Nov 03, 2015 Press Release for Alnylam
Alnylam Reports Positive Results from Ongoing Phase 2 Open-Label Extension (OLE) Studies for Patisiran and Revusiran, in Development for the Treatment of Transthyretin (TTR)-Mediated Amyloidosis (ATTR Amyloidosis)
Nov 03, 2015
- Patisiran Demonstrates Continued Evidence for Potential Halting of Neuropathy Progression and First-Ever Results Showing Statistically Significant Improvement in Nerve Fiber Density in Patients with Familial Amyloidotic Polyneuropathy (FAP) -
- Patisiran APOLLO Trial on Track to Complete Enrollment in Next 3-4 Months;
if Positive, Expect New Drug Application (NDA) Filing in 2017 -
- Revusiran Demonstrates Robust and Sustained Knockdown of Serum TTR of up to 98%, Representing Longest Human Target Gene Knockdown Experience with a GalNAc-siRNA Conjugate, and is Generally Well Tolerated in Majority of Patients with ATTR Cardiac Amyloidosis out to 10 Months of Treatment -
- Company to Host Conference Call Today,
"We believe that data from these ongoing Phase 2 OLE studies further
support the potential of RNAi therapeutics targeting TTR as innovative
investigational medicines for the treatment of ATTR amyloidosis," said
"Few treatment options exist for patients suffering from ATTR
amyloidosis. With patisiran, new data supporting the possibility of
halting neuropathic progression over 18 months of treatment is promising
in light of the rapid increase in neuropathy impairment scores observed
in analysis of other historical data sets. Indeed, the progressive
neuropathy associated with FAP leads to the inexorable loss in
ambulation - amongst other neurological deficits - with patients
becoming dependent on a cane or wheelchair as their disease advances,"
said
Patisiran Results Show Continued Evidence for Potential Halting of Neuropathy Progression and Mark First-Ever Evidence for Positive Effect on Nerve Regeneration
New results for patients (N=20) who reached the 18-month endpoint as of
a data cut off of September 22, 2015, showed that neuropathy impairment
scores were essentially unchanged from baseline values after 18 months
of treatment. Specifically, there was a mean increase in mNIS+7 of only
1.7 points, which compares favorably to an estimated increase in mNIS+7
of 22 to 26 points at 18 months based upon analysis of historical data
sets in untreated FAP patients with similar baseline characteristics
(
"With patisiran, we are pleased to see continued evidence for potential
halting of neuropathy progression after 18 months of treatment in the
ongoing OLE study. Indeed, we believe that the small 1.7-point increase
in mNIS+7 is encouraging, since mNIS+7 measured at 18 months is the
primary endpoint in our ongoing APOLLO Phase 3 trial with patisiran,"
said
"The increase in skin sweat gland nerve fiber density observed over 18
months in FAP patients treated with patisiran is an important finding,
as it is the first reported demonstration of potential peripheral nerve
regeneration in response to a therapeutic intervention in patients with
polyneuropathy. The potential clinical significance of this finding is
further underscored by a recent publication1 showing that a
lower sweat gland nerve fiber density in FAP patients is associated with
a greater degree of walking disability at the time of skin biopsy and
shorter time to loss of ambulation," said
Patisiran administration was also found to be generally well tolerated in FAP patients out to nearly two years, with minimal drug-related adverse events reported. The most common drug-related or possibly drug-related adverse events were flushing (25.9%) and infusion-related reactions (18.5%), which were both mild in severity and did not result in any discontinuations.
Sustained and Clamped TTR Knockdown out to 10 Months in Revusiran OLE Study Represents Longest Dosing Experience for a GalNAc-siRNA Conjugate Reported to Date
Initial results were presented for patients (N=18) who reached the
6-month endpoint as of a data transfer date of
"We are pleased to report initial data from our Phase 2 OLE trial with
revusiran, showing robust and sustained knockdown of serum TTR and a
favorable tolerability profile in the majority of patients with TTR
cardiomyopathy out to 10 months of treatment. Notably, the sustained and
clamped TTR knockdown observed represents the longest dosing experience
for a GalNAc-siRNA conjugate reported to date," said
Weekly dosing with revusiran appeared to be generally well tolerated in the majority of ATTR cardiac amyloidosis patients. Serious adverse events (SAEs) were observed in eight patients (32%), including one death due to infiltrative cardiomyopathy; none of the SAEs were deemed to be related to study drug. The majority of the adverse events (AEs) were mild or moderate in severity; injection site reactions (ISRs) were reported in 11 patients (44%). As previously reported, three patients discontinued due to recurrent localized reactions at the injection site or a diffuse rash; no further discontinuations due to ISRs have occurred.
Also at the meeting, Alnylam and collaborators presented initial results from the DISCOVERY study, a prospective, multi-center, observational study aimed at characterizing the frequency of TTR mutations in subjects with clinical features suggestive of cardiac amyloidosis. In over 600 patients suspected of having cardiac amyloidosis, TTR mutations were found in approximately 14% of patients. The primary pathogenic mutation was V122I (7% of total patients tested), with four other pathogenic mutations identified. Interestingly, two new, previously unreported TTR mutations were discovered. In addition, Alnylam and collaborators presented results from a natural history study of patients with Senile Systemic Amyloidosis (SSA), a form of cardiac amyloidosis caused by deposition of wild-type TTR in the heart.
Conference Call Information
Alnylam management will discuss
these data in a webcast conference call on Tuesday, November 3 at 7:00
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 70778772. A replay of
the call will be available beginning at 9:00 a.m. ET. To access the
replay, please dial 855-859-2056 (domestic) or 404-537-3406
(international), and refer to conference ID 70778772.
About the Patisiran Phase 2 OLE Study
The ongoing patisiran
OLE study is an open-label, multi-center trial designed to evaluate the
long-term safety and tolerability of patisiran administration in FAP
patients 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 Phase 3 APOLLO trial of patisiran in
FAP patients.
About the Revusiran Phase 2 OLE Study
The ongoing revusiran
OLE study is an open-label, multi-center trial designed to evaluate the
long-term safety and tolerability of revusiran administration in TTR
cardiac amyloidosis patients that were previously enrolled in a Phase 2
study. Patients receive a fixed subcutaneous dose of 500 mg of revusiran
once daily for five days, followed by once-weekly dosing. The study is
measuring a number of clinical endpoints every six months, including
effects on serum TTR and on mortality, hospitalization, and 6-minute
walk distance (6MWD). The changes in 6MWD and serum TTR from baseline to
18 months are the co-primary endpoints in the company's ENDEAVOUR Phase
3 trial of revusiran in FAC patients.
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 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 Genzyme will advance
the product in the ROW. In the case of revusiran, Alnylam and Genzyme
will co-develop/co-commercialize the product in
About Transthyretin-Mediated Amyloidosis
Transthyretin
(TTR)-mediated amyloidosis (ATTR amyloidosis) 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,
About LNP Technology
Alnylam has licenses to Tekmira LNP
intellectual property for use in RNAi therapeutic products using LNP
technology.
About GalNAc Conjugates and Enhanced Stabilization Chemistry
(ESC)-GalNAc Conjugates
GalNAc-siRNA conjugates are a
proprietary Alnylam delivery platform and are designed to achieve
targeted delivery of RNAi therapeutics to hepatocytes through uptake by
the asialoglycoprotein receptor. Alnylam's Enhanced Stabilization
Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing
with increased potency and durability, and a wide therapeutic index.
This delivery platform is being employed in nearly all of Alnylam's
pipeline programs, including programs in clinical development.
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 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
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 and revusiran,
the potential implications of reported results from its ongoing Phase 2
OLE studies of patisran and revusiran, expectations regarding the
reporting of additional clinical data from its ongoing Phase 2 OLE
studies of patisiran and revusiran, its expectations with respect to the
expected timing of regulatory filings, including its plan to file an NDA
for patisiran, assuming positive Phase 3 data, in 2017, 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 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.
1 Chao et al., Ann. Neurol., 2015;78:272-283.
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