Alnylam Pharmaceuticals, Inc. ALNY, a leading RNAi therapeutics
company, and collaborators announced today 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 paper, titled “First-in-Man Trial of an RNA Interference Therapeutic
Targeting VEGF and KSP in Cancer Patients with Liver Involvement” appears as
an OnlineFirst publication in the journal Cancer Discovery (Tabernero et al.,
Cancer Discovery CD-12-0429; Published OnlineFirst January 2013). 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.
“Our ALN-VSP Phase I clinical trial defines the most comprehensive human
experience for RNAi therapeutics delivered with lipid nanoparticle
formulations. Results from this study highlight safety and tolerability of
multiple doses of ALN-VSP, proof of RNAi activity in man, and evidence for
anti-tumor activity in a very advanced, heavily pre-treated cancer patient
population,” said Jared Gollob, M.D., Vice President, Clinical Research at
Alnylam. “We are encouraged by the anti-tumor activity observed in this study
in multiple patients who achieved stable disease or better; this includes 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 for RNAi therapeutics delivered with
lipid nanoparticle formulations, as patients received an average of over 11
months of treatment overall, including one patient who received treatment for
over two full years.”
ALN-VSP is a systemically delivered RNAi therapeutic using first-generation
lipid nanoparticle (LNP) or “SNALP” delivery technology that comprises two
siRNAs targeting two genes critical for the growth and development of cancer
cells: vascular endothelial growth factor (VEGF) and kinesin spindle protein
(KSP). 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.
Results from the extension study were previously presented at the American
Society of Clinical Oncology (ASCO) Annual Meeting in 2012 and demonstrated
that chronic dosing with ALN-VSP up to 1.0 mg/kg was generally safe and well
tolerated in this setting. On average, patients received bi-weekly treatments
for 11.3 months. An endometrial cancer patient achieved a complete response
(CR) after 20 months of treatment at 0.7 mg/kg and remained in remission upon
completion of 26 months of therapy. A patient with pancreatic neuroendocrine
tumor (PNET) treated at 1.0 mg/kg remained on study with stable disease (SD)
for 18 months, and two patients with renal cell carcinoma (RCC) treated at 1.0
mg/kg remained on study with SD for approximately 8-12 months. No new
toxicities were reported among the patients enrolled onto the extension study.
A PNET patient and an RCC patient who achieved SD at 1.0 mg/kg came off the
study after 5.5 and 8.5 months, respectively, for adverse events that included
grade 3 elevated alkaline phosphatase or grade 2 fatigue deemed possibly
related to study drug. A decrease in spleen volume, likely an on-target
anti-KSP effect and not associated with any adverse events, occurred to a
greater degree on the extension study than in the Phase I trial and was most
pronounced in patients receiving 12 or more doses.
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