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As Tekmira Puts Cholesterol Rx Trial on Hold, Questions Linger Over Target

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By Doug Macron

When Tekmira Pharmaceuticals announced earlier this month that it would delay the development of its hypercholesterolemia drug candidate, it marked the second time the program hit a serious roadblock.

The company chalked up the setback to the performance of the lipid nanoparticle used to deliver the drug, which it said did not meet its "expectations for the intended application." However, questions about the drug's target have lingered for some time, raising the possibility that the trouble goes beyond the delivery technology, which has been shown effective in animals, including non-human primates, with a variety of siRNA payloads.

The drug, dubbed TKM-apoB, is designed to down-regulate apolipoprotein B, a protein involved in cholesterol metabolism. It is being developed as a treatment for patients with high LDL cholesterol who do not respond to currently available treatments.

The first-generation version of the drug, called ApoB-SNALP, entered phase I testing about two years ago (GSN 7/9/2009). However, that trial was halted prematurely this January after a patient enrolled in the study experienced side effects consistent with immune stimulation triggered by the siRNA component (GSN 1/14/2010).

A month later, Tekmira President and CEO Mark Murray said that the company developed a "more sophisticated screening assay" to identify better apoB-targeting siRNAs, one of which would be used with an improved version of the company's core lipid nanoparticle delivery technology to create TKM-apoB (GSN 2/11/2010).

Although the new drug was to re-enter the clinic later this year, earlier this month Tekmira announced that it would delay the planned phase I/II trial after the nanoparticle formulation did not prove as effective as expected in non-clinical experiments (GSN 9/16/2010).

To date, Tekmira has published extensively on the efficacy of its delivery technology, previously known as stable nucleic acid-lipid particles, or SNALPs. In 2006, for example, company researchers reported in Nature that the nanoparticles were successfully used to carry apoB-targeting siRNAs into cynomolgus monkeys.

More recently, Tekmira published a paper in The Lancet demonstrating that the technology could be used in conjunction with siRNAs to protect non-human primates from a lethal dose of Ebola virus (GSN 6/3/2010).

However, "we are not satisfied with the performance of our current TKM-ApoB [lipid nanoparticle] formulation for its intended use and we are going to focus on selecting an alternative formulation and availing ourselves of our existing improvements in formulation technology before resuming clinical development," Murray said in a statement when Tekmira announced the latest delay.

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He noted last week at the Rodman & Renshaw Healthcare conference in New York that Tekmira anticipates being able to bring the drug back into human studies "some time next year."

Despite Murray's optimism, questions have been raised about the use of apoB as a cholesterol target, most notably by officials from Tekmira partner Alnylam Pharmaceuticals.

In May last year, Alnylam CEO John Maraganore said during a conference call that he viewed the target chosen by his company for its hypercholesterolemia program as "more compelling" than Tekmira's, adding that Alnylam passed on apoB as a target (GSN 5/14/2009).

About a month later, Alnylam Vice President of Drug Discovery Muthiah Manoharan told Gene Silencing News that the decision to go after a different target, specifically proprotein convertase subtilisn/kexin type 9, was in part due to safety concerns including the incidence of fatty liver disease observed when apoB was knocked down (GSN 6/11/2009).

Meanwhile, phase III data on Isis Pharmaceuticals' mipomersen, an antisense-based cholesterol drug that inhibits apoB, has shown that a number of patients receiving the drug experienced a significant increase in liver enzymes.

In 2009, Murray defended apoB as a target, calling it "well-validated," and pointing to mipomersen data as evidence that its inhibition can lower LDL cholesterol. Earlier this year, while commenting on the halted phase I trial of ApoB-SNALP, he noted that "primates aren't completely faithful with respect to replicating the human immune system," and that "when you're first into man, you're going to come across things that are only seen in man."

Tekmira officials did not return a request for comment this week.

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