CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today that upon the recommendation of the ENDEAVOUR Phase 3 study Data Monitoring Committee (DMC) to suspend dosing, the Company has decided to discontinue development of revusiran, an investigational RNA interference (RNAi) therapeutic that was being developed for the treatment of hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM). This decision was made yesterday evening and has been communicated to investigators, study sites, and regulatory authorities.
Following recent reports in the Phase 2 OLE study of new onset or worsening peripheral neuropathy, the ENDEAVOUR DMC assembled yesterday at the Company’s request to review these reports and ENDEAVOUR data on an unblinded basis. The DMC did not find conclusive evidence for a drug-related neuropathy signal in the ENDEAVOUR trial, but informed the Company that the benefit-risk profile for revusiran no longer supported continued dosing. The Company subsequently reviewed unblinded ENDEAVOUR data which revealed an imbalance of mortality in the revusiran arm as compared to placebo.
“Patient safety comes first. We have stopped all dosing and are actively monitoring patients across revusiran studies to ensure their safety. We will also continue to evaluate ENDEAVOUR data to understand the potential cause of these findings,” said John Maraganore, Ph.D., Chief Executive Officer at Alnylam. “While this outcome is disappointing given the lack of available treatment options for patients suffering from this devastating disease, we remain committed to serving the needs of the ATTR amyloidosis community. We would like to thank patients, caregivers, investigators, and study staff who have been so supportive of the revusiran program."
The decision to discontinue development of revusiran does not affect patisiran, which is currently in Phase 3 development for the treatment of hATTR amyloidosis with polyneuropathy (hATTR-PN), or any other Alnylam investigational RNAi therapeutic program in development.
Based on a current assessment of the safety data across the Company’s other programs, which include the ALN-PCSsc program partnered with The Medicines Company, there is no evidence of a drug-related neuropathy signal in over 800 treated subjects and patients with exposure of up to 34 months. This includes patisiran, which utilizes a lipid nanoparticle delivery formulation, and the seven other clinical programs in Alnylam’s pipeline, which all use Enhanced Stabilization Chemistry (ESC) GalNAc delivery technology. ESC-GalNAc conjugates enable dose and exposure levels that are 12-30 times lower than revusiran, which uses Standard Template Chemistry (STC) GalNAc delivery technology. The Company reaffirms its “Alnylam 2020” guidance and remains committed to the advancement of these investigational RNAi therapeutics for treatment of diseases with high unmet medical need.
If there are any questions regarding this announcement, please call the Clinical Trial Information Line at 866-330-0326 (toll-free within the U.S.) or 617-575-7400 (International). Alternatively, you may email any questions or comments to clinicaltrials@alnylam.com.
Conference Call Information
Alnylam management will discuss
these developments in a webcast conference call on Wednesday, October 5,
at 5:00 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 94969575. A replay of
the call will be available beginning at 8:00 p.m. ET. To access the
replay, please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 94969575.
About ATTR Amyloidosis
ATTR amyloidosis is a progressively
debilitating and often fatal disease caused by deposition of
transthyretin (TTR) in peripheral tissues. TTR protein is produced
primarily in the liver and is normally a carrier of vitamin A. In
hereditary ATTR amyloidosis (hATTR), mutations in TTR cause abnormal
amyloid proteins to accumulate and damage body organs and tissue, such
as the peripheral nerves and heart, resulting in intractable peripheral
sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy.
Hereditary ATTR amyloidosis represents a major unmet medical need with
significant morbidity and mortality; hATTR amyloidosis with
polyneuropathy (hATTR-PN) – also known as familial amyloidotic
polyneuropathy (FAP) – affects approximately 10,000 people worldwide and
hATTR amyloidosis with cardiomyopathy (hATTR-CM) – also known as
familial amyloidotic cardiomyopathy (FAC) – is estimated to affect at
least 40,000 people worldwide. hATTR-PN patients have a life expectancy
of 5 to 15 years from symptom onset, and the only approved treatment
options for early stage disease are liver transplantation and tafamidis
(approved in Europe, certain countries in Latin America and Japan, where
it is approved for all stages of disease). hATTR-CM is fatal within 2.5
to 5 years of diagnosis and treatment is currently limited to supportive
care. Wild-type ATTR amyloidosis (wtATTR) – previously called senile
systemic amyloidosis (SSA) – is a non-hereditary form of TTR cardiac
amyloidosis caused by idiopathic deposition of wild-type TTR; its
prevalence is generally unknown, but is associated with advanced age.
There is a significant need for novel therapeutics to treat patients
with ATTR amyloidosis.
Sanofi Genzyme Alliance
In January 2014, Alnylam and Sanofi
Genzyme, the specialty care global business unit of Sanofi, formed an
alliance to accelerate and expand the development and commercialization
of RNAi therapeutics across the world. The alliance is structured as a
multi-product geographic alliance in the field of rare diseases. Alnylam
retains product rights in North America and Western Europe, while Sanofi
Genzyme obtained the right to access certain programs in Alnylam's
current and future Genetic Medicines pipeline in the rest of the world
(ROW) through the end of 2019, together with certain broader
co-development/co-commercialization rights and global rights for certain
products. In the case of patisiran, Alnylam will advance the product
in North America and Western Europe, while Sanofi Genzyme will advance
the product in the ROW.
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 LNP Technology
Alnylam has licenses to Arbutus
Biopharma LNP intellectual property for use in RNAi therapeutic products
using LNP technology.
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 the continued development
of patisiran, its expectations regarding its discontinuation of
development of revusiran, and its ongoing evaluation of the safety data
from its revusiran and other clinical trials, its expectations regarding
the safety and tolerability of its products in clinical development,
including products utilizing ESC-GalNAc conjugates, and 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, including actions by regulators concerning product candidates
in addition to Alnylam’s decision to discontinue development of
revusiran, 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.
The scientific information discussed in this news release relating to Alnylam’s investigational therapeutics is preliminary and investigative. None of Alnylam’s investigational therapeutics have 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 therapeutics.
