Positive Results for Onyx’s Myeloma Drug Carfilzomib

This morning Onyx Pharmaceuticals shared good news about its multiple myeloma drug candidate carfilzomib- the compound helped 24% of the multiple myeloma patients enrolled in a Phase 2b clinical trial, all of whom have seen other therapies fail. Onyx's stock was up over 21% on the news, last we checked. The company is hammering out the details of filing a new drug application (NDA) for carfilzomib, something they intend to do by the end of 2010. Multiple myeloma is a type of blood cell cancer that's very challenging to treat, with relapses a fact of life. Patients in Onyx's trial "can expect to respond to therapy only 11 percent of the time and survive for only six to 10 months," Michael G. Kauffman, M.D., Ph.D., Chief Medical Officer of Onyx Pharmaceuticals, said in a press release. In these patients, when carfilzomib worked, the duration of the response was over seven months. Carfilzomib is part of a new generation of myeloma drugs that are just starting to emerge, as we wrote about in C&EN last year. Onyx got carfilzomib when it purchased the company Proteolix last October. The molecule inhibits the proteasome, the sophisticated protein machine in every cell that acts as a trash compactor for unneeded proteins. A first-in-class proteasome inhibitor is already on the market- Velcade (bortezomib), from Millennium, the Takeda Oncology Company. What's cool is that there are subtle chemical differences in how the two drugs work. Bortezomib blocks the proteasome reversibly. The molecule's boron-containing functional group interacts tightly with a key threonine in the proteasome's multiple protease enzyme active sites. But carfilzomib blocks the proteasome irreversibly, by virtue of its ketoepoxide functional group. "That functional group is a major reason that carfilzomib is highly selective for the proteasome," Mark K. Bennett, vice president of research at Proteolix, told C&EN last year. But will this make a difference in the clinic? Here's what Onyx told the New York Times's Andrew Pollack:
Onyx says its drug inhibits garbage disposal only in cancerous cells, not healthy ones, and therefore could have fewer side effects than Velcade.
What's the basis for this added selectivity? I'm not sure whether it has anything to do with reversibility. But I'll be watching for results from the next big irreversible proteasome inhibitor in the pipeline: Nereus Pharmaceuticals' NPI-0052. More reading: Pollack's blog post also has an excellent discussion of the limitations of Onyx's clinical trial. This is an excellent, if slightly old (2005) overview of the mechanisms of enzyme-targeted drugs. It discusses reversible versus non-reversible inhibition. Images:C&EN

Author: Carmen Drahl

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