Replies to post #41960 on Biotech Values

[rfj1862]

It's a good thing I'm self-employed, because I just spent the last 15 minutes pacing back and forth trying to figure out if there was a clinical situation or condition in which a VIII-targeted agent would be preferable to, say, a direct thrombin inhibitor.

I really can't think of any reason for this product, other than to have something novel. In clinical terms, inhibiting factor VIII is *probably* more than sufficient to prevent thrombotic events. However, in practical terms, doctors are going to question the value of inhibiting only one "branch" of the coagulation pathway when they can target thrombin directly.

Part of this goes back to one of the key precepts of modern pharmacologic design: get as close to the ultimate effector of a particular pathway as possible. I think most physicians are firm believers in this concept.

A parallel can be drawn with the antiplatelet market. The platelet aggregation pathway has a similarly branched structure. Thienopyridines (eg, clopidogrel) act by irreversibly blocking ADP receptors on platelet cell membranes; aspirin acts on a different branch by inhibiting COX-mediated prostanoid production. *Only* GP IIb-IIIa inhibitors act on the final common pathway of platelet aggregation--transition of the GP IIb-IIIa receptor from inactive to active form. In other words, both thienopyridines and aspirin can be bypassed, but GP IIb-IIIa inhibitors cannot.

Again, in practical terms, the GP IIb-IIIa inhibitors have made a lot of noise about this fact, and--until bivalirudin came along--the marketing was working quite well. I see something similar happening with a FVIII inhibitor vs direct thrombin inhibitors or even warfarin, eg a salesperson for the Medicines Company might say "why would you inhibit FVIII when you can inhibit the final common pathway of coagulation?"

Sorry for the long answer. I realized it has been about 3 weeks since my last value-added post, so I wanted to say something intelligent for once. My next intelligent post will occur on March 5, 2007.