Replies to post #120 on Idenix Pharmaceuticals (IDIX)

[DewDiligence]

Re: VX-950 rash and dosing regimens

>I read on this board (I believe) that the VX 950 9% discontinuation rate was largely associated with a skin rash SE. Dew (I believe) speculated that this SE might be the result of the VX950 enhancing the action of Riba, since skin rash is a known SE of Riba<

To my knowledge, VRTX has never claimed that VX-950 is synergistic with ribavirin. What VRTX did claim was that VX-950 is synergistic with interferon, which is itself known for generating a rash in some patients. I mused that the synergy between VX-950 and interferon could have made the interferon-induced rash more pronounced.

>Is it likely that there is a continuum of synergistic vs. antagonistic interaction with the best dosing/interaction performance occurring somewhere in the middle of the spectrum rather than at either of the extremes?<

For regulatory reasons and for ease of acceptance of study protocols by the participating trial centers, it behooves VRTX (and other HCV companies) to not tamper unduly with the standard of care in the control arm and the base treatment in the active arm. Hence, the tested treatment regimen in the active arm will not necessarily be optimal in terms of dosing.

With respect to ribavirin, specifically, I think we’ll see trial arms that either include ribavirin at the standard weight-based dose (#msg-15567086) or exclude it entirely. I don’t think we’re likely to see trial arms where ribavirin is included at a non-standard dose or frequency.

One exception to the above might be the deferred use of ribavirin following cessation of an agent such as NM283, as has been discussed on this board. Regards, Dew

[dewophile]

re dose modulation:

Is this likely to be easily addressed through Riba dosage modulation

Flatliner,
the paper I cited discusses dose modulation of riba and interferon during therapy to manage adverse effects. dose adjustments are rather frequent, usually to address laboratory abnormalities (in the case if riba to account for the hemolytic anemia most commonly, and in the case of interferon neutropenia). discontinuation for lab abnormalities is rare however, as dose adjustments often mitigate these events. as for the current protocols, I'm not sure what specific guidelines are in place regarding dose adjustment, but I'd have to think there is lattitude for the standard adjustments in both arms, or else discontinuation rates would be unreasonably high
ps welcome to the board