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Insmed Incorporated Message Board

  • fudfighter4 fudfighter4 Jun 24, 2013 9:31 AM Flag

    Clues to Phase III efficacy and safety

    How likely is a Phase III failure on efficacy?

    From the results of the 72-week Arikace CF Phase II extension study (49 patients) -

    "The data demonstrated that ARIKACE, delivered once-daily for 28 consecutive days, followed by 56 days off-treatment, for a total of six cycles, resulted in statistically significant improvement in lung function that was sustained over a 72 week period. Specifically, inhalation of 560 mg of ARIKACE produced a mean increase in pulmonary function (FEV 1 ) of 11.7% at the end of the 28 day treatment period of the sixth cycle ...

    During the course of the study, FEV 1 improvement was also sustained at the end of 56 days off-treatment in each of cycles one through six, with an estimated relative increase in FEV 1 of 5.7% ...

    Overall ... adverse events reported as consistent with those expected in a population of CF patients receiving inhaled medicines ...

    ARIKACE also demonstrated statistically significant reduction from baseline in Pseudomonas aeruginosa density, including mucoid strains, which was sustained during the treatment and off-treatment periods of the six cycles."

    A mean increase in FEV 1 of 11.7% at the end of the sixth treatment phase is miles better than anything either Tobi or Cayston has ever promised.

    The mean increase of 10% measured at the end of the third treatment phase was roughly what Tobi delivered in the study which supported its approval over ten years ago. But its efficacy has dropped off to such an extent during the intervening years that it recorded a maximum increase of just 2% during the study which supported the approval of Cayston.

    Given that the key outcome measure in this crucial Arikace vs Tobi study was change in FEV 1 28 days after the end of the third treatment phase, a point at which one would have expected the residual antibiotic effect of the Arikace liposomes to have really come into its own, it seems unlikely that Tobi came anywhere close.

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    • blehair Jun 24, 2013 9:57 AM Flag

      Not completely true, although it's an informative post.

      The endpoint is FEV1 change from baseline to END of treatment. That's to the end of the 3rd 28 off-days. The 11.7% figure you referenced is at the end of the 6th 28 ON-days.

      The 6 cycle study shows how consistent FEV1 improvement is maintained, so I'm confident we will see more than 4.5% FEV1 improvement at the end of the 3rd off-treatment phase. That estimate I took was from a very shoddy graphical estimate of the open label study turned into a 28-28 study. The 28-28 1-cycle study showed more than twice that at the end of the 28 off-days, so 4.5% is the MINIMUM improvement I expect.

      In comparison, Cayston goes from 8% at end of first 28-days, to less than 0% at the end of the third full cycle. The average improvement through the whole process was just 2%.

      TOBI, well who cares about TOBI, the only thing TOBI is good for in the Arikace P3 study is a safety profile and to show that the general CF population could use another treatment option.

      • 1 Reply to blehair
      • "The endpoint is FEV1 change from baseline to END of treatment."

        Why respond if you couldn't be bothered to read the entire post?

        As far as I am aware, no antibiotic currently available to the CF patient population has ever delivered a noticeable improvement in FEV-1 four weeks after the patient last took the drug. But the residual antibiotic effect of the Arikace liposomes is such that they still deliver an improvement at a point when other antibiotics have been completely cleared from the lungs and the pseudomonas has re-established itself.

    • How likely is a Phase III failure on safety?

      The recently completed three-cycle Arikace study entailed breaks between therapy phases of only 28 days, as opposed to the 56-day breaks in the 72-week extension study.

      It's tempting to contemplate the possibility that this has enabled Arikace to deliver a level of efficacy even higher than seen in the earlier studies. But we can't ignore the possibility of greater adverse effects.

      I guess the only clue we have here is in the design of the ongoing Arikace NTM study -

      "This is a randomized, double-blind study evaluating the efficacy and safety of Arikace® administration compared to placebo for 84 days in subjects with recalcitrant non-tuberculous mycobacterial lung disease on a stable multi-drug regimen. Subjects will be randomized 1:1 to either 560 mg Arikace® or placebo administered once a day via a PARI Investigational eFlow® nebulizer."

      The same dose of Arikace for the same overall period of therapy - but without any off-therapy phases.

      The reality here is that if Arikace has just equalled or bettered its performance at Phase II it will be the only drug available to the 70,000-strong CF patient population capable of making a real difference in their quality of life. Arikace will effectively have no competition.

      Patients and physicians will surely be eager to start using as soon as possible a therapy which delivers a significant improvement in the patients' breathing - promising revenue which warrants a share price of at least $200 with the current shares outstanding.

      The institutional shareholders asked to sell millions of shares before the end of June will clearly accept a lot less for 'cash in hand'. But I somehow doubt they'll be prepared to knock $190 off that $200.

      And that $200 doesn't reflect future sales of Arikace as a therapy for NTM / pneumonia / Tuberculosis.

      Why would anybody contemplate selling shares at a point so close to the Phase III results unless offered a price too good to refuse?

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