Provectus Biopharmaceuticals, Inc. (NYSE MKT:PVCT)
(http://www.pvct.com), a development-stage oncology and dermatology
biopharmaceutical company, provides shareholders with an update on
its corporate accomplishments, clinical progress and business
development efforts during 2013, and shares as well as insights on
upcoming plans and milestones for 2014.
Dear Shareholders,
Since our last letter, Provectus has gone through significant
changes on multiple levels. The past several months have placed us
in a much different, and stronger position than we had been
previously. This is true for our regulatory path, our scientific
situation, our corporate structure, our financial strength and our
commercial prospects. This is an ideal time to review where we have
been and to discuss where we are going in a continuing effort to be
as transparent as possible.
The most prominent development recently was the information
obtained from our application for Breakthrough Therapy Designation
(BTD) to the FDA for PV-10 in the treatment of locally advanced
cutaneous melanoma. In the interest of transparency, we announced
every step of the BTD process, including the date of submission of
our application and the release of the FDA’s response letter. While
the immediate result was not what we had hoped, we are enthusiastic
about the FDA’s statement that “The preliminary clinical data
provided in your request for Breakthrough Therapy designation are
indicative of drug activity in the treatment of local, satellite or
in-transit recurrence of malignant melanoma.” This communication
between the FDA and Provectus has proved quite valuable in
discerning our regulatory path forward.
PHASE 2 RESULTS
Our development plans for PV-10 stem from the results of our
phase 2 study. In that trial, tumors were no longer detectable in
50% of patients with locally advanced cutaneous melanoma who had
all of their existing lesions injected. Results from these patients
support the potential of PV-10 as a single agent, and provide
rationale for a phase 3 randomized controlled trial in patients
with unresectable, locally advanced cutaneous melanoma.
Top-line results from the phase 2 trial have been posted on
clinicaltrials.gov, for the study entitled “Phase 2 study of
Intralesional PV-10 for Metastatic Melanoma,” [NCT00521053].
http://clinicaltrials.gov/ct2/show/NCT00521053?term=NCT00521053&rank=1
When we completed data collection two years ago, we knew we had
a promising oncolytic agent with consistent response in injected
tumors, but we also had intriguing data on the bystander effect
that implicated a secondary immunologic mechanism of action. At
that time, we had no agreement with FDA on a proposed indication,
no phase 3 clinical trial drug supply and too many variables for
design of an efficient phase 3 trial.
The gap between completion of the data collection and the
outlining of our plans in the conference call of June 19, 2014,
stemmed from these regulatory hurdles and from our determination to
properly structure a study where we could adequately predict the
outcome. When preparing for phase 3 testing it is critical to
understand exactly what your drug is doing, which patients are most
likely to benefit, what other options these patients have, and what
endpoint or endpoints would be most convincing for government
agencies to approve the drug.
After presenting data from our phase 2 study in a Type C meeting
last December and in our BTD application submitted this spring, the
FDA confirmed that locally advanced cutaneous melanoma is a serious
condition. With this agreement on indication, our subgroup analysis
of data from these patients in the phase 2 trial, and an
appropriate phase 3 supply chain for our drug, we are now in a
position to embark on the phase 3 study.
PHASE 3 OUTLINE FOR MELANOMA
The planned phase 3 study will assess response to intralesional
PV-10 vs. that of systemic chemotherapy in patients with disease
confined to cutaneous and subcutaneous sites. These patients will
have failed or be ineligible for systemic immunotherapy. Patients
who would be eligible have extremely limited options, consisting
principally of systemic chemotherapy (such as DTIC or temozolomide)
or a clinical trial.
The primary endpoint of the study is progression-free survival
(PFS) assessed using standard RECIST 1.1 criteria. Secondary
endpoints are complete response rate and overall survival.
Progression-free survival and overall survival are standard
endpoints for oncology approvals. With these assessment methods and
endpoints we’re following what the FDA has suggested to document
the clinical benefit to patients after intralesional injection.
And, we’ll measure patient reported outcomes to better characterize
the relationship between complete response and symptoms of locally
advanced cutaneous melanoma, such as pain and bleeding.
Based on estimated effect size derived from the phase 2 data and
literature data for the comparator drugs, we project that
approximately 210 patients will be needed for the study, with 2 to
1 randomization. Meetings with scientific advisors, investigators
and advocates in the field have led us to expect a starting date
for the phase 3 study sometime in the second half of 2014. Based on
our experience enrolling similar patients in the mechanism of
action study we’re sponsoring at Moffitt Cancer Center, we are
confident about enrolling patients within an 18-month target,
starting with the eight existing PV-10 sites, which are currently
enrolling melanoma patients, and expanding to additional sites as
the study proceeds.
We have recently signed agreements with two manufacturers to
supply us with clinical-quality PV-10, and we now have sufficient
quantities of PV-10 available to commence this phase 3 trial and
undertake our other development activities. To assure smooth
execution of the study we’ve lined up specialty contract research
organizations (CROs) and other service providers with expertise in
clinical operations and integrated data management. As is standard
in our industry, this includes a full-service, international CRO
who will coordinate the global efforts of this team of
specialists.
We’ll work with this team to establish an independent Clinical
Trial Data Monitoring Committee (DMC). The FDA states “A clinical
trial DMC is a group of individuals with pertinent expertise that
reviews on a regular basis accumulating data from one or more
ongoing clinical trials. The DMC advises the sponsor regarding the
continuing safety of trial subjects and those yet to be recruited
to the trial, as well as the continuing validity and scientific
merit of the trial.” The DMC will ensure that our study provides
patients with maximum possible safety while protecting the
scientific validity and integrity of the data we gather.
THE INTRALESIONAL APPROACH TO TREATMENT
Provectus is not alone in advocating for an intralesional
approach in the treatment of cancer. For melanoma patients with
recurrent or in-transit disease confined to their skin this
approach has been used to treat patients for many years, as
evidenced by guidelines published by the National Comprehensive
Cancer Network (NCCN Guidelines®) defining the standard of care for
cancer treatment in the United States. Intralesional injection with
BCG and certain immunomodulatory agents, local ablation, topical
therapy for superficial lesions and regional radiotherapy are
consensus interventions for these patients, while systemic therapy
remains an option and participation in a clinical trial is the
preferred option. We believe that, in this context, PV-10 is well
positioned to show superiority in phase 3 testing as a single
agent.
And for those patients who do not have all disease accessible to
injection, medical oncologists have stated that using an agent like
PV-10 to prime the immune system could be synergistic in
combination with a systemic agent. Our patent application on this
strategy was published in 2012 and we’ve been vigorously pursuing
this approach. The nonclinical research we first presented at the
Society for Immunotherapy of Cancer (SITC) annual meeting that
year, together with ongoing translational clinical research on
PV-10’s mechanism of action we are sponsoring at Moffitt Cancer
Center and our own phase 2 data, provide a rationale for
combination testing of PV-10. This development track, separate from
the phase 3 study, using PV-10 in combination with checkpoint
protein inhibitors could present a path forward for patients with
significant disease burden not amenable to intralesional
injection.
LIVER AND METASTATIC CANCERS
We have recently expanded our exploratory phase 1 study of
cancers of the liver to 3 centers (St. Luke’s University Health
Network, Bethlehem, PA and The Southeastern Center for Digestive
Disorders & Pancreatic Cancer, Tampa, FL in addition to Sharp
Memorial Hospital, San Diego, CA), and we’re evaluating addition of
several additional centers to further advance this initial effort.
We’re working with our investigators to report results from
long-term follow-up of our initial patients in coming months. And
we’re assessing strategies to accelerate transition to phase 2
testing in a randomized controlled trail, either alone or in
combination with systemic therapy. Any combination studies in the
liver are likely to follow similar development strategies to those
outlined above for melanoma and rely on much of the same
foundational science.
The current phase 1 study, initially designed solely to
establish safety of percutaneous injection of PV-10 into liver
tumors (that is, injection through the skin), is providing valuable
data crucial for planning such phase 2 development. This trial is
open to patients with hepatocellular carcinoma or other cancers
metastatic to the liver who have at least one tumor that has either
originated in or spread to the liver and are not candidates for
surgery or transplant. All patients enrolled in this open-label
study receive the same treatment: an interventional radiologist
injects PV-10 percutaneously into a single liver tumor. Patients
with multiple injectable tumors may later receive further PV-10 to
their other tumors. We have received numerous inquiries about this
study from researchers as well as patients and their doctors, and
refer these to our investigators through the contact information
available on the clinicaltrials.gov website.
PH-10 FOR DERMATOLOGICAL TREATMENTS
So far over 220 patients have participated in phase 1 and 2
trials of PH-10. We anticipate posting results from these studies
on the clinicaltrials.gov website in the coming months and are
encouraged by what has been observed to date. Following the model
we’ve used successfully with PV-10, we’re planning a translational
clinical study to better understand the possible immunologic
mechanism of PH-10 in the skin in relation to psoriasis, eczema and
other inflammatory dermatoses. Our investigators are currently
evaluating the results of our studies. When their assessments are
complete, we will move forward with the necessary further trials
and regulatory requirements to bring this compound to patients who
need it.
PATENT PORTFOLIO
Provectus has built a solid portfolio of patents to protect our
shareholders’ value. Among recent additions to this portfolio are:
US Patent 8,557,298, “Medicaments for Chemotherapeutic Treatment of
Disease,” which provides detailed protection of PV-10; US Patent
8,530,675, “Process for the Synthesis of
4,5,6,7-tetrachloro-3’,6’-dyhydroxy-2’,4’,5’,7’-tetraiodo-3H-spiro[isobenzofuran-1,9’-xanthen]-3-one
(Rose Bengal) and Related Xanthenes,” which details our new process
for the manufacture of Rose Bengal and related iodinated xanthenes
in high purity; and US Patent Application 2012/0263677,
“Combination of Local and Systemic Immunomodulative Therapies for
Enhanced Treatment of Cancer,” which covers methods for treating
cancer through combination use of intralesional agents (such as
PV-10) with systematic anticancer agents (such as checkpoint
protein inhibitors).
SCIENTIFIC CONFERENCES
During the past several months, researchers have presented data
on PV-10 in multiple major international conferences. These include
annual meetings of the American Society of Clinical Oncology, the
European Association of Dermato-Oncology and the American
Association for Cancer Research. We believe participation in these
conferences is vital to bring a higher profile to PV-10 among
oncology researchers. This, in turn, will help us with patient
accrual and with further scientific work to support our belief in
the efficacy and safety of PV-10.
INTERNATIONAL LICENSING OPPORTUNITIES
Provectus has provided data on a confidential basis to both
potential global and geographic partners for both PV-10 for
oncology and PH-10 for dermatology via a secure electronic data
room. We are encouraged by the number of companies doing due
diligence on our technologies. For instance, we recently had a team
in India meeting with potential partners and have two teams focused
in China working with potential partners there.
Whenever we obtain a Memorandum of Understanding (MOU),
definitive agreement or similar indication of interest from a
potential partner, we will issue a press release and Form 8-K
filing to notify the market. Furthermore, the strategy of the
company for the benefit of shareholders is a series of partnerships
followed by an acquisition of the company along the lines of
Celgene/Abraxis.
We have already signed an advisory agreement with China's
TriRiver Capital to help identify distribution and joint venture
partners for PV-10 in China. This agreement is intended to enhance
our reach into China and will bolster our efforts in developing
partnering opportunities in various countries in Asia including
China, India and Japan, where we have held numerous detailed
discussions with pharmaceutical companies over the last year. We
are already seeing the results of efforts to enter into
partnerships from the activity in our electronic data room.
MONETIZING PV-10 AND PH-10
The primary financial objective of the Company is to
strategically monetize the core value of PV-10 and PH-10 through
the various transactions discussed elsewhere in this letter.
Ultimately, the Company wants to leverage value creation through
the sale of the business or a merger that may include upfront cash,
acquirer stock, and/or a contingency value right (CVR) as part of
the total consideration. A CVR represents the right for its holder
to receive certain defined payments upon the achievement of a
specified milestone and would be designed to facilitate potential
upside for the Company’s shareholders on a post-transaction basis.
A CVR could trade on an exchange. The Company is not in discussions
regarding the sale of its business and there can be no assurance,
however, that the Company will be able to monetize PV-10 or PH-10
in the manner described herein.
SUFFICIENT CAPITAL ON HAND
Our financial position and corporate governance are such that we
expect to continue to meet the relevant listing requirements of
NYSE MKT. We believe our efforts to obtain regulatory clarity will
be helpful to facilitate such transactions with potential partners.
Additionally, the existing and forthcoming clinical and nonclinical
mechanism of action data for both PV-10 and PH-10 are expected to
further aid in both regulatory clarity and transactions with
potential partners. The Company’s current cash position is
sufficient to meet our obligations. In addition, management is
returning $8.96 million to the Company as a result of the
previously announced settlement of a shareholder derivative lawsuit
(subject to a 2:1 credit to the executives, such that total actual
repayment by the executives may be $1.12 million per executive) and
further enhanced our strength by management’s recent exercise of
options. In total, we have adequate funds to operate without a
further injection of capital through mid-2015.
CORPORATE DEVELOPMENTS
We have changed our Company’s name to Provectus
Biopharmaceuticals, Inc. because it better communicates to the
public and to prospective corporate partners the current and future
nature of the Company’s business operations and enables us to
better implement the Company’s business plan. Further, we have
reincorporated in Delaware as this gives us more flexibility,
clarity and predictability with respect to our corporate
governance.
In addition, we have “up-listed” our stock onto the NYSE MKT.
Moreover, we have added several important individuals to our
Strategic Advisory Board:
- Jacob M. Plotsker, MBA, currently
Director of US Strategy and Lifecycle Management at Bayer
Healthcare. He currently serves on the board of directors of
Emisphere Technologies, a publicly traded drug delivery technology
company. From 2008 to 2014, he served on the board of directors of
Sharsheret, a national 501(c)(3) not-for-profit organization
providing support and resources to young women living with breast
cancer. He also served as President of Sharsheret from
2009-2012.
- Dr. Joseph M. Chalil, MD, MBA, FACHE,
Associate Director, Health Science Executives of Boehringer
Ingelheim, the world's largest privately held pharmaceutical
company. A veteran of the United States Navy Medical Corps, Dr.
Chalil is also board certified in healthcare management, and has
been awarded Fellowship by the American College of Healthcare
Executives. Dr. Chalil is an expert in US Healthcare policy and a
strong advocate for patient centered care, and has also served as
an advisor to various national political campaigns on healthcare
issues.
- Brendan O'Brien, MBA, currently VP of
Strategic Planning & Analysis for North American
Pharmaceuticals at Sanofi, responsible for business planning and
strategy development. He has also worked for Smithkline Beecham
Pharmaceuticals and for Pfizer.
Further, we have retained Roberti+White to assist in developing
a commercialization strategy for PV-10 by implementing a plan to
expand our congressional outreach to key Members of Congress,
Congressional Committees and Caucuses that address healthcare
issues. Roberti+White will also advise us on FDA regulatory issues
as they arise and develop action plans in response to such
developments. When conditions warrant, Roberti+White will also
assist the Company in development of an effective Medicare
coverage, coding and payment strategy for its products in
development.
We are grateful for the long-term support of our shareholders
and their faith in our Company’s future. The next several months
hold great promise for Provectus, and we look forward to sharing
the latest developments with you.
FORWARD-LOOKING STATEMENTS: This letter contains
“forward-looking statements” as defined under U.S. federal
securities laws. These statements reflect management’s current
knowledge, assumptions, beliefs, estimates, and expectations and
express management’s current views of future performance, results,
and trends and may be identified by their use of terms such as
“anticipate,” “believe,” “could,” “estimate,” “expect,” “intend,”
“may,” “plan,” “predict,” “project,” “will,” and other similar
terms. Forward-looking statements are subject to a number of risks
and uncertainties that could cause our actual results to materially
differ from those described in the forward-looking statements.
Readers should not place undue reliance on forward-looking
statements. Such statements are made as of the date hereof, and we
undertake no obligation to update such statements after this
date.
Risks and uncertainties that could cause our actual results to
materially differ from those described in forward-looking
statements include those discussed in our filings with the
Securities and Exchange Commission (including those described in
Item 1A of our Annual Report on Form 10-K for the year ended
December 31, 2013, and in our Quarterly Report on Form 10-Q for the
quarter ended March 31, 2014), and the following:
• our determination, based on guidance from the FDA,
whether to proceed with or without a partner with a phase 3 trial
of PV-10 to treat locally advanced cutaneous melanoma and the costs
associated with such a trial if it is necessary; • our
determination whether to license PV-10, our melanoma drug product
candidate, and other solid tumors such as liver cancer, if such
licensure is appropriate considering the timing and structure of
such a license, or to commercialize PV-10 on our own to treat
melanoma and other solid tumors such as liver cancer; • our ability
to license our dermatology drug product candidate, PH-10, on the
basis of our phase 2 atopic dermatitis and psoriasis results, which
are in the process of being further developed in conjunction with
mechanism of action studies; and • our ability to raise additional
capital if we determine to commercialize PV-10 and/or PH-10 on our
own, although our expectation is to be acquired by a prospective
pharmaceutical or biotech concern prior to commercialization.
Provectus Biopharmaceuticals, Inc.Peter R. Culpepper,
866-594-5999 #30CFO, COOorPorter, LeVay & Rose, Inc.Investor
RelationsMarlon Nurse, 212-564-4700DM, SVPorMedia RelationsBill
Gordon, 212-724-6312
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