Alnylam Reports that ALN-CC5 Achieves Up to 99 Percent Knockdown of Serum C5 and Up to 98 Percent Inhibition of Serum Hemolytic Activity with Durability Supportive of Once Monthly and Possibly Once Quarterly Subcutaneous Dose Regimen

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. Keppra (Levetiracetam) with free prescription (Nasdaq:ALNY), the leading RNAi therapeutics company, announced today positive interim results from its ongoing Phase 1/2 clinical study with ALN-CC5, an investigational RNAi therapeutic targeting complement C5 for the treatment of complement mediated diseases. Buy Motrin (Ibuprofen) with free prescription These new clinical data were presented at the American Society of Hematology (ASH) 2015 Annual Meeting, held December 5 – 8 in Orlando, Florida. Buy Plavix (Clopidogrel) with free prescription New results show that ALN-CC5 achieved up to 99 percent knockdown of serum C5 and up to 98 percent inhibition of serum hemolytic activity, an assay for complement activity. About Intal with no Rx In addition, ALN-CC5 administration resulted in low levels of residual C5, which – based on comparisons from separate studies – were at or below the estimated levels of free C5 observed at therapeutic doses of eculizumab, an approved anti-C5 monoclonal antibody. Cardizem (Diltiazem) without Rx The effects of ALN-CC5 were also found to be highly durable, with C5 knockdown and complement inhibition results supporting a once monthly and possibly a once quarterly subcutaneous dose regimen. Buy Horse Chestnut online Importantly, ALN-CC5 was shown to be generally well tolerated, with no clinically significant, drug-related adverse events to date. http://doctor-answers.blogspot.com/ Consistent with previous guidance, the company remains on track to initiate dosing by year’s end in Part C of the Phase 1/2 study, which is being conducted in patients with paroxysmal nocturnal hemoglobinuria (PNH), and expects to present initial results from this part of the study in mid-2016. “We believe that these new ALN-CC5 results meet our goal of achieving both inhibition of serum hemolytic activity at the 80% target level and highly robust knockdown of serum C5 to residual levels at or below those estimated – in separate studies –for free C5 at therapeutic doses of eculizumab. We’re also very pleased with the consistency and durability of ALN-CC5 clinical activity, which we believe supports at least a once monthly, and possibly a once quarterly subcutaneous dose regimen,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. “With these data in hand, we’re now transitioning our study to PNH patients, and plan to initiate dosing by the end of this year. We look forward to presenting initial results from this new stage of our Phase 1/2 study, including effects of ALN-CC5 on levels of lactate dehydrogenase (LDH) – a disease marker of endogenous red blood cell hemolysis – in mid-2016.” “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. In this regard, I believe that a new medicine providing both a consistent level of inhibition of complement activity and infrequent subcutaneous dosing would be a welcome addition to the treatment landscape,” 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 encouraged by the data from this ongoing Phase 1/2 trial, and, in particular, the results showing very low residual levels of serum C5. If these results can be duplicated in patients with PNH, I believe ALN-CC5 has the potential to offer a novel therapeutic option for these patients.” New data were presented in a poster at ASH, and include updated data (N=20) from the single ascending dose (SAD) cohorts, as well as initial data (N=12) from multiple ascending dose (MAD) cohorts. Safety data are as of a cutoff date of October 19, 2015, and clinical activity data are as of a cutoff date of up to November 6, 2015. Alnylam and collaborators will discuss these new clinical results with ALN-CC5 at the company’s upcoming R&D Day, to be held on Thursday, December 10, 2015, at the Sofitel New York in New York City. This event will be webcast live on the Investors section of the company’s website, .alnylam.com. An audio replay of the event will be available on the Alnylam website approximately 90 minutes after the event. Preliminary Phase 1/2 Study Clinical Activity Results In the SAD cohorts (N=20), ALN-CC5 achieved potent and dose-dependent knockdown of serum C5 of up to 99 percent, with a mean maximum knockdown of 98 ± 0.3 percent (p less than 0.01 compared with placebo) in the top dose cohort. After a single dose, nadir levels of residual C5 as low as 1.1 microgram/milliliter (mcg/mL) were achieved. This level of residual C5 in healthy volunteers is at or below the levels of free C5 estimated for eculizumab at therapeutic drug concentrations in an earlier published study in patients with atypical hemolytic uremic syndrome (aHUS)1. Maximal effects on C5 knockdown were achieved starting on day 20, and lasted for several months. For example, an up to 97.8 percent knockdown of serum C5 was still maintained at day 98 after just a single dose of drug in the top dose cohort. The company believes that the durable and clamped nature of C5 knockdown supports a once monthly and possibly a once quarterly, fixed dose subcutaneous regimen. In addition, single dose administration of ALN-CC5 was associated with potent, dose-dependent, and durable inhibition of complement activity. In particular, a single ALN-CC5 dose resulted in an up to 95 percent inhibition of complement alternative pathway (CAP) activity, an up to 97 percent inhibition of complement classical pathway (CCP) activity, and an up to 79 percent inhibition of serum hemolytic activity (mean maximum 74 ± 4.2 percent). In addition, as with C5 knockdown, the inhibitory effects of ALN-CC5 toward complement activity were found to be highly durable, lasting for several months after just a single dose. In MAD cohorts (N=12) receiving five weekly doses of ALN-CC5, an up to 99 percent knockdown of serum C5 was achieved with a mean maximum knockdown of 98 ± 0.2 percent (p less than 0.01 compared with placebo) in the top dose cohort. Following ALN-CC5 administration, nadir levels of residual C5 as low as 0.6 mcg/mL were observed. Regarding effects on complement activity, multiple doses of ALN-CC5 resulted in an up to 97 percent inhibition of CAP activity, an up to 97 percent inhibition of CCP activity, and an up to 98 percent inhibition of serum hemolytic activity (mean maximum 84 ± 7.6 percent). These effects on complement activity were statistically significant (p less than 0.05 compared with placebo). The level of CAP inhibition achieved in these healthy volunteers is comparable to results seen in people with homozygous C5 deficiency2,3, which highlights the highly robust knockdown of serum C5 levels achieved with ALN-CC5. Furthermore, multiple dose administration of ALN-CC5 achieved the 80 percent target level of serum hemolytic activity inhibition previously correlated with LDH reductions in PNH patients4. Finally, after the last dose of ALN-CC5, C5 knockdown and inhibition of complement activity were highly durable, with effects lasting several months. For example, after five weekly doses in the 200 mg cohort, an up to 98.3 percent knockdown of serum C5 was maintained at day 112. Preliminary Phase 1/2 Safety Results All safety results remain blinded as to treatment allocation. Single and multiple weekly subcutaneous doses of ALN-CC5 or placebo were generally well tolerated with no clinically significant, drug-related adverse events (AEs) reported to date. There were no serious adverse events (SAEs), study discontinuations, or clinically significant laboratory findings. In Part A of the study, a total of 29 AEs were observed, all of them mild or moderate in severity, of which 3 were deemed possibly related to ALN-CC5 or placebo. Two patients experienced mild, transient injection site reactions (ISRs). In Part B of the study, a total of 30 AEs were observed, all of them mild or moderate in severity, of which 12 AEs were deemed possibly related to ALN-CC5 or placebo. Four subjects experienced mild, transient ISRs. ALN-CC5 Phase 1/2 Study Design The ongoing Phase 1/2 trial of ALN-CC5 is being conducted in three parts. Parts A and B are randomized (3:1, drug:placebo), double-blind, placebo-controlled, SAD and MAD studies, respectively, which will enroll up to a total of 60 healthy adult volunteers. These parts of the study are designed to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-CC5. Additional objectives include clinical activity as measured by knockdown of serum C5 and levels of residual C5. In addition, additional objectives include measurement of effects on inhibition of serum complement activity, including measurements of CAP and CCP activity, and serum hemolytic activity. A total of 5 SAD cohorts were enrolled in the study, with fixed doses ranging from 50 to 900 mg. A total of 3 MAD cohorts have been enrolled in the study with fixed doses of 100, 200 or 400 mg, where subjects are receiving once weekly, subcutaneous doses of ALN-CC5 or placebo for 5 weeks. Part C is an open-label, multi-dose study in patients with PNH, to assess safety, tolerability, and clinical activity of ALN-CC5, administered for up to 13 weeks. This part of the study will include an exploratory evaluation of ALN-CC5 effects on levels of LDH, a measure of endogenous red blood cell hemolysis. About ALN-CC5 ALN-CC5 is an investigational RNAi therapeutic targeting the C5 component of the complement pathway, currently in early stage clinical development for the treatment of complement-mediated diseases. The safety and efficacy of ALN-CC5 have not been evaluated by the U.S. Food and Drug Administration or any other health authority. 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. 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. 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 RNAind 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.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, expectations regarding the timing of clinical trials with ALN-CC5 and the reporting of clinical data from these trials, including the expected reporting of additional data from its ongoing Phase 1/2 trial in mid-2016, its 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. 1 Lathia et al., 2014; ASCPT Annual Meeting; Abstract #387 2 Seelen et al., J Immunol Methods;296:187-198 (2005) 3 Cugno et al., J Thromb Haemost;12:1440-8 (2014) 4 Hill et al., Blood;106:2559-2565 (2005)