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ASCO Publishes Abstract on Phase I Data for Alnylam Liver Cancer Drug

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Alnylam Pharmaceuticals last week announced the publication of an abstract related to preliminary results from a phase I trial of the company's liver cancer drug ALN-VSP.

Notably, the abstract, which was published by the American Society of Clinical Oncology, indicates that one patient in the ongoing study died from liver failure following treatment, an adverse event that "was deemed possibly related to" the drug.

ALN-VSP comprises two siRNAs: one targeting vascular endothelial growth factor, which is associated with angiogenesis, and the other targeting kinesin spindle protein, which has been linked to cell proliferation in various cancers. It is formulated in a lipid nanoparticle developed by Alnylam partner Tekmira Pharmaceuticals.

About a year ago, Alnylam initiated the phase I trial, which is designed to enroll roughly 55 patients with advanced liver cancers, including hepatocellular carcinoma and other solid tumors with liver involvement, who are refractory to the standard of care.

In the open-label study, eight dose levels of ALN-VSP are being examined, ranging from 0.1 to 1.7 mg/kg, when administered via 15-minute intravenous infusions every two weeks. The primary endpoints are safety, tolerability, and pharmacokinetics, including a demonstration of the drug's maximum tolerated dose, according to the company.

Other objectives include the assessment of tumor response through published guidelines that define when a patient's disease improves, stabilizes, or progresses during treatment; change in tumor blood flow or vascular permeability; change in plasma biomarkers of angiogenesis; and an analysis of the pharmacodynamic effect of the drug on tumor biopsies, Alnylam added.

"As of December 2009, 12 patients, most with colorectal cancer, have been treated on the first four dose levels," translating to 41 administered doses, according to the ASCO abstract. The drug appeared well tolerated with no hepatotoxicity.

"The only significant adverse event was a grade two infusion reaction in one patient at 0.4 mg/kg [dose] that responded to slowing of the infusion," it adds. "At 0.7 mg/kg, a patient with [a] pancreatic neuroendocrine tumor extensively involving both lobes of the liver died of hepatic failure following the second dose" — an outcome possibly resulting from ALN-VSP.

"Two additional patients treated at 0.7 mg/kg did not exhibit hepatotoxicity or any other significant" adverse events, the abstract states.

Overall, ALN-VSP was "well tolerated by the majority of patients across the first four dose levels," the abstract concludes. Meanwhile, dynamic contrast enhanced-magnetic resonance imaging showed "preliminary evidence" of an anti-vascular endothelial growth factor effect.

In a statement released to RNAi News, Alnylam noted that serious adverse events "are common in advanced malignancy phase I studies."

The company also pointed out that the trial continues to actively enroll patients at all sites "with dose escalation continuing," and that "more complete data will be reviewed at ASCO, including results from a significant number of additional patients treated since the abstract was submitted."

"We are encouraged by the results we have seen with ALN-VSP in this phase I trial to date," Akshay Vaishnaw, senior vice president of clinical research at Alnylam, said in a statement. "The study is aimed at defining the maximum tolerated dose, which has not yet been reached.

"We look forward to sharing additional safety and tolerability data" during the ASCO annual meeting in early June, he added.

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