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Alnylam Releases Phase I Data Showing Liver Cancer Drug Reaches Target Tissue, Triggers RNAi

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By Doug Macron

Alnylam Pharmaceuticals this week released data from on ongoing phase I study of its siRNA-based liver cancer drug ALN-VSP showing that the agent could be systemically delivered at "pharmacologically relevant" levels in target tissue and trigger an RNAi effect.

The disclosure comes almost a year after Arrowhead Research subsidiary Calando Pharmaceuticals published phase I data demonstrating that its own cancer drug, CALAA-01, could knock down its intended target mRNA and protein inside a tumor through an RNA interference mechanism when delivered intravenously into humans (GSN 3/25/2010).

ALN-VSP comprises two siRNAs: one targeting vascular endothelial growth factor, which is associated with angiogenesis, and the other targeting kinesin spindle protein, which has been linked to cell proliferation in various cancers. It is formulated in a lipid nanoparticle developed by Tekmira Pharmaceuticals.

According to Alnylam, post-treatment tumor biopsies from eight patients in the study were analyzed for levels of the drug. Five of the samples were taken from tumor tissue in the liver, while the other three were obtained from tumor tissue outside the liver.

The patients had all received doses of ALN-VSP ranging from 0.4 to 1.25 mg/kg, the company noted.

The siRNAs that comprise the drug were found in "almost all" of the biopsy samples at concentrations ranging from 0.3 to 142 nanograms per gram of tissue, Alnylam said. "These levels of siRNA are pharmacologically relevant since in preclinical studies with systemically delivered siRNAs, a tissue level of 1 ng/g has been shown to be associated with 50 [percent] target gene silencing," it added.

In order to confirm that the siRNAs were triggering an RNAi effect, 5'-RACE was conducted on the three biopsies that were sufficient for such an analysis, all of which came from patients treated at the .4 mg/kg dose level.

"In two patients whose post-treatment biopsies were performed two days after dosing, the 5' RACE assay combined with deep sequencing showed that approximately 27 [percent] and 29 [percent] of all VEGF-derived mRNA fragments corresponded exactly to the predicted RNAi-mediated cleavage product based on the VEGF siRNA sequence," Alnylam said.

"By contrast, a pre-dose biopsy available for one of those patients contained only approximately 1 [percent] predicted VEGF cleavage product," while analysis of banked normal liver and tumor samples from untreated patients showed a background level of between 0.1 and 0.7 percent, the company added.

"Compared to these low background levels, the amount of predicted VEGF cleavage product in the two post-treatment biopsies was highly statistically significant," it said. "In the third patient at 0.4 mg/kg whose post-treatment biopsy was obtained 7 days post-dose, there was no detectable increase in the predicted VEGF cleavage product compared to the pre-dose biopsy."

"We have been able to quantify significant human tissue levels of siRNAs at concentrations that exceed our 1 ng/g target level that is associated with effective target gene silencing in pre-clinical animal models," Alnylam CEO John Maraganore said in a statement. "More importantly, we have demonstrated proof of RNAi mechanism in man with [lipid nanoparticle] delivery of siRNAs."

The phase I study of ALN-VSP is designed to enroll a total of 55 patients with advanced solid tumors with liver involvement, and its primary objectives are the evaluation of the safety and tolerability of eight possible dose levels ranging from 0.1 to 1.7 mg/kg.

Secondary objectives include characterization of pharmacokinetics, and assessment of pharmacodynamic effects and tumor response.

In November, Alnylam presented data showing that the drug is generally well tolerated at doses up to 1.25 mg/kg (GSN 11/11/2010).

Further Evidence

With the release of the data on ALN-VSP, the RNAi therapeutics space has now seen two demonstrations that RNAi can be achieved in humans in a therapeutic setting after Calando published data in Nature last March on CALAA-01.

The drug comprises a linear, cyclodextrin-based polymer decorated with a human transferrin protein targeting ligands on its surface, which are designed to engage transferrin receptors on the surface of cancer cells; polyethylene glycol to promote stability in biological fluids; and an siRNA payload targeting the M2 subunit of ribonucleotide reductase, an established cancer target.

According to the paper, patients with solid cancers refractory to standard-of-care therapies were treated with one of three doses of the drug on days 1, 3, 8, and 10 of a 21-day cycle by 30-minute intravenous infusion.

Biopsies from melanoma patients enrolled in the study not only showed the presence of the nanoparticles inside of the tumors, but that they also accumulated in a dose-dependent manner. Additionally, "a reduction was found in both the specific messenger RNA and the protein levels when compared to pre-dosing tissue," Calando researchers wrote in Nature.

"Most notably, we detect the presence of an mRNA fragment that demonstrates that siRNA-mediated mRNA cleavage occurs specifically at the sire predicted for an RNAi mechanism from a patient who received the highest dose of the nanoparticles," they added.

Calando is still enrolling patients in the phase I study of CALAA-01.


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