Kinase Chemistry – Just a year and a half behind the times.

VX-680, VX-667: Done

Posted by kinasepro on November 21, 2007

VX-680 halted as:

one patient experienced QTc prolongation.


and the follow-on, VX-667:

Failed to meet pharmacokinetic objectives in a Phase 1 trial


15 Responses to “VX-680, VX-667: Done”

  1. ATP->ADP said

    How sad…. After all the promise…… It will be interesting to see whether this effect is target related or compound related.

  2. milkshake said

    I am amazed they did not see it in animal model – Sutent for example got the management extremely worried at one time because the QTc prolongation showed up in animals (together with the adrenal necrosis and other stuff – and the drug has also an accumulation problem and a non-linear PK with a long-lived main active metabolite). Fortunately they were careful (and lucky) with dosing in the clinic.

  3. Jarza said

    Does anyone know how many patients had bee enrolled, the trial was supposed to enroll up to 272 when complete. This info would add some give some depth to the problem.

  4. Unrelated, but I wonder what happened to Vertex’s wonder covalently-binding peptide for Hepatitis C.

  5. Failed to meet pharmacokinetic objectives? Presumably their prediction of human PK was off target and it would be really interesting to know by how much. Interesting that the QTc prolongation didn’t show up before (this is reminding me of Derek’s quiz). Presumably the compound is clean in the hERG assays or was option C indeed an option? As Jarza asks, how many patients?

  6. PK said

    Something can (must) be problematic in their Phase-II clinical trial protocols. A big lesson learned for the antitumor filed (particularly for Merck) although, there, toxicity is a bit less sensitive in the trial. Marginal dose should be very carefully considered.

  7. Biotech said

    Good point raised by ATP->ADP…. target or drug related? However, if it was only one person out of the entire trial of >200, how do we know it was either?

  8. Just curious, what happens if they get rid of the basic nitrogen and try to retain potency? Do the hERG problems reduce?

  9. Jenkins said

    Thats probably what happened to the backup…

  10. pf01273 said

    Wavefunction looking at the Vertex WO 2004/000833 patent there’s only a few compounds without the dibasic piperazine-esque moity in their preferred list. In the crystal structure with the Abl-mutant this appears to be just a solubilizing group pointing out into solvent.
    Favourable PHA-739358 phase I data was presented recently; it will be interesting to see how this compound proceeds.

  11. milkshake said

    One has to be extra careful about the basicity of the side-chains. Oned should try to use amines with lower pKA whenever possible. Putting strongly basic side-chains often improves the in vivo potency through the organ accumulation – not quite something you would want.

  12. kinasepro said

    WO/2007/056221, and WO/2007/056164 are VX-680 follow-on apps, which appear to bear this in mind.

  13. In general, all other factors remaining the same, basic compounds have a greater volume of distribution and thus a longer half-life compared to acidic compounds.

  14. milkshake said

    The other effect is that they like to acumulate in lysosomes…

  15. rob said

    does anyone know which CRO was working on the VX-680 trial?

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