Alnylam presents interim data from ALN-VSP02 Phase I trial for liver cancer at ASCO 2010

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today preliminary clinical 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 are being presented at the ASCO meeting in a poster titled "Interim safety and pharmacodynamic results for ALN-VSP02, a novel RNAi therapeutic for solid tumors with liver involvement," in the Developmental Therapeutics - Experimental Therapeutics poster session being held from 8:00 a.m. to 12:00 p.m. CT in S Hall A2. The study results from the initial 19 patients in the first four dose cohorts demonstrate that ALN-VSP is well tolerated in most patients, and results from pharmacodynamic measurements provide preliminary evidence of clinical activity. The study has not yet reached a maximum tolerated dose and is continuing enrollment with dose escalation.

“a major scientific breakthrough that happens once every decade or so”

"Both primary liver cancer and metastatic disease of the liver are associated with poor prognosis for patients, and new therapies are clearly needed," said Josep Tabernero, M.D., Head of the Gastrointestinal Cancer and Phase I Program at Vall d'Hebron University Hospital in Barcelona, Spain. "The initial data with ALN-VSP are encouraging and we look forward to continued dose escalation to explore tolerability and potential for tumor response."

"The safety and tolerability of multiple doses of ALN-VSP demonstrated so far in these patients with advanced cancer and liver metastases are encouraging," said Charles Fuchs, M.D., M.P.H., Director for the Gastrointestinal Cancer Center at Dana-Farber Cancer Institute in Boston. "It is also notable that DCE-MRI results appear to show an anti-VEGF effect with ALN-VSP in the majority of these patients who have been previously exposed to multiple anti-VEGF and chemotherapy drugs. I look forward to seeing additional safety and pharmacodynamic data as dose escalation proceeds."

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 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.

ALN-VSP was well-tolerated in most patients to date. A total of 62 doses have been administered to 19 patients receiving 0.1, 0.2, 0.4, or 0.7 mg/kg ALN-VSP. The majority of these patients had colorectal cancer, a primary tumor that often metastasizes to the liver. There were two mild acute infusion reactions at 0.4 and 0.7 mg/kg; both patients had no further reactions with slowing of the infusion and stayed on the trial. At 0.7 mg/kg, a patient with advanced pancreatic neuroendocrine cancer with extensive involvement of the liver developed hepatic failure five days following the second dose and subsequently died; this was deemed possibly related to study drug. Six additional patients treated at 0.7 mg/kg did not exhibit any evidence of hepatotoxicity. Maximum tolerated dose has not yet been reached and active enrollment is continuing.

Pharmacokinetic data showed that Cmax (peak serum concentration of drug) and area under the curve (AUC) were dose proportional with no evidence of drug accumulation. In addition, DCE-MRI results 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). Molecular and cellular analyses of biopsy samples are ongoing.

"We are encouraged by the results we have seen to date with ALN-VSP in this trial, which include tolerability data, as well as preliminary data on potential pharmacodynamic effects in this very advanced cancer patient population. The maximum tolerated dose has not yet been reached, and we continue to enroll patients in a dose-escalating manner," said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President, Clinical Research at Alnylam. "We look forward to the further development of this promising agent and completion of this trial. Indeed, this is an important study that, to our knowledge, currently represents one of the most comprehensive clinical trials of systemically delivered RNAi therapeutics and also one of the most extensive experiences of RNAi therapeutics in cancer."

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 lipid nanoparticle developed by Tekmira Pharmaceuticals Corporation.