CAMBRIDGE, MA, USA I September 16, 2014 I 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.
“a major scientific breakthrough that happens once every decade or so”
“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-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 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 5×15™” 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 5×15” 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.
SOURCE: Alnylam Pharmaceuticals
