Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has completed enrollment in its Phase 2
clinical trial with revusiran (re-VOO-si-ran), the recommended
International Nonproprietary Name (INN) for ALN-TTRsc. Revusiran is an
investigational RNAi therapeutic targeting wild-type and all mutant
forms of transthyretin (TTR) and utilizes Alnylam’s proprietary
GalNAc-conjugate delivery platform that enables subcutaneous delivery of
RNAi therapeutics with a wide therapeutic index. The pilot Phase 2 study
enrolled 26 patients with TTR cardiac amyloidosis, who received
revusiran for a five week course of treatment. The company also
announced today that its open-label extension (OLE) study with revusiran
is now open for enrollment for patients who participated previously in
the Phase 2 clinical trial. The Phase 2 OLE study will evaluate the
safety and tolerability of long-term dosing with revusiran for up to two
years, and will also measure effects of treatment on clinical endpoints,
including mortality, hospitalization, and 6-minute walk distance
(6-MWD), in addition to cardiac amyloid burden and function, and cardiac
biomarkers. The company intends to report clinical data from this study
about once per year, with initial data expected in 2015. Finally,
Alnylam is also announcing today that it has completed its discussions
with regulatory authorities in the U.S. and EU regarding the design of a
Phase 3 study for revusiran in TTR cardiac amyloidosis patients; the
company remains on track to initiate the study before year’s end.
“We believe that revusiran has the potential to be an important
therapeutic option for the treatment of TTR cardiac amyloidosis – a
disease with significant morbidity and mortality, and no approved
therapies. Our Phase 1 clinical study demonstrated robust knockdown of
circulating TTR – the disease-causing gene – of up to 96%, and was
generally well tolerated,” said Jared Gollob, M.D., Vice President,
Clinical Research of Alnylam. “We have now completed enrollment in our
pilot Phase 2 study in 26 TTR cardiac amyloidosis patients, where
revusiran was administered over a five-week period, and we look forward
to presenting these initial results in the coming weeks. With the start
of our Phase 2 OLE study, we are pleased to be able to provide patients
the opportunity to continue receiving revusiran. We believe that longer
term treatment with revusiran in the OLE study will provide important
data on tolerability with chronic dosing and could provide potential
evidence for clinical activity. We plan on presenting data from the OLE
study at least once annually starting in 2015. Finally, we are pleased
to have completed our discussions with U.S. and EU regulatory
authorities on the design of our Phase 3 study, and are on track to
initiate the study before year’s end.”
TTR-mediated amyloidosis (ATTR) is an inherited, progressively
debilitating, and often fatal disease caused by mutations in the TTR
gene. These mutations cause misfolding of the protein and the formation
of amyloid fibrils that deposit in tissues. One of the clinical
manifestations of ATTR is familial amyloidotic cardiomyopathy (FAC), in
which TTR amyloid deposition in the heart leads to cardiac wall
thickening and heart failure. In addition, wild-type TTR can accumulate
as amyloid deposits in the heart of elderly people in a disease known as
senile systemic amyloidosis (SSA). FAC and SSA are fatal within 2.5 to 5
years of diagnosis and treatment is currently limited to supportive care.
The pilot Phase 2 study was aimed at evaluating the safety,
tolerability, pharmacodynamic and preliminary clinical activity of
revusiran in patients with FAC and SSA. This trial was conducted as an
open-label, multi-dose study, and completed enrollment with 26 patients,
including 14 diagnosed with FAC and 12 with SSA. Revusiran was
administered initially as daily subcutaneous doses for five days and
then once weekly at doses of 5 mg/kg or 7.5 mg/kg over a period of five
weeks for a total of 10 doses. The primary objective of the study was to
evaluate the safety and tolerability of revusiran. The secondary
objectives were to assess the pharmacodynamic effect on serum levels of
TTR and characterize the pharmacokinetic profile. In addition,
exploratory clinical endpoint data were collected at baseline and days
42 and 90 after start of dosing; this includes 6-MWD, echocardiogram and
cardiac MRI to assess cardiac amyloid burden and function, circulating
cardiac biomarkers including NT-proBNP and troponin to assess heart wall
stress and injury, and questionnaires to assess cardiomyopathy symptoms
and quality of life. Alnylam expects to present initial results from the
Phase 2 study at a meeting to be held during the American Heart
Association meeting in November.
The company has now initiated its Phase 2 OLE study of revusiran. All
patients that completed dosing in the Phase 2 trial are eligible to be
enrolled in the OLE study. Revusiran will be administered at a fixed
subcutaneous dose of 500 mg, with once-daily dosing for the first five
days followed by weekly dosing thereafter. The study is designed to
evaluate the tolerability and clinical activity of revusiran with
long-term dosing for up to two years. In addition to data on mortality,
hospitalization, general tolerability, and measurement of serum TTR
levels, the study will assess every six months the same clinical
measures included in the pilot Phase 2 trial noted above as well as
additional measures of amyloid burden including technetium imaging of
the heart and quantitation of amyloid in abdominal fat pad aspirates.
The company expects to present results from the revusiran Phase 2 OLE
study at least once annually starting in 2015.
Finally, Alnylam has now completed its meetings with regulatory
authorities from the U.S. and EU regarding the design of a Phase 3 trial
for revusiran in TTR cardiac amyloidosis. Specifically, the company
completed an End-of-Phase 2 meeting with the U.S. Food and Drug
Administration (FDA) and received scientific advice from the Committee
for Medicinal Products for Human Use (CHMP) of the European Medicines
Agency (EMA). Alnylam will provide details of the Phase 3 design upon
initiation of the study, which is expected by the end of this year.
In January 2014, Alnylam and Genzyme, a Sanofi company, 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. In the
case of revusiran, Alnylam and Genzyme are co-developing and
co-commercializing the investigational RNAi therapeutic in North America
and Western Europe, while Genzyme is developing and commercializing
revusiran in the rest of world.
About ATTR
Transthyretin (TTR)-mediated amyloidosis (ATTR)
is an inherited, progressively debilitating, and often fatal disease
caused by mutations in the TTR gene. TTR protein is produced primarily
in the liver and is normally a carrier of vitamin A. 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. ATTR represents a major unmet medical need with
significant morbidity and mortality; familial amyloidotic polyneuropathy
(FAP) affects approximately 10,000 people worldwide and familial
amyloidotic cardiomyopathy (FAC) is estimated to affect at least 40,000
people worldwide. FAP 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). FAC is fatal within 2.5 to 5 years of diagnosis and treatment
is currently limited to supportive care. 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 TTR amyloid
polyneuropathy and/or cardiomyopathy.
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 with a core focus on RNAi therapeutics as genetic
medicines, including programs as part of the company’s “Alnylam 5x15™”
product strategy. Alnylam’s genetic medicine programs are RNAi
therapeutics directed toward genetically defined targets for the
treatment of serious, life-threatening diseases with limited treatment
options for patients and their caregivers. These include: patisiran
(ALN-TTR02), an intravenously delivered RNAi therapeutic targeting
transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR)
in patients with familial amyloidotic polyneuropathy (FAP); revusiran
(ALN-TTRsc), a subcutaneously delivered RNAi therapeutic targeting TTR
for the treatment of ATTR in patients with TTR cardiac amyloidosis,
including familial amyloidotic cardiomyopathy (FAC) and senile systemic
amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin
(AT) for the treatment of hemophilia and rare bleeding disorders (RBD);
ALN-CC5, an RNAi therapeutic targeting complement component C5 for the
treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic
targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of
hepatic porphyrias including acute intermittent porphyria (AIP);
ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of
hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1
antitrypsin (AAT) for the treatment of AAT deficiency-associated liver
disease; ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus
(HBV) genome for the treatment of HBV infection; ALN-TMP, an RNAi
therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and
iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting
angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of
mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi
therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment
of hypertriglyceridemia; ALN-AGT, an RNAi therapeutic targeting
angiotensinogen (AGT) for the treatment of hypertensive disorders of
pregnancy (HDP), including preeclampsia; ALN-GO1, an RNAi therapeutic
targeting glycolate oxidase (GO) for the treatment of primary
hyperoxaluria type 1 (PH1); and other programs yet to be disclosed. As
part of its “Alnylam 5x15” strategy, as updated in early 2014, the
company expects to have six to seven genetic medicine product candidates
in clinical development – including at least two programs in Phase 3 and
five to six programs with human proof of concept – by the end of 2015.
The company’s demonstrated commitment to RNAi therapeutics has enabled
it to form major alliances with leading companies including Merck,
Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin,
Cubist, GlaxoSmithKline, Ascletis, Monsanto, and The Medicines Company.
In early 2014, Alnylam and Genzyme, a Sanofi company, formed a
multi-product geographic alliance on Alnylam's genetic medicine programs
in the rare disease field. Specifically, Alnylam will lead development
and commercialization of programs in North America and Europe, while
Genzyme will develop and commercialize products in the rest of world. In
addition, Alnylam and Genzyme will co-develop and co-commercialize
revusiran in North America and Europe. In March 2014, Alnylam acquired
Sirna Therapeutics, a wholly owned subsidiary of Merck. 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, 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 revusiran (ALN-TTRsc) for
the treatment of FAC, its expectations with respect to timing of
regulatory filings and the reporting of initial data from a clinical
trial for revusiran and the start of a Phase 3 trial, the potential
therapeutic opportunities for revusiran, as well as its expectations
regarding its “Alnylam 5x15” product strategy, and its plans regarding
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 may
differ materially from those indicated by these forward-looking
statements as a result of various important 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 drug candidates, the pre-clinical and
clinical results for its product candidates, which may not support
further development of product candidates, actions of regulatory
agencies, which may affect the initiation, timing and progress of
clinical trials, obtaining, maintaining and protecting intellectual
property, Alnylam’s ability to enforce its patents against infringers
and defend its patent portfolio against challenges from third parties,
obtaining regulatory approval for products, competition from others
using technology similar to Alnylam’s and others developing products for
similar uses, Alnylam’s ability to manage operating expenses, Alnylam’s
ability to 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, marketing, sales and distribution of products, the outcome
of litigation, 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
to update any forward-looking statements.
Copyright Business Wire 2014