Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today complete 18-month data from its ongoing Phase 2 open-label extension (OLE) study with patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN), also known as familial amyloidotic polyneuropathy (FAP). These new clinical data are being presented in an oral talk at the 68th Annual Meeting of the American Academy of Neurology (AAN) being held April 15 – 21, 2016 in Vancouver, British Columbia, Canada. Complete 18-month data (N=27) from the study provide continued evidence that patisiran has the potential to halt neuropathy progression in patients with hATTR-PN. In the first reported exploratory analysis of its kind, the degree of TTR knockdown observed in patients was shown to correlate with improvement in neuropathy impairment scores. Further, in this Phase 2 OLE trial, patisiran was found to be generally well tolerated with up to 25 months of treatment. Dosing continues in the patisiran Phase 2 OLE study, and the Company plans to report initial 24-month data from the trial in mid-2016.
"We are pleased to see continued evidence for potential halting of neuropathy progression after 18 months of treatment in the ongoing Phase 2 OLE study with patisiran. The mean 0.8-point decrease in mNIS+7 is an encouraging finding, as the change in mNIS+7 from baseline to 18 months is the primary endpoint in our ongoing APOLLO Phase 3 trial with patisiran. Furthermore, the safety profile of patisiran, with up to 25 months of treatment, continues to be encouraging,” said Eric Green, Vice President, General Manager, TTR Program. “In addition, we are excited to share data from an exploratory analysis showing statistically significant correlations between the degree of TTR knockdown and improvements in mNIS+7. Taken together, we believe the data from this ongoing Phase 2 OLE study further support patisiran’s potential as an innovative medicine for hATTR-PN, a progressive, debilitating disease with few treatment options. We look forward to the continued advancement of patisiran, including the expected readout of our ongoing APOLLO Phase 3 trial in mid-2017.”
New results presented at the AAN meeting were as of a data cut off of February 23, 2016, and showed that mean neuropathy impairment scores were essentially unchanged from baseline values after 18 months of treatment. Specifically, there was a mean decrease in mNIS+7 of 0.8 points, which compares favorably to an estimated mean increase in mNIS+7 of 22 to 26 points over 18 months based upon analysis of historical data sets in untreated hATTR-PN patients with similar baseline characteristics. Similar results were observed in patients with or without concurrent tetramer stabilizer use. In addition, patisiran administration was associated with a statistically significant, approximately 77% median improvement in nerve fiber density as read histologically in a blinded manner from distal thigh sweat gland biopsy samples (p less than 0.001). Over the 18 month period, patients with associated cardiomyopathy (N=11) showed stability in their echocardiographic, biomarker, and functional measures, including 10-meter-walk speed. Serum TTR levels were also measured throughout the OLE study, and showed sustained TTR knockdown for over 24 months with a mean maximal knockdown of 92% over the entire period and a mean post-dose knockdown of 87% at 18 months.
In addition, Alnylam also presented the results of an exploratory analysis examining the relationship between the degree of TTR knockdown with subsequent changes in mNIS+7. In the analysis, inter-subject differences in the degree of TTR knockdown were compared to changes in mNIS+7 at 6, 12, and 18 months to assess the effects of patisiran administration. There was a linear correlation between the degree of serum TTR knockdown and changes in mNIS+7. Specifically, greater degrees of TTR knockdown resulted in greater levels of mNIS+7 improvement; these results were significant at 6 and 12 months (p less than 0.01) and showed a trend at 18 months (p equal to 0.055). Importantly, this is the first reported evidence that correlates the degree of TTR knockdown with improvements in mNIS+7, supporting the therapeutic hypothesis that reduction of mutant and wild-type TTR may be associated with potential for a halting of neuropathy progression in patients with hATTR-PN.
Patisiran administration was also found to be generally well tolerated in hATTR-PN patients with 18 to up to 25 months of treatment. Of the most common adverse events reported in 10% or more of patients, the most frequent drug-related or possibly drug-related adverse events (AEs) were flushing (22.2%) and infusion-related reactions (18.5%), which were all mild in severity and did not result in any discontinuations. There were eight reports of serious adverse events (SAEs) in five patients, all of which were unrelated to study drug, including one discontinuation for gastroesophageal cancer at approximately 20 months in a patient who subsequently died. After the data cut-off date, an additional unrelated SAE of myocardial infarction was reported in a 79 year-old patient who subsequently died after having completed the full 24 months of treatment. Overall, there were no clinically significant changes in liver function tests, renal function, or hematologic parameters, including platelets.
To view the 18-month patisiran OLE study results, please visit www.alnylam.com/capella.
Conference Call Information
Alnylam management will discuss
these data in a webcast conference call on Wednesday, April 20 at 8:30
a.m. ET. A slide presentation will also be available on the 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 92074780. A replay of
the call will be available beginning at 10:30 a.m. ET. To access the
replay, please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 92074780.
About the Patisiran Phase 2 OLE Study
The ongoing patisiran
Phase 2 OLE study is an open-label, multi-center trial designed to
evaluate the long-term safety and tolerability of patisiran
administration in patients with hereditary ATTR amyloidosis with
polyneuropathy (hATTR-PN) that were previously enrolled in a Phase 2
study. Patisiran is being administered once every 3 weeks at a dose of
0.3 mg/kg by intravenous infusion. The study is 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 change in the mNIS+7 measurement from baseline to 18
months is the primary endpoint in the company's APOLLO Phase 3 trial of
patisiran in patients with hATTR-PN.
Sanofi Genzyme Alliance
In January 2014, Alnylam and Sanofi
Genzyme, the specialty care global business unit of Sanofi, 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 Sanofi
Genzyme obtained the right to access certain programs in Alnylam's
current 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
Sanofi Genzyme will advance the product in the ROW.
About hATTR
Hereditary transthyretin (TTR)-mediated
amyloidosis (hATTR) 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. hATTR represents a major unmet
medical need with significant morbidity and mortality; hATTR with
polyneuropathy (hATTR-PN) – also known as familial amyloidotic
polyneuropathy (FAP) – affects approximately 10,000 people worldwide and
hATTR with cardiomyopathy (hATTR-CM) – also known as familial
amyloidotic cardiomyopathy (FAC) – is estimated to affect at least
40,000 people worldwide. hATTR-PN 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, certain countries in Latin America and Japan, where
it is approved for all stages of disease). hATTR-CM is fatal within 2.5
to 5 years of diagnosis and treatment is currently limited to supportive
care. Wild-type amyloidosis (wtATTR) – also called 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 hATTR.
About LNP Technology
Alnylam has licenses to Arbutus
Biopharma LNP intellectual property for use in RNAi therapeutic products
using LNP technology.
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 Ionis, Novartis, Roche, Takeda, Merck,
Monsanto, The Medicines Company, and Sanofi Genzyme. 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 the potential of
patisiran to halt neuropathy progression in patients with hATTR-PN,
expectations regarding the reporting of data from the ongoing Phase 2
open-label extension trial and APOLLO Phase 3 trial with patisiran, its
expectations regarding its STAr pipeline growth 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 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.
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