Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has initiated its DISCOVERY trial, a
screening study examining the prevalence of transthyretin (TTR)
mutations in patients suspected of having cardiac amyloidosis. With this
study, Alnylam aims to identify and facilitate the diagnosis of familial
amyloidotic cardiomyopathy (FAC). Alnylam is advancing ALN-TTRsc, an
investigational candidate targeting TTR for the treatment of patients
with TTR cardiac amyloidosis, including FAC – which is caused by
mutations in TTR – and senile systemic amyloidosis (SSA) – which is
caused by idiopathic amyloid deposition of wild-type TTR in the heart.
“We believe that ALN-TTRsc has the potential to be an important
therapeutic for the treatment of FAC – an underdiagnosed disease with
significant morbidity and mortality, and no approved therapies.
With the initiation of DISCOVERY, we aim to identify and facilitate the
diagnosis of FAC by screening patients suspected of having cardiac
amyloidosis for the presence of TTR mutations,” said Pritesh Gandhi,
Vice President, Medical Affairs at Alnylam. “We are excited about the
potential for ALN-TTRsc for the treatment of patients with TTR cardiac
amyloidosis. Our clinical data to date with ALN-TTRsc have demonstrated
robust knockdown of circulating TTR – the disease-causing gene – of up
to 94%, with a very encouraging safety profile. We believe that
ALN-TTRsc holds promise as a potential new therapeutic option for
patients with TTR-mediated cardiac amyloidosis.”
DISCOVERY is a prospective, multi-center screening study designed to
enroll up to 1,000 patients suspected of having cardiac amyloidosis. The
study’s primary objective is to characterize the frequency of TTR
mutations. The study’s secondary objective is to further characterize
disease features in patients found to have a TTR mutation. Results from
DISCOVERY are expected to determine the frequency of TTR mutations in
patients with clinical and/or radiological findings of cardiac
amyloidosis and identify FAC patients who may be eligible for clinical
trials of novel investigational therapeutics such as ALN-TTRsc.
TTR-mediated amyloidosis (ATTR) is an inherited, progressively
debilitating, and often fatal disease caused by mutations in the TTR
gene. These mutations cause misfolding of the protein and the formation
of amyloid fibrils that deposit in tissues. One of the clinical
manifestations of ATTR is FAC, in which TTR deposits occur primarily in
heart tissue, resulting in cardiomyopathy. Amyloid deposition 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. FAC is an underdiagnosed disease; while the true prevalence is
unknown, FAC is estimated to affect at least 40,000 people worldwide. It
is predominantly caused by the V122I mutation which is found in up to 4%
of the African American population. It is believed that FAC is an
important cause of cardiac morbidity and mortality in African Americans
over the age of 65.
“FAC is under recognized, and it is our hope that the DISCOVERY study
will raise awareness amongst patients and health care professionals of
this debilitating and progressive disease,” said Herman Taylor, M.D.,
Endowed Professor and Director, Cardiovascular Research Institute at
Morehouse School of Medicine. “With accurate and earlier diagnosis of
FAC, we may have the potential to make an impact in the lives of these
patients.”
Alnylam is currently conducting a Phase 2 study of ALN-TTRsc aimed at
evaluating the safety, tolerability, pharmacodynamic and preliminary
clinical activity of ALN-TTRsc in patients with FAC and SSA. The Phase 2
trial is an open-label, multi-dose study of ALN-TTRsc, designed to
enroll approximately 25 TTR cardiac amyloidosis patients with FAC or
SSA. The primary objective of the study is to evaluate the safety and
tolerability of ALN-TTRsc. The secondary objectives are to assess the
pharmacodynamic effect of ALN-TTRsc on serum levels of TTR and
characterize the pharmacokinetics of ALN-TTRsc. In addition, a number of
exploratory clinical endpoint data are being collected. Alnylam expects
to present initial results from the Phase 2 study at a meeting to be
held during the American Heart Association meeting in November. Patients
completing the Phase 2 trial may be eligible to participate in an
open-label extension (OLE) study for further assessment of general
tolerability and clinical activity with long-term dosing; the ALN-TTRsc
Phase 2 OLE study is on track to be initiated in the coming weeks.
Alnylam expects to begin a Phase 3 trial in TTR cardiac amyloidosis
patients by the end of 2014. ALN-TTRsc employs an siRNA targeting
wild-type and all mutant forms of TTR and utilizes our proprietary
GalNAc-conjugate delivery platform which enables subcutaneous delivery
of our RNAi therapeutics with a wide therapeutic index.
About ATTR
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 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, durability, and a wide therapeutic index, and is
being employed in several of Alnylam’s genetic medicine 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 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 ALN-TTRsc for the
treatment of FAC and the DISCOVERY trial, its expectations with respect
to timing of regulatory filings and the reporting of initial data from a
clinical trial for ALN-TTRsc, the potential therapeutic opportunities
for ALN-TTRsc, its expectations regarding its “Alnylam 5x15” product
strategy, and its plans regarding commercialization of RNAi
therapeutics, including ALN-TTRsc, 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 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.
Copyright Business Wire 2014