– New Non-Human Primate (NHP) Data Show Potent
and Clamped C5 Knockdown of up to 98.7% and Inhibition of
Complement Activity of up to 96.8% with Monthly Subcutaneous Dosing
Regimen –
– ALN-CC5 Demonstrates Positive Efficacy in
Model of Membranous Nephropathy (MN), Highlighting Differentiated
Approach for Complement Inhibition in Setting of Renal Impairment
–
– Company Remains On Track to File Clinical
Trial Application (CTA) in Late 2014 and to Report Initial Clinical
Results in Mid-2015 –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi
therapeutics company, announced today new pre-clinical results with
ALN-CC5, a subcutaneously administered RNAi therapeutic targeting
complement component C5 in development for the treatment of
complement-mediated diseases. These results were presented at the
25th International Complement Workshop being held September 14 –
18, 2014, in Rio de Janeiro, Brazil. Amongst other results, new
positive data were reported from non-human primate (NHP) studies
evaluating a monthly subcutaneous ALN-CC5 dose regimen, and from a
rodent model of primary membranous nephropathy (MN) – a
complement-mediated progressive disease of the kidney with high
unmet need – where anti-C5 monoclonal antibody (mAb) therapy has
demonstrated incomplete effectiveness (Cunningham et al., J Am Soc
Nephrol 2005, 16:1214-1222). The company remains on track to file
its ALN-CC5 Clinical Trial Application (CTA) in late 2014 and
expects to present initial clinical results in mid-2015.
“These new results significantly strengthen our pre-clinical
data package with ALN-CC5. First, we have now demonstrated potent
and clamped C5 knockdown as well as robust inhibition of complement
activity in NHPs for up to 100 days with a subcutaneous, monthly
dosing regimen. We view these as promising results since there is
significant patient burden and cost associated with frequent
intravenous infusions of anti-C5 mAb therapy. A monthly
subcutaneous dose regimen could potentially offer patients a
significant improvement in the management of their disease,” said
Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief
Medical Officer of Alnylam. “We are also encouraged by our new data
in a rat model of membranous nephropathy, an area of high unmet
need. Specifically, ALN-CC5 administration resulted in a
significant reduction in proteinuria due to complement-mediated
disease activity in the kidney. We believe that these results
support a differentiated opportunity for RNAi-mediated C5 synthesis
inhibition with ALN-CC5 – as compared with serum C5 blockade with
mAbs – in settings with high-level proteinuria. We look forward to
filing a CTA for ALN-CC5 by the end of this year and expect to
present initial clinical results in mid-2015.”
“Primary membranous nephropathy is an idiopathic disease of the
kidney caused by immune complex formation and complement-mediated
damage of the glomerulus; progressive damage of the kidneys leads
to proteinuria and renal failure. MN is an orphan disease of high
unmet need afflicting 12,000 patients in the U.S. and EU. While
anti-C5 mAb therapy has shown great promise in a number of clinical
settings, clinical results in MN have been mixed, potentially due
to enhanced glomerular filtration of monoclonal antibodies in
patients with severe proteinuria. Accordingly, new therapeutic
strategies are needed for patients,” said David Salant, M.D.,
Chief, Section of Nephrology, and Professor of Medicine, Pathology
and Laboratory Medicine at Boston University School of Medicine. “I
am encouraged by these ALN-CC5 results showing a significant
reduction of proteinuria in a rat model of membranous nephropathy.
If these results extend to the clinic, I believe that ALN-CC5 could
represent an attractive therapeutic strategy and potential new
treatment option for patients with complement-mediated proteinuric
kidney diseases to prevent the development of renal
impairment.”
The new research findings included data on ALN-CC5 activity in
NHP and results in a rodent model of MN. New NHP studies were
performed to evaluate a monthly or twice-monthly subcutaneous
dosing regimen as compared with previously reported results with
weekly dosing. With either a monthly or twice-monthly dosing
regimen, ALN-CC5 administration at 5 mg/kg led to potent, clamped
knockdown of serum C5 of up to 98.7% (mean of 98.2 +/- 0.8%), 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. Results were presented for a period of 100 days from the
ongoing study. Based on human translational data for ESC-GalNAc
conjugates, dosing at less than 1 mg/kg and less than 1
mL/injection are expected to result in similar effects in humans.
The observed inhibitory effect toward complement activity in these
pre-clinical studies 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 mAb that binds to
serum C5 (Hillmen et al., N Engl J Med 2004, 350:552-559). In
addition, new pre-clinical results were reported for ALN-CC5 in the
rat passive Heymann nephritis model of MN (as described in Salant
et al., J Clin Invest 1980, 66:1339-1350). In the model, nephritis
is induced by administering a sheep anti-rat kidney fraction
antiserum that results in complement-mediated renal damage similar
to that reported in the human MN disease. As compared with placebo,
ALN-CC5 administration was associated with a statistically
significant (p < 0.05) reduction by over 70% in the proteinuria
associated with complement-mediated renal damage. These results
demonstrate pre-clinical efficacy for ALN-CC5 in the setting of
renal impairment, where clinical results with anti-C5 mAb therapy
have shown limited effects. Finally, as previously presented,
results in a mouse anti-collagen antibody induced arthritis (CAIA)
model showed that C5 knockdown with ALN-CC5 was as effective as an
anti-C5 mAb 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. New data presented today show that
RNAi-mediated C5 knockdown preserves joint histology and prevents
C3 deposition as effectively as inhibition with an anti-C5 mAb.
These results demonstrate that knockdown of liver-derived C5 is
sufficient to achieve a therapeutic effect, and show the absence of
a significant role for local complement production in this disease
model.
About ALN-CC5ALN-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, membranous nephropathy,
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 (mAb) 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 ConjugatesGalNAc-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 RNAiRNAi (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 PharmaceuticalsAlnylam 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 StatementsVarious 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 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.
Alnylam Pharmaceuticals, Inc.Cynthia Clayton,
617-551-8207Vice President, Investor Relations and Corporate
CommunicationsorMediaSpectrumLiz Bryan, 202-955-6222 x2526
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