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 Design
The 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 Results
Initial
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 Results
As 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 Information
Alnylam 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 Givosiran
Alnylam 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 Porphyrias
The 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 Conjugates
GalNAc-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 RNAi
RNAi (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 Pharmaceuticals
Alnylam 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 Statements
Various 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.
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