Alnylam
Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics
company, announced today six-month clinical data from its ongoing Phase
2 open-label extension (OLE) study with patisiran (ALN-TTR02), an
investigational RNAi therapeutic in development for the treatment of
transthyretin (TTR)-mediated amyloidosis (ATTR) in patients with
familial amyloidotic polyneuropathy (FAP). These data are being
presented at the American Neurological Association’s 2014 Annual Meeting
being held October 12 – 14 in Baltimore. Results showed a mean 0.95
point decrease in modified Neuropathy Impairment Score (mNIS+7) at six
months in 19 patients with mNIS+7 data available for the current
analysis. This decrease in neuropathy progression compares favorably
with the 7 to 10 point increase in mNIS+7 at six months that can be
estimated from historical data sets in untreated FAP patients with
similar baseline characteristics (Adams
et al., International Symposium on Amyloidosis, April 2014;
Berk et al., JAMA 310: 26588-67, 2013; Tafamidis European
Medicines Agency Assessment Report, 2011). In addition, patisiran
treatment achieved a sustained mean serum TTR knockdown at the 80%
target level for over nine months, with an up to 89.6% knockdown
achieved between doses. Patisiran was found to be generally well
tolerated in this study out to one year of therapy, with no drug-related
serious adverse events to date, and all 27 patients enrolled in the
study continue to receive drug treatment.
“In this open-label study with patisiran, we are very encouraged to see
what we believe to be evidence for possible stabilization of neuropathy
progression after the first six months of treatment. Indeed, we believe
the approximate one point decrease in neuropathy impairment score is an
encouraging result in light of multiple historical data sets that would
have predicted an increase of 7 to 10 points for untreated patients with
similar baseline characteristics. These data will be increasingly
meaningful as we monitor neuropathy progression in patisiran-treated
patients over time, and we look forward to sharing those results at
least once annually hereafter,” said Akshay Vaishnaw, M.D., Ph.D.,
Executive Vice President and Chief Medical Officer of Alnylam. “In
addition, patisiran treatment showed robust knockdown of serum TTR of up
to 90% for over nine months, and was associated with a favorable
tolerability profile out to one year of treatment. We believe the
potent, rapid, and durable knockdown of TTR achieved by patisiran could
be important since TTR protein reduction in patients with ATTR may have
the potential to delay or even reverse disease progression with
associated clinical benefit. We will continue to treat patients
on our OLE study, and are enrolling FAP patients in our APOLLO Phase 3
study in sites around the world.”
Alnylam’s ongoing OLE study is treating patients that were previously
enrolled in a Phase 2 study of patisiran in ATTR patients with FAP. The
OLE study is an open-label, multi-center trial designed to evaluate the
long-term safety and tolerability of patisiran administration. The
two-year study has completed enrollment with 27 patients who receive 0.3
mg/kg of patisiran once every three weeks. This study is also measuring
a number of clinical endpoints every six months, including mNIS+7 which
is an evaluation of muscle weakness, sensory and autonomic function, and
nerve conductance, where neuropathy progression leads to an increased
score over time. The mNIS+7 measurement is the primary endpoint in the
company’s Phase 3 APOLLO trial of patisiran in FAP patients. A number of
additional clinical measures are also being assessed, including: quality
of life (QOL); timed 10-meter walk test (10MWT) to evaluate mobility;
hand grip strength test; modified body mass index (mBMI) as a measure of
nutritional status; level of disability by R-ODS; and nerve fiber
density in skin biopsies. Patients with cardiac abnormalities at
baseline comprise a cardiac subgroup (N=11) where cardiac biomarkers
(NT-proBNP and troponin I) and echocardiographic parameters are measured
at baseline and every three to six months. In addition, serum TTR levels
are being measured throughout the study.
The initial
results from the ongoing open-label study showed that after six
months of treatment with patisiran, neuropathy impairment scores were
essentially unchanged from baseline values. As noted above, there was a
mean decrease in mNIS+7 of 0.95 points (N=19), which compares favorably
to the rapid increase in mNIS+7 of 7 to 10 points estimated at six
months from historical data sets in untreated FAP patients with similar
baseline characteristics. Similar results were observed for the change
in Neuropathy Impairment Score (NIS), where there was a mean increase of
0.22 points at six months (N=20). The stabilization in mNIS+7 was
similar in patients with or without concurrent use of TTR tetramer
stabilizers. In addition, no significant evidence for disease worsening
was observed in measurements of QOL, 10MWT, mBMI, R-ODS, and nerve fiber
density, amongst other clinical assessments performed. In the cardiac
subgroup, there were no significant changes in cardiac biomarkers (N=5)
or in echocardiographic parameters (N=7) after six months of dosing.
Finally, repeat dosing of patisiran achieved sustained TTR knockdown at
the 80% target level for over nine months, and an up to 89.6% level of
TTR knockdown was achieved in post-dose measurements. A similar degree
of TTR knockdown was observed in patients with or without concurrent use
of TTR tetramer stabilizers.
“These preliminary clinical activity and safety data from Alnylam’s OLE
study with patisiran are quite encouraging. In particular, the
stabilization in neuropathy impairment scores at six months may have
important implications for patients suffering from this debilitating,
progressive and life-threatening disease,” said David Adams, M.D.,
Ph.D., Head of Department of Neurology and Coordinator of the French
Reference Center for FAP (NNERF)/APHP/CHU Bicêtre/France. “I very
much look forward to continuing to participate in the clinical
advancement of this investigational RNAi therapeutic, including treating
patients on the ongoing Phase 2 OLE study and enrolling patients onto
the APOLLO Phase 3 study, as there are currently few options for our
patients suffering from FAP.”
Patisiran administration was found to be generally well tolerated in FAP
patients (N=27), with minimal adverse events reported for a period of up
to one year. As of the time of the data cutoff on September 8, 2014, 282
doses had been administered with a median of 11 doses per patient. Mean
treatment duration was seven months and the longest treatment duration
was out to one year. There were no drug-related serious adverse events.
Infusion-related reactions were infrequent (14.8%), mild in severity,
and did not result in any discontinuations. All other reported adverse
events were mild to moderate, and there were no clinically significant
changes in liver function tests, renal function tests, or other
laboratory or hematological parameters.
Conference Call Information
Alnylam management will discuss these new Phase 2 open-label extension
study results with patisiran for the treatment of familial amyloidotic
polyneuropathy in a webcast conference call on Monday, October 13 at
8:00 a.m. ET. A slide presentation will also be available on the News &
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 19356541. A replay of
the call will be available beginning at 11:00 a.m. ET. To access the
replay, please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 19356541.
About Transthyretin-Mediated Amyloidosis
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 LNP Technology
Alnylam has licenses to Tekmira LNP intellectual property for use in
RNAi therapeutic products using LNP technology.
About the Genzyme Collaboration
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. Alnylam
retains product rights in North America and Western Europe, while
Genzyme obtains the right to access Alnylam’s current “5x15” and future
genetic medicines pipeline in the rest of the world (ROW), including
co-development/co-commercialization and/or global product rights for
certain programs. In the case of patisiran, Alnylam will advance the
product in North America and Western Europe, while Genzyme will advance
the product in the ROW.
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); 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; 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
ALN-TTRsc 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 patisiran for the treatment of FAP, its expectations regarding
its “Alnylam 5x15” product strategy, its expectations with respect to
the design, timing, and success of its clinical trials, including its
Phase 3 APOLLO study, its expectations regarding the reporting of data
from its clinical trials and the potential implications of early
clinical data reported, 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 manage operating expenses, 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 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