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Alnylam Presents New Pre-clinical Data on Subcutaneously Delivered RNAi Therapeutics for Cardiovascular Metabolic Disease at Arteriosclerosis, Thrombosis and Vascular Biology 2014 Scientific Sessions

Companies mentioned in this article: Alnylam Pharmaceuticals, Inc.

CAMBRIDGE, Mass. -- (BUSINESS WIRE) -- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has presented new pre-clinical data from RNAi therapeutic programs toward genetically validated targets in cardiovascular metabolic diseases, including ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia, and a newly named program, ALN-AC3, targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia. These data are being presented at the Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) 2014 Scientific Sessions being held May 1-3 in Toronto, Ontario. In an oral presentation titled “A Subcutaneous, Potent and Durable RNAi Platform Targeting Metabolic Diseases, Genes PCSK9, ApoCIII and ANGPLT3” new pre-clinical data utilizing the company’s GalNAc-siRNA conjugate platform demonstrated robust and durable knockdown of these key cardiovascular metabolic disease targets. Amongst other data, Alnylam presented new single-dose durability data for ALN-PCSsc showing robust knockdown of PCSK9 and reductions in LDL-C that support once-monthly and possibly once-quarterly subcutaneous dosing regimens. Specifically, a single dose of ALN-PCSsc maintained greater than 50% LDL-C reductions for over three months in the absence of statin co-administration. The company plans to file an investigational new drug (IND) application, or IND equivalent, for ALN-PCSsc by late 2014 or early 2015.

“As evidenced by these data presented at ATVB, we are building the beginnings of a promising pipeline of RNAi therapeutics toward genetically validated disease targets in the cardio-metabolic space. We see this as an attractive area for continued investment for Alnylam given the large number of liver-expressed disease-causing genes and the emerging profile of our GalNAc-conjugate platform enabling subcutaneous delivery with potent disease gene knockdown, a wide therapeutic index, and highly durable effects. These features are exemplified with ALN-PCSsc, where new non-human primate pre-clinical results demonstrate significant knockdown of PCSK9 and reductions in LDL-C with very durable effects, lasting over three months. We believe that this level of durability should readily support a once-monthly and possibly a once-quarterly subcutaneous dosing regimen, and thus represents what should be a highly competitive profile with anti-PCSK9 monoclonal antibodies. We look forward to advancing ALN-PCSsc toward clinical trials by the end of this year or early next,” said Kevin Fitzgerald, Ph.D., Senior Director, Research at Alnylam. “In addition, new rodent data with ALN-AC3, our GalNAc-siRNA conjugate targeting apoCIII, showed up to 95% knockdown of ApoCIII and up to 68% reduction in triglycerides. These pre-clinical results warrant further efforts to advance this new RNAi therapeutic program into later stages of development.”

Alnylam is developing ALN-PCSsc as a subcutaneously delivered RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia. The ALN-PCS program is partnered with The Medicines Company, where, under the terms of the agreement, Alnylam will complete certain pre-clinical studies and a Phase 1 clinical study of ALN-PCSsc and The Medicines Company is responsible for leading and funding development from Phase 2 forward and commercializing the ALN-PCS program, if successful.

As detailed in the table below, new pre-clinical data in non-human primates (NHP) demonstrated that a single dose of ALN-PCSsc significantly reduced plasma PCSK9 protein by up to 96%, with mean PCSK9 knockdown at nadir of 88% at the top dose. Results also showed lowering of low density lipoprotein cholesterol (LDL-C, or ‘bad cholesterol’) of up to 77%, with a mean reduction of 69% at the top dose; these results were observed in the absence of statin co-administration. Knockdown of PCSK9 and lowering of LDL-C were rapid and durable, with maximal effects lasting greater than 90 days and returning to baseline at approximately 160 days. At the top dose of 10 mg/kg, an over 50% reduction in LDL-C was maintained for over 90 days. Moreover, there was sustained and clamped knockdown of PCSK9 and reduction of LDL-C across this entire time period, which contrasts with the cyclical variation in LDL-C observed with monthly dose regimens of anti-PCSK9 monoclonal antibodies (Stein, Curr Opin Lipidol 2013, 24:510–517). All together, these data are supportive of a once-monthly dosing and possibly once-quarterly dosing regimen, and could represent a highly competitive target product profile.

Summary of Knockdown of PCSK9 and Reduction of LDL-C with ALN-PCSsc in NHP

      ALN-PCSsc

3 mg/kg (N=3)

    ALN-PCSsc

6 mg/kg (N=3)

    ALN-PCSsc

10 mg/kg (N=3)

Maximum PCSK9 KD at Nadir (% Baseline)     79.3     95.9     92.2
Mean PCSK9 KD at Nadir (% Baseline +/- SD)     76.2 ± 2.8*     85 ± 10.4*     88.3 ± 4.3*
Mean PCSK9 KD at 1 mo (% Baseline +/- SD)     62.2 ± 16.4*     77.5 ± 10.5*     80.8 ± 8.1*
Mean PCSK9 KD at 3 mos (% Baseline +/- SD)     34.3 ± 16.4†     22.9 ± 36.2     72.3 ± 4.7*
                   
Maximum LDL-C reduction at Nadir (% Baseline)     60.3     77.3     73.4
Mean LDL-C Reduction at Nadir (% Baseline +/- SD)     52.4 ± 12.8*     69.6 ± 8.8*     68.8 ± 7.6*
Mean LDL-C Reduction at 1 mo (% Baseline +/- SD)     49.9 ± 17.7†     63.5 ± 21*     67.8 ± 8.7*
Mean LDL-C Reduction at 3 mos (% Baseline +/- SD)     24.8 ± 6.1†     33 ± 11.9†     52.6 ± 7.6*

† comparison vs. Day -3 (predose) values significant at p < 0.05
* comparison vs. Day -3 (predose) values significant at Bonferroni-corrected p < 0.01

In addition, pre-clinical safety studies evaluating five weekly doses confirm that ALN-PCSsc has a wide therapeutic index, with a no adverse event level (NOAEL) of greater than 300 mg/kg in two rodent species and in NHP. Further, the company showed results of a new analysis from its ALN-TTRsc – a GalNAc-siRNA conjugate RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis – Phase 1 study demonstrating prolonged duration of clinical activity in humans as compared with NHP, further supporting an infrequent dose regimen for ALN-PCSsc.

Alnylam also presented pre-clinical data from a new program: ALN-AC3, a subcutaneously administered RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia. ApoCIII is a component of lipoprotein particles in the blood, and inhibits lipoprotein lipase and hepatic lipase and reduces hepatic uptake of triglyceride-rich particles. Polymorphisms in apoCIII have been associated with hypertriglyceridemia; specifically a gain-of function leads to higher apoCIII and triglyceride levels, and reduced triglyceride clearance. ApoCIII loss-of-function results in greater triglyceride hydrolysis into free fatty acids and increased triglyceride clearance; heterozygous individuals have lower triglycerides and lower very low density lipoprotein (VLDL). Recent studies have identified rare loss of function variants in apoCIII which appear to be cardioprotective (Tachmazidou et al., Nat. Comm, 2013; Bochem et.al., Clin Genet., 2014). Data presented at ATVB were conducted in mouse models that match human genetics. Specifically, administration of a GalNAc-conjugated siRNA targeting apoCIII resulted in knockdown of apoCIII levels of up to 95% and a reduction in triglyceride levels of up to 68% with durability out to over 20 days. Alnylam plans to continue to conduct additional pre-clinical work in this program to finalize its Development Candidate.

“Cardiovascular disease remains the leading cause of mortality worldwide. Elevated LDL-C and triglycerides are two well validated and modifiable risk factors. A substantial number of patients, especially those at high risk for cardiovascular disease, are unable to achieve reduced levels of LDL-C and triglycerides with current drugs, such as statins or cholesterol absorption inhibitors, and it is clear that new therapeutic options are needed,” said Daniel J. Rader, M.D., Chair, Department of Genetics, Perelman School of Medicine at the University of Pennsylvania. Dr. Rader also serves on Alnylam's Scientific Advisory Board. “As a key regulator of LDL-C receptor levels, liver-expressed PCSK9 is an important and well-validated novel target in molecular medicine for the treatment of hypercholesterolemia. Likewise, human genetics studies indicate that a loss-of-function mutation in apoCIII is associated with lower triglycerides and increased post-prandial triglyceride clearance. It is encouraging that an investigational RNAi-based therapeutic targeting apoCIII expression in the liver reproduced these effects in a mouse model. The medical community will continue to monitor advancement of novel RNAi therapeutics toward these important disease targets.”

In addition to ALN-PCSsc and ALN-AC3, Alnylam is also advancing ALN-ANG targeting ANGPTL3 for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia. ANGPTL3 is an inhibitor of cellular lipases involved in the metabolism of lipoproteins. Human genetic as well as exome sequencing studies have identified a statistically significant relationship of loss-of-function mutations in ANGPTL3 with decreased levels of triglycerides and LDL-C (Musunuru et al., N. Engl. J. Med (2010) 363:2220-2227). Data presented at the American Heart Association (AHA) Scientific Sessions in 2013 demonstrated that a single dose of a GalNAc-siRNA targeting ANGPTL3 led to robust, dose-dependent knockdown of ANGPTL3 protein, with a single dose ED50 of approximately 1 mg/kg. In a multi-dose experiment, subcutaneous doses of 3.0 mg/kg led to a greater than 95% knockdown of ANGPTL3 protein. These studies were performed in an “ob/ob” mouse model of obesity and mixed hyperlipidemia. This ANGPLT3 protein reduction resulted in a greater than 95% reduction in triglycerides, and a more than 85% reduction in LDL-C. In addition, total cholesterol was reduced by greater than 60%. These data with ALN-ANG support further advancement of this program for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia, which are associated with increased risk of coronary artery disease and/or recurrent pancreatitis. Alnylam is conducting additional pre-clinical research to finalize its Development Candidate for the ALN-ANG program.

About Hypercholesterolemia

Hypercholesterolemia 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.

About Mixed Hyperlipidemia and Hypertriglyceridemia

Mixed hyperlipidemia is a genetically inherited condition characterized by very high levels of cholesterol and triglycerides in the blood, both of which are known to increase the risk of coronary artery disease, the leading cause of death in the U.S. It is estimated that as many as 1 out of every 100 individuals have mixed hyperlipidemia and are at increased risk of developing cardiovascular disease. Some forms of mixed hyperlipidemia can be treated through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation), and medicines such as statins or fibrates; however, a large portion of mixed hyperlipidemia patients are unable to reach either their LDL-C and/or triglyceride goals with the current standard of care. Patients with severe, inherited forms of hypertriglyceridemia (e.g., familial chylomicronemia syndrome, or “FCS”) are at extremely high risk of developing recurrent pancreatitis. FCS is a rare orphan genetic disease that affects 1 to 2 individuals per million.

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 5x15TM” 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 TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); 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; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; 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, The Medicines Company, and Genzyme, a Sanofi company. 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, 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 The Medicines Company

The Medicines Company's purpose is to save lives, alleviate suffering and contribute to the economics of healthcare by focusing on 3000 leading acute/intensive care hospitals worldwide. Its vision is to be a leading provider of solutions in three areas: acute cardiovascular care, surgery and perioperative care, and serious infection disease care. The company operates in the Americas, Europe and the Middle East, and Asia Pacific regions with global centers today in Parsippany, NJ, USA and Zurich, Switzerland.

About “Alnylam 5x15™” and Genetic Medicines

The “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 TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) in development for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); 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; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, a subcutaneously administered RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; and other programs yet to be disclosed. In 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam’s genetic medicine programs. 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 ALN-TTRsc in North America and Europe.

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-PCSsc, ALN-AC3, and ALN-ANG for the treatment of cardiovascular metabolic disease, its expectations with respect to further advancing ALN-AC3 and ALN-ANG in development, the filing of an IND application for ALN-PCSsc, its expectations with respect to the timing and success of clinical trials with ALN-PCSsc, its expectations regarding the potential market opportunity for ALN-PCSsc, 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 manage operating expenses, 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 Annual Report on Form 10-K 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.


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