Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), 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.
“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.”
"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.
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