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Alnylam Demonstrates RNAi in Man with Systemically Delivered RNAi Therapeutics
- Analysis of Liver Biopsy Samples from Patients in ALN-VSP Phase I Trial Shows Achievement of Pharmacologically Relevant Tissue Drug Levels and Specific RNAi-Mediated Cleavage of Target mRNA -

CAMBRIDGE, Mass., Jan 04, 2011 (BUSINESS WIRE) --

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, today presented new clinical data from its ALN-VSP Phase I liver cancer trial in a presentation at the Dana-Farber Cancer Institute in Boston. Results from molecular analysis of human biopsy samples showed achievement of pharmacologically relevant siRNA drug levels in tissues. In addition, using a highly precise polymerase chain reaction (PCR)-based technique known as 5'- rapid amplification of cDNA ends (5'-RACE), analysis of human tissue samples showed proof of RNAi-mediated target mRNA cleavage, and thus RNAi in man with the systemically delivered RNAi therapeutic. These results provide significant human proof of concept for Alnylam's efforts in advancing RNAi therapeutics to patients.

"These data provide conclusive evidence that RNAi can be harnessed in man and, as such, represent a notable and important milestone in the advancement of RNAi therapeutics as a potential new class of medicines," said Phillip Sharp, Ph.D., Institute Professor, The Koch Institute for Integrative Cancer Research, MIT, and Chairman of Alnylam Scientific Advisory Board and Alnylam Director. "I applaud Alnylam scientists, clinicians, and their collaborators for reaching this important achievement and I look forward to the results of their continued efforts."

Post-treatment tumor biopsies from eight patients were analyzed for ALN-VSP drug levels. All biopsy samples were obtained on a voluntary basis using a CT-guided procedure. Five of these biopsy samples were obtained from tumor in the liver and three were taken from tumor located outside the liver in patients receiving doses of ALN-VSP ranging from 0.4 to 1.25 mg/kg. The two siRNAs targeting VEGF and KSP that comprise ALN-VSP were detected in almost all of these biopsy samples at concentrations ranging from 0.3 to 142 ng/g tissue. These levels of siRNA are pharmacologically relevant since in pre-clinical studies with systemically delivered siRNAs, a tissue level of 1 ng/g has been shown to be associated with 50% target gene silencing (Landesman et al., Silence, 1:16, 2010).

RNAi is an endogenous cellular enzymatic process whereby siRNAs mediate sequence-dependent cleavage of target mRNAs; cleavage of the target mRNA is highly precise, occurring exactly 10 nucleotide positions from the 5'-end of the siRNA antisense strand. In order to establish RNAi-mediated effects in vivo, 5'RACE has been established as a robust method for detecting the specific cleavage products of siRNA pharmacology in pre-clinical animal models (Soutschek et al., Nature, 432: 173-8, 2004; Zimmermann et al., Nature, 441: 111-4, 2006). As a PCR-based technique, 5'RACE is not a quantitative measurement; a positive result simply confirms that there is evidence of RNAi-mediated target mRNA cleavage.

As currently analyzed, three patients had biopsies that were of sufficient quality to permit blinded 5' RACE analysis for the VEGF target mRNA following the first dose of ALN-VSP; additional analyses are ongoing. All three biopsy samples were from the 0.4 mg/kg dose group, and post-treatment biopsy samples were comprised of 80% to 100% normal liver. In two patients whose post-treatment biopsies were performed two days after dosing, the 5' RACE assay combined with deep sequencing showed that approximately 27% and 29% of all VEGF-derived mRNA fragments corresponded exactly to the predicted RNAi-mediated cleavage product based on the VEGF siRNA sequence. By contrast, a pre-dose biopsy available for one of those patients contained only approximately 1% predicted VEGF cleavage product, and analysis of banked normal liver and tumor samples from untreated patients showed a background level of only 0.1% to 0.7%. Compared to these low background levels, the amount of predicted VEGF cleavage product in the two post-treatment biopsies was highly statistically significant (p<0.0001). In the third patient at 0.4 mg/kg whose post-treatment biopsy was obtained 7 days post-dose, there was no detectable increase in the predicted VEGF cleavage product compared to the pre-dose biopsy. These positive 5' RACE data from human biopsies provide clear evidence for RNAi in man following systemic administration of lipid nanoparticle (LNP)-formulated siRNA.

"Achievement of these results is very important for Alnylam's overall RNAi therapeutics efforts, and has many implications. First, we have been able to quantify significant human tissue levels of siRNAs at concentrations that exceed our 1 ng/g target level that is associated with effective target gene silencing in pre-clinical animal models. More importantly, we have demonstrated proof of RNAi mechanism in man with LNP delivery of siRNAs, an important milestone in overall human translation of RNAi therapeutics," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "As this systemic delivery platform is employed in our pipeline of clinical and development-stage programs, we believe that we have now made a major leap forward in advancing RNAi therapeutics to patients."

About ALN-VSP Clinical Program

ALN-VSP is Alnylam's first systemic RNAi program and represents the company's first clinical program in oncology. ALN-VSP is a systemically delivered RNAi therapeutic comprising two siRNAs designed to target two genes critical for the growth and survival of cancer cells: vascular endothelial growth factor (VEGF) and kinesin spindle protein (KSP), also known as eglin 5 (Eg5). The drug is formulated in a first generation LNP developed by Tekmira Pharmaceuticals Corporation. The ongoing Phase I trial is a multi-center, open label, dose escalation study designed to enroll approximately 55 patients with advanced solid tumors with liver involvement who have failed to respond to or have progressed after standard treatment. The primary objective is to evaluate safety and tolerability of eight potential dose levels ranging from 0.1 to 1.7 mg/kg. Secondary objectives include characterization of pharmacokinetics, and assessment of pharmacodynamic effects and tumor response through Response Evaluation Criteria for Solid Tumors (RECIST), a set of published guidelines that define when cancer patients' disease improves, stabilizes, or progresses during treatment; change in tumor blood flow or vascular permeability as measured by Dynamic Contrast - Enhanced Magnetic Resonance Imaging (DCE-MRI); change in plasma biomarkers of angiogenesis; and, molecular and cellular analyses of tumor biopsy samples.

Prior data presented at the November 2010 Chemotherapy Foundation Symposium showed that 127 doses of ALN-VSP at dose levels of 0.1 to 1.25 mg/kg had been administered to 28 patients and was generally well tolerated. A total of two dose limiting toxicites were reported to be possibly or probably related to drug treatment. The maximum tolerated dose had not yet been reached and dose escalation was continuing. In addition to the data presented in November, DCE-MRI results were previously presented at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting. DCE-MRI results from patients treated at the 0.1 to 0.7 mg/kg dose levels were found to be suggestive of an anti-VEGF effect in the majority of treated patients. In 62% of evaluable liver tumors, there was a greater than 40% decline in Ktrans (measure of blood flow), an effect that is comparable to what has been observed with other anti-VEGF drugs in solid tumors (Cannistra et al., Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S, 2006; and Siegel et al., Journal of Clinical Oncology, Vol 26, No 18: pp. 2992-2998, 2008).

About Liver Cancers

Cancer affecting the liver, known as either primary or secondary liver cancer, is associated with one of the poorest survival rates in oncology and represents a major unmet medical need affecting a large number of patients worldwide. Primary liver cancer, or hepatocellular carcinoma (HCC), is one of the most common cancers worldwide, with more than 600,000 people diagnosed each year. Secondary liver cancer, also known as metastatic liver cancer, is cancer that spreads to the liver from another part of the body due to other common cancers like colon, lung, or breast cancer. Worldwide, more than 500,000 people are diagnosed with secondary liver cancer each year.

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 RNAs (siRNAs), 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 applying its therapeutic expertise in RNAi to address significant medical needs, many of which cannot effectively be addressed with small molecules or antibodies, the current major classes of drugs. Alnylam is leading the translation of RNAi as a new class of innovative medicines with peer-reviewed research efforts published in the world's top scientific journals including Nature, Nature Medicine, and Cell. The company is leveraging these capabilities to build a broad pipeline of RNAi therapeutics for the treatment of a wide range of disease areas, including respiratory syncytial virus (RSV), liver cancers, TTR-mediated amyloidosis (ATTR), hypercholesterolemia, and Huntington's disease. In addition, Alnylam formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for application in manufacturing processes for biotherapeutic products, including recombinant proteins and monoclonal antibodies. The company's leadership position in fundamental patents, technology, and know-how relating to RNAi has enabled it to form major alliances with leading companies including Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, and Cubist. Alnylam and Isis are majority owners of Regulus Therapeutics Inc., a company focused on the discovery, development, and commercialization of microRNA therapeutics. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

Alnylam Forward-Looking Statement

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, its expectations regarding the progress of its ongoing research and development programs for its RNAi therapeutic candidates, including ALN-VSP, its interpretation of early data from its ALN-VSP clinical trial, and its expectations regarding the effectiveness of its systemic delivery platform for 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: Alnylam's ability to discover and develop novel drug candidates, including ALN-VSP, and successfully demonstrate the efficacy and safety of drug candidates such as ALN-VSP in human clinical trials; results from pre-clinical testing or early clinical trials of a product candidate, including ALN-VSP, that may not predict the results that will be obtained in subsequent human clinical trials; as well as those risks more fully discussed in the "Risk Factors" section of its most recent quarterly report on Form 10-Q on file with the Securities and Exchange Commission. 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 does not assume any obligation to update any forward-looking statements.

SOURCE: Alnylam Pharmaceuticals, Inc.

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton (Investors), 617-551-8207
Amanda Sellers (Media), 202-955-6222 x2597
"Safe Harbor" Statement under the Private Securities Litigation Reform Act of 1995: Statements in this press release regarding Alnylam Pharmaceuticals's business which are not historical facts are "forward-looking statements" that involve risks and uncertainties. For a discussion of such risks and uncertainties, which could cause actual results to differ from those contained in the forward-looking statements, see "Risk Factors" in the Company's Annual Report or Form 10-K for the most recently ended fiscal year.