Alnylam Presents New Pre-Clinical Data with ALN-CC5, a Subcutaneously Administered RNAi Therapeutic Targeting Complement Component C5 in Development for the Treatment of Complement-Mediated Diseases
Sep 16, 2014
- 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 -
"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
"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
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-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, 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 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 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
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 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
Vice
President, Investor Relations and Corporate Communications
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