Alnylam Pharmaceuticals, Inc. announced the publication of complete study results from a Phase I trial with ALN-VSP, a systemically delivered RNAi therapeutic for the treatment of advanced solid tumors with liver involvement. The study results document anti-tumor activity for ALN-VSP in a heavily pre-treated and advanced patient population, including a complete response in an endometrial cancer patient who had multiple hepatic metastases. In addition, this study provided proof of RNAi mechanism in man based on molecular analysis of biopsy samples from patients.

Finally, in this study -- the most comprehensive study of a systemically administered RNAi therapeutic to date -- chronic dosing of ALN-VSP for up to 26 months was found to be generally safe and well tolerated. The ALN-VSP Phase I trial was designed as a multi-center, open-label, dose-escalation study in patients with advanced solid tumors with liver involvement who failed to respond to or had progressed after standard treatment. A total of 41 patients were enrolled.

The primary objective was to evaluate the safety, tolerability, and pharmacokinetics of intravenously administered ALN-VSP given every two weeks. Other secondary and exploratory objectives included: assessment of tumor response using Response Evaluation Criteria for Solid Tumors (RECIST); quantitation of change in tumor blood flow and vascular permeability as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); and, analysis of pharmacodynamic effects of ALN-VSP on tumors as measured in patients electing to proceed with voluntary pre- and post-treatment biopsies. Results of the Phase I study in 41 patients were previously presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2011 and demonstrated proof of RNAi mechanism based on liver biopsy samples and disease control (stable disease or better after first two months) in 13/31 (42%) patients treated at doses greater than or equal to 0.4 mg/kg.

ALN-VSP was generally safe and well tolerated up to a dose of 1.0 mg/kg. The most common adverse events were grade 1-2 fatigue (24% of patients), nausea (17% of patients) and fever (17% of patients), with no clear dose relationship. There were also no dose-dependent changes in liver function tests.

Grade 2 infusion-related reactions were observed in 15% of patients, or 3% of total doses administered; these reactions responded to slowing of the infusion of drug, and no patients discontinued therapy because of an infusion reaction. Dose-limiting toxicities included: liver failure and death in one patient with extensive hepatic metastases involving greater than 70% of liver mass and prior splenectomy/partial hepatectomy at 0.7 mg/kg; transient grade 3 thrombocytopenia in two patients at 1.25 mg/kg; and grade 3 hypokalemia in one patient at 1.5 mg/kg. The ALN-VSP extension study was designed to enable continued dosing with ALN-VSP in patients who had achieved stable disease or better after completing four months of treatment on the Phase I trial.

Patients enrolled onto the extension study were permitted to receive bi-weekly ALN-VSP at the same dose level that they had been safely treated with in the Phase I study until disease progression or unacceptable toxicity; a total of seven patients were enrolled. The primary objective was to collect long-term safety data. The secondary objective was to assess tumor response.