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Alnylam Presents Phase I Data at ASCO Showing Liver Cancer Drug Well Tolerated

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By Doug Macron

Alnylam Pharmaceuticals this week reported additional phase I data on its liver cancer drug ALN-VSP02, showing that the drug appears “generally” well tolerated, although the company did report a number of serious adverse events that were “possibly related” to treatment.

The data were presented at the American Society for Clinical Oncology's annual meeting in Chicago.

ALN-VSP02 comprises siRNAs against two targets: vascular endothelial growth factor, which is associated with angiogenesis, and kinesin spindle protein, which has been linked to cell proliferation in various cancers. It is formulated in lipid nanoparticles developed by partner Tekmira Pharmaceuticals, and is administered intravenously.

According to Alnylam, 41 patients with advanced solid tumors with liver involvement who have either not responded to standard treatment or whose disease has progressed after treatment received multiple doses of the drug at doses ranging from 0.1 mg/kg to 1.5 mg/kg.

ALN-VSP02 was generally well tolerated, with the most common side effects including fatigue, nausea, and fever. Some dose-limiting toxicities were observed, including a previously reported liver failure and death in one patient with “extensive hepatic metastases” at the 0.7 mg/kg dose level; transient thrombocytopenia in two patients at the 1.25 mg/kg dose level; and hypokalemia in one patient at the 1.5 mg/kg dose level.

Additionally, two patients with endometrial cancer experienced elevated white blood cell counts that were “possibly related” to ALN-VSP02 treatment, but these patients continued in the study.

“Based on these safety data, the recommended dose for advancement of ALN-VSP into phase II is 1 mg/kg,” the company said.

There were also indications of anti-tumor activity with treatment, Alnylam noted.

“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,” according to the company. “Fifty percent of patients evaluable for response attained stable disease or better with ALN-VSP doses greater than or equal to 0.7 mg/kg, compared to only 8 percent at doses less than or equal to 0.4 mg/kg.”

One patient with endometrial cancer and multiple liver lesions, meantime, experienced a roughly 70 percent reduction in tumor burden at the 0.7 mg/kg dose, and continues to receive the drug after one full year of treatment, Alnylam said.

In the study, 29 tumor biopsies were obtained from 15 patients across dose levels ranging from 0.4 mg/kg to 1.5 mg/kg, including liver tumor biopsies from 11 patients and extra-hepatic tumor biopsies from four patients, the company said. The siRNAs comprising ALN-VSP02 were detected in “nearly all” of the biopsy material evaluable for drug levels at “pharmacologically relevant” concentrations

“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,” Alnylam said. Additionally, 5' RACE analysis demonstrated RNAi-mediated mRNA cleavage.

"We believe the results from our ALN-VSP phase I trial represent an important milestone in the advancement of RNAi therapeutics,” Alnylam CEO John Maraganore said in a statement. “Clearly, 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 pipeline of systemically delivered RNAi therapeutics.”

Alnylam reiterated its expectation that further clinical development of ALN-VSP in phase II studies will occur once the drug has been partnered, ideally sometime in 2012.

Officials from Alnylam were not available for additional comment on the data.

Tekmira's Take

Even as it presses forward with a lawsuit charging Alnylam with misappropriation of its proprietary siRNA delivery know-how and trade secrets (see related story, this issue), Tekmira lauded the ALN-VSP02 data as a validation of its lipid technology used in the drug.

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"To date, this is the second completed human clinical trial that has reported Tekmira's [lipid nanoparticle] technology is safe and well tolerated,” Tekmira President and CEO Mark Murray said in a statement. “We anticipate further clinical data being presented from a number of LNP-enabled products over the remainder of 2011.”

In addition to ALN-VSP, Alnylam is using Tekmira's lipid nanoparticle technology with its phase I TTR amyloidosis drug ALN-TTR. Tekmira is also applying the technology to its own stable of RNAi drugs, which include the phase I hypercholesterolemia treatment TKM-ApoB, which has since been shelved as the company evaluates improved siRNA payloads and delivery vehicles, and the phase I cancer drug TKM-PLK1.

Separately this week, Tekmira also announced that it has expanded its pipeline to include two new oncology programs.

The first targets WEE1, a tyrosine kinase that regulates cell-cycle progression and the response to DNA damage, and the second targets CSN5, a multi-protein complex involved in regulating protein degradation via the ubiquitin proteasome pathway, according to the company.

Both programs will take advantage of Tekmira's lipid nanoparticle technologies, it said.


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