Phase I ALN-VSP Trial Data /Liver Cancer

Alnylam Presents Additional Interim Phase I Data for ALN-VSP, an RNAi Therapeutic for the Treatment of Liver Cancer
-- 28 Patients Treated to Date with 127 Total Number of Doses as High as 1.25 mg/kg with Dose Escalation Continuing --

CAMBRIDGE, Mass., Nov 10, 2010 (BUSINESS WIRE) -- -- Results to Date Demonstrate Tolerability and Evidence for Pharmacodynamic Activity, Providing Key Human Data for Alnylam Systemic Delivery Platform --

Alnylam Pharmaceuticals, Inc. /quotes/comstock/15*!alny/quotes/nls/alny (ALNY 12.39, +0.10, +0.81%) , a leading RNAi therapeutics company, today presented additional interim data from its ongoing Phase I trial with ALN-VSP, a systemically delivered RNAi therapeutic for the treatment of advanced solid tumors with liver involvement. The data were presented at the Chemotherapy Foundation Symposium being held in New York City. Data from pharmacodynamic measurements shown earlier this year provided preliminary evidence of clinical activity, and new results from the initial 28 patients in the first six dose cohorts demonstrate that ALN-VSP is generally well tolerated. The study has not yet reached a maximum tolerated dose (MTD) and the trial continues to enroll patients with dose escalation. Importantly, the safety results from this study provide a significant human experience database applicable to broader elements of the Alnylam systemic delivery pipeline, including ALN-TTR01, an RNAi therapeutic for the treatment of transthyretin-mediated amyloidosis (ATTR) which is also in a Phase I clinical trial.

"We continue to be encouraged by the data emerging from our ALN-VSP program, as they represent key clinical results from our most advanced systemically delivered RNAi therapeutic. Indeed, these data are not only important for the continued advancement of our ALN-VSP program, but they also significantly increase our confidence in our entire platform of systemically delivered RNAi therapeutics, including ALN-TTR01 which is in a Phase I study for ATTR," said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President, Clinical Research. "In our ALN-VSP Phase I study, the MTD has not yet been reached and we continue to enroll patients in a dose-escalating manner. In addition, several patients with stable disease have advanced to an extension study. The next steps in this program include continued patient accrual to determine MTD, and further assessment of safety and activity in the MTD expansion phase of the study. We have also obtained a significant number of human biopsy samples in this study with which we intend to perform molecular analyses for RNAi delivery and pharmacology. We expect to further update these results at the annual ASCO meeting in 2011."

"Both primary liver cancer and metastatic disease of the liver are associated with poor prognosis for patients, and new therapies are clearly needed. These interim data with multiple doses of ALN-VSP, combined with the data presented earlier in the year, are encouraging and we look forward to continued dose escalation to explore tolerability and potential for tumor response," said Howard A. (Skip) Burris, III, M.D., Chief Medical Officer; Director, Drug Development of the Sarah Cannon Research Institute in Nashville, Tennessee, and a Principal Investigator for the ALN-VSP Phase I study. "To our knowledge, ALN-VSP is the most advanced RNAi therapeutic for the treatment of cancer, and the clinical experience to date represents the most extensive experience in advancing this promising approach to patients."

Data presented today demonstrate that ALN-VSP is well tolerated in most patients. The maximum tolerated dose has not yet been reached and enrollment in the trial is continuing in a dose escalating manner. A total of 127 doses of ALN-VSP ranging from 0.1 to 1.25 mg/kg have been administered to 28 patients, with two to 13 doses administered per patient. The majority of these patients have colorectal cancer, a primary tumor that often metastasizes to the liver.

Several patients enrolled in the higher dose groups have achieved stable disease. Patients who achieved stable disease have been enrolled in a dose extension study which continues to actively enroll. This trial is designed to enroll patients that have completed four months of dosing cycles and achieved designation of at least stable disease.

No dose-dependent trends have been observed in clinical or laboratory adverse events, including liver function tests (LFT). As previously presented at the ASCO 2010 meeting, a patient with advanced pancreatic neuroendocrine cancer with extensive involvement of the liver developed hepatic failure five days following the second dose at 0.7 mg/kg, and subsequently died; this was deemed possibly related to study drug. At 1.25 mg/kg, a patient experienced grade three thrombocytopenia after the first dose; this was deemed related to study drug and was resolved within five days. There have been three acute infusion reactions at 0.4, 0.7, and 1.25 mg/kg; all three patients tolerated further treatment with prolongation of infusion duration. None of these events preclude further dose-escalation.

This Phase I trial is also designed to obtain tumor biopsies from patient volunteers. To date, 17 biopsies have been obtained from nine patients. These include liver and extrahepatic tumors biopsies that have been obtained in patients who have received ALN-VSP at doses ranging from 0.4 to 1.25 mg/kg. Histopathological and molecular analyses are ongoing to assess drug delivery, RNAi mediated activity, and mRNA target engagement. Alnylam anticipates obtaining multiple additional biopsies as the study progresses.

As previously presented at the ASCO 2010 meeting, DCE-MRI results from patients treated at the 0.1 to 0.7 mg/kg dose levels were 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). Also, as previously presented at ASCO 2010, pharmacokinetic data shows that Cmax (peak serum concentration of drug) and area under the curve (AUC) were dose proportional with no evidence of drug accumulation.

About ALN-VSP Clinical Program

ALN-VSP is Alnylam's first systemic RNAi program and represents the company's first clinical program in oncology. The drug is formulated in a first generation lipid nanoparticle developed by Tekmira Pharmaceuticals Corporation. 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 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.

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, Alnylam's views with respect to the potential for RNAi therapeutics, including ALN-VSP, its expectations with respect to the timing and success of its clinical trial of ALN-VSP, and its plan to disclose additional data from that clinical trial, 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, such as ALN-VSP for the treatment of liver cancers, and successfully demonstrate the efficacy and safety of ALN-VSP and other drug candidates 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.


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