Alnylam
Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics
company, announced today new pre-clinical results with its Development
Candidate (DC) for ALN-CC5, a subcutaneously administered
investigational RNAi therapeutic targeting complement component C5 in
development for the treatment of complement-mediated diseases. These
results were presented at the 7th International Conference on
Complement Therapeutics being held June 6 – 11, 2014, in Olympia,
Greece. New
data demonstrate that ALN-CC5 led to an up to 98.7% knockdown of
serum C5 and an up to 96.8% inhibition of complement activity in
non-human primates (NHP) with weekly subcutaneous dose administration.
Alnylam believes that ALN-CC5 – part of the company’s “Alnylam 5x15”
product strategy – could represent a novel approach for the treatment of
complement-mediated diseases, with a potentially competitive profile
compared with intravenously administered anti-C5 monoclonal antibody
therapy. ALN-CC5 utilizes the company’s Enhanced Stabilization Chemistry
(ESC)-GalNAc-conjugate technology, which enables subcutaneous dosing
with increased potency and durability and a wide therapeutic index.
ESC-GalNAc conjugates are a clinically validated platform based on recent
preliminary Phase 1 study results from the company's ALN-AT3 program
in development for the treatment of hemophilia. The company is on track
to file its ALN-CC5 IND or IND equivalent in late 2014, and is now
guiding that it expects to present initial clinical results in mid-2015.
“These new pre-clinical data with our recently selected Development
Candidate for ALN-CC5 demonstrate potent C5 knockdown and robust
inhibition of complement activity in NHPs with weekly subcutaneous
dosing. We believe that these are promising results since an over 80%
inhibition of complement activity has been shown to be associated with
clinical benefit. Further, comparative studies in a mouse arthritis
model showed ALN-CC5 to be as effective as an anti-C5 antibody in
reducing disease activity, demonstrating a necessary and sufficient role
for liver-expressed C5 in localized complement-mediated disease,” said
Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical
Officer of Alnylam. “ALN-CC5 employs our ESC-GalNAc-siRNA conjugate
platform that has recently been validated in preliminary data from human
studies and where we observe a further ten-fold increase in potency as
compared with studies in NHPs. Accordingly, we believe we are seeing the
emergence of a compelling therapeutic profile for ALN-CC5, which could
make it competitive with anti-C5 monoclonal antibody therapy. We look
forward to filing an IND or IND-equivalent by the end of this year, and
are now guiding that we expect to present initial clinical results in
mid-2015.”
In a presentation titled “RNAi-Mediated C5 Silencing for Complement
Inhibition,” Alnylam scientists presented new pre-clinical data with
ALN-CC5. In NHP studies, weekly subcutaneous doses of ALN-CC5 at 5 mg/kg
led to serum C5 knockdown of up to 98.7% (mean of 97.9 +/- 0.7%), as
well as inhibition of complement activity of up to 91.3% (mean of 84.9
+/- 7.1%) by serum hemolytic activity assay and up to 96.8% (mean of
94.6. +/- 1.8%) by complement alternative pathway (CAP) ELISA. Based on
early human translational data for ESC-GalNAc conjugates, weekly dosing
at less than 1 mg/kg is expected to result in similar effects in humans.
The observed inhibitory effect toward complement activity is notable
since an over 80% level of complement inhibition has been shown to yield
clinical benefit in paroxysmal nocturnal hemoglobinuria (PNH) based on
published data with eculizumab, an intravenously administered monoclonal
antibody that binds to serum C5 (Hillmen et al., N Engl J Med 2004,
350:552-559). The company is continuing dosing in the primate study
to explore twice-monthly and once-monthly subcutaneous dosing regimens,
and expects to report additional pre-clinical data later this year. In
addition, in vitro reconstitution studies in human serum were
performed to evaluate the potential anti-C5 monoclonal antibody (anti-C5
mAb) dose sparing effects of ALN-CC5. Specifically, in serum in which C5
was reduced to 5% of normal (i.e., a level corresponding to 95% C5
knockdown with RNAi), the concentration of anti-C5 mAb required to
achieve 80% inhibition of hemolytic activity was found to be reduced
approximately 20-fold. This lower concentration requirement could reduce
frequent dose requirements and the high costs of anti-C5 antibody
therapy. Finally, results were presented from a study comparing
subcutaneous doses of ALN-CC5 to a high, intravenously administered dose
of an anti-C5 mAb in a mouse anti-collagen antibody induced arthritis
(CAIA) model. Results showed that C5 knockdown with ALN-CC5 was as
effective as the anti-C5 antibody in reducing clinical disease activity,
with both treatments resulting in an approximately 80% reduction in
clinical disease activity score. Moreover, ALN-CC5 maintained its
knockdown effect toward C5 following lipopolysaccharide (LPS) treatment,
showing the ability of RNAi to blunt induction of C5 as part of an
inflammatory response. These results demonstrate that knockdown of
liver-derived C5 should be fully sufficient to achieve a therapeutic
effect, and show the absence of a significant role for local complement
production in this disease model.
“The complement system evolved as part of the innate immune system and
plays a key role in host defenses. Dysregulation of the complement
system can lead to serious complications in a wide range of human
diseases including paroxysmal nocturnal hemoglobinuria, atypical
hemolytic uremic syndrome, and neuromyelitis optica,” said Anita Hill,
MBChB (Hons), MRCP, FRCPath, Ph.D., Consultant Haematologist for Leeds
Teaching Hospitals NHS Trust, UK, and Honorary Senior Lecturer at the
University of Leeds. “I am very encouraged by these pre-clinical data
showing potent and durable knockdown of serum C5 with robust inhibition
of complement activity using a subcutaneously administered RNAi
therapeutic. If these results can be extended to the clinical setting, I
believe that they could represent an attractive therapeutic strategy and
potential new treatment option for patients with complement-mediated
diseases.”
About ALN-CC5
ALN-CC5 is an RNAi therapeutic targeting the C5 component of the
complement pathway for the treatment of complement-mediated diseases.
The complement system plays a central role in immunity as a protective
mechanism for host defense, but its dysregulation results in
life-threatening complications in a broad range of human diseases
including paroxysmal nocturnal hemoglobinuria (PNH), atypical
hemolytic-uremic syndrome (aHUS), myasthenia gravis, neuromyelitis
optica, amongst others. Complement component C5, which is predominantly
expressed in liver cells, is a genetically and clinically validated
target; loss of function human mutations are associated with an
attenuated immune response against certain infections and intravenous
anti-C5 monoclonal antibody therapy has demonstrated clinical activity
and tolerability in a number of complement-mediated diseases. A
subcutaneously administered RNAi therapeutic that silences C5 represents
a novel approach to the treatment of complement-mediated diseases.
ALN-CC5 utilizes Alnylam's ESC-GalNAc conjugate technology, which
enables subcutaneous dosing with increased potency and durability and a
wide therapeutic index.
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
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 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 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-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; 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.
Alnylam is also developing ALN-HBV, an RNAi therapeutic targeting the
hepatitis B virus (HBV) genome for the treatment of HBV infection. 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 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, 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 TTR cardiac amyloidosis, including familial amyloidotic
cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); 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 aminolevulinic acid synthase-1 (ALAS-1) in
development for the treatment of hepatic porphyrias 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-associated liver disease; ALN-TMP, an RNAi
therapeutic targeting TMPRSS6 in development 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, a subcutaneously administered RNAi therapeutic targeting
apolipoprotein C-III (apoCIII) for the treatment of
hypertriglyceridemia; and other programs yet to be disclosed. 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 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-CC5 for the treatment of complement mediated diseases, its
expectations with respect to timing of regulatory filings and the
reporting of initial data from a clinical trial for ALN-CC5, the
potential therapeutic opportunities for ALN-CC5, its expectations
regarding its “Alnylam 5x15” product strategy, and its plans regarding
commercialization of RNAi therapeutics, including ALN-CC5, 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.
Copyright Business Wire 2014