– In First Cohort (N=4) of Porphyria Patients
with Recurrent Attacks, Givosiran Achieves a 74% Mean Decrease in
Annualized Attack Rate –
– Company to Meet with Regulatory Authorities
for Potential Phase 3 Start in Late 2017 –
– Management to Discuss New Clinical Data in
Webcast Conference Call Tomorrow, Sunday, December 4 at 1:00 p.m.
ET –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, today announced positive initial results from
Cohorts 1 and 2 of Part C of its Phase 1 study with givosiran
(gi-VOH-si-ran), the International Nonproprietary Name for ALN-AS1,
an investigational RNAi therapeutic targeting aminolevulinic acid
synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias.
These results were presented today in a poster at the 58th Annual
Meeting of the American Society of Hematology (ASH), held December
3 – 6, 2016 in San Diego, California.
Part C of the Phase 1 study is a randomized, double-blind,
placebo-controlled study in patients with acute intermittent
porphyria (AIP) experiencing recurrent attacks. Results
demonstrated robust and durable lowering of aminolevulinic acid
(ALA) and porphobilinogen (PBG), the toxic heme intermediates that
are believed to mediate porphyria symptoms and acute attacks.
Moreover, in the first unblinded treatment cohort, givosiran
demonstrated initial evidence for clinical activity in AIP patients
with meaningful reductions in the number and frequency of porphyria
attacks. In addition, aggregated and currently blinded results from
the second cohort provided further evidence for clinical activity.
In the first two dose cohorts, givosiran was found to be generally
well tolerated with no drug-related serious adverse events. In the
third dose cohort, which remains blinded, one death was reported
after the data transfer date due to acute pancreatitis complicated
by a pulmonary embolism and following an earlier hospitalization
for bacteremia; the death was considered to be unlikely related to
givosiran or placebo by the investigator and the study's Safety
Review Committee. The Company plans to initiate a Phase 3 study in
late 2017, subject to successful global regulatory
interactions.
“Acute hepatic porphyrias are a group of ultra-rare orphan
diseases with enormous unmet medical need. There are currently no
approved or optimal treatment options for the prevention of
recurrent attacks, and novel therapies are greatly needed. We
believe these initial results from the first unblinded cohort of
patients with AIP show that givosiran has the potential to achieve
meaningful reductions in the number and frequency of porphyria
attacks. These initial results were supported further with
aggregated data from the second cohort of AIP patients, who
currently remain blinded to treatment allocation. We look forward
to further exploring givosiran’s clinical activity, safety, and
tolerability in two additional dose cohorts, which are now fully
enrolled,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice
President of R&D and Chief Medical Officer of Alnylam. “We
believe that a therapeutic agent that can prevent attacks and that
could be administered via a low volume, subcutaneous injection
once-monthly or quarterly has the potential to be a transformative
treatment option for patients with this debilitating and
potentially life-threatening disease. Based on these encouraging
early results, we plan to meet with regulatory authorities with the
goal of advancing this investigational medicine into a Phase 3
trial in late 2017.”
Study DesignThe Phase 1 study of givosiran is being
conducted in three parts. Parts A and B, which have completed
dosing, were randomized, single-blind, single-dose (Part A) and
multi-dose (Part B), dose-escalation studies that enrolled 23
subjects who were “asymptomatic high excreters” (ASHE). Per
protocol, ASHE subjects in the study have a defined mutation in the
porphobilinogen deaminase (PBGD) gene and elevated urinary levels
of ALA and PBG, but do not have a recent history of porphyria
attacks or disease activity. Interim data from Parts A and B were
presented at the Society for the Study of Inborn Errors of
Metabolism (SSIEM) meeting in September 2016. Part C is a
randomized (3:1, drug:placebo), double-blind, multi-dose study in
up to 20 patients with AIP who experience recurrent porphyria
attacks. Patients are initially followed in a 3-month run-in phase,
where the number and frequency of porphyria attacks and levels of
ALA and PBG are measured prospectively. Patients who experience at
least one porphyria attack during the run-in phase are then
eligible to enter the 6-month treatment phase of the study, where
they are randomized to receive 2 once-quarterly doses or 4
once-monthly doses of placebo or givosiran at doses of 2.5 or 5.0
mg/kg. During the treatment phase, the effects of placebo or
givosiran on the number and frequency of porphyria attacks, as well
as on the levels of ALA and PBG, are measured prospectively in a
blinded manner and then compared to run-in phase results.
Additional measures include safety, tolerability, hospitalizations,
use of hemin, levels of ALAS1 mRNA, and givosiran pharmacokinetics.
Hemin is an FDA-approved agent used to treat porphyria attacks when
they occur. Following the treatment phase, all patients are
eligible to receive givosiran in an open-label extension study.
Clinical Activity ResultsInitial results from Part C
presented at ASH include all available data as of the data transfer
date of November 7, 2016. Data presented include unblinded
results for Cohort 1 (N=4, 2.5 mg/kg given once-quarterly) and
aggregated, blinded results for Cohort 2 (N=4, 2.5 mg/kg given
once-monthly) given that the patients in Cohort 2 are still in the
treatment phase of the study. Consistent with results in ASHE
patients, givosiran administration resulted in robust and durable
lowering of ALA and PBG. In Cohort 1, givosiran administration
resulted in meaningful reductions in the number and frequency of
porphyria attacks. Specifically, as compared with the run-in phase,
there was a 74 percent mean decrease in the annualized attack rate
and a 75 percent mean reduction in annualized hemin administration.
In addition, the maximum attack-free interval (i.e., the greatest
period of time between porphyria attacks) was a mean of
approximately 10.5 times that observed during the run-in phase.
Favorable treatment effects in all three parameters were seen in
each of the givosiran-treated patients. In contrast, the single
placebo patient in Cohort 1 showed a generally similar number and
frequency of porphyria attacks and a generally similar amount of
hemin usage during the run-in and treatment phases. Finally, the
aggregated blinded data for Cohort 2 patients, with approximately 3
months of treatment phase data, provided additional evidence of
clinical activity. Specifically, as compared with the run-in phase,
Cohort 2 patients receiving placebo or givosiran showed a 50
percent mean reduction in annualized attack rate and a 76 percent
mean reduction in annualized hemin doses administered; the maximum
attack-free interval was a mean of approximately 2.4 times that
observed during the run-in phase. Results are provided in the table
below.
Summary of Porphyria Attacks and Hemin Doses for Cohorts 1
and 2
Patient Annualized Attack Number
Maximum Attack-Free Interval (Days)
Annualized Hemin Doses
Run-In Phase Treatment
Phase Run-In Phase
Treatment Phase Run-In
Phase Treatment Phase COHORT
1 Givosiran-1 38 14
10 42
102 19 Givosiran-2
47 15 6
62 55 29
Givosiran-3 35 2
10 169 44
2 Placebo 34
26 9 16
43 29
COHORT 2
Aggregate Data* 17 9
23 56
15 4
* Cohort 2 remains blinded; data are for 84 days in the
treatment phase and include combined results (N=4) for placebo and
givosiran-treated patients
Safety ResultsAs of the data transfer on November 7,
2016, there were no drug-related serious adverse events (SAEs)
reported in Cohorts 1-4. In Cohort 3, which remains blinded, one
death was reported after the data transfer date due to acute
pancreatitis, with evidence of sludge in the gallbladder,
complicated by a pulmonary embolism and following an earlier
hospitalization for bacteremia; the death was considered to be
unlikely related to givosiran or placebo by the investigator and
the study's Safety Review Committee. Of note, increases in
pancreatic enzymes and acute pancreatitis have been reported in the
literature in patients with acute hepatic porphyria (Shen et al.,
Acta Neurol Taiwan, 2008;17:177-183; Shiraki et al., Nihon Rinsho,
1995;53:1479-1483). In Cohorts 1 and 2, there were no
discontinuations due to adverse events (AEs). Possibly or
definitely related AEs reported in two or more cases were injection
site reactions and myalgia; all of these events were mild. There
were no other clinically significant changes in vital signs,
electrocardiograms, clinical laboratory parameters, or physical
examination.
To view the givosiran clinical results described in this press
release, please visit www.alnylam.com/capella.
Conference Call InformationAlnylam management will
discuss these clinical data in a webcast conference call
tomorrow, Sunday, December 4, at 1:00 p.m.
ET. A slide presentation will also be available on the Investors
page of the company's website, www.alnylam.com, to accompany
the conference call. To access the call, please dial 877-312-7507
(domestic) or 631-813-4828 (international) five minutes prior to
the start time and refer to conference ID 28671881. A replay of the
call will be available beginning at 4:00 p.m. ET. To access
the replay, please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 28671881.
About GivosiranAlnylam is developing givosiran (formerly
known as ALN-AS1), a subcutaneously administered, investigational
RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1)
for the treatment of acute hepatic porphyrias, including acute
intermittent porphyria (AIP). AIP is an ultra-rare autosomal
dominant disease caused by loss of function mutations in
porphobilinogen deaminase (PBGD), an enzyme in the heme
biosynthesis pathway that can result in accumulation of toxic heme
intermediates, including aminolevulinic acid (ALA) and
porphobilinogen (PBG). Patients with AIP can suffer from acute
and/or recurrent life-threatening attacks characterized by severe
abdominal pain, neuropathy (affecting the central, peripheral or
autonomic nervous system), and neuropsychiatric manifestations.
Givosiran is an ESC-GalNAc-siRNA conjugate targeting ALAS1, a
liver-expressed, rate-limiting enzyme upstream of PBGD in the heme
biosynthesis pathway. Inhibition of ALAS1 is known to reduce the
accumulation of heme intermediates that cause the clinical
manifestations of AIP. Givosiran has the potential to be a
prophylactic approach for the prevention of recurrent attacks, as
well as for the treatment of acute porphyria attacks. Givosiran is
an investigational compound, currently in early stage clinical
development. The safety and efficacy of givosiran have not been
evaluated by the U.S. Food and Drug Administration or any other
health authority.
About Acute Hepatic PorphyriasThe porphyrias are a family
of rare metabolic disorders with mostly autosomal dominant
inheritance predominately caused by a genetic mutation in one of
the eight enzymes responsible for heme biosynthesis. Acute hepatic
porphyrias (AHP) constitute a subset where the enzyme deficiency
occurs within the liver, and includes acute intermittent porphyria
(AIP), hereditary coproporphyria (HCP), and variegate porphyria
(VP). Exposure of AHP patients to certain drugs, dieting, or
hormonal changes can trigger strong induction of aminolevulinic
acid synthase 1 (ALAS1), another enzyme in the heme biosynthesis
pathway, which can lead to accumulation of neurotoxic heme
intermediates that precipitate disease symptoms. Patients with AHP
can suffer from a range of symptoms that, depending on the specific
type, can include acute and/or recurrent life-threatening attacks
with severe abdominal pain, peripheral and autonomic neuropathy,
neuropsychiatric manifestations, cutaneous lesions and possibly
paralysis and death if untreated or if there are delays in
treatment. The only approved treatment for acute attacks is hemin
for injection (Panhematin® or Normosang®), a preparation of heme
derived from human blood. Hemin requires administration through a
large vein or a central intravenous line and is associated with a
number of complications including thrombophlebitis or coagulation
abnormalities. There are no approved therapeutics for prophylactic
use (i.e., the prevention of acute attacks), although hemin is
sometimes used in this manner in patients who experience recurrent
attacks. Chronic administration of hemin may result in renal
insufficiency, iron overload, systemic infections (due to the
requirement for central venous access) and, in some instances,
tachyphylaxis.
About GalNAc Conjugates and Enhanced Stabilization Chemistry
(ESC)-GalNAc ConjugatesGalNAc-siRNA conjugates are a
proprietary Alnylam delivery platform and are designed to achieve
targeted delivery of RNAi therapeutics to hepatocytes through
uptake by the asialoglycoprotein receptor. Alnylam's Enhanced
Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables
subcutaneous dosing with increased potency and durability, and a
wide therapeutic index. This delivery platform is being employed in
nearly all of Alnylam's pipeline programs, including programs in
clinical development.
About RNAiRNAi (RNA interference) is a revolution in
biology, representing a breakthrough in understanding how genes are
turned on and off in cells, and a completely new approach to drug
discovery and development. Its discovery has been heralded as "a
major scientific breakthrough that happens once every decade or
so," and represents one of the most promising and rapidly advancing
frontiers in biology and drug discovery today which was awarded the
2006 Nobel Prize for Physiology or Medicine. RNAi is a natural
process of gene silencing that occurs in organisms ranging from
plants to mammals. By harnessing the natural biological process of
RNAi occurring in our cells, the creation of a major new class of
medicines, known as RNAi therapeutics, is on the horizon. Small
interfering RNA (siRNA), the molecules that mediate RNAi and
comprise Alnylam's RNAi therapeutic platform, target the cause of
diseases by potently silencing specific mRNAs, thereby preventing
disease-causing proteins from being made. RNAi therapeutics have
the potential to treat disease and help patients in a fundamentally
new way.
About Alnylam PharmaceuticalsAlnylam is a
biopharmaceutical company developing novel therapeutics based on
RNA interference, or RNAi. The company is leading the translation
of RNAi as a new class of innovative medicines. Alnylam's pipeline
of investigational RNAi therapeutics is focused in 3 Strategic
Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline
of RNAi therapeutics for the treatment of rare diseases;
Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics
toward genetically validated, liver-expressed disease targets for
unmet needs in cardiovascular and metabolic diseases; and Hepatic
Infectious Disease, with a pipeline of RNAi therapeutics that
address the major global health challenges of hepatic infectious
diseases. In early 2015, Alnylam launched its "Alnylam 2020"
guidance for the advancement and commercialization of RNAi
therapeutics as a whole new class of innovative medicines.
Specifically, by the end of 2020, Alnylam expects to achieve a
company profile with 3 marketed products, 10 RNAi therapeutic
clinical programs – including 4 in late stages of development –
across its 3 STArs. The company's demonstrated commitment to RNAi
therapeutics has enabled it to form major alliances with leading
companies including Ionis, Novartis, Roche, Takeda, Merck,
Monsanto, The Medicines Company, and Sanofi Genzyme. In addition,
Alnylam holds an equity position in Regulus Therapeutics Inc., a
company focused on discovery, development, and commercialization of
microRNA therapeutics. Alnylam scientists and collaborators have
published their research on RNAi therapeutics in over 200
peer-reviewed papers, including many in the world's top scientific
journals such as Nature, Nature Medicine, Nature Biotechnology,
Cell, New England Journal of Medicine, and The Lancet. Founded in
2002, Alnylam maintains headquarters in Cambridge, Massachusetts.
For more information about Alnylam's pipeline of investigational
RNAi therapeutics, please visit www.alnylam.com.
Alnylam Forward Looking StatementsVarious statements in
this release concerning Alnylam's future expectations, plans and
prospects, including without limitation, Alnylam's views with
respect to the potential for RNAi therapeutics, including
givosiran, its expectations regarding the timing of clinical
studies, including the initiation of a Phase 3 trial for givosiran
following interactions with regulatory authorities, its
expectations regarding its STAr pipeline growth strategy, and its
“Alnylam 2020” guidance for the advancement and commercialization
of RNAi therapeutics, constitute forward-looking statements for the
purposes of the safe harbor provisions under The Private Securities
Litigation Reform Act of 1995. Actual results and future plans may
differ materially from those indicated by these forward-looking
statements as a result of various important risks, uncertainties
and other factors, including, without limitation, Alnylam's ability
to discover and develop novel drug candidates and delivery
approaches, successfully demonstrate the efficacy and safety of its
product candidates, the pre-clinical and clinical results for its
product candidates, which may not be replicated or continue to
occur in other subjects or in additional studies or otherwise
support further development of product candidates for a specified
indication or at all, actions or advice of regulatory agencies,
which may affect the design, initiation, timing, continuation
and/or progress of clinical trials or result in the need for
additional pre-clinical and/or clinical testing, delays,
interruptions or failures in the manufacture and supply of our
product candidates, obtaining, maintaining and protecting
intellectual property, Alnylam's ability to enforce its
intellectual property rights against third parties and defend its
patent portfolio against challenges from third parties, obtaining
and maintaining regulatory approval, pricing and reimbursement for
products, progress in establishing a commercial and ex-United
States infrastructure, competition from others using technology
similar to Alnylam's and others developing products for similar
uses, Alnylam's ability to manage its growth and operating
expenses, obtain additional funding to support its business
activities, and establish and maintain strategic business alliances
and new business initiatives, Alnylam's dependence on third parties
for development, manufacture and distribution of products, the
outcome of litigation, the risk of government investigations, and
unexpected expenditures, as well as those risks more fully
discussed in the "Risk Factors" filed with Alnylam's most recent
Quarterly Report on Form 10-Q filed with the Securities and
Exchange Commission (SEC) and in other filings that Alnylam
makes with the SEC. In addition, any forward-looking
statements represent Alnylam's views only as of today and should
not be relied upon as representing its views as of any subsequent
date. Alnylam explicitly disclaims any obligation, except to the
extent required by law, to update any forward-looking
statements.
The scientific information referenced in this news release
relating to givosiran is preliminary and investigative. Givosiran
has not been approved by the U.S. Food and Drug Administration,
European Medicines Agency, or any other regulatory authority and no
conclusions can or should be drawn regarding its safety or
effectiveness.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20161203005013/en/
Alnylam Pharmaceuticals, Inc.Investors and MediaChristine
Regan Lindenboom, 617-682-4340orInvestorsJosh Brodsky,
617-551-8276
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