Alnylam Reports Initial ALN-CC5 Results in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) from Ongoing Phase 1/2 Study

Jun 11,2016

- Initial Data Support Potential for ALN-CC5 to Reduce Dose and Frequency of Eculizumab -

- Initial Results Also Support Potential for ALN-CC5 to Improve Disease Control in Eculizumab Inadequate Responders -

- Company to Host Conference Call Today, June 11, at 8:30 am ET to Discuss Results -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, and collaborators today presented initial results from Part C of its ongoing 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 - in an oral talk at the 21st Congress of the European Hematology Association in Copenhagen, Denmark. Part C evaluated the tolerability and clinical activity of ALN-CC5 in six patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disease where acquired mutations in the PIG-A gene lead to complement-mediated destruction of red blood cells (RBC). In this study, ALN-CC5 was evaluated as a monotherapy or as an adjunct to eculizumab, an approved anti-C5 monoclonal antibody indicated for the treatment of PNH. Preliminary results demonstrate that ALN-CC5 achieved clamped knockdown of serum C5 and lowering of lactate dehydrogenase (LDH) - a biomarker of RBC hemolysis - in patients with PNH, and support further development of ALN-CC5 to potentially reduce the dose and frequency of eculizumab for PNH patients, and also to potentially improve disease control in patients with an inadequate response to eculizumab. As previously guided, the Company plans to initiate a Phase 2 trial by late 2016.

"We believe that ALN-CC5 has the potential to transform the management of PNH, where clamped inhibition of hepatic C5 synthesis may provide the foundation for reduced frequency and doses of anti-C5 monoclonal antibody therapy. Preliminary data from a small number of PNH patients in our ongoing Phase 1/2 study suggest that ALN-CC5 has the potential to reduce the dose and frequency of eculizumab treatment, and also potentially improve disease control as seen in a patient with an inadequate response to eculizumab who was experiencing breakthrough hemolysis," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "Based on its durability of action, we believe that once-quarterly subcutaneous injections of ALN-CC5 have the potential to enable reduced doses and frequency of eculizumab, and we look forward to evaluating this further both in ongoing analyses of the PNH patients in the current Phase 1/2 study and in a new Phase 2 study, initially in inadequate responder patients, that we expect to start by year's end. In addition, we look forward to evaluating ALN-CC5 as monotherapy in other complement-mediated diseases, with studies that we expect to start in 2017."

"Dysregulated complement activity drives disease pathophysiology in many disease settings, including PNH. Eculizumab has been effective in managing many patients with PNH, but a significant proportion of patients experience breakthrough haemolysis. There remains an economic burden, and improvements in the current biweekly intravenous infusion maintenance schedule would be welcomed by both patients and the PNH community," said Anita Hill, M.D., Ph.D., MRCP, FRCPath, Consultant Haematologist for Leeds Teaching Hospitals NHS Trust, UK, and Lead for the National PNH Service in England. "The preliminary data coming from this small study provide promising early evidence of a potential new paradigm in the long-term treatment of patients with PNH, and I am excited about exploring this in further clinical studies."

A total of six patients with PNH were enrolled in Part C of the trial and completed dosing (N=3 eculizumab naïve, N=3 on background eculizumab). ALN-CC5 was administered at weekly doses of 200 or 400 mg for 2 to 16 weeks. Initial results below are based on data transferred up to June 6, 2016.

In eculizumab naïve PNH patients (N=3), ALN-CC5 monotherapy achieved C5 knockdown and inhibition of complement activity, and was associated with 37-50 percent maximal reductions in LDH, but LDH levels remained above the goal of less than 1.5 times the upper limit of normal (ULN). ALN-CC5 administration resulted in mean maximum serum C5 knockdown greater than 98 percent and residual C5 levels less than 1 mcg/mL. ALN-CC5 also demonstrated robust inhibition of complement activity as measured in complement classical pathway (CCP C5b-9 ELISA) and sheep RBC (sRBC) hemolysis assays. In the latter assay, ALN-CC5 achieved a mean maximum inhibition of approximately 75 percent. These effects on C5 knockdown and complement activity were similar to those reported previously in healthy volunteers enrolled in Parts A and B of the ongoing Phase 1/2 study.

An exploratory data analysis was conducted to understand the potential for ALN-CC5 to reduce eculizumab dose and frequency. After ALN-CC5 dosing was completed, eculizumab naïve patients were initiated on eculizumab for the treatment of remaining hemolysis. In the setting of ongoing ALN-CC5-mediated knockdown of serum C5 of greater than 95 percent, investigators chose to administer a single eculizumab dose of 600 mg and monitor the patients' clinical responses. Upon administration of this single eculizumab infusion, all three patients achieved rapid lowering of LDH below 1.5 times the ULN which was sustained out to 4 weeks. These results provide preliminary exploratory evidence that inhibition of hepatic C5 synthesis by ALN-CC5 has the potential to reduce the dose and frequency of eculizumab. It is important to note that in eculizumab naïve patients, a single 600 mg eculizumab dose over 28 days represents 25 percent of the labeled induction dose (600 mg every week for the first 4 weeks) of eculizumab.

In the patients being treated with background eculizumab (N=3), ALN-CC5 also achieved robust C5 knockdown and inhibition of complement activity. In this group, one patient was enrolled who was experiencing breakthrough hemolysis and elevated LDH at baseline despite higher than labeled doses of eculizumab of 1200 mg every 2 weeks. In this inadequate response patient, ALN-CC5 administration resulted in rapid reduction of LDH to below 1.5 times the ULN and an over 1 g/dL increase in hemoglobin. Following ALN-CC5 administration, the investigator successfully reduced eculizumab to the labeled dose of 900 mg every 2 weeks. Finally, eculizumab plasma levels were measured to evaluate any effects of ALN-CC5 on eculizumab pharmacokinetics. Notably, ALN-CC5 knockdown of serum C5 resulted in an over 3-fold increase of pre-dose eculizumab trough levels. In summary, we believe that these preliminary results in eculizumab-treated patients suggest that ALN-CC5 can potentially improve disease control in inadequate responders and also potentially improve eculizumab pharmacokinetic properties.

ALN-CC5 was generally well tolerated in patients with PNH after multiple doses with the majority of adverse events (AEs) being mild or moderate in severity. There were no drug related serious AEs or discontinuations due to AEs in the study. One patient, who was also taking eculizumab, cyclosporine and anabolic steroids as concomitant medications, experienced a transient asymptomatic grade 3 elevation of liver transaminases that was deemed possibly related to study drug and dosing was interrupted. All other AEs reported were mild or moderate in severity. Mild and transient injection site reactions were reported in 3 of 6 patients. There were no clinically significant changes in vital signs, EKG, physical exams or clinical laboratory results.

To view these results from Part C of the Phase 1/2 study with ALN-CC5, please visit

Conference Call Information

Alnylam management will discuss these data in a webcast conference call on Saturday, June 11 at 8:30 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 22804624. A replay of the call will be available beginning at 10:30 a.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 22804624.

About the 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 enrolled 56 healthy adult volunteers. These parts of the study were 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, and by effects on inhibition of serum complement activity, including measurements of complement alternative pathway (CAP C5b-9 ELISA) and complement classical pathway (CCP C5b-9 ELISA) activity, as well as serum sheep red blood cell (sRBC) 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 healthy adult volunteers are receiving once weekly, subcutaneous doses of ALN-CC5 or placebo for 5 weeks. Part C is an open-label, multi-dose study component that enrolled 6 patients with PNH, to assess safety, tolerability, and clinical activity of ALN-CC5, administered for up to 16 weeks. This part of the study included an exploratory evaluation of ALN-CC5 effects on levels of LDH, a biomarker 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, and 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.

Sanofi Genzyme Alliance

In January 2014, Alnylam and Sanofi Genzyme, the specialty care global business unit of Sanofi, 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 Sanofi 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 (ROW), including co-development/co-commercialization and/or global product rights for certain programs.

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 Ionis, Novartis, Roche, Takeda, Merck, Monsanto, The Medicines Company, and Sanofi Genzyme. 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, expectations regarding the conduct of additional analyses of data from the ongoing Phase 1/2 study, its plans and expected timing for the initiation of a new Phase 2 study of ALN-CC5 in PNH patients, as well as the expected initiation of additional studies in other indications, 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.

Alnylam Pharmaceuticals, Inc.
Investors and Media
Christine Regan Lindenboom, 617-682-4340
Josh Brodsky, 617-551-8276

Source: Alnylam Pharmaceuticals, Inc.

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