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.
Copyright Business Wire 2015