Analysis of human tissue samples in a Phase I human clinical trial with ALN-VSP (Alnylam Pharmaceuticals), for the first time demonstrated strong proof of RNAi in man. ALN-VSP, an RNAi therapeutic for the treatment of hepatocellular carcinoma and other solid tumors with liver involvement, contains two small interfering RNAs (siRNAs) formulated in a proprietary first generation lipid nanoparticle (LNP) formulation developed by Tekmira Pharmaceuticals Corporation.

Primary liver cancer or hepatocellular carcinoma (HCC) is associated with poor survival rates and represents a major unmet medical need affecting a large number of patients worldwide. HCC is also 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, affects more than 500,000 people worldwide each year.

RNAi therapeutics represents a breakthrough in understanding how genes are turned on and off in cells, and offer a completely new approach to drug discovery and development. This approach, which harnesses the natural biological process of RNAi occurring in our cells, has the potential to treat a broad number of human diseases by ?silencing? disease causing genes, has been heralded as ?a major scientific breakthrough that happens once every decade or so.? The therapeutic approach based on RNAi has the potential to treat disease and help patients in a fundamentally new way.

ALN-VSP is designed to target kinesin spindle protein, or KSP (also known as eglin 5 or Eg5), required for tumor proliferation and vascular endothelial growth factor, or VEGF, required for tumor growth. Pre-clinical data in mouse tumor model studies have demonstrated efficacy of ALN-VSP, including suppression of targeted genes, demonstration of an RNAi mechanism of action, tumor reduction, and extension of survival. Commenting on the results, Dr. Mark J. Murray, Tekmira’s President and CEO, said, “This human proof-of-concept is an important advancement in the field of RNAi drug development.”

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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 trial evaluated eight potential dose levels from 0.1 to 1.7 mg/kg. The primary objective is to evaluate the safety, tolerability, and pharmacokinetics of intravenous ALN-VSP, including demonstration of the maximum tolerated dose.

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RNAi therapeutics, such as siRNAs, require delivery technology to be systemically effective. The proprietary LNP technology, formerly referred to as stable nucleic acid-lipid particles or SNALP, is one of the most widely used siRNA delivery approaches for systemic administration. John Maraganore, Ph.D., Chief Executive Officer of Alnylam noted: ?With major advances in RNAi delivery we believe that now is the time for clinical advancement and potential product commercialization.”

The LNP technology encapsulates siRNAs with high efficiency in uniform lipid nanoparticles that are effective in delivering RNAi therapeutics to disease sites in numerous preclinical models.

Milestones
In November 2010, during the Chemotherapy Foundation Symposium held in New York City, researchers presented interim pharmacodynamic data from the ongoing Phase I trial showing that the initial 28 patients in the first six dose cohorts demonstrate that the drug candidate is generally well tolerated. This data follows the preliminary evidence of clinical activity.

“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. These data significantly increase our confidence in our entire platform of systemically delivered RNAi therapeutics” said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President, Clinical Research at Alnylam. “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.”

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. [1,2]

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.

Reference:
[1] Cannistra SA, Matulonis U, Penson R, Wenham R, Armstrong D, Burger RA, Mackey H, Douglas J, Hambleton J, McGuire W. Bevacizumab in patients with advanced platinum-resistant ovarian cancer. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 5006
[2] Siegel AB, Cohen EI, Ocean A, Lehrer D, Goldenberg A, Knox JJ, Chen H, Clark-Garvey S, Weinberg A, Mandeli J, Christos P, Mazumdar M, Popa E, Brown RS, Rafii S, Schwartz JDPhase II Trial Evaluating the Clinical and Biologic Effects of Bevacizumab in Unresectable Hepatocellular Carcinoma Journal of Clinical Oncology , Vol 26, No 18: pp. 2992-2998, 2008.

For more information (Clinical Trials):
– Dose Escalation Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Intravenous ALN-VSP02 In Patients With Advanced Solid Tumors With Liver Involvement. Trial Identifier: NCT00882180
– Multi-center, Open Label, Extension Study of ALN-VSP02 in Cancer Patients Who Have Responded to ALN-VSP02 Treatment. Trial Identifier: NCT01158079

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