Alnylam Reports Positive Initial Clinical Results for ALN-CC5, an Investigational RNAi Therapeutic Targeting Complement Component C5 for the Treatment of Complement-Mediated Diseases

CAMBRIDGE, Mass.--Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, today announced initial positive results from its ongoing Phase 1/2 clinical trial with ALN-CC5, an investigational RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. These new clinical dataare being presented at the 20th Congress of the European Hematology Association (EHA) held June 11 – 14 in Vienna, Austria. Initial study results from 12 healthy volunteer subjects showed that single subcutaneous dose administration of ALN-CC5 resulted in potent, dose-dependent, durable, and statistically significant knockdown of serum C5 of up to 96%. In addition, single dose administration of ALN-CC5 achieved inhibition of serum complement activity of up to 92%, including an up to 61% inhibition of serum hemolytic activity. Further, ALN-CC5 has been found to be generally well tolerated to date. The company is continuing to dose healthy volunteer subjects in both the single ascending dose (SAD) and multiple ascending dose (MAD) stages of the study, and expects to present additional data from the trial in late 2015. Consistent with previous guidance, the company also plans to begin enrolling patients with paroxysmal nocturnal hemoglobinuria (PNH) into the trial by the end of 2015.

"We believe that ALN-CC5 – as a first-in-class C5 synthesis inhibitor – represents an innovative, differentiated, and well-validated approach for the treatment of complement-mediated diseases. Our initial single-dose data from our ongoing Phase 1/2 clinical trial demonstrate clinical activity for ALN-CC5 with an up to 96% knockdown of serum C5 and up to 92% inhibition of serum complement activity, including an up to 61% inhibition of serum hemolytic activity. We believe these are encouraging initial proof-of-concept results, and we expect – based on our experience in non-human primates, or NHPs – that this level of single-dose activity should meet our target profile as we progress in multi-dose cohorts. In addition, we are encouraged that ALN-CC5 has been generally well tolerated to date," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer at Alnylam. "ALN-CC5 now becomes our fourth RNAi therapeutic program to demonstrate clinical activity and excellent translation from NHP to humans, continuing to highlight the reproducible and modular features of our RNAi therapeutics platform. Indeed, in the case of ALN-CC5, we appear to observe a three- to five-fold enhanced potency in humans compared with NHPs. We are now advancing ALN-CC5 in the multi-dose phase of the Phase 1/2 study, and look forward to reporting additional data from healthy volunteer subjects in this trial in late 2015. Furthermore, we remain on track to begin enrolling PNH patients in the trial by the end of this year."

"Significant progress has been made in the treatment of complement-mediated diseases, including PNH, but we continually strive for even further improvements for our patients. I believe that a new medicine to treat excessive complement activity that could be given by infrequent, subcutaneous administration would be a welcome addition to the treatment landscape," said Anita Hill, M.D., Ph.D., MRCP, FRCPath, Consultant Haematologist for Leeds Teaching Hospitals NHS Trust, UK, and Lead Clinician for the National PNH Service in England. "I am encouraged by the emerging initial single dose data from this Phase 1/2 trial, and I look forward to the continued clinical development of this novel therapeutic approach."

The Phase 1/2 trial of ALN-CC5 is being conducted in the U.K., in three parts. Parts A and B are 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. To mitigate against the risk of Neisseria meningitides, subjects received meningococcal vaccination and oral ciprofloxacin. Subjects in Part A are receiving a single subcutaneous administration of ALN-CC5 at fixed doses of 50, 200, 400, or 600 mg. Subjects in Part B are receiving multiple ascending doses of ALN-CC5, at a fixed dose level of 100 mg in the first cohort, administered once weekly for up to five weeks; bi-weekly and monthly dosing schedules may also be evaluated. 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. Additional objectives include evaluation of clinical activity for ALN-CC5 as measured by knockdown of serum C5 and inhibition of serum complement activity, including measurements of complement alternative pathway (CAP) and complement classical pathway (CCP) activity by ELISA and serum hemolytic activity toward sheep erythrocytes. Part C will be an open-label, multi-dose study in up to eight patients with PNH, and will assess safety, tolerability, and clinical activity of ALN-CC5, administered as multiple subcutaneous doses for up to 13 weeks. 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 endogenous red blood cell hemolysis.

Initial Phase 1/2 study results from 12 healthy volunteer subjects are being presented in an oral presentation at EHA and include all available data out to as long as 98 days from the 50, 200, and 400 mg SAD cohorts. Safety data are as of a data cut-off date of May 26, 2015, and clinical activity data are as of a data cut-off date of June 4, 2015. In the ongoing study, single doses of ALN-CC5 were found to be generally well tolerated, with no serious adverse events (including infections), study discontinuations, or significant clinical laboratory findings reported to date.

The key additional objectives of the study were to evaluate the clinical activity of ALN-CC5 as measured toward C5 knockdown and effects on serum complement activity, including serum hemolytic activity. Single subcutaneous doses of ALN-CC5 resulted in potent, dose-dependent, statistically significant, and highly durable knockdown of serum C5 demonstrating human proof-of-concept. Specifically, a single ALN-CC5 dose resulted in an up to 96% knockdown of serum C5. A mean maximum knockdown of 94 +/- 2.0% (p less than 0.003 compared with placebo) was achieved in the 400 mg SAD cohort. Nadir C5 knockdown for all treated subjects was achieved between days 28 and 70 and effects were durable over a period of months. For example, an up to 94% knockdown of serum C5 was achieved at day 70 after a single dose of drug. The company believes that the durable and clamped nature of C5 knockdown could potentially support a once-monthly, fixed dose subcutaneous regimen. Finally, the level of C5 knockdown in humans after single dose administration was found to correlate closely (r2=0.83, p less than 0.0001) with corresponding single dose data in non-human primates. From these data, there appears to be an approximately three- to five-fold increased potency for ALN-CC5 in humans as compared with NHPs.

In addition, single dose administration of ALN-CC5 was associated with potent, dose-dependent, and durable inhibitory effects toward complement activity. In particular, single dose ALN-CC5 administration resulted in an up to 87% inhibition of CAP activity (mean maximum 75 ± 7.2%), an up to 92% inhibition of CCP activity (mean maximum 82 ± 6.1%), and an up to 61% inhibition of serum hemolytic activity (mean maximum 43 ± 9.1%). These effects on complement activity were statistically significant (p less than 0.005 compared with placebo). In addition, the inhibitory effects of ALN-CC5 toward complement activity were found to be highly durable. For example, an up to 82% inhibition of CCP activity was observed at day 70 following a single dose administration. As seen in NHP studies with ALN-CC5 and consistent with all other Alnylam GalNAc-conjugate programs, further increases in inhibitory effects toward serum complement activity are expected with multi-dose administration. As reported at the American Society of Hematology meeting in December 2014, results in NHPs showed that a twice-monthly subcutaneous dose regimen of ALN-CC5 at 5 mg/kg achieved inhibition of serum hemolytic activity of over 80%. In contrast, additional NHP studies show that a single dose of ALN-CC5 at 5 mg/kg (comparable to the 400 mg fixed dose in the Phase 1/2 study) achieved a 49 ± 4.5% mean maximal inhibition of serum hemolytic activity. The company expects to present initial multi-dose data from the ongoing Phase 1/2 study in late 2015.

Genzyme Alliance

In January 2014, Alnylam and Genzyme, a Sanofi company, formed an alliance to accelerate and expand the development and commercialization of RNAi therapeutics across the world. The alliance is structured as a multi-product geographic alliance in the field of rare diseases. Alnylam retains product rights in North America and Western Europe, while Genzyme obtained the right to access certain programs in Alnylam's current and future Genetic Medicines pipeline, including ALN-CC5, in the rest of the world. In certain defined instances, Genzyme has co-development/co-commercialization and/or global product rights. Genzyme's rights are structured as an opt-in that is triggered upon achievement of human proof-of-principle.

Conference Call Information

Alnylam management will discuss these new Phase 1/2 clinical results with ALN-CC5 for the treatment of complement-mediated diseases in a webcast conference call on Friday, June 12 at 7:00 a.m. ET. A slide presentation will also be available on the Investors page of the company's website,, to accompany the conference call. To access the call, please dial 877-312-7507 (domestic) or 631-813-4828 (international) five minutes prior to the start time and refer to conference ID 64369692. A replay of the call will be available beginning at 10:00 a.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 64369692.

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 and durability, and a wide therapeutic index. This delivery platform is being employed in nearly all of Alnylam's pipeline 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. Alnylam's pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs – including 4 in late stages of development – across its 3 STArs. The company's demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. 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 about Alnylam's pipeline of investigational RNAi therapeutics, please visit

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, expectations regarding the reporting of data from clinical studies, in particular the ongoing Phase 1/2 clinical trial of ALN-CC5, expectations regarding the durability of ALN-CC5, the clinical activity that could be achieved with multiple doses of ALN-CC5 and the market opportunity for ALN-CC5, expectations regarding its STAr pipeline growth 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 be replicated or continue to occur in other subjects or in additional studies or otherwise 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.