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  • thirdmeinvestor thirdmeinvestor Dec 8, 2012 1:50 AM Flag

    Making the case for VX-809/Kalydeco

    You are right here in determining the %FEV1 change from Day 1 to Day 56.

    It takes a good amount of time to clear airways of clogging thick mucus after the drug starts pumping chloride ions and hydrate dry mucus. According to CSO, there were a great deal of respiratory symptoms during the first 14 days of Kalydeco treatment of 551 patients. The same would be true for 508 treatment. All can lower %FEV1 in the initial dosing periond. After the symptoms clear, FEV1 should increase. It rose 20% even from Day 42 to Day 56, and could rise further from Day 56 to Day 70.

    The effect of removal of inhaled antibiotics during the combination treatment should not be as great as for the placebo group because the effect is mediated through increased rate of infection and inflammation. The drug combo should clear some infection without antibiotics. So, the placebo is not a good control for the treatment when the antibiotics is withdrawn. But I think that 5-6% is a good range to shoot for.

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    • Third, I thought the inhaled antibiotics were continued throughout the phase 2 VX-809/Kalydeco trial. There was a presentation by Michael Boyle, MD with a slide showing baseline characteristics for the phase 2 study participants. The 600 mg VX-809/Kalydeco group had 86% on inhaled antibiotics and the placebo group had 91% on inhaled antibiotics. Stopping the inhaled antibiotics at any point during the study would add a confounding variable. The phase 3 Ataluren study showed it was more difficult to show improvement when patients are using inhaled antibiotics. Therefore the 6.7% improvement seen with those receiving the combo compared to placebo is more impressive if most of the patients were using inhaled antibiotics.

      • 1 Reply to swhitemd50
      • What I remember from the early May conf call is that the trial participants were on antibiotics during the monotherapy phase but off of it during the combo phase of the trial. CFers on antibiotics take it for a month and don't take it for a month. So, it was possible to synchronize the drug dosing to the antibiotic cycle. I don't remember who was saying at the cc, but he [speculated] that the reason the FEV1 of the placebo arm went down so much during the 2nd half of the trial was because the participants were off the antibiotics during the period.
        In the coming Phase III trial the trial period would be 6 month or so, several antibiotics cycles can be put in, and the effects of taking antibiotics would be apparent both for the placebo and drug arms.

        I would think that removal of antibiotics would certainly increase pulmonary distress, and ensueing respiratory distress such as pulmonary exacerbation or dispnea would depress FEV1. This can happen in both placebo and treatment arms. If antibiotics were given to the 200mg and 400mg arms, the FEV1 would be higher. But for the 600 mg arm the effects of antibiotics would be less because the drugs by themselves clear infection and inflammation.

 
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