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Gene Knockdown At BIO, Parties, Protesters, and Good News for Antisense

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As usual, the 2005 annual meeting of the Biotechnology Industry Organization resembled a circus. Aside from the usual throng of protesters in the street bellowing against the use of genetically modified foodstuffs (several people were arrested), the exhibit hall hummed as thousands of attendees hobnobbed and networked with representatives from biotechnology companies from across the globe — and the countless regional business development officers accompanying them.

Among the companies vying for attention at the conference, Vancouver-based OncoGenex represented a particularly interesting case. Unlike more fashionable firms devoted to commercializing RNA interference technology as a therapeutic system, OncoGenex has chosen an older and less flashy mRNA knockdown method: antisense — albeit second-generation antisense technology.

Founded in 2000 by Martin Gleave, a professor of surgery at the University of British Columbia who now also serves as CSO, OncoGenex was built to commercialize developments of the Prostate Center at Vancouver General Hospital, says Scott Cormack, the company’s cofounder and CEO. Gleave and Cormack saw promise in drug targets identified by researchers at UBC and Vancouver General working at the Prostate Center, but they found that several of the most promising were considered undruggable by small molecule or monoclonal antibody means due to the targets’ intracellular location and serum concentration. After surveying the landscape of alternative therapeutic strategies to small molecule compounds — RNAi was deemed too risky because of challenges to drug delivery — Gleave and Cormack settled on second-generation antisense technology developed by Isis Pharmaceuticals.

Cormack says first-generation antisense chemistry ran into difficulties when applied as a therapeutic because of unwanted side effects and problems delivering sustained doses of the drug. The second-generation antisense chemistry developed by Isis, however, adds a methoxyethyl modification to the antisense molecule to increase its ability to bind with the target sequence and resist degradation in the body, says Cormack. “First-generation antisense was a little iffy,” he says, “but with the second-generation technology we can deliver the drug only once a week systemically.”

OncoGenex’s most advanced drug so far targets the production of clusterin, a cell-survival protein that is up-regulated in response to standard anti-cancer treatments such as hormone ablation in patients with advanced prostate cancer. In July, OncoGenex said it had initiated the first of four Phase II clinical trials of the antisense-derived drug.

— John S. MacNeil

 

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