales and marketing personnel and medical science liaisons in the U.S.;
-
-
the unproven ability of our sales and marketing personnel to obtain access to and educate adequate numbers of physicians about prescribing
VIBATIV, or any future products, in appropriate clinical situations;
-
-
the lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies with
more extensive product lines; and
-
-
bearing the full costs of further U.S. development of telavancin, the compound that is the basis of VIBATIV.
If
we are not successful in maintaining an internal sales and marketing organization with appropriate experience, technical expertise, supporting infrastructure, distribution capability
and the ability to obtain access to and educate adequate numbers of physicians about prescribing VIBATIV, or any future products, in appropriate clinical situations, we will have difficulty
commercializing VIBATIV, or any future products, in the U.S., which would adversely affect our business and financial condition and the price of our securities could fall.
Any delay in commencing or completing clinical studies for product candidates and any adverse results from
clinical or non-clinical studies or regulatory obstacles product candidates may face, would harm our business and the price of our securities could fall.
Each of our product candidates must undergo extensive non-clinical and clinical studies as a condition to regulatory approval. Non-clinical and
clinical studies are expensive, take many years to complete and study results may lead to delays in further studies, new requirements for conducting future studies or decisions to terminate programs.
The commencement and completion of clinical
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studies
for our product candidates may be delayed and programs may be terminated due to many factors, including, but not limited to:
-
-
lack of effectiveness of product candidates during clinical studies;
-
-
adverse events, safety issues or side effects relating to the product candidates or their formulation into medicines;
-
-
inability to raise additional capital in sufficient amounts to continue our development programs, which are very expensive;
-
-
inability to enter into partnering arrangements relating to the development and commercialization of our programs and product candidates;
-
-
the need to sequence clinical studies as opposed to conducting them concomitantly in order to conserve resources;
-
-
our inability or the inability of our collaborators or licensees to manufacture or obtain from third parties materials sufficient for use in
non-clinical and clinical studies;
-
-
governmental or regulatory delays and changes in regulatory requirements, policy and guidelines;
-
-
failure of our partners to advance our product candidates through clinical development;
-
-
delays in patient enrollment and variability in the number and types of patients available for clinical studies;
-
-
difficulty in maintaining contact with patients after treatment, resulting in incomplete data;
-
-
varying regulatory requirements or interpretations of data among the FDA and foreign regulatory authorities; and
-
-
a regional disturbance where we or our collaborative partners are enrolling patients in clinical trials, such as a pandemic, terrorist
activities or war, political unrest or a natural disaster.
Our ongoing drug discovery and development efforts might not generate additional successful product
candidates or approvable drugs.
Our compounds in clinical trials and our future leads for potential drug compounds are subject to the risks and failures inherent in the
development of pharmaceutical products. These risks include, but are not limited to, the inherent difficulty in selecting the right drug and drug target and avoiding unwanted side effects, as well as
unanticipated problems relating to product development, testing, enrollment, obtaining regulatory approvals, maintaining regulatory compliance, manufacturing, competition and costs and expenses that
may exceed current estimates.
Clinical
studies involving our product candidates may reveal that those candidates are ineffective, inferior to existing approved medicines, unacceptably toxic, or that they have other
unacceptable side effects. In addition, the results of preclinical studies do not necessarily predict clinical success, and larger and later-stage clinical studies may not produce the same results as
earlier-stage clinical studies.
Frequently,
product candidates that have shown promising results in early preclinical or clinical studies have subsequently suffered significant setbacks or failed in later non-clinical
or clinical studies. In some instances, there can be significant variability in safety and/or efficacy results between different trials of the same product candidate due to numerous factors, including
changes in trial protocols, differences in size and type of the patient populations, varying levels of adherence to the dosing regimen and other trial protocols and the rate of dropout among clinical
trial participants. Clinical and non-clinical studies of product candidates often reveal that it is not possible or practical to continue development efforts for these product candidates. In addition,
the design of a clinical trial can
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determine
whether its results will support regulatory approval and flaws in the design of a clinical trial may not become apparent until the clinical trial is well underway. If our ongoing clinical
studies for our current product candidates, such as the Phase 3 development program for revefenacin for the treatment of COPD and the earlier stage clinical studies for our JAK inhibitor
program or our NEP inhibitor program, are substantially delayed or fail to meet their designated end points, we could fail to receive regulatory approval for one or more of these product candidates.
In addition, our product candidates may have undesirable side effects or other unexpected characteristics that could cause us or regulatory authorities to interrupt, delay or halt clinical trials and
could result in a more restricted label or the delay or denial of regulatory approval by regulatory authorities.
If our product candidates are not approved by regulatory authorities, including the FDA, we will be unable to
commercialize them.
The FDA must approve any new medicine before it can be marketed and sold in the U.S. We will not obtain this approval for a product candidate
unless and until the FDA approves a new drug application ("NDA"). We, or our collaborative partners, must provide the FDA and similar foreign regulatory authorities with data from preclinical and
clinical studies that demonstrate that our product candidates are safe and effective for a defined indication before they can be approved for commercial distribution. FDA or foreign regulatory
authorities may disagree with our trial design and our interpretation of data from preclinical studies and clinical trials. The processes by which regulatory approvals are obtained from the FDA and
foreign regulatory authorities to market and sell a new product are complex, require a number of years, depend upon the type, complexity and novelty of the product candidate and involve the
expenditure of substantial resources for research, development and testing. The FDA has substantial discretion in the drug approval process and may require us to conduct additional nonclinical and
clinical testing or to perform post-marketing studies. Further, the implementation of new laws and regulations, and revisions to FDA clinical trial design guidance may lead to increased uncertainty
regarding the approvability of new drugs. In addition, over the past decade, the FDA has implemented additional standards for approval of new drugs, including recommended advisory committee meetings
for certain new molecular entities, and formal risk evaluation and mitigation requirements at the FDA's discretion. Even if we receive regulatory approval
of a product, the approval may limit the indicated uses for which the drug may be marketed or impose significant restrictions or limitations on the use and/or distribution of such product.
In
addition, in order to market our medicines in foreign jurisdictions, we, or our collaborative partners, must obtain separate regulatory approvals in each country. The approval
procedure varies among countries and can involve additional testing, and the time required to obtain approval may differ from that required to obtain FDA approval. Approval by the FDA does not ensure
approval by regulatory authorities in other countries, and approval by one foreign regulatory authority does not ensure approval by regulatory authorities in other foreign countries or by the FDA.
Conversely, failure to obtain approval in one or more jurisdictions may make approval in other jurisdictions more difficult. These laws, regulations, additional requirements and changes in
interpretation could cause non-approval or further delays in the FDA's review and approval of our and our collaborative partner's product candidates, which would materially harm our business and
financial condition and could cause the price of our securities to fall.
We rely on a single manufacturer for the Active Pharmaceutical Ingredient ("API") for telavancin and a
separate, single manufacturer for VIBATIV drug product supply. Our business will be harmed if either of these single-source manufacturers are not able to satisfy demand and alternative sources are not
available.
We have a single source of supply of API for telavancin and another, separate single source of supply of VIBATIV drug product. If, for any
reason, either single-source third-party manufacturer of telavancin API or of VIBATIV drug product is unable or unwilling to perform, or if the performance
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of
either does not meet regulatory requirements, including maintaining current Good Manufacturing Practice ("cGMP") compliance, we may not be able to locate alternative manufacturers, enter into
acceptable agreements with them or obtain sufficient quantities of API or drug product in a timely manner. We expect it would take approximately 24 months for an alternative manufacturer to be
qualified by us and begin producing drug product for us. We currently have sufficient quantities of VIBATIV drug product on hand to meet our anticipated needs only through approximately December 2017.
We have manufactured additional VIBATIV drug product supply which is currently undergoing our internal quality review prior to release. We will not know whether this supply is suitable for release
until we complete our internal quality review. If we are able to release this additional supply we would have sufficient quantities of VIBATIV drug product available to meet our anticipated needs
through the fall of 2018. This supply was manufactured by Pfizer, our single source manufacturer for VIBATIV, at its McPherson, Kansas facility. As recently publicly reported, Pfizer has received an
FDA warning letter relating to a 2016 inspection of this facility. None of the lots cited in the warning letter are manufactured VIBATIV drug product. We also plan to have additional VIBATIV drug
product
manufactured for us at this facility in 2017. Given the time required to locate and qualify another acceptable drug product manufacturer, any supply delay, suspension or cessation in the manufacture
and release of VIBATIV drug product would adversely affect the commercialization of VIBATIV and our obligations to our partners, as well as our Phase 3 registrational study for the treatment of
patients with
Staphylococcus aureus
bacteremia. Similarly, any inability to acquire sufficient quantities of API in a timely manner from current or
future sources would adversely affect the commercialization of VIBATIV and our ability to satisfy our obligations to our partners. If either of these were to occur, our business would be harmed.
Our
previous VIBATIV commercialization partner (at the time with Innoviva) failed to maintain a reliable source of drug product supply which resulted in critical product shortages and,
eventually, suspension of commercialization for well over a year. Our current agreement with Pfizer to supply VIBATIV drug product was entered into May 2012. In June 2013, the FDA approved Pfizer as a
VIBATIV drug product manufacturer. On September 29, 2016, we amended our agreement with Pfizer to extend the term of the agreement to December 31, 2020. If our supply relationship with
Pfizer terminates for any reason, we would need to arrange for the advance manufacture and purchase of drug product in order to manage the transition to a new supplier and such advance manufacturing
and purchasing entails significant uncertainties, including the risk of purchasing excess or insufficient quantities relative to our future needs and the possible expiration of excess inventories. Any
difficulties in continuing or transitioning our single source suppliers would adversely affect the commercialization of VIBATIV and our ability to satisfy our obligations to our partners and the price
of our securities could fall.
We rely on a single source of supply for a number of our product candidates, and our business will be harmed
if any of these single-source manufacturers are not able to satisfy demand and alternative sources are not available.
We have limited in-house production capabilities for preclinical and clinical study purposes, and depend primarily on a number of third-party
API and drug product manufacturers. We may not have long-term agreements with these third parties and our agreements with these parties may be terminable at will by either party at any time. If, for
any reason, these third parties are unable or unwilling to perform, or if their performance does not meet regulatory requirements, we may not be able to locate alternative manufacturers or enter into
acceptable agreements with them. Any inability to acquire sufficient quantities of API and drug product in a timely manner from these third parties could delay preclinical and clinical studies and
prevent us from developing our product candidates in a cost-effective manner or on a timely basis. In addition, manufacturers of our API and drug product are subject to the FDA's cGMP regulations and
similar foreign standards and we do not have control over compliance with these regulations by our manufacturers.
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Our
manufacturing strategy presents the following additional risks:
-
-
because of the complex nature of many of our compounds, our manufacturers may not be able to successfully manufacture our APIs and/or drug
products in a cost effective and/or timely manner and changing manufacturers for our APIs or drug products could involve lengthy technology transfer, validation and regulatory qualification activities
for the new manufacturer;
-
-
the processes required to manufacture certain of our APIs and drug products are specialized and available only from a limited number of
third-party manufacturers;
-
-
some of the manufacturing processes for our APIs and drug products have not been scaled to quantities needed for continued clinical studies or
commercial sales, and delays in scale-up to commercial quantities could delay clinical studies, regulatory submissions and commercialization of our product candidates; and
-
-
because some of the third-party manufacturers are located outside of the U.S., there may be difficulties in importing our APIs and drug
products or their components into the U.S. as a result of, among other things, FDA import inspections, incomplete or inaccurate import documentation or defective packaging.
We are subject to extensive and ongoing regulation, oversight and other requirements by the FDA with respect
to VIBATIV and failure to comply with these regulations and requirements may subject us to penalties that may adversely affect our financial condition or our ability to commercialize VIBATIV.
With VIBATIV approved in certain countries, we are subject to continuing regulatory obligations, such as safety reporting requirements and
additional post-marketing obligations, including regulatory oversight of promotion and marketing. Prescription drug advertising and promotion are closely scrutinized by the FDA, including
substantiation of promotional claims, disclosure of risks
and safety information, and the use themes and imagery in advertising and promotional materials. As with all companies selling and marketing products regulated by the FDA in the U.S., we are
prohibited from promoting any uses of VIBATIV that are outside the scope of use that has been expressly approved by the FDA as safe and effective on the VIBATIV label.
The
U.S. labeling for VIBATIV contains a boxed warning. Products with boxed warnings are subject to more restrictive advertising regulations than products without such warnings and FDA
regulations prohibit the use of reminder advertising for VIBATIV. Further, based on its boxed warning, VIBATIV has been classified by the National Institute of Occupational Safety and Hazards (NIOSH)
as a drug that represents a reproductive hazard. Beginning in mid-2018, hospitals and pharmacies that handle these classified drugs will be required to comply with a variety of procedures designed to
promote patient safety, worker safety and environmental protection. We believe this classification of VIBATIV is erroneous and overstates the hazard presented to healthcare workers when handling
VIBATIV, and we are working to remove VIBATIV from this list. If we fail to do so, however, the commercialization of VIBATIV could be adversely impacted as certain healthcare providers and
institutions may not be in a position to comply with the additional handling requirements imposed by NIOSH.
In
addition, the VIBATIV labeling for hospital-acquired and ventilator associated bacterial pneumonia ("HABP/VABP") in the U.S. and the European Union ("EU") specifies that VIBATIV
should be reserved for use when alternative treatments are not suitable. These restrictions add complexity to the marketing of VIBATIV.
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The FDA has also required that we evaluate the safety of VIBATIV use during pregnancy by developing and maintaining a prospective, observational pregnancy
exposure registry study conducted in the United States. This postmarketing study remains ongoing and will continue through the end of 2019. In addition, the FDA has required that we comply with a risk
evaluation and mitigation strategy ("REMS") to inform healthcare providers and patients of key risks via a communication plan. Healthcare providers periodically receive letters reminding them of the
major potential risks associated with VIBATIV and patients receive a medication guide with each course of antibiotic use. The healthcare provider letter is also available on the product website. The
REMS stipulates that we make assessments of the efficacy of these educational efforts and provide reports to FDA at specified intervals.
The
manufacturing, labeling, packaging, adverse event reporting, advertising, promotion and recordkeeping for the approved product remain subject to extensive and ongoing regulatory
requirements. If we become aware of previously unknown problems with an approved product in the U.S. or overseas or at a contract manufacturer's facilities, a regulatory authority may impose
restrictions on the product, the contract manufacturers or on us, including requiring us to reformulate the product, conduct additional clinical studies, change the labeling of the product, withdraw
the product from the market or require the contract manufacturer to implement changes to its facilities.
We
are also subject to regulation by regional, national, state and local agencies, including the Department of Justice, the Federal Trade Commission, the Office of Inspector General of
the U.S. Department of Health and Human Services ("OIG") and other regulatory bodies with respect to VIBATIV, as well as governmental authorities in those foreign countries in which any of our product
candidates are approved for commercialization. The Federal Food, Drug, and Cosmetic Act, the Public Health Service Act and other federal and state statutes and regulations govern to varying degrees
the research, development, manufacturing and commercial activities relating to prescription pharmaceutical products, including non-clinical and clinical testing, approval, production, labeling, sale,
distribution, import, export, post-market surveillance, advertising, dissemination of information and promotion. If we or any third parties that provide these services for us are unable to comply, we
may be subject to regulatory or civil actions or penalties that could significantly and adversely affect our business.
Regulatory
approval for our product candidates, if any, may include similar or other limitations on the indicated uses for which we can market our medicines or the patient population
that may utilize our medicines, which may limit the market for our medicines or put us at a competitive disadvantage relative to alternative therapies.
Any
failure to maintain regulatory approval will limit our ability to commercialize VIBATIV or our product candidates and if we fail to comply with FDA regulations and requirements
regarding VIBATIV or any of our product candidates, the FDA could potentially take a number of enforcement actions against us, including the issuance of untitled letters, warning letters, preventing
the introduction or delivery of VIBATIV into interstate commerce in the United States, misbranding charges, product seizures, injunctions, and civil monetary penalties, which would materially and
adversely affect our business and financial condition and may cause the price of our securities to fall.
The
risks identified in this risk factor relating to regulatory actions and oversight by agencies in the U.S. and throughout the world also apply to the commercialization of any
partnered products by our collaboration partners, and such regulatory actions and oversight may limit our collaboration partners' ability to commercialize such products, which could materially and
adversely affect our business and financial condition, and which may cause the price of our securities to fall.
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We may face competition from companies seeking to market generic versions of VIBATIV.
For a discussion of the risk of generic competition to VIBATIV, please see the following risk factor below "
If our
efforts to protect the proprietary nature of the intellectual property related to our technologies are not adequate, we may not be able to compete effectively in our current or future
markets
."
If our partners do not satisfy their obligations under our agreements with them, or if they terminate our
partnerships with them, we may not be able to develop or commercialize our partnered product candidates as planned.
We have an exclusive development and commercialization agreement with Alfa Wassermann for velusetrag, our lead compound in the 5 HT4 program,
covering the EU, Russia, China, Mexico and certain other countries. The Alfa Wassermann agreement was assigned to us in the Spin-Off and provides research and development funding for the program under
license. In October 2012, we (at the time with Innoviva) also entered into a research collaboration and license agreement with Merck & Co., Inc. ("Merck") to discover, develop and
commercialize novel small molecule therapeutics for the treatment of cardiovascular disease, which Merck terminated in September 2013. In January 2015, we entered into a collaboration agreement with
Mylan for the development and commercialization of a nebulized formulation of our LAMA revefenacin (TD-4208). Under the terms of the agreement, we and Mylan will co-develop nebulized revefenacin for
COPD and other respiratory diseases. In June 2016, we entered into a License and Collaboration Agreement with an indirect wholly-owned subsidiary of Takeda, in order to establish a collaboration for
the development and commercialization of TD-8954, a selective 5-HT4 receptor agonist. Under the terms of the Agreement, Takeda will be responsible for worldwide development and commercialization of
TD-8954. In connection with these agreements, these parties have certain rights regarding the use of its patents and technology with respect to the compounds in our development programs, including
development and marketing rights.
We
also have commercialization agreements with various partners for the commercialization of VIBATIV outside of the United States, including Canada, Middle East, North Africa, Israel,
Russia, China and India. In August 2016, we and Clinigen reached a mutual decision that Clinigen will return commercial rights to market and distribute VIBATIV in the EU to Theravance Biopharma. On
November 4, 2016, the European Commission authorized the transfer of the centralized marketing authorization for VIBATIV to our wholly-owned Irish subsidiary, Theravance Biopharma Ireland
Limited. Therefore, we are now subject to all applicable EU regulatory obligations as the new marketing authorization holder of VIBATIV in the EU. We do not intend to commercialize VIBATIV in the EU
without a partner. Therefore, if we fail to find a suitable partner to commercialize VIBATIV in the EU, we will not receive any product revenue from that region.
Our
partners might not fulfill all of their obligations under these agreements, and, in certain circumstances, they or we may terminate our partnership with them as Astellas did in
January 2012 with its VIBATIV agreement, as Merck did in September 2013 with the cardiovascular disease collaboration and as we and Clinigen did in August 2016 with the commercialization agreement for
VIBATIV in the EU and certain other European countries. In either event, we may be unable to assume the development and commercialization responsibilities covered by the agreements or enter into
alternative arrangements with a third-party to develop and commercialize such product candidates. If a partner elected to promote alternative products and product candidates such as its own products
and product candidates in preference to those licensed from us, does not devote an adequate amount of time and resources to our product candidates or is otherwise unsuccessful in its efforts with
respect to our products or product candidates, the development and commercialization of product candidates covered by the agreements could be delayed or terminated, and future payments to us could be
delayed, reduced or eliminated and our business and financial condition could be materially and adversely affected. Accordingly, our ability to receive any revenue from the product candidates covered
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by
these agreements is dependent on the efforts of our partners. If a partner terminates or breaches its agreements with us, otherwise fails to complete its obligations in a timely manner or alleges
that we have breached our contractual obligations under these agreements, the chances of successfully developing or commercializing product candidates under the collaboration could be materially and
adversely affected. We could also become involved in disputes with a partner, which could lead to delays in or termination of our development and commercialization programs and time-consuming and
expensive litigation or arbitration. Furthermore, termination of an agreement by a partner could have an adverse effect on the price of our ordinary shares or other securities even if not material to
our business.
Because GSK is a strategic partner of Innoviva, a strategic partner of TRC and a significant shareholder of
us, it may take actions that in certain cases are materially harmful to our business and to our other shareholders.
Based on our review of publicly available filings, as of December 31, 2016, GSK beneficially owned approximately 18.3% of our outstanding
ordinary shares. GSK is also a strategic partner to Innoviva with rights and obligations under the strategic alliance agreement and under the collaboration agreement assigned to TRC (the "GSK-Innoviva
Agreements") that may cause GSK's interests to differ from the interests of us and our other shareholders. In particular, if the Closed Triple or a MABA/ICS in either the U.S. or the EU is approved,
GSK's diligent efforts obligations under the GSK-Innoviva Agreements with regard to commercialization matters will have the objective of focusing on the best interests of patients and maximizing the
net value of the overall portfolio of products under the GSK-Innoviva Agreements. Following such regulatory approval, GSK's commercialization efforts will be guided by a portfolio approach across
products in which we have an indirect interest through TRC and products in which we have no interest. Accordingly, GSK's commercialization efforts may have the effect of reducing the value of our
interest in TRC. Furthermore, GSK has a substantial
respiratory product portfolio in addition to the products covered by the GSK-Innoviva Agreements. GSK may make respiratory product portfolio decisions or statements about its portfolio which may be,
or may be perceived to be, harmful to the respiratory products partnered with Innoviva and TRC. For example, GSK could promote its own respiratory products and/or delay or terminate the development or
commercialization of the respiratory programs covered by the GSK-Innoviva Agreements. Also, given the potential future royalty payments GSK may be obligated to pay under the GSK-Innoviva Agreements,
GSK may seek to acquire us or acquire our interests in TRC in order to effectively reduce those payment obligations and the price at which GSK might seek to acquire us may not reflect our true value.
Although the actions GSK may take to acquire us are limited under our governance agreement with GSK (the "Governance Agreement"), this agreement will expire on December 31, 2017. The timing of
when GSK may seek to acquire us could potentially be when it possesses information regarding the status of drug programs covered by the GSK-Innoviva Agreements that has not been publicly disclosed and
is not otherwise known to us. As a result of these differing interests, GSK may take actions that it believes are in its best interest but which might not be in the best interests of either us or our
other shareholders. In addition, GSK could also seek to challenge our or Innoviva's post-Spin-Off operations as violating or allowing it to terminate the GSK-Innoviva Agreements, including by
violating the confidentiality provisions of those agreements or the master agreement between GSK, Innoviva and us entered into in connection with the Spin-Off, or otherwise violating its legal rights.
While we believe our operations fully comply with the GSK-Innoviva Agreements, the master agreement and applicable law, there can be no assurance that we or Innoviva will prevail against any such
claims by GSK. Moreover, regardless of the merit of any claims by GSK, we may incur significant cost and diversion of resources in defending them. In addition, any other action or inaction by either
GSK or Innoviva that results in a material dispute, allegation of breach, litigation, arbitration, or significant disagreement between those parties may be interpreted negatively by the market or by
our investors, could harm our business and cause the price of our securities to fall.
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Examples
of these kinds of issues include but are not limited to non-performance of contractual obligations and allegations of non-performance, disagreements over the relative marketing and sales
efforts for Innoviva's partnered products and other GSK respiratory products, disputes over public statements, and similar matters. In general, any uncertainty about the respiratory programs partnered
with GSK, the enforceability of the GSK-Innoviva Agreements or the relationship/partnership between Innoviva and GSK could result in significant reduction in the market price of our securities and
other material harm to our business.
Agreements entered into with or for the benefit of GSK in connection with the Spin-Off may significantly
restrict our business and affairs.
On March 3, 2014, in connection with the Spin-Off, we, Innoviva and GSK entered into a number of agreements that may significantly
restrict our business and affairs. In particular, we, Innoviva and GSK entered into a three-way master agreement (the "Master Agreement") that, among
other things, requires GSK's consent to make any changes to (A) the Separation and Distribution Agreement and ancillary agreements that would, individually or in the aggregate, reasonably be
expected to adversely affect GSK in any material respect or (B) the TRC Limited Liability Company Agreement, which consent is not to be unreasonably withheld, conditioned or delayed, provided
that GSK may withhold, condition or delay such consent in its sole discretion with respect to certain sections of the TRC Limited Liability Company Agreement and any changes to the governance
structure of TRC, the confidentiality restrictions, the consent rights, and the transfer restrictions in the TRC Limited Liability Company Agreement. We and GSK also entered into (i) the
Governance Agreement that, among other things, provides share purchase rights to GSK and exempts GSK from triggering our Rights Agreement until December 31, 2017, (ii) a registration
rights agreement that gives GSK certain registration rights with respect to our ordinary shares held by GSK and (iii) an extension agreement that extends to us certain restrictive covenants
similar to those applicable to Innoviva under the GSK-Innoviva Agreements. There can be no assurance that these restrictions will not materially harm our business, particularly given that GSK's
interests may not be aligned with the interests of our business or our other shareholders.
We depend on third parties in the conduct of our clinical studies for our product candidates.
We depend on independent clinical investigators, contract research and manufacturing organizations and other third-party service providers in
the conduct of our non-clinical and clinical studies for our product candidates. We rely heavily on these parties for execution of our non-clinical and clinical studies, and control only certain
aspects of their activities. Nevertheless, we are responsible for ensuring that our clinical studies are conducted in accordance with good clinical, laboratory and manufacturing practices ("GXPs") and
other regulations as required by the FDA and foreign regulatory authorities, and the applicable protocol. Failure by these parties to comply with applicable regulations and practices in conducting
studies of our product candidates can result in a delay in our development programs or non-approval of our product candidates by regulatory authorities.
The
FDA, and equivalent authorities in other countries, enforces GXPs and other regulations through periodic inspections of trial sponsors, clinical research organizations ("CROs"),
principal investigators and trial sites. If we or any of the third parties on which we have relied to conduct our clinical studies are determined to have failed to comply with GXPs (or other
equivalent regulations outside the United States), the study protocol or applicable regulations, the clinical data generated in our studies may be deemed unreliable. This could result in non-approval
of our product candidates by the FDA, or equivalent authorities in other countries, or we, the FDA, or equivalent authorities in other countries may decide to conduct additional audits or require
additional clinical studies, which would delay our development programs, could result in significant additional costs and the price of our securities could fall.
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We face substantial competition from companies with more resources and experience than we have, which may
result in others discovering, developing, receiving approval for or commercializing products before or more successfully than we do.
Our ability to succeed in the future depends on our ability to demonstrate and maintain a competitive advantage with respect to our approach to
the discovery, development and commercialization of medicines. Our objective is to discover, develop and commercialize new small molecule medicines with superior efficacy, convenience, tolerability
and/or safety using our proprietary insight in chemistry, biology and multivalency, where applicable. We expect that any medicines that we commercialize with or without our collaborative partners will
compete with existing or future market-leading medicines.
Many
of our current and potential competitors have substantially greater financial, technical and personnel resources than we have. In addition, many of these competitors have
significantly greater commercial infrastructures than we have. Our ability to compete successfully will depend largely on our ability to leverage our experience in drug discovery and development, and,
more recently, commercialization, to:
-
-
discover and develop medicines that are superior to other products in the market;
-
-
attract and retain qualified personnel;
-
-
obtain patent and/or other proprietary protection for our medicines and technologies;
-
-
obtain required regulatory approvals;
-
-
develop and effectively implement commercialization strategies, with or without collaborative partners; and
-
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successfully collaborate with pharmaceutical companies in the discovery, development and commercialization of new medicines.
Pharmaceutical
companies, including companies with which we collaborate, may invest heavily to quickly discover and develop or in-license novel compounds that could make our product
candidates obsolete. Accordingly, our competitors may succeed in obtaining patent protection, receiving FDA or equivalent regulatory approval outside the United States or discovering, developing and
commercializing medicines before we do. Other companies are engaged in the discovery of medicines that would compete with the product candidates that we are developing.
Any
new medicine that competes with a generic or proprietary market leading medicine must demonstrate compelling advantages in efficacy, convenience, tolerability and/or safety in order
to overcome severe price competition and be commercially successful. VIBATIV must demonstrate these advantages in certain circumstances, as it competes with vancomycin, linezolid and daptomycin,
relatively inexpensive generic drugs that are manufactured by a number of companies, and a number of existing antibacterial drugs marketed by major and other pharmaceutical companies. If we are not
able to compete effectively against our current and future competitors, our business will not grow, our financial condition and operations will suffer and the price of our securities could fall.
Certain of our directors and officers may have actual or potential conflicts of interest because of their
equity ownership in Innoviva, which actual or potential conflicts may harm our business, prospects and financial condition and result in the diversion of corporate opportunities to Innoviva.
Certain of our directors and executive officers hold shares of Innoviva's common stock or rights to acquire such shares, and these holdings may
be significant for some of these individuals compared to their total assets. This ownership of Innoviva common stock by our officers and most of our directors may create, or may create the appearance
of, conflicts of interest when these directors and officers are
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faced
with decisions that could have different implications for Innoviva and for us. For example, potential or actual conflicts could arise relating to: our relationship with Innoviva, including
Innoviva's and our respective rights and obligations under agreements entered into in connection with the Spin-Off; Innoviva's management of TRC, particularly given that we and Innoviva have different
economic interests in TRC; and corporate opportunities that may be available to both companies in the future. Although we and Innoviva have implemented policies and procedures to identify and properly
address such potential and actual conflicts of interest, there can be no assurance that, when such conflicts are resolved in accordance with applicable laws, such conflicts of interest will not harm
our business, prospects and financial condition and result in the diversion of corporate opportunities to Innoviva.
If we lose key management or scientific personnel, or if we fail to attract and retain key employees, our
ability to discover and develop our product candidates and commercialize VIBATIV and any other products that may be approved in the future will be impaired.
We are highly dependent on principal members of our management team and scientific staff, and in particular, our Chief Executive Officer, Rick E
Winningham, to operate our business. Mr. Winningham has significant pharmaceutical industry experience. The loss of Mr. Winningham's services could impair our ability to discover,
develop and commercialize new medicines.
If
we fail to retain our qualified personnel or replace them when they leave, we may be unable to continue our discovery, development and commercialization activities, which may cause
the price of our securities to fall.
In
addition, our U.S. operating subsidiary's facility and most of its employees are located in northern California, headquarters to many other biotechnology and biopharmaceutical
companies and many academic and research institutions. As a result, competition for certain skilled personnel in our market is intense. None of our employees have employment commitments for any fixed
period of time and they all may leave our employment at will. If we fail to retain our qualified personnel or replace them when they leave, we may be unable to continue our development and
commercialization activities and the price of our securities could fall.
Our business and operations would suffer in the event of significant disruptions of information technology
systems or security breaches.
We rely extensively on computer systems to maintain information and manage our finances and business. In the ordinary course of business, we
collect, store and transmit large amounts of confidential information (including but not limited to trade secrets or other intellectual property, proprietary business information and personal
information) and it is critical that we maintain the confidentiality and integrity of such confidential information. Although we have security measures in place, our internal information technology
systems and those of our CROs and other service providers, including cloud-based and hosted applications, data and services, are vulnerable to service interruptions and security breaches from
inadvertent or intentional actions by our employees, service providers and/or business partners, from cyber-attacks by malicious third parties, and/or from, natural disasters, terrorism, war and
telecommunication and electrical failures. Cyber-attacks are increasing in their frequency, sophistication, and intensity, and have become increasingly difficult to detect. Significant disruptions of
information technology systems or security breaches could adversely affect our business operations and result in financial, legal, business and reputational harm to us, including significant liability
and/or significant disruption to our business. If a disruption of information technology systems or security breach results in a loss of or damage to our data or regulatory applications, unauthorized
access, use, or disclosure of, or the prevention of access to, confidential information, or other harm to our business, we could incur liability and reputational harm, we could be required to comply
with federal and/or state breach notification laws and foreign law equivalents, the further development of
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our
product candidates could be delayed and the price of our securities could fall. For example, the loss of clinical trial data from completed or ongoing clinical trials of our product candidates
could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. Although we have security and fraud prevention measures in place, we
have been subject to immaterial payment fraud activity. Moreover, there can be no assurance that such security measures will prevent service interruptions or security breaches that could adversely
affect our business.
Our U.S. operating subsidiary's facility is located near known earthquake fault zones, and the occurrence of
an earthquake, extremist attack or other catastrophic disaster could cause damage to our facilities and equipment, which could require us to cease or curtail operations.
Our U.S. operating subsidiary's facility is located in the San Francisco Bay Area near known earthquake fault zones and therefore will be
vulnerable to damage from earthquakes. In October 1989, a major earthquake struck this area and caused significant property damage and a
number of fatalities. We are also vulnerable to damage from other types of disasters, including power loss, attacks from extremist organizations, fire, floods, communications failures and similar
events. If any disaster were to occur, our ability to operate our business could be seriously impaired. In addition, the unique nature of our research activities and of much of our equipment could
make it difficult and costly for us to recover from this type of disaster. We may not have adequate insurance to cover our losses resulting from disasters or other similar significant business
interruptions and we do not plan to purchase additional insurance to cover such losses due to the cost of obtaining such coverage. Any significant losses that are not recoverable under our insurance
policies could seriously impair our business and financial condition, which could cause the price of our securities to fall.
Global health and economic, political and social conditions may harm our ability to do business, increase our
costs and negatively affect our stock price.
Worldwide economic conditions remain uncertain due to the election by the United Kingdom to withdraw from the European Union (often referred to
as "Brexit"), new political leadership in the United States, current economic challenges in Asia and other disruptions to global and regional economies and markets. External factors, such as potential
terrorist attacks, acts of war, geopolitical and social turmoil or epidemics and other similar outbreaks in many parts of the world, could prevent or hinder our ability to do business, increase our
costs and negatively affect our stock price. In addition, our operations also depend upon favorable trade relations between the U.S. and those foreign countries in which our materials suppliers have
operations. A protectionist trade environment in either the U.S. or those foreign countries in which we do business, such as a change in the current tariff structures, export compliance or other trade
policies, may materially and adversely affect our operations. These geopolitical, social and economic conditions could harm our business.
If we are unable to maintain effective internal controls, our business, financial position and results of
operations could be adversely affected.
If we are unable to maintain effective internal controls, our business, financial position and results of operations could be adversely
affected. We are subject to the reporting and other obligations under the Exchange Act, including the requirements of Section 404 of the Sarbanes-Oxley Act of 2002, which require annual
management assessments of the effectiveness of our internal control over financial reporting. Our management is responsible for establishing and maintaining adequate internal control over financial
reporting as defined in Rules 13a-15(f) under the Exchange Act. Our internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of
financial reporting and the preparation of financial statements for external purposes in accordance with accounting principles generally accepted in the United States. Any failure to achieve and
maintain effective internal controls could have an adverse effect on our business, financial position and results of
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operations.
In addition, since we are a "large accelerated filer" rather than an "emerging growth company" (each as defined in the Exchange Act) as of December 31, 2016 our independent
registered public accounting firm will be required to attest to the effectiveness of our internal control over financial reporting annually. If our independent registered public accounting firm is
unable to attest to the effectiveness of our internal control over financial reporting, investor confidence in our reported results will be harmed and the price of our securities may fall. These
reporting and other obligations place significant demands on our management and administrative and operational resources, including accounting resources.
We have only been operating as a stand-alone entity since June 2, 2014 and therefore we have a limited
history operating as an independent company upon which you can evaluate us.
We have only been operating as a stand-alone entity since June 2, 2014 and therefore we have a limited operating history as an
independent company upon which you can evaluate us. While our biopharmaceutical business has constituted a substantial part of the historic operations of Innoviva, we did not operate as a stand-alone
company.
In
addition, our historical financial information prior to the Spin-Off does not necessarily reflect what our financial position, results of operations or cash flows would have been as a
stand-alone company during the periods presented and is not necessarily indicative of our future financial position, future results of operations or future cash flows.
We may be treated as a U.S. corporation for U.S. federal income tax purposes.
For U.S. federal income tax purposes, a corporation generally is considered tax resident in the place of its incorporation. Theravance Biopharma
is incorporated under Cayman Islands law and established tax residency in Ireland effective July 1, 2015. Therefore, it should be a non-U.S. corporation under this general rule. However,
Section 7874 of the Internal Revenue Code of 1986, as amended (the "Code"), contains rules that may result in a foreign corporation being treated as a U.S. corporation for U.S. federal income
tax purposes. The application of these rules is complex and there is little guidance regarding certain aspects of their application.
Under
Section 7874 of the Code, a corporation created or organized outside the U.S. will be treated as a U.S. corporation for U.S. federal tax purposes if (i) the foreign
corporation directly or indirectly acquires substantially all of the properties held directly or indirectly by a U.S. corporation, (ii) the former shareholders of the acquired U.S. corporation
hold at least 80% of the vote or value of the shares of the foreign acquiring corporation by reason of holding stock in the U.S. acquired corporation, and (iii) the foreign corporation's
"expanded affiliated group" does not have "substantial business activities" in the foreign corporation's country of incorporation relative to its expanded affiliated group's worldwide activities. For
this purpose, "expanded affiliated group" generally means the foreign corporation and all subsidiaries in which the foreign corporation, directly or indirectly, owns more than 50% of the stock by vote
and value, and "substantial business activities" generally means at least 25% of employees (by number and compensation), assets and gross income of our expanded affiliated group are based, located and
derived, respectively, in the country of incorporation.
We
do not expect to be treated as a U.S. corporation under Section 7874 of the Code, because we do not believe that the assets contributed to us by Innoviva constituted
"substantially all" of the properties of Innoviva (as determined on both a gross and net fair market value basis). However, the Internal Revenue Service ("IRS") may disagree with our conclusion on
this point and assert that, in its view, the assets contributed to us by Innoviva did constitute "substantially all" of the properties of Innoviva. In addition, there could be legislative proposals to
expand the scope of U.S. corporate tax residence and there could be changes to Section 7874 of the Code or the Treasury Regulations
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promulgated
thereunder that could apply retroactively and could result in Theravance Biopharma being treated as a U.S. corporation.
If
it were determined that we should be treated as a U.S. corporation for U.S. federal income tax purposes, we could be liable for substantial additional U.S. federal income tax on our
post-Spin-Off taxable income. In addition, payments of dividends to non-U.S. holders may be subject to U.S. withholding tax.
Taxing authorities may challenge our structure and transfer pricing arrangements.
We are incorporated in the Cayman Islands, maintain subsidiaries in the Cayman Islands, the United States, the United Kingdom and Ireland, and
effective July 1, 2015, we migrated our tax residency from the Cayman Islands to Ireland. Due to economic and political conditions various countries are actively considering changes to existing
tax laws. We cannot predict the form or timing of potential legislative changes that could have a material adverse impact on our results of operations. In
addition, significant judgment is required in determining our worldwide provision for income taxes. Various factors may have favorable or unfavorable effects on our income tax rate including, but not
limited to the performance of certain functions and ownership of certain assets in tax-efficient jurisdictions such as the Cayman Islands and Ireland, together with intra-group transfer pricing
agreements. Taxing authorities may challenge our structure and transfer pricing arrangements through an audit or lawsuit. Responding to or defending such a challenge could be expensive and consume
time and other resources, and divert management's time and focus from operating our business. We cannot predict whether taxing authorities will conduct an audit or file a lawsuit challenging
this structure, the cost involved in responding to any such audit or lawsuit, or the outcome. We may be required to pay taxes for prior periods, interest, fines or penalties, and may be obligated to
pay increased taxes in the future which could result in reduced cash flows and have a material adverse effect on our business, financial condition and growth prospects.
We were a passive foreign investment company, or "PFIC," for 2014 but we believe that we are not a PFIC for
2015 and 2016, and we do not expect to be a PFIC for the foreseeable future.
For U.S. federal income tax purposes, we generally would be classified as a PFIC for any taxable year if either (i) 75% or more of our
gross income (including gross income of certain 25% or more owned corporate subsidiaries) is "passive income" (as defined for such purposes) or (ii) the average percentage of our assets
(including the assets of certain 25% or more owned corporate subsidiaries) that produce passive income or that are held for the production of passive income is at least 50%. In addition, whether our
company will be a PFIC for any taxable year depends on our assets and income over the course of each such taxable year and, as a result, cannot be predicted with certainty until after the end of the
year.
Based
upon our assets and income during the course of 2014, we believe that our company and one of our company's wholly owned subsidiaries, Theravance Biopharma R&D, Inc. was a
PFIC for 2014. Based upon our assets and income during the course of 2015 and 2016, we do not believe that our company is a PFIC for 2015 or 2016. We do not expect to be a PFIC for the foreseeable
future based on our current business plans and current business model. For any taxable year (or portion thereof) in which our company is a PFIC that is included in the holding period of a U.S. holder,
the U.S. holder is generally subject to additional U.S. federal income taxes plus an interest charge with respect to certain distributions from Theravance Biopharma or gain recognized on a sale of
Theravance Biopharma shares. Similar rules would apply with respect to distributions from or gain recognized on an indirect sale of Theravance Biopharma R&D, Inc. U.S. holders of our ordinary
shares may have filed an election with respect to company shares held at any time during 2014 to be treated as owning an interest in a "qualified electing fund" ("QEF") or to "mark to market" their
ordinary shares to avoid the otherwise applicable interest charge consequences of PFIC treatment with respect to our
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ordinary
shares. A foreign corporation will not be treated as a QEF for any taxable year in which such foreign corporation is not treated as a PFIC. QEF and mark to market elections generally apply to
the taxable year for which the election is made and all subsequent taxable years unless the election is revoked with consent of the Secretary of Treasury. U.S. holders of our ordinary shares should
consult their tax advisers regarding the tax reporting implications with respect to any QEF and mark to market elections made with respect to our company and with respect to their indirect interests
in Theravance Biopharma R&D, Inc.
If we are required to indemnify Innoviva, or if we are not able to collect on indemnification rights from
Innoviva, our business prospects and financial condition may be harmed.
We agreed to indemnify Innoviva from and after the Spin-Off with respect to (i) all debts, liabilities and obligations transferred to us
in connection with the Spin-Off (including our failure to pay, perform or otherwise promptly discharge any such debts, liabilities or obligations after the Spin-Off), (ii) any misstatement or
omission of a material fact resulting in a misleading statement in our Information Statement distributed to Innoviva stockholders in connection with the Spin-Off and (iii) any breach by us of
certain agreements entered into with Innoviva in connection with the Spin-Off (namely, the Separation and Distribution Agreement, the Transition Services Agreement, the Employee Matters Agreement, the
Tax Matters Agreement, and the Facility Sublease Agreement). We are not aware of any existing indemnification obligations at this time, but any such indemnification obligations that may arise could be
significant. Under the terms of the Separation and Distribution Agreement, Innoviva agreed to indemnify us from and after the Spin-Off with respect to (i) all debts, liabilities and obligations
retained by Innoviva after the Spin-Off (including its failure to pay, perform or otherwise promptly discharge any such debts, liabilities or obligations after the Spin-Off) and (ii) any breach
by Innoviva of the Separation and Distribution Agreement, the Transition Services Agreement, the Employee Matters Agreement, the Tax Matters Agreement, and the Facility Sublease Agreement. Our and
Innoviva's ability to satisfy these indemnities, if called upon to do so, will depend upon our and Innoviva's future financial strength. If we are required to indemnify Innoviva, or if we are not able
to collect on indemnification rights from Innoviva, our business prospects and financial condition may be harmed.
RISKS RELATED TO LEGAL AND REGULATORY UNCERTAINTY
If our efforts to protect the proprietary nature of the intellectual property related to our technologies are
not adequate, we may not be able to compete effectively in our current or future markets.
We rely upon a combination of patents, patent applications, trade secret protection and confidentiality agreements to protect the intellectual
property related to our technologies. Any involuntary disclosure to or misappropriation by third parties of this proprietary information could enable competitors to quickly duplicate or surpass our
technological achievements, thus eroding our competitive position in our market. The status of patents in the biotechnology and pharmaceutical field involves complex legal and scientific questions and
is very uncertain. As of December 31, 2016, we or one of our wholly-owned subsidiaries owned 434 issued United States patents and 1,681 granted foreign patents, as well as additional pending
United States and foreign patent applications. Our patent applications may be challenged or fail to result in issued patents and our existing or future patents may be invalidated or be too narrow to
prevent third parties from developing or designing around these patents. If the sufficiency of the breadth or strength of protection provided by our patents with respect to a product candidate is
threatened, it could dissuade companies from collaborating with us to develop product candidates and threaten our ability to commercialize products. Further, if we encounter delays in our clinical
trials or in obtaining regulatory approval of our product candidates, the patent lives of the related product candidates would be reduced.
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In
addition, we rely on trade secret protection and confidentiality agreements to protect proprietary know-how that is not patentable, for processes for which patents are difficult to
enforce and for any other elements of our drug discovery and development processes that involve proprietary know-how, information and technology that is not covered by patent applications. Although we
require our employees, consultants, advisors and any third parties who have access to our proprietary know-how, information and technology to enter into confidentiality agreements, we cannot be
certain that this know-how, information and technology will not be disclosed or that competitors will not otherwise gain access to our trade secrets or independently develop substantially equivalent
information and techniques. Further, the laws of some foreign countries do not protect proprietary rights to the same extent as the laws of the United States. As a result, we may encounter significant
problems in protecting and defending our intellectual property both in the United States and abroad. If we are unable to prevent material disclosure of the intellectual property related to our
technologies to third parties, we will not be able to establish or, if established, maintain a competitive advantage in our market, which could materially adversely affect our business, financial
condition and results of operations, which could cause the price of our securities to fall.
Under
the Drug Price Competition and Patent Term Restoration Act of 1984, a company may submit an abbreviated new drug application (ANDA) under section 505(j) of the Federal Food,
Drug, and Cosmetic Act to market a generic version of an approved drug. Because a generic applicant does not conduct its own clinical studies, but instead relies on the FDA's finding of safety and
effectiveness for
the approved drug, it is able to introduce a competing product into the market at a cost significantly below that of the original drug. Although we have multiple patents protecting VIBATIV until at
least 2027 that are listed in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations, commonly known as the Orange Book, generic applicants could potentially submit
"paragraph IV certifications" to FDA stating that such patents are invalid or will not be infringed by the applicant's product. We have not received any such paragraph IV notifications
but if any competitors successfully challenge our patents, we would face substantial competition. If we are not able to compete effectively against such future competition, our business will not grow,
our financial condition and operations will suffer and the price of our securities could fall.
Litigation or third-party claims of intellectual property infringement would require us to divert resources
and may prevent or delay our drug discovery and development efforts.
Our commercial success depends in part on us and our partners not infringing the patents and proprietary rights of third parties. Third parties
may assert that we or our partners are using their proprietary rights without authorization. There are third-party patents that may cover materials or methods for treatment related to our product
candidates. At present, we are not aware of any patent infringement claims with merit that would adversely and materially affect our ability to develop our product candidates, but nevertheless the
possibility of third-party allegations cannot be ruled out. In addition, third parties may obtain patents in the future and claim that use of our technologies infringes upon these patents.
Furthermore, parties making claims against us or our partners may obtain injunctive or other equitable relief, which could effectively block our ability to further develop and commercialize one or
more of our product candidates. Defense against these claims, regardless of their merit, would involve substantial litigation expense and would be a substantial diversion of employee resources from
our business.
In
the event of a successful claim of infringement against us, we may have to pay substantial damages, obtain one or more licenses from third parties or pay royalties. In addition, even
in the absence of litigation, we may need to obtain licenses from third parties to advance our research or allow commercialization of our product candidates, and we have done so from time to time. We
may fail to obtain any of these licenses at a reasonable cost or on reasonable terms, if at all. In that event, we would be unable to further develop and commercialize one or more of our product
candidates,
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which
could harm our business significantly. In addition, in the future we could be required to initiate litigation to enforce our proprietary rights against infringement by third parties. Prosecution
of these claims to enforce our rights against others would involve substantial litigation expenses and divert substantial employee resources from our business. If we fail to effectively enforce our
proprietary rights against others, our business will be harmed and the price of our securities could fall.
If the efforts of our partners or future partners to protect the proprietary nature of the intellectual
property related to collaboration assets are not adequate, the future commercialization of any medicines resulting from collaborations could be delayed or prevented, which would materially harm our
business and could cause the price of our securities to fall.
The risks identified in the two preceding risk factors may also apply to the intellectual property protection efforts of our partners or future
partners and to GSK with respect to the GSK-Partnered Respiratory Programs in which we hold an economic interest. To the extent the intellectual property protection of any partnered assets are
successfully challenged or encounter problems with the United States Patent and Trademark Office or other comparable agencies throughout the world, the future commercialization of these potential
medicines could be delayed or prevented. Any challenge to the intellectual property protection of a late-stage development asset, particularly those of the GSK-Partnered Respiratory Programs in which
we hold an economic interest, could harm our business and cause the price of our securities to fall.
Product liability lawsuits could divert our resources, result in substantial liabilities and reduce the
commercial potential of our medicines.
The risk that we may be sued on product liability claims is inherent in the development and commercialization of pharmaceutical products. Side
effects of, or manufacturing defects in, products that we or our partners develop or commercialize could result in the deterioration of a patient's condition, injury or even death. The VIBATIV
prescribing information describes several potential adverse effects observed during clinical trials, including increased mortality versus vancomycin in patients with HABP/VABP who had pre-existing
moderate to severe renal impairment, decreased clinical response in patients with cSSSI who had pre-existing moderate/severe renal impairment, and other renal adverse events. The prescribing
information includes a black box warning regarding increased mortality in patients with pre-existing moderate/severe renal impairment who were treated with VIBATIV for HABP/VABP, new onset or
worsening renal impairment, use in women of childbearing potential or during pregnancy and adverse developmental outcomes observed in 3 animal species. Once a product is approved for sale and
commercialized, the likelihood of product liability lawsuits tends to increase. Claims may be brought by individuals seeking relief for themselves or by individuals or groups seeking to represent a
class, asserting injuries based both on potential adverse effects described in the label as well as adverse events not yet observed. Also, changes in laws outside the U.S. are expanding our potential
liability for injuries that occur during clinical trials. These lawsuits may divert our management from pursuing our business strategy and may be costly to defend. In addition, if we are held liable
in any of these lawsuits, we may incur substantial liabilities and may be forced to limit or forgo further commercialization of the applicable products.
Although
we maintain general liability and product liability insurance, this insurance may not fully cover potential liabilities and we cannot be sure that our insurer will not disclaim
coverage as to a
future claim. In addition, inability to obtain or maintain sufficient insurance coverage at an acceptable cost or to otherwise protect against potential product liability claims could prevent or
inhibit the commercial production and sale of our products, which could adversely affect our business. The cost of defending any product liability litigation or other proceeding, even if resolved in
our favor, could be substantial and uncertainties resulting from the initiation and continuation of product liability litigation or other proceedings could have a material adverse effect on our
ability to compete in the marketplace. Product liability claims could also harm our reputation, which may adversely affect our and our partners' ability to commercialize our products successfully and
the price of our securities could fall.
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Changes in healthcare law and implementing regulations, including government restrictions on pricing and
reimbursement, as well as healthcare policy and other healthcare payor cost-containment initiatives, may negatively impact our ability to generate revenues.
The continuing efforts of the government, insurance companies, managed care organizations and other payors of health care costs to contain or
reduce costs of health care may adversely affect one or more of the following:
-
-
our or our collaborators' ability to set and collect a price we believe is reasonable for our product;
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-
our ability to generate revenues and achieve profitability; and
-
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the availability of capital.
The
pricing and reimbursement environment for VIBATIV and any future products may change in the future and become more challenging due to, among other reasons, policies advanced by the
current or any new presidential administration, federal agencies, new healthcare legislation passed by Congress or fiscal challenges faced by all levels of government health administration
authorities. Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare
costs, improving quality and expanding access to healthcare. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major
legislative initiatives. We expect to experience pricing pressures in connection with the sale of VIBATIV and other products we may bring to market, due to the trend toward managed healthcare, the
increasing influence of health maintenance organizations and additional legislative proposals.
The
Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (together the "Healthcare Reform Act"), is a sweeping measure
intended to expand healthcare coverage within the United States, primarily through the imposition of health insurance mandates on employers and individuals and expansion of the Medicaid program. This
law substantially changes the way healthcare is financed by both governmental and private insurers, and significantly impacts the pharmaceutical industry. The Healthcare Reform Act contains a number
of provisions that impact our business and operations. Changes that may affect our business include those governing enrollment in federal healthcare programs, reimbursement changes, benefits for
patients within a coverage gap in the Medicare Part D prescription drug program (commonly known as the "donut hole"), rules regarding prescription drug benefits under the health insurance
exchanges, changes to the Medicare Drug Rebate program, expansion of the Public Health Service's 340B drug pricing program, fraud and abuse and enforcement. These changes impact existing government
healthcare programs and are resulting in the development of new programs, including Medicare payment for performance initiatives and improvements to the physician quality reporting system and feedback
program.
Details
of the changes to the Medicaid Drug Rebate program and the 340B program are discussed below under the risk factor "
If we fail to comply with
our reporting and payment obligations under the Medicaid Drug Rebate program or other governmental pricing programs, we could be subject to additional reimbursement requirements, penalties, sanctions
and fines, which could have a material adverse effect on our business, financial condition, results of operations and growth prospects.
" In particular, on February 1,
2016, the Centers for Medicare and Medicaid Services ("CMS"), the federal agency that administers the Medicare and Medicaid programs, issued final regulations to implement the changes to the Medicaid
Drug Rebate program under the Healthcare Reform Act. These regulations
became effective on April 1, 2016. Congress could enact additional legislation that further increases Medicaid drug rebates or other costs and charges associated with participating in the
Medicaid Drug Rebate program. The issuance of regulations and coverage expansion by various governmental agencies relating to the
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Medicaid
Drug Rebate program has and will continue to increase our costs and the complexity of compliance, has been and will be time-consuming, and could have a material adverse effect on our results
of operations.
Some
states have elected not to expand their Medicaid programs by raising the income limit to 133% of the federal poverty level, as is permitted under the Healthcare Reform Act. For each
state that does not choose to expand its Medicaid program, there may be fewer insured patients overall, which could impact our sales, business and financial condition. Where Medicaid patients receive
insurance coverage under any of the new options made available through the Healthcare Reform Act, manufacturers may be required to pay Medicaid rebates on drugs used under these circumstances, which
could impact manufacturer revenues. In addition, the federal government has also announced delays in the implementation of key provisions of the Healthcare Reform Act. The implications of these delays
for our sales, business and financial condition, if any, are not yet clear.
Moreover,
legislative changes to the Healthcare Reform Act remain possible and appear likely in the 115th United States Congress and under the Trump Administration. We expect that
the Healthcare Reform Act, as currently enacted or as it may be amended in the future, and other healthcare reform measures that may be adopted in the future, could have a material adverse effect on
our industry generally and on our ability to maintain or increase sales of our existing products or to successfully commercialize our product candidates, if approved.
In
addition, there have been proposals to impose federal rebates on Medicare Part D drugs, requiring federally-mandated rebates on all drugs dispensed to Medicare Part D
enrollees or on only those drugs dispensed to certain groups of lower income beneficiaries. If any of these proposals are adopted they could result in Theravance owing additional rebates, which could
have a negative impact on revenues from sales of our products.
Beginning
on April 1, 2013, Medicare payments for all items and services under Part A and B, including drugs and biologicals, were reduced by 2% under the sequestration
(i.e., automatic spending reductions) as required by federal law, which requires sequestration for most federal programs, excluding Medicaid, Social Security, and certain other programs. The
law caps the cuts to Medicare payments for items and services at 2% and this will continue to 2025. As long as these cuts remain in effect, they could adversely impact payment for VIBATIV and our
product candidates. We expect that additional state
and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could
result in reduced demand for our product candidates or additional pricing pressures.
If we fail to comply with our reporting and payment obligations under the Medicaid Drug Rebate program or
other governmental pricing programs, we could be subject to additional reimbursement requirements, penalties, sanctions and fines, which could have a material adverse effect on our business, financial
condition, results of operations and growth prospects.
We participate in and have certain price reporting obligations to the Medicaid Drug Rebate program and other governmental pricing programs, and
we have obligations to report average sales price under the Medicare program.
Under
the Medicaid Drug Rebate program, we are required to pay a rebate to each state Medicaid program for our covered outpatient drugs that are dispensed to Medicaid beneficiaries and
paid for by a state Medicaid program as a condition of having federal funds being made available to the states for our drugs under Medicaid and Medicare Part B. Those rebates are based on
pricing data reported by us on a monthly and quarterly basis to CMS, the federal agency that administers the Medicaid Drug Rebate program. These data include the average manufacturer price and, in the
case of innovator products, the best price for each drug which, in general, represents the lowest price available
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from
the manufacturer to any entity in the United States in any pricing structure, calculated to include all sales and associated rebates, discounts and other price concessions.
The
Healthcare Reform Act made significant changes to the Medicaid Drug Rebate program, such as expanding rebate liability from fee-for-service Medicaid utilization to include the
utilization of Medicaid managed care organizations as well and changing the definition of average manufacturer price. The Healthcare Reform Act also increased the minimum Medicaid rebate; changed the
calculation of the rebate for certain innovator products that qualify as line extensions of existing drugs; and capped the total rebate amount at 100% of the average manufacturer price. Finally, the
Healthcare Reform Act requires pharmaceutical manufacturers of branded prescription drugs to pay a branded prescription drug fee to the federal government.
On
February 1, 2016, CMS issued final regulations to implement the changes to the Medicaid Drug Rebate program under the Healthcare Reform Act. These regulations became effective
on April 1, 2016. The issuance of regulations and coverage expansion by various governmental agencies relating to the Medicaid Drug Rebate program has and will continue to increase our costs
and the complexity of compliance, has been and will be time-consuming, and could have a material adverse effect on our results of operations.
Federal
law requires that any company that participates in the Medicaid Drug Rebate program also participate in the Public Health Service's 340B drug pricing program in order for federal
funds to be available for the manufacturer's drugs under Medicaid and Medicare Part B. The 340B program requires participating manufacturers to agree to charge no more than the 340B "ceiling
price" for the manufacturer's covered outpatient drugs to a variety of community health clinics and other entities that receive health services grants from the Public Health Service, as well as
hospitals that serve a disproportionate share of low-income patients. The Healthcare Reform Act expanded the list of covered entities to include certain free-standing cancer hospitals, critical access
hospitals, rural referral centers and sole community hospitals. The 340B ceiling price is calculated using a statutory formula based on the average manufacturer price and rebate amount for the covered
outpatient drug as calculated under the Medicaid Drug Rebate program. Changes to the definition of average manufacturer price and the Medicaid rebate amount under the Healthcare Reform Act and CMS's
final regulations implementing those changes also could affect our 340B ceiling price calculations and negatively impact our results of operations.
The
Healthcare Reform Act obligates the Secretary of the HHS to update the agreement that manufacturers must sign to participate in the 340B program to obligate a manufacturer to offer
the 340B price to covered entities if the manufacturer makes the drug available to any other purchaser at any price and to report to the government the ceiling prices for its drugs. The Health
Resources and Services Administration ("HRSA"), the federal agency that administers the 340B program, recently initiated the process of updating the agreement with participating manufacturers. The
Healthcare Reform Act also obligates the Secretary of the HHS to create regulations and processes to improve the integrity of the 340B program. In 2015, HRSA issued proposed omnibus guidance that
addresses many aspects of the 340B program, and in August 2016, HRSA issued a proposed regulation regarding an administrative dispute resolution process for the 340B program. It is unclear when or
whether the guidance or regulation will be released in final form under the Trump Administration. On January 5, 2017, HRSA issued a final regulation regarding the calculation of 340B ceiling
price and the imposition of civil monetary penalties on manufacturers that knowingly and intentionally overcharge covered entities. The Trump Administration has directed that this regulation, which
was slated to become effective March 6, 2017, be temporarily delayed until March 21, 2017, and the regulation could be subject to further delay or other modification. Implementation of
this final rule and the issuance of any other final regulations and guidance could affect our obligations under the 340B program in ways we cannot anticipate. In addition, legislation may be
introduced that, if passed, would further expand the
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340B
program to additional covered entities or would require participating manufacturers to agree to provide 340B discounted pricing on drugs used in the inpatient setting.
Federal
law also requires that a company that participates in the Medicaid Drug Rebate program report average sales price information each quarter to CMS for certain categories of drugs
that are paid under the Medicare Part B program. Manufacturers calculate the average sales price based on a statutorily defined formula as well as regulations and interpretations of the statute
by CMS. CMS uses these submissions to determine payment rates for drugs under Medicare Part B. Statutory or regulatory changes or CMS binding guidance could affect the average sales price
calculations for our products and the resulting Medicare payment rate, and could negatively impact our results of operations. Also, the Medicare Part B drug payment methodology is subject to
change based on potential demonstration projects undertaken by CMS or potential legislation enacted by Congress.
Pricing
and rebate calculations vary across products and programs, are complex, and are often subject to interpretation by us, governmental or regulatory agencies and the courts. In the
case of our Medicaid pricing data, if we become aware that our reporting for a prior quarter was incorrect, or has changed as a result of recalculation of the pricing data, we are obligated to
resubmit the corrected data for up to three years after those data originally were due. Such restatements and recalculations increase our costs for complying with the laws and regulations governing
the Medicaid Drug Rebate program and could result in an overage or underage in our rebate liability for past quarters. Price recalculations also may affect the ceiling price at which we are required
to offer our products under the 340B drug discount program.
We
are liable for errors associated with our submission of pricing data. In addition to retroactive rebates and the potential for 340B program refunds, if we are found to have knowingly
submitted any false price information to the government, we may be liable for civil monetary penalties in the amount of $178,156 per item of false information. If we are found to have made a
misrepresentation in the reporting of our average sales price, the Medicare statute provides for civil monetary penalties of up to $12,856 for each misrepresentation for each day in which the
misrepresentation was applied. Our failure to submit the required price data on a timely basis could result in a civil monetary penalty of $17,816 per day for each day the information is late beyond
the due date. Such failure also could be grounds for CMS to terminate our Medicaid drug rebate agreement, pursuant to which we participate in the Medicaid program. In the event that CMS terminates our
rebate agreement, federal payments may not be available under Medicaid or Medicare Part B for our covered outpatient drugs.
CMS
and the OIG have pursued manufacturers that were alleged to have failed to report these data to the government in a timely manner. Governmental agencies may also make changes in
program interpretations, requirements or conditions of participation, some of which may have implications for amounts previously estimated or paid. We cannot assure you that our submissions will not
be found by CMS to be incomplete or incorrect.
In
order to be eligible to have our products paid for with federal funds under the Medicaid and Medicare Part B programs and purchased by the VA, Department of Defense, Public
Health Service, and Coast Guard (the "Big Four agencies") and certain federal grantees, we are required to participate in the Department of Veterans Affairs ("VA") Federal Supply Schedule ("FSS")
pricing program, established under Section 603 of the Veterans Health Care Act of 1992. Under this program, we are obligated to make VIBATIV available for procurement on an FSS contract and
charge a price to the Big Four agencies that is no higher than the Federal Ceiling Price ("FCP"), which is a price calculated pursuant to a statutory formula. The FCP is derived from a calculated
price point called the "non-federal average manufacturer price" ("Non-FAMP"), which we calculate and report to the VA on a quarterly and annual basis. Pursuant to applicable law, knowing provision of
false information in connection with a Non-FAMP filing can subject a manufacturer to penalties of $178,156 for each item of false information. The FSS contract also contains extensive disclosure and
certification requirements.
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Under
Section 703 of the National Defense Authorization Act for FY 2008, we are required to pay quarterly rebates on utilization of innovator products that are dispensed through
the Tricare network pharmacies to Tricare beneficiaries. The rebates are calculated as the difference between the annual Non-FAMP and FCP. If we overcharge the government in connection with the FSS
contract or Tricare Retail Pharmacy Rebate Program, whether due to a misstated FCP or otherwise, we are required to refund the difference to the government. Failure to make necessary disclosures
and/or to identify contract overcharges can result in allegations against us under the False Claims Act and other laws and regulations. Unexpected refunds to the government, and any response to
government investigation or enforcement action, would be expensive and time-consuming, and could have a material adverse effect on our business, financial condition, results of operations and growth
prospects.
If we fail to comply with data protection laws and regulations, we could be subject to government enforcement
actions (which could include civil or criminal penalties), private litigation and/or adverse publicity, which could negatively affect our operating results and business.
We are subject to data protection laws and regulations (i.e., laws and regulations that address privacy and data security). In the U.S.,
numerous federal and state laws and regulations, including state data breach notification laws, state health information privacy laws, and federal and state consumer protection laws
(e.g., Section 5 of the FTC Act), govern the collection, use, disclosure, and protection of health-related and other personal information. Failure to comply with data protection laws and
regulations could result in government enforcement actions and create liability for us (which could include civil and/or criminal penalties), private litigation and/or adverse publicity that could
negatively affect our operating results and business. In addition, we may obtain health information from third parties (e.g., healthcare providers who prescribe our products) that are subject
to privacy and security requirements under the Health Insurance Portability and Accountability Act of 1996, as
amended by the Health Information Technology for Economic and Clinical Health Act ("HIPAA"). Although we are not directly subject to HIPAAother than potentially with respect to providing
certain employee benefitswe could be subject to criminal penalties if we knowingly obtain or disclose individually identifiable health information maintained by a
HIPAAcovered entity in a manner that is not authorized or permitted by HIPAA. HIPAA generally requires that healthcare providers and other covered entities obtain written authorizations
from patients prior to disclosing protected health information of the patient (unless an exception to the authorization requirement applies). If authorization is required and the patient fails to
execute an authorization or the authorization fails to contain all required provisions, then we may not be allowed access to and use of the patient's information and our research efforts could be
impaired or delayed. Furthermore, use of protected health information that is provided to us pursuant to a valid patient authorization is subject to the limits set forth in the authorization
(e.g., for use in research and in submissions to regulatory authorities for product approvals). In addition, HIPAA does not replace federal, state, international or other laws that may grant
individuals even greater privacy protections.
EU
Member States and other jurisdictions where we operate have adopted data protection laws and regulations, which impose significant compliance obligations. For example, the EU Data
Protection Directive imposes strict obligations and restrictions on the ability to collect, analyze and transfer personal data, including health data from clinical trials and adverse event reporting.
Switzerland has adopted similar restrictions. Data protection authorities from the different EU Member States may interpret the applicable laws differently, and guidance on implementation and
compliance practices are often updated or otherwise revised, which adds to the complexity of processing personal data in the EU. Although there are legal mechanisms to allow for the transfer of
personal data from the EEA to the U.S., a decision of the European Court of Justice in the
Schrems
case (Case C-362/14 Maximillian Schrems v. Data
Protection Commissioner) that invalidated the safe harbor framework has increased uncertainty around compliance with EU privacy law requirements. As a result of the decision, it was no longer possible
to rely on the safe harbor certification as a legal basis for the transfer of personal data
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from
the EU to entities in the U.S. On February 29, 2016, however, the European Commission announced an agreement with the United States Department of Commerce (DOC) to replace the invalidated
Safe Harbor framework with a new EU-U.S. "Privacy Shield." On July 12, 2016, the European Commission adopted a decision on the adequacy of the protection provided by the Privacy Shield. The
Privacy Shield is intended to address the requirements set out by the European Court of Justice in its ruling by imposing more stringent obligations on companies, providing stronger monitoring and
enforcement by the DOC and Federal Trade Commission, and making commitments on the part of public authorities regarding access to information. U.S. companies have been able to certify to the U.S.
Department of Commerce their compliance with the privacy principles of the Privacy Shield since August 1, 2016.
On
September 16, 2016, the Irish privacy advocacy group Digital Rights Ireland brought an action for annulment of the EC decision on the adequacy of the Privacy Shield before the
European Court of Justice (Case T-670/16). Case T-670/16 is still pending before the Court. If, however, the European
Court of Justice invalidates the Privacy Shield, it will no longer be possible to rely on the Privacy Shield certification to support transfer of personal data from the EU to entities in the US.
Adherence to the Privacy Shield is not, however, mandatory. U.S.-based companies are permitted to rely either on their adherence to the Privacy Shield or on the other authorized means and procedures
to transfer personal data provided by the EU Data Protection Directive. If we or our vendors fail to comply with applicable data privacy laws, or if the legal mechanisms we or our vendors rely upon to
allow for the transfer of personal data from the EEA or Switzerland to the U.S. (or other countries not considered by the European Commission to provide an adequate level of data protection) are not
considered adequate, we could be subject to government enforcement actions and significant penalties against us, and our business could be adversely impacted if our ability to transfer personal data
outside of the EEA or Switzerland is restricted, which could adversely impact our operating results. In December 2015, a proposal for an EU General Data Protection Regulation, intended to replace the
current EU Data Protection Directive, was agreed between the European Parliament, the Council of the European Union and the European Commission. The EU General Data Protection Regulation entered into
force on May 24, 2016 and will apply from May 25, 2018. The Regulation will introduce new data protection requirements in the EU, as well as substantial fines for breaches of the data
protection rules. The EU General Data Protection Regulation will increase our responsibility and liability in relation to personal data that we process, and we may be required to put in place
additional mechanisms to ensure compliance with the new EU data protection rules.
Our relationships with customers and third-party payors are subject to applicable anti-kickback, fraud and
abuse, transparency and other healthcare laws and regulations, which could expose us to criminal sanctions, civil penalties, exclusion, contractual damages, reputational harm and diminished profits
and future earnings.
Healthcare providers, physicians, distributors and third-party payors play a primary role in the distribution, recommendation and prescription
of any pharmaceutical product for which we obtain marketing approval. Our arrangements with third-party payors and customers expose us to broadly applicable fraud and abuse and other healthcare laws
and regulations that may constrain the business or financial arrangements through which we market, sell and distribute any products for which we have obtained or may obtain marketing approval.
Restrictions under applicable federal and state healthcare laws and regulations include the following:
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-
The federal healthcare Anti-Kickback Statute prohibits any person from, among other things, knowingly and willfully offering, paying,
soliciting, or receiving remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchasing, leasing, ordering or arranging for
or recommending of any good or service for which payment may be made, in whole or in part, under federal and state healthcare programs such as Medicare and Medicaid. The term "remuneration" has been
broadly interpreted to include
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anything
of value. The Anti-Kickback Statute is subject to evolving interpretation and has been applied by government enforcement officials to a number of common business arrangements in the
pharmaceutical industry. The government can establish a violation of the Anti-Kickback Statute without proving that a person or entity had actual knowledge of the statute or specific intent to violate
it. There are a number of statutory exemptions and regulatory safe harbors protecting some common activities from prosecution; however, those exceptions and safe harbors are drawn narrowly. Failure to
meet all of the requirements of a particular statutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute, but the legality of the arrangement
will be evaluated on a case-by-case basis based on the totality of the facts and circumstances. We seek to comply with the available statutory exemptions and safe harbors whenever possible, but our
practices may not in all cases meet all of the criteria for safe harbor protection from anti-kickback liability. Moreover, there are no safe harbors for many common practices, such as educational and
research grants or patient assistance programs.
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The federal civil False Claims Act imposes civil penalties, and provides for whistleblower or qui tam actions, against individuals or entities
for, among other things, knowingly presenting, or causing to be presented, claims for payment of government funds that are false or fraudulent, or knowingly making, or using or causing to be made or
used, a false record or statement material to a false or fraudulent claim to avoid, decrease, or conceal an obligation to pay money to the federal government. In recent years, several pharmaceutical
and other healthcare companies have faced enforcement actions under the federal False Claims Act for, among other things, allegedly submitting false or misleading pricing information to government
health care programs and providing free product to customers with the expectation that the customers would bill federal programs for the product. Federal enforcement agencies also have showed
increased interest in pharmaceutical companies' product and patient assistance programs, including reimbursement and co-pay support services, and a number of investigations into these programs have
resulted in significant civil and criminal settlements. Other companies have faced enforcement actions for causing false claims to be submitted because of the company's marketing the product for
unapproved, and thus non-reimbursable, uses. In addition, a claim including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim
for purposes of the federal civil False Claims Act. False Claims Act liability is potentially significant in the healthcare industry because the statute provides for treble damages and mandatory
penalties of $5,500 to $11,000 per false claim or statement. As a result of a recent interim final rule issued by the Department of Justice (DOJ), the penalties assessed after August 1, 2016
for violations occurring after November 2, 2015 will increase to per claim or statement penalties of $10,781 to $21,563. Because of the potential for large monetary exposure, healthcare and
pharmaceutical companies often resolve allegations without admissions of liability for significant and material amounts to avoid the uncertainty of treble damages and per claim penalties that may be
awarded in litigation proceedings. Companies may be required, however, to enter into corporate integrity agreements with the government, which may impose substantial costs on companies to ensure
compliance. Criminal prosecution is also possible for making or presenting a false or fictitious or fraudulent claim to the federal government.
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HIPAA, among other things, imposes criminal and civil liability for executing a scheme to defraud any healthcare benefit program and also
imposes obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable health information. HIPAA also prohibits
knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement or representation, or making or using any false writing
or document
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The
shifting commercial compliance environment and the need to build and maintain robust and expandable systems to comply with different compliance or reporting requirements in multiple
jurisdictions increase the possibility that we or our partners may fail to comply fully with one or more of these requirements. Efforts to ensure that our business arrangements with third parties will
comply with applicable healthcare laws and regulations may involve substantial costs. It is possible that governmental authorities will conclude that our business practices may not comply with
applicable fraud and abuse or other healthcare laws and regulations or guidance. If our operations are found to be in violation of any of these laws or any other governmental regulations that may
apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, exclusion from government funded healthcare programs, such as Medicare and Medicaid, and the
curtailment or restructuring of our operations. If any of the physicians or other providers or entities with whom we do or expect to do business are found to not be in compliance with applicable laws,
they may be subject to criminal, civil or administrative sanctions, including exclusions from government funded healthcare programs. Even if we are not determined to have violated these laws,
government investigations into these issues typically require the expenditure of significant resources and generate negative publicity, which could harm our financial condition and divert resources
and the attention of our management from operating our business.
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Our business and operations, including the use of hazardous and biological materials may result in
liabilities with respect to environmental, health and safety matters.
Our research and development activities involve the controlled use of potentially hazardous substances, including chemical, biological and
radioactive materials. In addition, our operations produce hazardous waste products, including hazardous waste. Federal, state and local laws and regulations govern the use, manufacture, management,
storage, handling and disposal of hazardous materials and wastes. We may incur significant additional costs or liabilities to comply with, or for
violations of, these and other applicable laws in the future. Also, even if we are in compliance with applicable laws, we cannot completely eliminate the risk of contamination or injury resulting from
hazardous materials and we may incur liability as a result of any such contamination or injury. Further, in the event of a release of or exposure to hazardous materials, including at the sites we
currently or formerly operate or at sites such as landfills where we send wastes for disposal, we could be held liable for cleanup costs or damages or subject to other costs or penalties and such
liability could exceed our resources. We do not have any insurance for liabilities arising from hazardous materials or under environmental laws. Compliance with or liability under applicable
environmental laws and regulations or with respect to hazardous materials may be expensive, and current or future environmental regulations may impair our research, development and production efforts,
which could harm our business, which could cause the price of our securities to fall.
RISKS RELATING TO OUR ORDINARY SHARES
The market price for our shares has and may continue to fluctuate widely, and may result in substantial
losses for purchasers of our ordinary shares.
Our ordinary shares began trading on June 3, 2014, and the market price for our shares has and may continue to fluctuate widely, and may
result in substantial losses for purchasers of our ordinary shares. To date, there is limited securities analyst coverage of our company. Limited securities analyst coverage of our company and shares
is likely to reduce demand for our shares from potential investors, which likely will reduce the market price for our shares. To the extent that historically low trading volumes for our ordinary
shares continues, our stock price may fluctuate significantly more than the stock market as a whole or the stock prices of similar companies. Without a larger public float of actively traded shares,
our ordinary shares are likely to be more sensitive to changes in sales volumes, market fluctuations and events or perceived events with respect to our business, than the shares of common stock of
companies with broader public ownership, and as a result, the trading prices for our ordinary shares may be more volatile. Among other things, trading of a relatively small volume of ordinary shares
may have a greater effect on the trading price than would be the case if our public float of actively traded shares were larger. In addition, as further described below under the risk factor entitled
"
Concentration of ownership will limit your ability to influence corporate matters,"
a number of shareholders hold large concentrations of
our shares which, if sold within a relatively short timeframe, could cause the price of our shares to drop significantly.
Market
prices for securities of biotechnology and biopharmaceutical companies have been highly volatile, and we expect such volatility to continue for the foreseeable future, so that
investment in our ordinary shares involves substantial risk. By separating from Innoviva, there is a risk that our company may be more susceptible to market fluctuations and other adverse events than
we would have been
were we still a part of Innoviva. Additionally, the stock market from time to time has experienced significant price and volume fluctuations unrelated to the operating performance of particular
companies.
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The
following are some of the factors that may have a significant effect on the market price of our ordinary shares:
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any adverse developments or results or perceived adverse developments or results with respect to the GSK-Partnered Respiratory Programs,
including, without limitation, any delays in development in these programs, any halting of development in these programs, any difficulties or delays encountered with regard to the FDA or other
regulatory authorities in these programs, or any indication from clinical or non-clinical studies that the compounds in such programs are not safe or efficacious;
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any adverse developments or results or perceived adverse developments or results with respect to our key clinical programs (for example,
revefenacin or our JAK inhibitor program), including, without limitation, any delays in development in these programs, any halting of development in these programs, any difficulties or delays
encountered with regard to the FDA or other regulatory authorities in these programs, or any indication from clinical or non-clinical studies that the compounds in such programs are not safe or
efficacious;
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any further adverse developments or perceived adverse developments with respect to the commercialization of VIBATIV;
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whether we achieve increased sales for VIBATIV;
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any announcements of developments with, or comments by, the FDA or other regulatory authorities with respect to products we or our partners
have under development, are manufacturing or have commercialized;
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any adverse developments or agreements or perceived adverse developments or agreements with respect to the relationship of Innoviva or TRC, on
the one hand, and GSK, on the other hand, including any such developments or agreements resulting from or relating to the Spin-Off;
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any adverse developments or perceived adverse developments with respect to our relationship with any of our research, development or
commercialization partners, including, without limitation, disagreements that may arise between us and any of those partners;
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any adverse developments or perceived adverse developments in our programs with respect to partnering efforts or otherwise;
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announcements of patent issuances or denials, technological innovations or new commercial products by us or our competitors;
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publicity regarding actual or potential study results or the outcome of regulatory review relating to products under development by us, our
partners or our competitors;
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regulatory developments in the United States and foreign countries;
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announcements with respect to governmental or private insurer reimbursement policies;
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announcements of equity or debt financings;
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economic and other external factors beyond our control;
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loss of key personnel;
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likelihood of our ordinary shares to be more sensitive to changes in sales volume, market fluctuations and events or perceived events with
respect to our business due to our small public float;
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low public market trading volumes for our ordinary shares related in part to the concentration of ownership of our shares;
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the sale of large concentrations of our shares within a relatively short timeframe;
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developments or disputes as to patent or other proprietary rights;
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approval or introduction of competing products and technologies;
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results of clinical trials;
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failures or unexpected delays in timelines for our potential products in development, including the obtaining of regulatory approvals;
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delays in manufacturing adversely affecting clinical or commercial operations;
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fluctuations in our operating results;
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market reaction to announcements by other biotechnology or pharmaceutical companies;
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initiation, termination or modification of agreements with our collaborators or disputes or disagreements with collaborators;
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litigation or the threat of litigation;
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public concern as to the safety of drugs developed by us; and
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comments and expectations of results made by securities analysts or investors.
If
any of these factors causes us to fail to meet the expectations of securities analysts or investors, or if adverse conditions prevail or are perceived to prevail with respect to our
business, the price of the ordinary shares would likely drop significantly. A significant drop in the price of a company's securities often leads to the filing of securities class action litigation
against the company. This type of litigation against us could result in substantial costs and a diversion of management's attention and resources.
Concentration of ownership will limit your ability to influence corporate matters.
Based on our review of publicly available filings, as of December 31, 2016 GSK beneficially owned approximately 18.3% of our outstanding
ordinary shares and our directors, executive officers and investors affiliated with these individuals beneficially owned approximately 6.8% of our outstanding ordinary shares. Based on our review of
publicly available filings, as of December 31, 2016 our three largest shareholders other than GSK collectively owned approximately 50% of our outstanding ordinary shares. GSK also has a right
to maintain its percentage ownership in our company under the Governance Agreement, including by participating in offerings of our ordinary shares or securities convertible into our shares. These
shareholders and GSK could control the outcome of actions taken by us that require shareholder approval, including a transaction in which shareholders might receive a premium over the prevailing
market price for their shares.
Certain provisions in our constitutional documents may discourage our acquisition by a third-party, which
could limit your opportunity to sell shares at a premium.
Our constitutional documents include provisions that could limit the ability of others to acquire control of us, modify our structure or cause
us to engage in change-of-control transactions, including, among other things, provisions that:
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require supermajority shareholder voting to effect certain amendments to our amended and restated memorandum and articles of association;
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establish a classified board of directors;
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restrict our shareholders from calling meetings or acting by written consent in lieu of a meeting;
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limit the ability of our shareholders to propose actions at duly convened meetings; and
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authorize our board of directors, without action by our shareholders, to issue preferred shares and additional ordinary shares.
These
provisions could have the effect of depriving you of an opportunity to sell your ordinary shares at a premium over prevailing market prices by discouraging third parties from
seeking to acquire control of us in a tender offer or similar transaction.
Our shareholders may face difficulties in protecting their interests because we are incorporated under Cayman
Islands law.
Our corporate affairs are governed by our amended and restated memorandum and articles of association, by the Companies Law (2016 Revision) of
the Cayman Islands and by the common law of the Cayman Islands. The rights of our shareholders and the fiduciary responsibilities of our directors under the laws of the Cayman Islands are different
from those under statutes or judicial precedent in existence in jurisdictions in the U.S. Therefore, you may have more difficulty in protecting your interests than would shareholders of a corporation
incorporated in a jurisdiction in the U.S., due to the different nature of Cayman Islands law in this area.
Shareholders
of Cayman Islands exempted companies such as our company have no general rights under Cayman Islands law to inspect corporate records and accounts or to obtain copies of
lists of shareholders. Our directors have discretion under our amended and restated memorandum and articles of association to determine whether or not, and under what conditions, our corporate records
may be inspected by our shareholders, but are not obliged to make them available to our shareholders. This may make it more difficult for you to obtain the information needed to establish any facts
necessary for a shareholder motion or to solicit proxies from other shareholders in connection with a proxy contest.
Our
Cayman Islands counsel, Maples and Calder, is not aware of any reported class action having been brought in a Cayman Islands court. Derivative actions have been brought in the Cayman
Islands courts, and the Cayman Islands courts have confirmed the availability for such actions. In most cases, the company will be the proper plaintiff in any claim based on a breach of duty owed to
it, and a claim against (for example) our officers or directors usually may not be brought by a shareholder. However, based on English authorities, which would in all likelihood be of persuasive
authority and be applied by a court in the Cayman Islands, exceptions to the foregoing principle apply in circumstances in which:
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a company is acting, or proposing to act, illegally or beyond the scope of its authority;
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the act complained of, although not beyond the scope of the authority, could be effected if duly authorized by more than the number of votes
which have actually been obtained; or
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those who control the company are perpetrating a "fraud on the minority."
A
shareholder may have a direct right of action against the company where the individual rights of that shareholder have been infringed or are about to be infringed.
There is uncertainty as to shareholders' ability to enforce certain foreign civil liabilities in the Cayman
Islands.
We are incorporated as an exempted company limited by shares with limited liability under the laws of the Cayman Islands. A material portion of
our assets are located outside of the United States. As a result, it may be difficult for our shareholders to enforce judgments against us or judgments obtained in U.S. courts predicated upon the
civil liability provisions of the federal securities laws of the United States or any state of the United States.
We
have been advised by our Cayman Islands legal counsel, Maples and Calder, that the courts of the Cayman Islands are unlikely (i) to recognize or enforce against Theravance
Biopharma judgments of courts of the United States predicated upon the civil liability provisions of the securities laws of the
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United
States or any State; and (ii) in original actions brought in the Cayman Islands, to impose liabilities against Theravance Biopharma predicated upon the civil liability provisions of the
securities laws of the United States or any State, on the grounds that such provisions are penal in nature. However, in the case of laws that are not penal in nature, although there is no statutory
enforcement in the Cayman Islands of judgments obtained in the United States, the courts of the Cayman Islands will recognize and enforce a foreign money judgment of a foreign court of competent
jurisdiction without retrial on the merits based on the principle that a judgment of a competent foreign court imposes upon the judgment debtor an obligation to pay the sum for which judgment has been
given provided certain conditions are met. For a foreign judgment to be enforced in the Cayman Islands, such judgment must
be final and conclusive and for a liquidated sum, and must not be in respect of taxes or a fine or penalty, inconsistent with a Cayman Islands' judgment in respect of the same matter, impeachable on
the grounds of fraud or obtained in a manner, and or be of a kind the enforcement of which is, contrary to natural justice or the public policy of the Cayman Islands (awards of punitive or multiple
damages may well be held to be contrary to public policy). A Cayman Islands court, including the Grand Court of the Cayman Islands, may stay proceedings if concurrent proceedings are being brought
elsewhere, which would delay proceedings and make it more difficult for our shareholders to bring action against us.
We do not anticipate paying any cash dividends on our capital shares in the foreseeable future; as a result,
capital appreciation, if any, of our ordinary shares will be your sole source of gain for the foreseeable future.
We have never declared or paid cash dividends on our capital shares. We do not anticipate paying any cash dividends on our capital shares in the
foreseeable future. We currently intend to retain all available funds and any future earnings to fund the development and growth of our business. In addition, the terms of any future debt financing
arrangement may contain terms prohibiting or limiting the amount of dividends that may be declared or paid on our ordinary shares. As a result, capital appreciation, if any, of our ordinary shares
will be your sole source of gain for the foreseeable future.