– Company Suspends Fitusiran Dosing due to
Thrombotic Event and Aims to Resume Dosing as Soon as Possible upon
Agreement with Global Regulatory Authorities –
– Company Achieves Alignment with FDA on
Givosiran Phase 3 Program Design, Including Interim Analysis Based
on Reduction of Urinary Aminolevulinic Acid (ALA) as Surrogate
Endpoint Reasonably Likely to Predict Clinical Benefit –
– New Givosiran Phase 3 Plan Enables Potential
for NDA Filing of Interim Analysis Results at or Around Year-End
2018 –
– Company to Host Conference Call Today at 8:00
a.m. ET, as well as Previously Scheduled RNAi Roundtable Webinar on
Givosiran at 10:30 am ET –
Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY), the leading RNAi
therapeutics company, announced today an update on the company's
fitusiran and givosiran investigational RNAi therapeutic programs.
With fitusiran, an RNAi therapeutic in development for the
treatment of hemophilia A and B with or without inhibitors, Alnylam
is reporting a fatal thrombotic event in a patient with hemophilia
A without inhibitors in the Phase 2 open-label extension (OLE)
study of fitusiran. As a result, the Company has suspended dosing
in all ongoing fitusiran studies pending further review of the
safety event and development of a risk mitigation strategy. Based
on overall consideration of fitusiran’s benefit-risk profile,
Alnylam is guiding that it aims to resume dosing as soon as
possible upon agreement with global regulatory authorities and with
appropriate protocol amendments in place for enhanced patient
safety monitoring. With givosiran, an RNAi therapeutic in
development for the treatment of acute hepatic porphyrias (AHP),
Alnylam has reached alignment with the U.S. Food and Drug
Administration (FDA) on a Phase 3 study design which includes an
interim analysis based on reduction of a urinary biomarker,
aminolevulinic acid (ALA), as a surrogate endpoint reasonably
likely to predict clinical benefit. Based on the new givosiran
Phase 3 design, the Company is now guiding that pending FDA review
of the program at the time of interim analysis and assuming
positive results, it expects to submit an NDA at or around year-end
2018.
Fitusiran Program Update
"We are deeply saddened to learn of this patient’s death, and we
extend our sympathies to his family," said Akshay Vaishnaw, M.D.,
Ph.D, Executive Vice President of R&D at Alnylam. "We believe
that fitusiran holds great promise as a potential treatment option
for patients with hemophilia, and we remain fully committed to its
ongoing development. Following further investigation of this safety
finding, implementation of a risk mitigation strategy, and
alignment with global regulatory authorities, we expect to resume
fitusiran dosing in our clinical studies as soon as possible,
potentially as early as late 2017, with a goal of advancing this
innovative investigational medicine to hemophilia patients in
need."
Fitusiran clinical studies include the ongoing Phase 2 OLE study
of hemophilia A and B patients with and without inhibitors and the
ATLAS Phase 3 program, which has recently been initiated but in
which patient dosing has yet to begin. Alnylam recently became
aware of a fatal serious adverse event (SAE) that occurred in a
patient with hemophilia A who was receiving fitusiran in the Phase
2 OLE study. Approximately nine days prior to hospital admission,
he developed exercise-induced right hip pain that was treated with
a total of three doses of factor VIII concentrate (31-46 IU/kg) on
three separate days. Four days prior to admission, when the patient
received his third dose of factor, he developed a severe headache.
While he was initially suspected of having viral meningitis, the
patient was diagnosed with subarachnoid hemorrhage on the basis of
CT imaging, and treated with factor VIII concentrate administered
two to three times daily. Over a 14-day hospitalization, his
medical condition worsened despite the administration of factor and
the patient died from subsequent cerebral edema. The initial
diagnosis of subarachnoid hemorrhage was reported by the
investigator as not related to fitusiran. For a more complete
understanding, the Company initiated further investigation of the
SAE, including review of the patient's CT scans by three
independent neuro-radiologists, who all confirmed on September 1,
2017, that the initiating event was a cerebral venous sinus
thrombosis, and not a subarachnoid hemorrhage. As a result of this
new information, Alnylam suspended dosing in fitusiran studies in
order to further investigate the safety event, now considered to be
possibly related, and to develop a risk mitigation plan. The
Company also notified study investigators and global regulatory
authorities.
Based on today’s program update, Alnylam will postpone its
fitusiran RNAi Roundtable webinar previously scheduled for
September 12th until a later date.
Givosiran Program Update
"We believe that givosiran has shown very promising results as
an innovative approach to potentially preventing debilitating and
painful attacks in patients with acute hepatic porphyrias, a family
of ultra-rare orphan diseases with enormous symptomatic burden and
unmet need. Based on our ongoing clinical study results, we are
very pleased with the support from global regulatory authorities
who share our commitment to evaluate and establish the efficacy and
safety of givosiran as a therapeutic option for patients as rapidly
as possible," said Jeff Miller, General Manager of the givosiran
program. "We have now reached alignment with the FDA on a Phase 3
program that includes an interim analysis based on reduction of
urinary levels of ALA, a biomarker that the FDA considers to be
reasonably likely to predict clinical benefit. Based on this new
design, Alnylam now expects – pending FDA review of the program at
the time of the interim analysis and assuming positive results – to
be in a position to submit an NDA at or around year-end 2018, which
represents a significant acceleration in our efforts to bring this
investigational medicine to patients."
In interim Phase 1 study results presented at the 2017
International Congress on Porphyrins and Porphyrias (ICPP) from a
randomized, double-blind, placebo-controlled study in patients with
acute intermittent porphyria (AIP), givosiran demonstrated an over
80 percent mean reduction of urinary ALA and an over 70 percent
mean decrease relative to placebo in the estimated annualized
number of porphyria attacks requiring treatment at a healthcare
facility or with intravenous hemin administration. Excluding
porphyria attacks, three patients had four SAEs, including one
previously reported fatal episode of hemorrhagic pancreatitis; none
of these SAEs were assessed as related to study drug. Based on
these results, givosiran received PRIME designation by the European
Medicines Agency (EMA) and Breakthrough Therapy Designation by the
FDA. The Company has achieved alignment with the FDA on a
randomized, double-blind, placebo-controlled Phase 3 study design
that includes an interim analysis with reduction in urinary levels
of ALA at three months of treatment as a biomarker that is
reasonably likely to predict clinical benefit; discussions
with other global regulatory authorities are ongoing. Alnylam
expects to initiate a Phase 3 study of givosiran in late 2017 with
interim analysis data available in mid-2018.
As previously scheduled, Alnylam will discuss the givosiran
program, including the Phase 3 study and interim analysis design,
at an RNAi Roundtable event today at 10:30 a.m. ET. This event will
be webcast live on the Investors page of the Alnylam website,
www.alnylam.com, and a replay will be posted approximately three
hours after the event.
Conference Call Details
Management will discuss these updates via conference call
today, Thursday, September 7, 2017, at 8:00 a.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 81805520. A replay of the
call will be available beginning at 11:00 a.m.
ET on September 7, 2017. To access the replay, please
dial 855-859-2056 (domestic) or 404-537-3406 (international), and
refer to conference ID 81805520.
About Fitusiran
Fitusiran is an investigational, once-monthly, subcutaneously
administered RNAi therapeutic targeting antithrombin (AT) for the
treatment of hemophilia A and B, with and without inhibitors.
Fitusiran also has the potential to be used for rare bleeding
disorders. Fitusiran is designed to lower levels of AT with the
goal of promoting sufficient thrombin generation to restore
hemostasis and prevent bleeding. Fitusiran utilizes Alnylam's
ESC-GalNAc conjugate technology, which enables subcutaneous dosing
with increased potency and durability. The clinical significance of
this technology is under investigation.
The safety and efficacy of fitusiran have not been evaluated by
the FDA, the EMA or any other health authority.
About Hemophilia
Hemophilia is a hereditary bleeding disorder characterized by an
underlying defect in the ability to generate adequate levels of
thrombin needed for effective clotting, thereby resulting in
recurrent bleeds into joints, muscles, and major internal organs.
There are approximately 200,000 persons diagnosed worldwide with
hemophilia A and hemophilia B.
Standard treatment for persons with hemophilia currently
involves replacement of the deficient clotting factor either as
prophylaxis or "on-demand" therapy, which can lead to a temporary
restoration of thrombin generation capacity. However, as many as
one third of people with severe hemophilia A will develop a
neutralizing antibody to their replacement factor - a very serious
complication; individuals with these ‘inhibitors' become refractory
to standard replacement factor therapy. Inhibitors may also develop
in severe Hemophilia B patients, albeit at a lower rate.
About Givosiran
Alnylam is developing givosiran (formerly known as ALN-AS1), a
subcutaneously administered, investigational RNAi therapeutic
targeting ALAS1 for the treatment of AHP, including AIP. AIP is the
most common of the porphyrias, 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
ALA and PBG. 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
novel treatment approach for the prevention of recurrent attacks.
Givosiran has been granted the following regulatory designations:
PRIME by European Medicines Agency (EMA), Breakthrough Designation
by the U.S. Food and Drug Administration (FDA) and Orphan Drug
Designation by both EMA and FDA for the treatment of AHP.
The safety and efficacy of givosiran have not been evaluated by
the FDA, the EMA or any other health authority.
About Acute Hepatic Porphyrias
The porphyrias are a family of rare metabolic disorders with
mostly autosomal dominant inheritance predominantly 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) and ALAD-deficiency porphyria
(ADP). 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. There are no approved treatments for the prevention of
attacks; 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. 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.
Alnylam - Sanofi Genzyme Alliance
In January 2014, Alnylam and Sanofi Genzyme, the specialty care
global business unit of Sanofi, formed an alliance to accelerate
the advancement of RNAi therapeutics as a potential new class of
innovative medicines for patients around the world with rare
genetic diseases. The alliance enables Sanofi Genzyme to expand its
rare disease pipeline with Alnylam’s novel RNAi technology and
provides access to Alnylam’s R&D engine, while Alnylam benefits
from Sanofi Genzyme’s proven global capabilities to advance
late-stage development and, upon commercialization, accelerate
market access for these promising genetic medicine products.
In November 2016, Sanofi Genzyme elected to co-develop (through
Sanofi R&D) and co-commercialize fitusiran in the United
States, Canada and Western Europe, in addition to commercializing
fitusiran in its rest of world territories.
About RNAi
RNAi (RNA interference) is a revolution in biology, representing
a breakthrough in understanding protein synthesis 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, with the goal of preventing
disease-causing proteins from being made.
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 patients who have
limited or inadequate treatment options. Based on Nobel
Prize-winning science, RNAi therapeutics represent a powerful,
clinically validated approach for the treatment of a wide range of
debilitating diseases. Founded in 2002, Alnylam is delivering on a
bold vision to turn scientific possibility into reality, with a
robust discovery platform and deep pipeline of investigational
medicines, including three product candidates that are in
late-stage development or will be in 2017. 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. For more information
about our people, science and pipeline, please visit
www.alnylam.com and engage with us on Twitter at @Alnylam.
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 planned interactions with
regulatory authorities and the expected resumption of dosing in its
fitusiran clinical studies, the potential for fitusiran for the
treatment of patients with hemophilia A and B, with or without
inhibitors, the potential for givosiran for the treatment of
hepatic porphyrias, expectations regarding the initiation of a
Phase 3 clinical study for givosiran and the possibility of an
interim analysis in such study, the anticipated filing date of an
NDA for givosiran, 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, 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.
Fitusiran and givosiran have 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 the safety or effectiveness of these
investigational therapeutics.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20170907005750/en/
Alnylam Pharmaceuticals, Inc.Investors and MediaChristine
Regan Lindenboom, 617-682-4340orInvestorsJosh Brodsky,
617-551-8276
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