Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today its key “Alnylam 5x15™” pipeline goals. The company also announced today that it now expects to exceed its original “Alnylam 5x15” guidance from 2011, where Alnylam had guided to have five genetic medicine programs in the clinic by the end of 2015. Alnylam now expects to end 2015 with six to seven genetic medicine programs in the clinic, including at least two programs in Phase 3 and five to six programs that will have achieved human proof-of-concept results supporting further development. “2013 was a year of remarkable accomplishments, as we continued to lead the translation of RNAi therapeutics as a new class of medicines, and we believe this progress positions us well for continued execution on our ‘Alnylam 5x15’ pipeline product strategy. Moreover, we believe our recent advances highlight Alnylam’s unique opportunity for shareholder value creation with a modular and reproducible approach for development and, ultimately, commercialization of innovative genetic medicines,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “As a result of the achievements of the past period, we now believe that we will exceed our original ‘Alnylam 5x15’ guidance as issued in 2011, when we stated we expected to have 5 programs in clinical development by the end of 2015. Indeed, we now expect to significantly exceed that guidance with six to seven programs in clinical development by the end of 2015, including at least two programs in Phase 3 and five to six programs that will have achieved human proof-of-concept results.” “We fully expect that 2014 will be another exciting year for Alnylam, as we advance and broaden our pipeline of RNAi therapeutics in development. Specifically, we will be enrolling patients in our APOLLO Phase 3 trial of patisiran and also collecting key clinical endpoint data from our ongoing Phase 2 open-label extension study with results in late 2014. We also plan on starting our company’s second Phase 3 trial, in this case with ALN-TTRsc in the cardiac amyloidosis indication; an ongoing Phase 2 study of this drug will also read out data by year-end,” said Barry Greene, President and Chief Operating Officer of Alnylam. “In our hemophilia program, ALN-AT3 is positioned to start Phase 1 in the coming weeks, and we expect to report interim proof-of-concept data by end of the year. We also expect to advance our pipeline with 2 additional IND filings this year from a few of our development stage programs including ALN-CC5 for complement-mediated diseases, ALN-AS1 for hepatic porphyrias, and ALN-PCSsc for hypercholesterolemia. Of course, we intend to also continue to significantly invest in our genetic medicine discovery pipeline, where we see a large number of potentially attractive opportunities for innovative RNAi therapeutics. In sum, we fully expect 2014 to bring us closer to market with our Phase 3 trials, yield multiple data read outs that may provide expanded proof of concept, and broaden our opportunities with a significant growth in our clinical pipeline of potential high impact genetic medicines.”
“Alnylam 5x15” and Genetic Medicine Pipeline Goals
- Continue to Advance Patisiran (ALN-TTR02) in APOLLO Phase 3 Pivotal Clinical Trial and Phase 2 Open Label Extension Study. Alnylam is currently enrolling patients in its APOLLO Phase 3 clinical study with patisiran, an intravenously delivered RNAi therapeutic targeting TTR for the treatment of ATTR. The APOLLO trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in up to 200 ATTR patients with FAP. In addition, Alnylam continues to treat FAP patients in its Phase 2 open-label extension (OLE) study with patisiran. The primary objective of this study is to evaluate the long-term safety and tolerability of patisiran administration. The study will also measure a number of clinical endpoints, which are the same as those in the APOLLO Phase 3 study. The company expects to present data from the Phase 2 OLE study approximately once a year, with an initial data report in late 2014.
- Continue to Advance ALN-TTRsc in Ongoing Phase 2 Clinical Study, Initiate Phase 2 Open-Label Extension Study, and Start Phase 3 Pivotal Trial in ATTR Patients with Cardiac Amyloidosis. Alnylam is currently enrolling patients in a Phase 2 clinical study with ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR. The pilot Phase 2 trial is aimed at evaluating the tolerability and preliminary clinical activity of ALN-TTRsc in approximately 15 TTR cardiac amyloidosis patients with familial amyloidotic cardiomyopathy (FAC) – which is caused by autosomal dominant mutations in the TTR gene – or senile systemic amyloidosis (SSA) – which is caused by idiopathic accumulation of wild-type TTR in the heart. In addition, the study will assess preliminary clinical activity as measured by knockdown of serum TTR levels and additional exploratory tests, such as cardiac imaging (including echocardiography and cardiac MRI), circulating cardiac biomarkers (NT-proBNP and troponins T and I), 6-minute walk test, New York Heart Association (NYHA) classification, and measures of heart failure symptoms and quality of life (Kansas City Cardiomyopathy Questionnaire and EQ-5D QOL). The company expects to present data from the Phase 2 trial in late 2014. Patients completing the Phase 2 trial will be eligible to participate in an open-label extension (OLE) study for further assessment of general tolerability and clinical activity with long-term dosing; the ALN-TTRsc Phase 2 OLE study is expected to be initiated in mid-2014. Assuming positive results, Alnylam expects to begin a Phase 3 trial in TTR cardiac amyloidosis patients by the end of 2014.
- Start Phase 1 Clinical Trial with ALN-AT3 for the Treatment of Hemophilia and Rare Bleeding Disorders. ALN-AT3 is a subcutaneously delivered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD). Alnylam expects to begin a Phase 1 trial with ALN-AT3 in early 2014. The study will be conducted in the U.K. as a single- and multi-dose, dose-escalation study consisting of two parts. The first part will be a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, enrolling up to 24 healthy volunteer subjects. Only low doses of ALN-AT3 will be administered in this part of the study with stopping rules at greater than 40% AT knockdown, which is believed to be a well-tolerated level of AT knockdown based on pre-clinical studies, in addition to data from people with heterozygous AT deficiency. The primary objective of the first part of the study is to evaluate the safety and tolerability of a single dose of ALN-AT3. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels. The second part of the study will be an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate to severe hemophilia A or B. The primary objective of this part of the study is to evaluate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in ex vivo thrombin generation. Ex vivo thrombin generation is known to be a biomarker for bleeding frequency and severity in people with hemophilia (Dargaud, et al., Thromb Haemost; 93, 475-480 (2005)). Alnylam expects to begin the first part of the study early in 2014 and the second part in mid-2014, with initial data expected in late 2014.
- File Two INDs from Ongoing Development Programs Including ALN-CC5 for Complement-Mediated Diseases, ALN-AS1 for Hepatic Porphyrias, and ALN-PCSsc for Hypercholesterolemia, with the Third IND to be Filed in Early 2015.
- ALN-CC5 is a subcutaneously administered RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic-uremic syndrome (aHUS), myasthenia gravis, neuromyelitis optica, amongst others. Alnylam has presented pre-clinical data demonstrating that administration of ALN-CC5 in non-human primates (NHPs) resulted in an up to 98% knockdown of serum C5 and an up to 94% inhibition of hemolytic activity. A greater than 80% inhibition of hemolytic activity has been validated as associated with clinical benefit in patients with PNH (Hillmen et al., N. Engl. J. Med. (2004) 350:552-559). The company expects to identify its final Development Candidate for ALN-CC5 in early 2014 and to file an Investigational New Drug (IND) application or IND equivalent in late 2014 or early 2015.
- ALN-AS1 is a subcutaneously administered RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias, including acute intermittent porphyria (AIP). The company has presented pre-clinical data showing that subcutaneous administration of a GalNAc-siRNA targeting ALAS-1 results in a rapid, dose-dependent, and long-lasting knockdown of ALAS-1 mRNA and complete inhibition of the toxic intermediates that mediate the symptoms and pathology of AIP. The company has selected its ALN-AS1 Development Candidate and expects to file an IND or IND equivalent for this RNAi therapeutic in late 2014 or early 2015.
- ALN-PCSsc is a subcutaneously administered RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia. Pre-clinical data in NHPs has shown that ALN-PCSsc leads to an up to a 90% PCSK9 knockdown and an up to 68% lowering of LDL cholesterol in the absence of statins, with a pharmacodynamic profile supportive of dosing as infrequently as once or twice per month. The ALN-PCSsc program is partnered with The Medicines Company, where, under the terms of the agreement, Alnylam will complete certain pre-clinical and additional Phase 1 clinical studies and The Medicines Company is responsible for leading and funding development from Phase 2 forward and commercializing the ALN-PCS program, if successful. Alnylam and The Medicines Company have selected the ALN-PCSsc Development Candidate and Alnylam expects to file an IND or IND equivalent for this program in late 2014 or early 2015.
- Continue to Advance Additional Genetic Medicine Pipeline Programs with One to Two New Development Candidates by End of Year. Alnylam also expects to continue to advance additional RNAi therapeutic genetic medicine programs towards the clinic with the nomination of one to two new Development Candidates by the end of the year. These include: ALN-AAT for the treatment of alpha-1-antitrypsin (AAT) deficiency associated liver disease; ALN-TMP for the treatment of beta-thalassemia and iron-overload disorders; and ALN-ANG for the treatment of mixed hyperlipidemia and severe hypertriglyceridemia.
- Identify Additional Genetic Medicine Programs to Build Pipeline for Future. Alnylam also expects to advance additional as yet undisclosed RNAi therapeutic genetic medicine discovery programs, and expects to present or publish pre-clinical results from one or more of these programs in 2014.
Alnylam management will present a company overview at the 32nd Annual J.P. Morgan Healthcare Conference on Monday, January 13, 2014 at 11:30 a.m. PT (2:30 p.m. ET) at the Westin St. Francis Hotel in San Francisco, Calif. A live audio webcast of the presentation will be available on the News & Investors section of the company’s website, www.alnylam.com. A replay of the presentation will be available on the Alnylam website within 48 hours after the event.About RNA Interference (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 PharmaceuticalsAlnylam 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 TM” 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 familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; 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 liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; and ALN-ANG, an RNAi therapeutic for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia, amongst other programs. 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, 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, the 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. About “Alnylam 5x15™” and Genetic MedicinesThe “Alnylam 5x15” strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics as genetic medicines. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of diseases with high unmet medical need. These programs share several key characteristics including: a genetically defined target and disease expressed in the liver; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi platform with clinically proven delivery to the liver; the opportunity to monitor an early biomarker in Phase 1 clinical trials for human proof of concept; and the existence of clinically relevant endpoints for the filing of a new drug application (NDA) with a focused patient database and possible accelerated paths for commercialization. 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 “Alnylam 5x15” programs include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR in development for the treatment of ATTR in patients with familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) in development for the treatment of porphyria including acute intermittent porphyria (AIP); ALN-CC5, an RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases; ALN-PCS, an RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 in development for the treatment of beta-thalassemia and iron-overload disorders; and ALN-ANG, an RNAi therapeutic for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia, amongst other programs. About Transthyretin-Mediated AmyloidosisTransthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and fatal disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein. Mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy. ATTR represents a major unmet medical need with significant morbidity and mortality; familial amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy (FAC) affects at least 40,000 people worldwide. FAP patients have a life expectancy of five to 15 years from symptom onset, and the only approved treatment options for early stage disease are liver transplantation, and tafamidis (approved in Europe). The mean survival for FAC patients is approximately 2.5 years, and there are no approved therapies. Senile systemic amyloidosis (SSA) is a non-hereditary form of TTR cardiac amyloidosis caused by idiopathic deposition of wild-type TTR; its prevalence is generally unknown, but is associated with advanced age. There is a significant need for novel therapeutics to treat patients with TTR amyloid polyneuropathy and/or cardiomyopathy. About Hemophilia and Rare Bleeding Disorders (RBD)Hemophilias are hereditary disorders caused by genetic deficiencies of various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major internal organs. Hemophilia A is defined by loss-of-function mutations in factor VIII, and there are greater than 40,000 registered patients in the U.S. and E.U. Hemophilia B, defined by loss-of-function mutations in factor IX, affects greater than 9,500 registered patients in the U.S. and E.U. Other Rare Bleeding Disorders (RBD) are defined by congenital deficiencies of other blood coagulation factors, including Factors II, V, VII, X, and XI, and there are about 1,000 patients worldwide with a severe bleeding phenotype. Standard treatment for hemophilia patients involves replacement of the missing clotting factor either as prophylaxis or on-demand therapy. However, as many as one third of hemophilia A patients will develop an antibody to their replacement factor – a very serious complication; these 'inhibitor' patients become refractory to standard replacement therapy. There exists a small subset of hemophilia patients who have co-inherited a prothrombotic mutation, such as factor V Leiden, antithrombin deficiency, protein C deficiency, and prothrombin G20210A. Hemophilia patients that have co-inherited these prothrombotic mutations are characterized as having a later onset of disease, lower risk of bleeding, and reduced requirements for factor VIII or factor IX treatment as part of their disease management. There exists a significant need for novel therapeutics to treat hemophilia patients. About Complement Mediated DiseaseALN-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, 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 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 proprietary GalNAc conjugate delivery platform enabling subcutaneous dose administration. About Acute Intermittent PorphyriaAcute intermittent porphyria (AIP) is an ultra-rare autosomal dominant disease caused by loss-of-function mutations in porphobilinogen deaminase (PBGD), an enzyme in the heme biosynthesis pathway. Exposure of AIP patients to certain drugs, dieting, or hormonal changes can trigger strong induction of aminolevulinate synthase-1 (ALAS-1), another enzyme in the heme biosynthesis pathway, which can lead to accumulation of heme intermediates upstream of PBGD that precipitate attack symptoms. Patients with AIP can suffer acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, and neuropsychiatric manifestations, and possible death if left untreated. Approximately 5,000 patients in the U.S. and Europe suffer acute porphyria attacks annually, and approximately 500 patients are afflicted with recurrent debilitating attacks. Treatment options for AIP patients suffering from an acute attack are limited; patients are treated with intravenous heme analogues that have a slow onset and can result in severe thrombophlebitis and iron overload. Currently there is no approved prophylactic treatment available to prevent recurrent attacks, which often occur monthly in women associated with menses. There exists a significant need for therapies for AIP patients. About HypercholesterolemiaHypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood which is known to increase the risk of coronary artery disease, the leading cause of death in the U.S. Some forms of hypercholesterolemia can be treated through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation) and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not achieving target LDL-C goals with statin therapy, including genetic familial hypercholesterolemia patients, acute coronary syndrome patients, high-risk patient populations (e.g., patients with coronary artery disease, diabetics, symptomatic carotid artery disease, etc.) and other patients that are statin intolerant. Severe forms of hypercholesterolemia are estimated to affect more than 500,000 patients worldwide, and as a result, there is a significant need for novel therapeutics to treat patients with hypercholesterolemia whose disease is inadequately managed by existing therapies. Alnylam Forward-Looking StatementsVarious statements in this press release concerning Alnylam’s future expectations, plans and prospects, including without limitation, Alnylam’s expectations regarding its “Alnylam 5x15” product strategy, Alnylam’s views with respect to the potential for RNAi therapeutics, including patisiran (ALN-TTR02), ALN-TTRsc, ALN-AT3, ALN-CC5, ALN-AS1, ALN-PCSsc, ALN-AAT, ALN-TMP, and ALN-ANG, its expectations with respect to the timing and success of its clinical and pre-clinical trials, the expected timing of regulatory filings, including its plan to file IND or IND equivalent applications and initiate clinical trials for ALN-TTRsc, ALN-AT3, ALN-CC5, ALN-AS1, and ALN-PCSsc, and its expectations regarding reporting data from its ongoing and planned clinical studies, including its studies for patisiran, ALN-TTRsc and ALN-AT3, as well as other research programs and technologies, and its expected cash position as of December 31, 2013, 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 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.