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American Society of Clinical Oncology (ASCO) 2010 Annual Meeting

Progress of ALN-VSP Program
Jared Gollob, M.D.

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Alnylam Presents Preliminary Phase I Data at American Society of Clinical Oncology (ASCO) Meeting for ALN-VSP, an RNAi Therapeutic for the Treatment of Liver Cancers

Alnylam's ALN-VSP Abstract Published by American Society of Clinical Oncology (ASCO)

Liver Cancers

ALN-VSP: Liver Cancers

Alnylam has advanced its RNAi therapeutic, ALN-VSP, for the treatment of liver cancers and potentially other solid tumors.

ALN-VSP targets two key genes each involved in the disease pathway of liver cancer: kinesin spindle protein, or KSP is involved in cancer proliferation, and vascular endothelial growth factor, or VEGF, is involved in the growth of new blood vessels that feed tumors. We believe that a dual-target approach in cancer increases the potential for a significant therapeutic benefit.

In April 2009, Phase I clinical trials were initiated for ALN-VSP. Preliminary results of this trial were presented at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting early June 2010. 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.

In pre-clinical studies, ALN-VSP demonstrated the ability to silence both tumor KSP and VEGF and stopped the proliferation of cancer cells. In these animal models, ALN-VSP showed a clear reduction in the growth and number of significant tumor masses in the liver. In addition, pre-clinical data have demonstrated a statistically significant increase in survival in animals treated with ALN-VSP.

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, known as stable nucleic acid-lipid particle (SNALP), developed by Tekmira Pharmaceuticals Corporation.

We filed our IND for ALN-VSP. Human clinical trials with this innovative medicine are expected to start in the first half of 2009

Phase I human clinical trial of ALN-VSP were initiated to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with advanced liver cancers, including hepatocellular carcinoma and other solid tumors with liver involvement.

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.

Primary liver cancer – hepatocellular carcinoma, or 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 cancers like colon, lung, or breast cancer. Worldwide, more than 500,000 people are diagnosed with secondary liver cancer each year.