Alnylam Files Clinical Trial Application (CTA) for ALN-CC5, an RNAi Therapeutic Targeting Complement C5 in Development for the Treatment of Complement-Mediated Diseases

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today that it has filed a Clinical Trial Application (CTA) with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a Phase 1/2 clinical trial with ALN-CC5, a subcutaneously administered investigational RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. As per the CTA filing, the intended clinical study of ALN-CC5 will be performed in normal human volunteers and, then, in patients with paroxysmal nocturnal hemoglobinuria (PNH). Following approval of the CTA, the company expects to initiate the Phase 1/2 study in early 2015, with initial data expected to be reported in mid-2015. In addition, Alnylam scientists presented new pre-clinical data at the 56th Annual Meeting of the American Society of Hematology (ASH). Amongst other reported research findings, new data showed an up to 99.2% knockdown of serum C5 and up to 96.2% inhibition of serum hemolytic activity in non-human primates (NHPs) with continued dosing for over seven months.

“As a first-in-class C5 synthesis inhibitor, we believe that ALN-CC5 represents an innovative, differentiated, and well-validated approach for the treatment of complement-mediated diseases. New non-human primate data presented at ASH demonstrate the ability of ALN-CC5 to clamp down levels of serum C5, with knockdown of up to 99.2% and sustained effects with continuous dosing for over seven months. This level of knockdown was associated with a greater than 90% inhibition of hemolytic activity, exceeding the 80% threshold established by existing therapies to be associated with clinical benefit. Based on human translational data for our ESC-GalNAc conjugates, we believe that similar results could be achieved in humans using a low-dose, low-volume monthly subcutaneous dosing regimen for ALN-CC5. Accordingly, we’re very excited to advance this investigational RNAi therapeutic to clinical stages with this new CTA filing,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “ALN-CC5 now becomes our fourth RNAi therapeutic that utilizes our proprietary, clinically validated GalNAc conjugate delivery platform to enter a clinical development stage, and the third that utilizes our optimized ESC-GalNAc technology. We look forward to the continued advancement of ALN-CC5, including the start of our Phase 1/2 clinical trial in healthy volunteers and patients with PNH in the coming months, with initial data expected in mid-2015.”

“Although significant progress has been made in the treatment of complement-mediated diseases, including paroxysmal nocturnal hemoglobinuria, there is scope for further significant improvements. Patients would welcome an infrequent subcutaneous dosing option, and the continuous inhibition of complement activity for all patients would provide improved management of these diseases,” said Peter Hillmen, MB ChB, F.R.C.P., F.R.C.Path., Ph.D., Professor of Experimental Haematology and Honorary Consultant Haematologist at Leeds Teaching Hospitals NHS Trust, U.K. “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 PNH and other complement-mediated diseases.”

ALN-CC5 is a subcutaneously administered investigational RNAi therapeutic that utilizes Alnylam’s proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugate delivery platform. ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor, and enable subcutaneous dosing with increased potency and durability and a wide therapeutic index. As per the filed CTA, the Phase 1/2 trial of ALN-CC5 will be conducted in three parts. Parts A and B will be randomized (3:1, drug:placebo), double-blind, placebo-controlled, single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 60 healthy adult volunteers. The primary objective of these first two parts of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-CC5. Secondary objectives include evaluation of clinical activity for ALN-CC5 as measured toward knockdown of serum C5 and inhibition of serum complement activity. Part C will be an open-label, multi-dose study in up to eight patients with PNH, and will assess safety, tolerability, PK/PD, and clinical activity of multiple doses of ALN-CC5 in PNH patients. In addition, this part of the study will include an exploratory evaluation of the effects of ALN-CC5 on levels of lactate dehydrogenase (LDH), a measure of red blood cell hemolysis.

In a poster presentation at ASH, Alnylam scientists presented new data showing that twice-monthly or monthly, subcutaneous doses of ALN-CC5 led to potent and clamped knockdown of serum C5 of up to 99.2% (mean 98.4 ± 0.7%) in NHPs. With continued dosing, this level of knockdown was sustained for over seven months, the last time point measured in the ongoing study. In addition, data showed an up to 96.9% inhibition of alternative pathway (CAP) activity (mean 95.1 ± 0.93%), and up to 96.2% inhibition of hemolysis (mean 88.0 ± 6.1%) with twice-monthly dosing. Based on human translational data for ESC-GalNAc conjugates, the company believes that this level of activity can be achieved in humans using a low-dose (less than 1 mg/kg), low-volume (less than 1 mL) monthly subcutaneous dosing regimen. Further, new pre-clinical results were reported for a C5 GalNAc-siRNA in the rat passive Heymann nephritis model of membranous nephropathy (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. Administration of a C5-targeted GalNAc-siRNA resulted in a similar reduction in urinary albumin as achieved with complete complement depletion by administration of cobra venom factor (CVF) and prevented the deposition of the C5b-9 complex in the kidney glomeruli. Further, knockdown of C5 was shown to be specific to the liver, with no effect on expression of C5 mRNA in the kidney. These results demonstrate that knockdown of liver-expressed C5 results in disease modifying effects in the MN model, while local expression of C5 plays no significant role. In addition, the company presented results from the non-clinical toxicology studies with ALN-CC5 that enabled the CTA filing. Data from 4-week GLP toxicology studies in NHPs and rats confirmed a wide therapeutic index, with a No Observed Adverse Event Level (NOAEL) greater than 100 mg/kg in NHPs and greater than 50 mg/kg in rats, the highest doses tested in each species. In ongoing 13-week GLP toxicology studies in NHPs and rats, there have been no in-life findings to date at all test doses.

About ALN-CC5

ALN-CC5 is an investigational 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 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) targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc) 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 targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5 targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-TMP targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting apolipoprotein C-3 (apoC3) for the treatment of hypertriglyceridemia; ALN-AGT targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); ALN-HDV targeting the hepatitis delta virus (HDV) genome for the treatment of HDV infection; ALN-PDL targeting programmed death ligand 1 (PD-L1) for the treatment of chronic liver infections; 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 revusiran 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 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, the design and timing of clinical studies, the expected timing for reporting of data from clinical studies, its expectations regarding the potency and therapeutic index of GalNAc-siRNA conjugates, including Enhanced Stabilization Chemistry (ESC)-GalNAc conjugates, its expectations regarding its “Alnylam 5x15” product strategy, and its plans regarding commercialization of RNAi therapeutics, 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.