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Liver Cancers
ALN-VSP: Liver Cancers
Alnylam has advanced its RNAi therapeutic, ALN-VSP, into the clinic for the treatment of liver cancers and potentially other solid tumors with liver involvement.
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. Results of this trial were presented at the American Society of Clinical Oncology (ASCO) 2011 Annual Meeting early June 2011. ALN-VSP is Alnylam's first systemic RNAi program and the Phase I trial results represent an important milestone in the advancement of RNAi therapeutics. Data demonstrate for the first time both clinical activity and RNAi mechanism for an RNAi therapeutic.
The Phase I study showed that ALN-VSP was generally well tolerated. ALN-VSP was administered to 41 patients at doses ranging from 0.1 to 1.5 mg/kg; a total of 209 doses have been administered, with a range of 1 to 28 doses per patient. Based the safety data, the recommended dose for advancement of ALN-VSP into Phase II studies is 1.0 mg/kg. In this study, 29 tumor biopsies were obtained voluntarily from 15 patients across multiple dose levels (from 0.4 to 1.5 mg/kg) using a CT-guided procedure; these included hepatic (liver) tumor biopsies from 11 patients and extra-hepatic tumor biopsies from four patients. The two siRNAs targeting VEGF and KSP that comprise ALN-VSP were detected in nearly all of the biopsy samples evaluable for drug levels at siRNA concentrations ranging from 0.3 to 142 ng/g tissue. These levels of siRNA are pharmacologically relevant since pre-clinical studies have shown that siRNA tissue levels of 1 ng/g are associated with 50% target gene silencing (Landesman et al., Silence, 1:16, 2010).
In June 2012, results from our Phase I extension study were presented at the ASCO Annual Meeting. These data include safety and tolerability of multiple doses of ALN-VSP, as well as evidence for anti-tumor activity in this very advanced, heavily pre-treated cancer patient population. Multiple patients achieved stable disease or better, including a patient with endometrial cancer metastatic to the liver who achieved a complete response. Results from the extension study also give us increased confidence in long-term chronic dosing with RNAi therapeutics delivered via LNPs, as patients have received drug twice a month for up to nearly two years, and approximately 11 months on average. In this study, chronic dosing of up to 23 months with ALN-VSP was found to be generally safe and well tolerated.
The drug is formulated using a first generation lipid nanoparticle developed by Tekmira Pharmaceuticals Corporation. The ALN-VSP program is partnered with Ascletis for HCC in China, and Alnylam will retain all rights in the rest of the world.
ALN-VSP Clinical Timeline
A total of 62 doses had 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 had not yet been reached. ALN-VSP was well-tolerated in most patients to date.
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).
Safety
ALN-VSP was administered to 41 patients at doses ranging from 0.1 to 1.5 mg/kg. A total of 209 doses were administered, with a range of 1 to 28 doses per patient. Disease control (stable disease or better) was observed in 13 of 31 evaluable patients (42%) treated at doses of 0.4 to 1.5 mg/kg. The average duration of disease control is approximately five months, with a range of two to 14 months. Currently, five patients with disease control continue to receive ALN-VSP under an extension protocol; these include an endometrial cancer patient treated at 0.7 mg/kg with an ongoing partial response, as well as two renal cell cancer and two pancreatic neuroendocrine tumor patients treated at 1.0 mg/kg who have had stable disease for over four months.
Results from this Phase I study show that ALN-VSP was generally well tolerated. The most common adverse events were grade 1-2 fatigue (24% of patients), nausea (17% of patients) and fever (15% of patients), with no clear dose dependence. There were also no dose-dependent changes in liver function tests. Based on these safety data, the recommended dose for advancement of ALN-VSP into Phase II studies is 1.0 mg/kg.
Anti-tumor Activity
Patients participating in the study were heavily pre-treated, having received an average of 4.3 prior treatment regimens for their metastatic cancer, including both chemotherapy and anti-angiogenic drugs. Fifty percent (12 of 24) of patients evaluable for response attained stable disease (SD) or better with ALN-VSP doses greater than or equal to 0.7 mg/kg, compared to only 8% (1 of 13) at doses less than or equal to 0.4 mg/kg. Results include one major ongoing response in a patient with endometrial cancer and multiple liver metastases treated at 0.7 mg/kg. This patient, whose treatment is ongoing after over one full year, has so far had a partial response (PR) with an approximately 70% reduction in tumor burden. Sixty four percent (7 of 11) of patients achieved SD at the recommended Phase II dose of 1.0 mg/kg and 45% (5 of 11) continue to receive drug on study.
Proof of RNAi Mechanism
In this study, 29 tumor biopsies were obtained voluntarily from 15 patients across multiple dose levels (from 0.4 to 1.5 mg/kg) using a CT-guided procedure; these included hepatic (liver) tumor biopsies from 11 patients and extra-hepatic tumor biopsies from four patients. The two siRNAs targeting VEGF and KSP that comprise ALN-VSP were detected in nearly all of the biopsy samples evaluable for drug levels at siRNA concentrations ranging from 0.3 to 142 ng/g tissue. These levels of siRNA are pharmacologically relevant since pre-clinical studies have shown that siRNA tissue levels of 1 ng/g are associated with 50% target gene silencing (Landesman et al., Silence, 1:16, 2010). While there was no dose-dependence to the levels of VEGF and KSP siRNAs detected in biopsy samples, this finding was consistent with the high degree of variability in proportion of tumor, fibrotic/necrotic tissue, and normal tissue in biopsy samples, which impacts the quantitative interpretations of molecular results.
The extension study included patients enrolled in the ALN-VSP Phase I trial who achieved stable disease (SD) or better after four months of treatment; patients were eligible to continue on the extension study until disease progression. Main objectives included continued evaluation of safety and tolerability and assessment of disease response. Seven of 37 patients (18.9%) evaluable for response went onto the extension study. These included 1 of 7 (14.2%) at 0.4 mg/kg, 2 of 5 (40%) at 0.7 mg/kg, and 4 of 11 (36.3%) at 1.0 mg/kg. At the time of enrollment, six patients had SD and one had an unconfirmed partial response. For these patients treated on both the Phase I trial and extension study, the average length of time on treatment was 10.5 months, with a range of five to 23 months. As of today, two patients remain on the extension study, including an endometrial cancer patient on study for 23 months who achieved a CR after 20 months of treatment at 0.7 mg/kg and one patient with pancreatic neuroendocrine tumor (PNET) with continued SD after 14.5 months of treatment at 1.0 mg/kg. A PNET patient and a renal cell carcinoma patient and a PNET patient who achieved SD at 1.0 mg/kg came off the study after 85.5 and 58.5 months, respectively, for adverse events that included grade 2 fatigue or grade 3 elevated alkaline phosphatase or grade 2 fatigue deemed possibly related to study drug. Results from the extension study showed that chronic bi-weekly dosing with ALN-VSP up to 1.0 mg/kg was generally safe and well tolerated in this setting. No new toxicities were reported among the seven patients enrolled onto the extension study.
