Natural History Study Results Describe an
Average Decline of Approximately 140 Meters in 6-Minute Walk
Distance (6-MWD) over 18 Months, Further Validating Co-Primary
Endpoint in ENDEAVOUR Phase 3 Study of Revusiran in FAC
Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi
therapeutics company, announced today results from a retrospective
natural history study evaluating disease progression in
transthyretin (TTR)-mediated amyloidosis (ATTR amyloidosis)
patients with familial amyloidotic cardiomyopathy (FAC). Amongst
other findings, study results showed a mean decline of 140 meters
in 6-minute walk distance (6-MWD) over an 18-month period in FAC
patients with mild-to-moderate heart failure. These natural history
findings support the company’s co-primary endpoint for its Phase 3
ENDEAVOUR clinical study with revusiran. In addition, Alnylam
announced today that it presented complete results from its Phase 2
clinical trial with revusiran in a poster at the American College
of Cardiology (ACC) Annual Scientific Session being held March 14 –
16 in San Diego. Consistent with preliminary results presented last
year, revusiran achieved an up to 98.2% knockdown of serum TTR –
the disease-causing protein – and was found to be generally well
tolerated in the Phase 2 trial in FAC patients. Alnylam is
developing revusiran (ALN-TTRsc), an investigational RNAi
therapeutic targeting TTR, for the treatment of FAC.
“With our recently initiated ENDEAVOUR Phase 3 study, we are
committed to the advancement of revusiran as a potential
disease-modifying therapy for ATTR amyloidosis patients with
cardiomyopathy. As presented at ACC today, these Phase 2 study
results provide further evidence that revusiran is generally well
tolerated in TTR cardiac amyloidosis patients with significant
disease burden. Moreover, we continue to be impressed with the
level of TTR knockdown achieved with revusiran of up to 98.2%,”
said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President,
R&D, and Chief Medical Officer of Alnylam. “In addition, we
have now reported our FAC natural history study results.
Specifically, this retrospective analysis evaluated disease
progression in FAC patients and demonstrated a clear and robust
decline in 6-minute walk distance over an 18-month period. These
findings give us confidence that our ENDEAVOUR Phase 3 trial of
revusiran in FAC patients is appropriately designed to show the
potential impact of TTR lowering on functional decline. In
addition, these data provide important context for our ongoing
Phase 2 open-label extension study of revusiran in TTR cardiac
amyloidosis, where we plan on reporting data at least once per year
beginning in late 2015.”
ATTR amyloidosis is an inherited, progressively debilitating,
and often fatal disease caused by mutations in the TTR gene. These
mutations cause misfolding of the TTR protein and the formation of
amyloid fibrils that deposit in tissues. One of the clinical
manifestations of ATTR amyloidosis is FAC, in which TTR amyloid
deposition in the heart leads to cardiac wall thickening and heart
failure. 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.
“TTR cardiac amyloidosis represents a significant unmet medical
need for the growing population of older adults with this
condition, for which there is no approved therapy. TTR cardiac
amyloidosis is known to be associated with a high rate of mortality
and hospitalization, in addition to a progressive decline in
function. Our natural history study results confirm the significant
disease burden in patients with FAC, with a median survival of
under three years after presentation to the centers, and a steep
rate of functional decline as measured by 6-MWD,” said Mathew S.
Maurer, M.D., Arnold and Arlene Goldstein Professor of Cardiology,
Columbia University. “I look forward to continuing to work with
Alnylam as they advance revusiran in clinical development,
including in the ongoing Phase 3 ENDEAVOUR study. Indeed, we are
hopeful that an RNAi therapeutic that stops production of the
disease-causing protein has the potential to halt progression in
patients with FAC and provide an important treatment option for
management of this disease.”
Findings from the natural history study were presented at a
meeting with members of the Association of Black Cardiologists
(ABC). This study was performed to characterize disease severity
and rate of progression in a multinational population of FAC
patients. Demographics and time from first visit to death were
collected retrospectively on 137 FAC patients from two countries at
two large amyloidosis centers: The National Amyloidosis Centre
(NAC) in London (N=88); and Columbia University in New York (N=49).
The majority of patients had mild-to-moderate heart failure (40%
NYHA class II, 43% NYHA class III) and the V122I TTR mutation
(85%), with a median age of 72 years. Serial 6-MWD data were
collected retrospectively in 39 patients followed at NAC, while
hospitalizations were captured in the 49 patients followed at
Columbia. Median survival was 34.1 months for the pooled group of
137 patients, and median time to first cardiovascular
hospitalization was 26.7 months. There was a clear decline in 6-MWD
over 18 months. Specifically, at 12 and 18 months, the mean decline
in 6-MWD was 106 +/- 24 meters and 140 +/- 39 meters, respectively.
These results are consistent with the 91 meter and 118 meter
decline compared to baseline at 12 and 18 months, respectively,
observed in 10 FAC patients in the published TRACS study (Ruberg et
al., Am Heart J 2012). There was no consistent change over time in
NT-proBNP levels among 78 patients from the NAC with data available
for analysis. Based on these findings, Alnylam believes that the
ongoing Phase 3 ENDEAVOUR trial of revusiran in FAC patients has
the potential to show an impact of TTR lowering on the co-primary
endpoint of decline from baseline in 6-MWD at 18 months. In
addition, Alnylam has assembled natural history data from academic
collaborators on approximately 250 patients with SSA and plans to
present those findings at a future meeting.
Alnylam also announced today complete results from its Phase 2
clinical trial with revusiran. The revusiran Phase 2 study was
aimed at evaluating the safety, tolerability, pharmacodynamics, and
preliminary clinical activity of revusiran in patients with FAC and
SSA. Revusiran was found to be generally well tolerated in both FAC
and SSA patients with advanced disease. The most common adverse
event was a low incidence of transient mild liver function test
(LFT) changes in 4 patients (15%) that, in all cases, resolved
without discontinuing therapy. In 3 of the 4 patients, these
elevations appeared to be clinically insignificant and were less
than 1.5 times the upper limit of normal (ULN). One patient had an
approximate 4-fold elevation in liver transaminases that was deemed
a serious adverse event (SAE) and mild in severity; this event
resolved during continued dosing. The next most common adverse
event was injection site reactions (ISR) that occurred in 15% of
patients. These were all mild in severity and were similar to the
ISRs observed and previously reported in the revusiran Phase 1
study. There were no discontinuations and no significant changes in
renal function or any other laboratory chemistry or hematologic
parameters. Revusiran demonstrated clinical activity in TTR cardiac
amyloidosis patients as measured by knockdown of serum TTR, the
disease-causing protein. Specifically, administration of revusiran
resulted in potent, rapid, and durable knockdown of serum TTR of up
to 98.2%, with a mean maximum knockdown of 85.9% +/- 9.2%. After
five weeks of treatment in this small study population, there were
no significant changes observed in the exploratory clinical
measurements performed. Alnylam has also recently initiated its
Phase 2 open-label extension (OLE) study of revusiran. The study is
designed to evaluate the tolerability and clinical activity of
revusiran with long-term dosing for up to two years. The company
expects to present results from the revusiran Phase 2 OLE study at
least once annually, starting in late 2015.
Alnylam is currently enrolling subjects in its ENDEAVOUR Phase 3
trial, a randomized, double-blind, placebo-controlled, global study
designed to evaluate the efficacy and safety of revusiran in
patients with FAC. The co-primary endpoints of the study are the
change compared to baseline in 6-MWD at 18-months and the percent
reduction in TTR burden between placebo- and revusiran-treated
patients over 18 months. The trial is designed to enroll up to 200
FAC patients with a documented TTR mutation, including V122I or
other mutations, in addition to amyloid deposits as identified by
biopsy. Patients will be randomized 2:1, revusiran:placebo, with
revusiran administered subcutaneously at 500 mg daily for five days
then weekly for 18 months. The study was designed with 90% power to
detect as little as 39% difference in the 18-month change from
baseline for 6-MWD between treatment groups, with a significance
level of p < 0.05. All patients completing the ENDEAVOUR Phase 3
study will be eligible to enroll in a Phase 3 OLE study.
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 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 Merck, Medtronic,
Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist,
GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and
Genzyme, a Sanofi company. 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 revusiran (ALN-TTRsc) for the treatment of
FAC and SSA, the design and timing of clinical studies,
expectations regarding the reporting of data from clinical studies,
expectations regarding its STAr pipeline growth strategy, and its
plans regarding commercialization of RNAi therapeutics, including
with its collaborator Genzyme, 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 be
replicated or continue to occur in other subjects or in additional
studies or otherwise 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 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 to
update any forward-looking statements.
Alnylam Pharmaceuticals, Inc.Cynthia Clayton,
617-551-8207Vice President, Investor Relations and Corporate
CommunicationsorMedia:SpectrumLiz Bryan, 202-955-6222 x2526
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