− Givosiran Meets Primary and Majority of
Secondary Endpoints, with Significant Reduction in Annualized Rate
of Composite Porphyria Attacks Relative to Placebo –
− Alnylam Intends to Complete Filing of New
Drug Application (NDA) and Marketing Authorisation Application
(MAA) in mid-2019 –
− Full Results to be Presented at the European
Association for the Study of the Liver (EASL) International
Liver Congress™ in April –
− Alnylam to Host Conference Call Today at 8:00
a.m. EST –
Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the leading
RNAi therapeutics company, announced today that the ENVISION Phase
3 study of givosiran, an investigational RNAi therapeutic targeting
aminolevulinic acid synthase 1 (ALAS1) in development for the
treatment of acute hepatic porphyria (AHP), met its primary
efficacy endpoint and the majority of secondary endpoints.
Specifically, givosiran met the primary endpoint of reduction in
the annualized rate of composite porphyria attacks relative to
placebo (p less than 0.00000001) and achieved statistically
significant results for five of nine secondary endpoints (p less
than 0.0001), with a safety and tolerability profile that the
Company believes is encouraging, especially in this high unmet
disease. Based on these results, the Company plans to complete its
rolling submission of a New Drug Application (NDA) and file a
Marketing Authorisation Application (MAA) in mid-2019.
“Patients living with AHP experience debilitating and sometimes
life-threatening neurovisceral attacks as well as chronic disease
manifestations which negatively impact their quality of life. We
believe the ENVISION results demonstrate a robust therapeutic
benefit of givosiran treatment on the debilitating aspects of this
disease. Based on these results, we believe givosiran has the
potential, if approved, to be a transformative medicine for AHP
patients and their families,” said Akshay Vaishnaw, M.D., Ph.D.,
President, R&D at Alnylam. “We extend our profound thanks to
all the patients, investigators, and study staff who participated
in the ENVISION study.”
“These positive ENVISION results represent another landmark
event in Alnylam’s pioneering efforts to advance RNAi therapeutics
as a whole new class of medicines. Notably, givosiran is the first
GalNAc-conjugate siRNA to achieve positive Phase 3 results, and the
second example of Alnylam’s R&D strategy bearing fruit due to
our focus on genetically validated targets for the advancement of
potential high impact medicines,” said John Maraganore, Ph.D., CEO
of Alnylam. “Assuming favorable regulatory review, we very much
look forward to adding givosiran as the second product in our
global commercialization efforts. Indeed, we believe today’s news
brings us one important step closer to meeting our Alnylam 2020
goals of building a multi-product, global commercial company with a
deep clinical pipeline for continued growth and a robust product
engine for sustainable innovation.”
Givosiran has received Breakthrough Therapy and Prime
designation by the FDA and EMA, respectively, and has Orphan Drug
status in the U.S. and EU for the treatment of AHP. The Phase 1
results of givosiran were recently published in The New England
Journal of Medicine1. Full ENVISION study results will be presented
in an oral plenary session on Saturday, April 13 at EASL in Vienna,
Austria. The ENVISION results have not yet been reviewed by
regulatory authorities.
ENVISION Study Results
ENVISION, a randomized, double-blind, placebo-controlled trial,
enrolled 94 patients with AHP (including 89 with
genetically-confirmed acute intermittent porphyria [AIP], the most
common subtype of AHP), at 36 study sites in 18 countries around
the world, and is the largest ever interventional study conducted
in AHP. Patients were randomized 1:1 to givosiran or placebo, with
givosiran administered subcutaneously at 2.5 mg/kg monthly. The
primary endpoint for the study was reduction relative to placebo in
the annualized rate of composite porphyria attacks, defined as
those requiring hospitalization, urgent healthcare visit, or hemin
administration, in patients with AIP over six months.
At six months, givosiran met the primary endpoint in patients
with AIP (p less than 0.00000001). All the components of the
composite primary endpoint and all subgroup analyses for the
primary endpoint favored givosiran. Secondary endpoints listed
below also demonstrated statistically significant favorable
differences in the givosiran arm compared to placebo (p less than
0.0001):
- Urinary ALA levels at three months in
AIP patients;
- Urinary ALA levels at six months in AIP
patients;
- Urinary PBG levels at six months in AIP
patients;
- Annualized days of administered hemin
doses in AIP patients; and
- Annualized attack rate in patients with
AHP (including AIP).
The remaining four secondary endpoints did not meet the
hierarchical threshold for significance and included: daily worst
pain (p equal to 0.053), daily worst fatigue (p equal to 0.29),
daily worst nausea (p equal to 0.25), and the physical component
summary of the SF-12 health survey in AIP patients (p equal to
0.022).
Adverse events (AEs) were reported in 43/48 (89.6 percent) of
givosiran and 37/46 (80.4 percent) of placebo patients and serious
adverse events (SAEs) were reported in 10/48 (20.8 percent) of
givosiran and 4/46 (8.7 percent) of placebo patients. There were no
deaths in the study. One patient, described below, in the givosiran
arm (2.1 percent) discontinued treatment due to an AE. AEs reported
in greater than 10 percent of givosiran patients and seen more
frequently compared to placebo were: nausea, injection site
reactions, chronic kidney disease and fatigue; those reported in
greater than 10 percent of placebo patients and seen more
frequently than in givosiran-treated patients were headache,
urinary tract infection, vomiting and pyrexia. The AEs of chronic
kidney disease were reported in five givosiran-treated patients
(10.4 percent) and no placebo patients; these events were all in
patients with renal dysfunction at baseline and patients continued
dosing throughout the study. Liver transaminase increases greater
than three times upper limit of normal (ULN) were observed in 7/48
(14.6 percent) patients on givosiran and 1/46 (2.2 percent)
patients on placebo; all had evidence of iron overload or liver
disease at baseline. As previously reported and as noted above, one
patient on givosiran discontinued treatment due to an increase in
alanine aminotransferase (ALT) levels greater than 8 times ULN, a
protocol-defined stopping rule; this elevation did not meet Hy’s
Law and subsequently resolved. Peak ALT levels in the other six
givosiran-treated patients ranged from 3.0-5.4 times ULN and were
not accompanied by bilirubin increases. The patients were
asymptomatic, and all events resolved with continued dosing (n=5)
or after a brief pause in dosing (n=1).
Upon completion of dosing in the ENVISION double-blind period,
all eligible patients (93/94 or 99 percent) enrolled in the
ENVISION open-label extension (OLE) study, receiving monthly
givosiran administration. In addition, patients continue dosing in
the Phase 1/2 OLE study with over two years of exposure to
givosiran.
Conference Call Information
Management will discuss these results via conference call on
Wednesday, March 6, 2019 at 8:00 am ET. A webcast presentation will
also be available on the Investors page of the Company’s website,
www.alnylam.com. To access the call, please dial 800-682-0995
(domestic) or 334-323-0509 (international) five minutes prior to
the start time and refer to conference ID 5900752. A replay of the
call will be available beginning at 11:00 am ET on the day of the
call. To access the replay, please dial 888-203-1112 (domestic) or
719-457-0820 (international) and refer to conference ID
5900752.
About Acute Hepatic Porphyria
AHP refers to a family of rare, genetic diseases characterized
by potentially life-threatening attacks and for some patients
chronic debilitating symptoms that negatively impact daily
functioning and quality of life. AHP is comprised of four subtypes,
each resulting from a genetic defect leading to deficiency in one
of the enzymes of the heme biosynthesis pathway in the liver: AIP,
hereditary coproporphyria (HCP), variegate porphyria (VP), and
ALAD-deficiency porphyria (ADP). These defects cause the
accumulation of neurotoxic heme intermediates aminolevulinic acid
(ALA) and porphobilinogen (PBG), with ALA believed to be the
primary neurotoxic intermediate responsible for causing both
attacks and ongoing symptoms between attacks. Common symptoms of
AHP include severe, diffuse abdominal pain, weakness, nausea, and
fatigue. The nonspecific nature of AHP signs and symptoms can often
lead to misdiagnoses of other more common conditions such as
irritable bowel syndrome, appendicitis, fibromyalgia, and
endometriosis, and consequently, patients afflicted by AHP often
remain without a proper diagnosis for up to 15 years. In addition,
long-term complications of AHP and its treatment can include
chronic neuropathic pain, hypertension, chronic kidney disease and
liver disease, including iron overload, fibrosis, cirrhosis and
hepatocellular carcinoma. Currently, there are no treatments
approved to prevent debilitating attacks or to treat the chronic
manifestations of the disease.
About Givosiran
Givosiran is an investigational, subcutaneously administered
RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1)
in development for the treatment of AHP. Monthly administration of
givosiran has the potential to significantly lower induced liver
ALAS1 levels in a sustained manner and thereby decrease neurotoxic
heme intermediates, aminolevulinic acid ALA and PBG, to near normal
levels. By reducing accumulation of these intermediates, givosiran
has the potential to prevent or reduce the occurrence of severe and
life-threatening attacks, control chronic symptoms, and decrease
the burden of the disease. Givosiran utilizes Alnylam’s Enhanced
Stabilization Chemistry ESC-GalNAc conjugate technology, which
enables subcutaneous dosing with increased potency and durability
and a wide therapeutic index. The safety and efficacy of givosiran
were evaluated in the ENVISION Phase 3 trial with positive results;
these results have not been evaluated by the FDA, the EMA or any
other health authority and no conclusions should be drawn regarding
the safety and effectiveness of this investigational
therapeutic.
About RNAi
RNAi (RNA interference) is a natural cellular process of gene
silencing that represents one of the most promising and rapidly
advancing frontiers in biology and drug development today. Its
discovery has been heralded as “a major scientific breakthrough
that happens once every decade or so,” and was recognized with the
award of the 2006 Nobel Prize for Physiology or Medicine. By
harnessing the natural biological process of RNAi occurring in our
cells, a new class of medicines, known as RNAi therapeutics, is now
a reality. Small interfering RNA (siRNA), the molecules that
mediate RNAi and comprise Alnylam's RNAi therapeutic platform,
function upstream of today’s medicines by potently silencing
messenger RNA (mRNA) – the genetic precursors – that encode for
disease-causing proteins, thus preventing them from being made.
This is a revolutionary approach with the potential to transform
the care of patients with genetic and other diseases.
About Alnylam Pharmaceuticals
Alnylam (Nasdaq: ALNY) is leading the translation of RNA
interference (RNAi) into a whole new class of innovative medicines
with the potential to transform the lives of people afflicted with
rare genetic, cardio-metabolic, hepatic infectious, and central
nervous system (CNS)/ocular diseases. Based on Nobel Prize-winning
science, RNAi therapeutics represent a powerful, clinically
validated approach for the treatment of a wide range of severe and
debilitating diseases. Founded in 2002, Alnylam is delivering on a
bold vision to turn scientific possibility into reality, with a
robust discovery platform. Alnylam’s first U.S. FDA-approved RNAi
therapeutic is ONPATTRO® (patisiran) lipid complex injection
available in the U.S. for the treatment of the polyneuropathy of
hereditary transthyretin-mediated (hATTR) amyloidosis in adults. In
the EU, ONPATTRO is approved for the treatment of hATTR amyloidosis
in adults with stage 1 or stage 2 polyneuropathy. Alnylam has a
deep pipeline of investigational medicines, including five product
candidates that are in late-stage development. Looking forward,
Alnylam will continue to execute on its "Alnylam 2020" strategy of
building a multi-product, commercial-stage biopharmaceutical
company with a sustainable pipeline of RNAi-based medicines to
address the needs of patients who have limited or inadequate
treatment options. Alnylam employs over 1,000 people worldwide and
is headquartered in Cambridge, MA. For more information about our
people, science and pipeline, please visit www.alnylam.com and
engage with us on Twitter at @Alnylam or on LinkedIn.
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 benefits of
givosiran, its plans to complete an NDA submission and file an MAA
in mid-2019, the expected timing for the report of full results
from the ENVISION study, and expectations regarding 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 its
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, successfully launching, marketing and
selling its approved products globally, Alnylam’s ability to
successfully expand the indication for ONPATTRO in the future,
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 Annual Report on Form 10-K 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.
1 Sardh E, Harper P, Balwani M, Stein P, Rees D, Bissell DM,
Desnick R, Parker C, Phillips J, Bonkovsky HL, Vassiliou D, Craig
Penz C, Chan-Daniels A, He Q, Querbes W, Fitzgerald K, Kim JB, Garg
P, Vaishnaw A, Simon AR, and Anderson KE. Phase 1 Trial of an RNA
Interference Therapy for Acute Intermittent Porphyria. N Engl J
Med. 2019;380:549-58.
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version on businesswire.com: https://www.businesswire.com/news/home/20190306005240/en/
Alnylam Pharmaceuticals, Inc.Christine Regan
Lindenboom(Investors and Media)617-682-4340
Josh Brodsky(Investors)617-551-8276
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