Alnylam
Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics
company, announced today that it has initiated a Phase 1 study with
ALN-AT3, a subcutaneously administered RNAi therapeutic targeting
antithrombin (AT) for the treatment of hemophilia and rare bleeding
disorders (RBD). ALN-AT3 has demonstrated efficacy in animal models of
hemophilia, including in non-human primate models of induced hemophilia.
Moreover, pre-clinical studies of ALN-AT3 support a wide therapeutic
index in the hemophilia setting. ALN-AT3 is a key program in the
company’s “Alnylam 5x15” product strategy, which is aimed at advancing
multiple RNAi therapeutic genetic medicine programs into clinical
development. Alnylam recently announced that it expects to exceed its
original “Alnylam 5x15” guidance with six to seven genetic medicine
programs in clinical development by the end of 2015, including at least
two programs in Phase 3 and five to six programs that will have achieved
human proof-of-concept results supporting further development.
“Hemophilia and other rare bleeding disorders are characterized by
deficiencies in specific clotting factors that ultimately lead to
inadequate thrombin generation and a bleeding diathesis. ALN-AT3 is
aimed at correcting these bleeding disorders by knockdown of AT - an
endogenous anticoagulant - thus, increasing thrombin generation and
improving hemostasis,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice
President and Chief Medical Officer of Alnylam. “Our pre-clinical
results have demonstrated a promising activity profile for ALN-AT3 in
hemophilia animal models, and our results in non-human primate studies
are particularly encouraging in light of the excellent human translation
we have seen with RNAi therapeutics. In addition, we have shown in
preclinical studies that ALN-AT3 administration is associated with a
very wide therapeutic index in the hemophilia setting. We are excited to
be advancing this product candidate – notably, our second
GalNAc-conjugate program – into a Phase 1 trial, and look forward to
sharing initial data by the end of the year.”
The Phase 1 study is being conducted in the U.K. as a single- and
multi-dose, dose-escalation study consisting of two parts. Part A will
be a randomized, single-blind, placebo-controlled, single-dose,
dose-escalation study, enrolling up to 24 healthy volunteer subjects.
The primary objective of this part of the study is to evaluate the
safety and tolerability of a single low dose of ALN-AT3, with the
potential secondarily to show changes in AT plasma levels at
sub-pharmacologic doses. Part B of the study will be an open-label,
multi-dose, dose-escalation study enrolling up to 18 people with
moderate to severe hemophilia A or B. The primary objective of this part
of the study is to evaluate the safety and tolerability of multiple
doses of subcutaneously administered ALN-AT3 in hemophilia subjects.
Secondary objectives include assessment of clinical activity as
determined by knockdown of circulating AT levels and increase in
thrombin generation at pharmacologic doses of ALN-AT3. Thrombin
generation is known to be a biomarker for bleeding frequency and
severity in people with hemophilia (Dargaud, et al., Thromb Haemost;
93, 475-480 (2005)). The company expects to present initial data from
the Phase 1 study in late 2014.
“The unmet need for new therapeutic options to treat people with
hemophilia remains very high, particularly in those patients that
develop inhibitory antibodies to their replacement factor. Indeed,
availability of a safe and effective subcutaneously administered
therapeutic with a long duration of action would represent a marked
improvement over currently available approaches for prophylaxis,” said
Claude Negrier, M.D., head of the Hematology Department and director of
the Haemophilia Comprehensive Care Centre at Edouard Herriot University
Hospital in Lyon. “I continue to be encouraged by Alnylam’s
progress to date with ALN-AT3, including pre-clinical data demonstrating
correction of impaired thrombin generation in a non-human primate
‘inhibitor’ model. These results are particularly important since
clinical studies have demonstrated that thrombin generation correlates
strongly with bleeding phenotype; severe hemophilia patients have low
thrombin generation as compared to moderate and mild patients who have
significantly higher levels. I look forward to the continued
advancement of this innovative therapeutic candidate in clinical
studies.”
Alnylam presented pre-clinical
data at the XXIV Congress of the International Society on Thrombosis
and Haemostasis (ISTH) in July 2013. Results showed that ALN-AT3
achieves rapid, dose-dependent, and durable knockdown of AT in rodents
and non-human primates. In non-human primates, weekly subcutaneous doses
as low as 0.125 mg/kg led to a 50% knockdown of AT, while weekly doses
of 0.50 mg/kg led to approximately 90% knockdown. In addition, ALN-AT3
administration was found to normalize thrombin generation and improve
hemostasis in hemophilia mice and fully correct thrombin generation in a
non-human primate (NHP) hemophilia “inhibitor” model. More recently, at
the 55th Annual Meeting of the American Society of Hematology (ASH) in
December 2013, Alnylam presented pre-clinical
results showing that repeat administration of ALN-AT3 was well
tolerated in Hemophilia A (HA) mice, with no adverse findings up to dose
levels 200 times greater than those required to achieve 50% AT
knockdown. Results from these studies also demonstrated that ALN-AT3
administration achieved complete correction of the activated Partial
Thromboplastin Time (aPTT) - an ex vivo measure of blood
coagulation that is significantly prolonged in hemophilia - in HA mice.
Collectively, the company believes these data suggest a substantially
expanded therapeutic index of AT knockdown in the hemophilia disease
condition, and confirm the potential of ALN-AT3 to reset insufficient
thrombin generation and improve hemostasis in people with hemophilia.
In early 2014, Alnylam formed a broad multi-product, geographic alliance
with Genzyme, a Sanofi company, related to the global development and
commercialization of Alnylam’s “5x15” and future genetic medicine
programs. In the case of ALN-AT3, Genzyme will have the right to opt-in
after completion of human proof-of-concept to either co-develop
and co-promote with Alnylam in North America and Western Europe - with
Genzyme commercializing in the rest of world (ROW) - or to
commercialize the product in the ROW. In both circumstances, Alnylam
will lead and control development and commercialization in North America
and Western Europe. This transaction has been approved by the boards of
both companies, and is subject to customary closing conditions and
clearances under the Hart-Scott Rodino Antitrust Improvements Act.
About Hemophilia and Rare Bleeding Disorders
Hemophilias are hereditary disorders caused by genetic deficiencies of
various blood clotting factors, resulting in recurrent bleeds into
joints, muscles, and other major internal organs. Hemophilia A is
defined by loss-of-function mutations in Factor VIII, and there are
greater than 40,000 registered patients in the U.S. and E.U. Hemophilia
B, defined by loss-of-function mutations in Factor IX, affects greater
than 9,500 registered patients in the U.S. and E.U. Other Rare Bleeding
Disorders (RBD) are defined by congenital deficiencies of other blood
coagulation factors, including Factors II, V, VII, X, and XI, and there
are about 1,000 patients worldwide with a severe bleeding phenotype.
Standard treatment for hemophilia patients involves replacement of the
missing clotting factor either as prophylaxis or on-demand therapy.
However, as many as one third of people with severe hemophilia A will
develop an antibody to their replacement factor - a very serious
complication; these 'inhibitor' patients become refractory to standard
replacement therapy. There exists a small subset of hemophilia patients
who have co-inherited a prothrombotic mutation, such as Factor V Leiden,
antithrombin deficiency, protein C deficiency, and prothrombin G20210A.
Hemophilia patients that have co-inherited these prothrombotic mutations
are characterized as having a later onset of disease, lower risk of
bleeding, and reduced requirements for Factor VIII or Factor IX
treatment as part of their disease management. There exists a
significant need for novel therapeutics to treat hemophilia patients.
About Antithrombin (AT)
Antithrombin (AT, also known as “antithrombin III” and "SERPINC1") is a
liver expressed plasma protein and member of the "serpin" family of
proteins that acts as an important endogenous anticoagulant by
inactivating Factor Xa and thrombin. AT plays a key role in normal
hemostasis, which has evolved to balance the need to control blood loss
through clotting with the need to prevent pathologic thrombosis through
anticoagulation. In hemophilia, the loss of certain procoagulant factors
(Factor VIII and Factor IX, in the case of hemophilia A and B,
respectively) results in an imbalance of the hemostatic system toward a
bleeding phenotype. In contrast, in thrombophilia (e.g., Factor V
Leiden, protein C deficiency, antithrombin deficiency, amongst others),
certain mutations result in an imbalance in the hemostatic system toward
a thrombotic phenotype. Since co-inheritance of prothrombotic mutations
may ameliorate the clinical phenotype in hemophilia, inhibition of AT
defines a novel strategy for improving hemostasis.
About 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. Research
findings demonstrate potent and durable target gene silencing, as well
as a wide therapeutic index, with subcutaneously administered
GalNAc-siRNAs from multiple "Alnylam 5x15" programs.
About RNA Interference (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 5x15TM” 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 familial amyloidotic cardiomyopathy (FAC); 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
aminolevulinate 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 liver
disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the
treatment of beta-thalassemia and iron-overload disorders; and ALN-ANG,
an RNAi therapeutic for the treatment of genetic forms of mixed
hyperlipidemia and severe hypertriglyceridemia, amongst other programs.
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, The Medicines Company, and
Genzyme, a Sanofi company. In January 2014, Alnylam agreed to acquire
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, the 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.
About “Alnylam 5x15™” and Genetic Medicines
The “Alnylam 5x15” strategy, launched in January 2011, establishes a
path for development and commercialization of novel RNAi therapeutics as
genetic medicines. Alnylam’s genetic medicine programs are RNAi
therapeutics directed toward genetically defined targets for the
treatment of diseases with high unmet medical need. These programs share
several key characteristics including: a genetically defined target and
disease expressed in the liver; the potential to have a major impact in
a high unmet need population; the ability to leverage the existing
Alnylam RNAi platform with clinically proven delivery to the liver; the
opportunity to monitor an early biomarker in Phase 1 clinical trials for
human proof of concept; and the existence of clinically relevant
endpoints for the filing of a new drug application (NDA) with a focused
patient database and possible accelerated paths for commercialization.
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 “Alnylam 5x15” programs
include: patisiran (ALN-TTR02), an intravenously delivered RNAi
therapeutic targeting transthyretin (TTR) in development for the
treatment of TTR-mediated amyloidosis (ATTR) in patients with familial
amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered
RNAi therapeutic targeting TTR in development for the treatment of ATTR
in patients with familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an
RNAi therapeutic targeting antithrombin (AT) in development for the
treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an
RNAi therapeutic targeting complement component C5 in development for
the treatment of complement-mediated diseases; ALN-AS1, an RNAi
therapeutic targeting aminolevulinate synthase-1 (ALAS-1) in development
for the treatment of porphyria including acute intermittent porphyria
(AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 in development for
the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic
targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency
liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 in
development for the treatment of beta-thalassemia and iron-overload
disorders; and ALN-ANG, an RNAi therapeutic for the treatment of genetic
forms of mixed hyperlipidemia and severe hypertriglyceridemia, amongst
other programs. In 2014, Alnylam and Genzyme, a Sanofi company, formed a
multi-product geographic alliance on Alnylam’s genetic medicine
programs. 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.
Alnylam Forward-Looking Statements
Various statements in this press release concerning Alnylam’s future
expectations, plans and prospects, including without limitation,
Alnylam’s expectations regarding its “Alnylam 5x15” product strategy,
Alnylam’s views with respect to the potential for RNAi therapeutics,
including ALN-AT3, and its expectations regarding reporting data from
its ongoing and planned clinical studies, including its studies for
ALN-AT3, 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 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