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Tekmira CEO Sheds New Light on Halted Cholesterol Rx Trial, RXi Continues to Define Pipeline

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By Doug Macron

Tekmira Pharmaceuticals' chief executive this week confirmed that the company will begin a second phase I study in its hypercholesterolemia program with a second-generation drug candidate in the second half of 2010, while providing a few new details about the problems experienced with the initial therapeutic agent.

Also this week, RXi Pharmaceuticals' new CEO, Noah Beerman, said that the company remains focused on defining its pipeline this year, but offered no timing on when the firm may meet its previously disclosed goals for 2010 of selecting a lead product candidate or securing at least one corporate partnership.

Both executives made their statements during the BIO-CEO and Investor conference held in New York this week.

Tekmira's cholesterol drug, called ApoB SNALP, is an siRNA designed to inhibit apolipoprotein B, a protein involved in cholesterol metabolism. It is delivered using the company's proprietary SNALP, or stable nucleic acid-lipid particle, technology.

In July, Tekmira announced that it had begun a phase I study of ApoB SNALP that was designed to evaluate the safety, tolerability, and pharmacokinetics of escalating single doses of the drug in about 30 patients with elevated low-density lipoprotein cholesterol (see RNAi News, 7/9/2009).

In January, however, the company said that it had halted the trial early after a patient in the study experienced side effects associated with the drug's siRNA payload (see RNAi News, 1/14/2010).

According to Tekmira President and CEO Mark Murray, the placebo-controlled trial ultimately enrolled 23 patients, 17 of which received ApoB SNALP.

"We're happy to say that the primary endpoint of safety and tolerability was established," he said this week. And while the drug has generally "proven to be well tolerated in human subjects … we did observe one subject that had a moderate, flu-like symptom [that] was caused by the siRNA payload we delivered." It was this observation that prompted the company to stop the study.

This finding, he noted during BIO-CEO, "is an illustration [that] primates aren't completely faithful with respect to replicating the human immune system. … It's [also] an illustration of when you're first into man, you're going to come across things that are only seen in man."

Following the setback, Tekmira developed a newer, "more sophisticated screening assay" to identify better apoB-targeting siRNAs, he noted, although he declined to provide additional details.

Using this assay, the company is considering a number of "slightly more modified" siRNAs that "will not stimulate the immune system" for evaluation in the second phase I hypercholesterolemia trial, Murray said. In addition, the siRNA will be delivered using a "new and improved" second-generation SNALP formulation, he noted.

RXi

After being spun out of CytRx as a pure-play RNAi drug developer, RXi has expressed interest in a number of different disease areas and indications at different times. Among them are neurodegenerative disorders including Alzheimer's disease and amyotrophic lateral sclerosis; oncology; metabolic diseases including obesity and type II diabetes; and inflammatory conditions.

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But in its short history, the company has yet to commit to any one program. Most recently, in June, the company's then-CEO Tod Woolf indicated that RXi was most interested in inflammatory diseases, buoyed by the promise of an oral drug-delivery technology, and that it expected to name its first drug candidate before the end of 2009 (see RNAi News, 6/25/2009).

The company missed that goal, and around the end of last year announced that Woolf had stepped down, to be replaced by Beerman. In an interview with RNAi News at the time, RXi's new top executive said that his near-term goal would be to winnow down potential areas of therapeutic focus to a manageable number for a small biotech (see RNAi News, 11/19/2009).

Speaking at BIO-CEO this week, Beerman reiterated this focus, noting that "one of our areas of aggressive development is to hone in on those areas that really have the greatest promise.

"What we will be doing over the course of 2010 is really focusing our efforts on three or four key disease areas that we will be taking forward into development and selecting development candidates as we move forward," he added.

According to Beerman, RXi sees potential in a variety of areas where local administration of RNAi therapeutics would be appropriate, including diseases involving compromised skin, respiratory conditions, central nervous system disorders, and ocular disease. In regards to systemic drug delivery, the company is eyeing oncology, inflammatory disorders, and metabolic diseases such as obesity.

And while RXi intends to pursue only a handful of these, "this isn't to say we have to abandon some of the other areas" where the firm's technology has promise, Beerman said. "But I think it's quite important to emphasize that we do need to focus our efforts on a manageable number of disease areas, and other areas … can be the basis of partnerships with pharmaceutical companies."

As with all RNAi drug shops, partnerships with big pharma and biotech are a key goal, and RXi has long been predicting it would forge major deals. In late 2008, RXi's former CFO Stephen DiPalma said the company would forge its first industry partnership before the end of that year — a goal that was not achieved.

In November, Beerman told RNAi News that RXi was continuing to pursue alliances, but declined to provide a timeline. In January, however, the company said at the Biotech Showcase 2010 that completing "one or more corporate partnerships" was a 2010 goal.

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