– Results Show a Mean 0.95 Point Decrease in
Modified Neuropathy Impairment Score (mNIS+7) at Six Months,
Comparing Favorably with Historical Data Sets in FAP Showing Rapid
Increase in Neuropathy Progression –
– Patisiran Also Achieved Sustained Knockdown
of Serum Transthyretin (TTR) of Up to 90% for Over Nine Months, and
was Generally Well Tolerated in Patients Treated Up to One Year
–
– Company to Host Conference Call Today at 8:00
a.m. ET to Discuss Results –
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.
Alnylam Pharmaceuticals, Inc.Cynthia Clayton,
617-551-8207Vice President, Investor Relations andCorporate
CommunicationsorMedia:SpectrumLiz Bryan, 202-955-6222 x2526
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