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Alnylam Presents Clinical Data from Cholesterol Drug Trial, Animal Data from Huntington's Program

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By Doug Macron

Alnylam Pharmaceuticals this week released new data on two of its drug-development programs including preliminary clinical results from an ongoing phase I study of a second-generation version of its hypercholesterolemia treatment ALN-PCS and findings from a preclinical study of its Huntington's disease therapy ALN-HTT.

“We are extremely pleased with these data from our ALN-PCS trial, which represent what we believe is the first ever demonstration of efficacy for an RNAi therapeutic toward a clinically validated endpoint, namely LDL-C, a defined risk factor for coronary artery disease and acute myocardial infarction,” Alnylam CMO Akshay Vaishnaw said in a statement.

ALN-PCS comprises siRNAs against proprotein convertase subtilisn/kexin type 9, which has been shown to regulate low-density lipoprotein receptor levels and play a role in plasma LDL clearance. It incorporates a second-generation lipid nanoparticle technology called MC3.

The phase I study, which is being conducted in the UK, is designed to test single, escalating doses of the drug in up to 32 healthy volunteers with elevated baseline low-density lipoprotein levels. Notably, patients enrolled in the study are not being treated with statins or other lipid-lowering agents.

According to Alnylam, data from 20 patients in five sequential dose cohorts ranging from 0.015 mg/kg to 0.25 mg/kg or placebo show that ALN-PCS triggered “rapid, dose-dependent, and durable silencing of PCSK9 protein levels in plasma of up to 66 [percent] relative to baseline, with a statistically significant mean reduction of 60 [percent] at day four in the current high dose group of 0.25 mg/kg.”

Treatment with the drug also resulted in dose-dependent reductions in LDL-C of up to 50 percent relative to baseline, with a statistically significant mean reduction of 39 percent at day four at the highest dose level.

“Nadir effects on PCSK9 and LDL-C were achieved rapidly and occurred approximately four days after administration of a single dose,” Alnylam said. “There was also a dose-dependent increase in the proportion of subjects who achieved target levels of LDL-C of less than 100 mg/dL,” with all subjects in the two highest dose groups achieving target and a mean LDL-C of 84 mg/dL, versus 21.4 percent of subjects achieving target levels in any other group. 

Alnylam noted that these effects were “durable,” supporting the once-monthly dose regimen expected in future clinical studies.

Treatment was safe and well tolerated, with no serious adverse events observed.

Additional data from the phase I trial are expected to be released in the first half of this year.

“These data mark an important milestone … as they are the first to demonstrate safety, tolerability, and clinical efficacy of an RNAi therapeutic utilizing our second-generation lipid nanoparticle delivery technology,” Alnylam CEO John Maraganore said in a statement.

Not everyone fully agrees, however.

Alnylam partner Tekmira Pharmaceuticals this week released its own announcement regarding the ALN-PCS data, stating that while the data from the clinical study were positive, the delivery technology, in fact, belongs to Tekmira — a point of contention in a lawsuit between the companies.

In March, Tekmira sued Alnylam for allegedly stealing trade secrets related to its lipid delivery technology (GSN 3/17/2011). In the suit, Tekmira specifically cites the MC3 technology as misappropriated by Alnylam.

Tekmira said late last year that a trial date has been set for Oct. 30.

Hunting Huntington's

Alnylam's Huntington's disease treatment is an siRNA designed to silence the huntingtin gene, which causes the disease when mutated. It is being developed through a long-standing collaboration with Medtronic, which is developing a device to deliver the agent directly into the brain.

According to Alnylam, new data show that direct delivery of the huntingtin siRNA to the striatum using an implantable infusion system and a convection-enhanced delivery approach for seven days resulted in broad distribution of the siRNA across the striatum and surrounding brain regions of non-human primates.

This level of distribution of the siRNA resulted in the silencing of the huntingtin gene throughout the putamen by an average of approximately 45 percent, as well as reductions in the levels of huntingtin protein when evaluated by immunohistochemistry,” Alnylam said.

Alnylam expects to file an investigational new drug application for ALN-HTT this year.


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