Posts Tagged Pharma

“My baby” is about to graduate! FDA panel recommends Vertex Pharma’s telaprevir for approval to treat hepatitis C

This week, panels of non-FDA experts reviewed the clinical data for Merck’s* boceprevir and Vertex’s telaprevir for potential market approval as first-in-class** treatments for patients infected with hepatitis C.

Panel to FDA: Give OK to Vertex hepatitis C drug

Are telaprevir and boceprevir perfect drugs? No. Each has side effects. I’ll note, however, that the “nasty rash,” the most common adverse effect (AE) of telaprevir, was generally mild to moderate and treatable with antihistamines or corticosteroid creams. Only 2% of subjects discontinued treatment because of the rash. So it’s an AE that is tolerable.

The drugs will also be quite expensive: $35-40K per course of treatment. Yikes almighty! Yet these are complex molecules that are not facile to synthesize. Also, consider that a liver transplant costs in the order of $250K to $310K (and higher).

VX-950 a.k.a. Telaprevir

That’s the structure of “my baby” above. Of course, it’s not strictly mine. Not by a long shot, but with all the work I did on that molecule, I feel like one of its many parents. We had a hell of a team at Vertex, and there’s a critical piece of the molecule that was added by Mark T., a wicked smart medicinal chemist, who was then at Lilly (former collaborators; Lilly and Vertex had, uh, differences in approach and thus had a fairly amicable divorce). My contribution was to study the detailed inhibition kinetics of VX-950, using isolated HCV protease for in vitro assays. I demonstrated that VX-950 was a slow binding inhibitor with a slow off-rate. It’s sticky in other words, and hangs onto the the protease for a good while before being hydrolyzed off the enzyme by water in the cell.

The close teamwork of biochemists/enzymologists and virologists at Vertex proved to be a very powerful combination. The virology team was able to demonstrate the efficacy of the protease inhibition in their viral RNA replication assay, and that the slow off-rate appears to play a role. These experiments were performed in 2003/2004, and became pivotal elements of the package, which included major contributions from medicinal chemistry, protein chemistry, process chemistry, toxicology, and pharmacokinetics, which brought VX-950 (telaprevir) forward as a clinical candidate. And now…well, I wonder what its brand name will be?

The odds of a compound at the bench becoming a drug are incredibly small, e.g., for every 10,000 compounds that enter the drug discovery pipeline, only 250 will progress to pre-clinical development (2.5-5%); 5 move forward into human testing, Phase I studies (0.1-0.5%); and only a single compound will survive through Phase II and Phase III studies to be an approved drug (0.01%).

So this is a rare thing, and telaprevir is not just any drug. It will meet a significant unmet medical need. Anyway, forgive me for so much gratuitous backslapping, but I’m proud to have been part of the team — a great group of scientists, many of whom (including myself) no longer work at Vertex — who discovered the compound and brought it to clinical candidate status.

*Boceprevir is actually from the former Schering-Plough, which Merck acquired.
** Strictly speaking, boceprevir is the first approved HCV protease inhibitor and thus truly “first-in-class,” but I use the phrase collectively here, as the approvals were almost back-to-back.

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