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Zalicus Inc. Message Board

  • rul6t2 rul6t2 Nov 4, 2013 4:15 PM Flag

    a detailed examination of Napodano's tweet today - PART ONE

    Joe Napodano explained a tweet he made on Monday assessing the chances of Phase Two trial success for Z160. He summed up the negative argument this way--

    "The general conclusion that can be drawn from these 3 conversations is that PHN studied [sic] have notoriously high placebo response, so Z160 better be a damn strong drug to separate from the control - and the low side-effect profile just doesn't match up with the powerful efficacy." -- J. Napodano

    In other words, his three sources are saying that you just can't have a drug that is strong enough to significantly reduce pain with the low side-effects that have been reported for Z-160. The obvious counter-example is, of course, Z944.

    Z944 - PAIN RELIEF WITH LOW CNS SIDE-EFFECTS

    Z944 (a near molecular twin to Z160) was just tested in Germany in a human pain model that both objectively measures response in the subjects' brain (through EEG) and checks for self-reported pain reduction. In both metrics there was significant and meaningful pain relief. And the central nervous system (CNS) side-effects were in fact low.

    Obviously this speaks very loudly against the idea that such a drug cannot exist on principle. In a very real sense that is the end of the argument. But for the sake of thoroughness let's examine all this in more detail. It all centers around one question--

    Z-160 SHOWS FEW AND VERY TOLERABLE CNS SIDE-EFFECTS. WHY?

    That the drug Z160, like sister molecule Z944, has low CNS side-effects isn't up to debate. That's a matter of scientific record. Zalicus scientists tell us this is due to a phenomenon called state dependence.

    (more in PART TWO)

    Sentiment: Strong Buy

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    • CONTINUED FROM - PART ONE)

      STATE DEPENDENCE

      State-dependence in a pain drug means that the drug not only targets one particular pain channel but further discriminates between active or inactive states. In other words state dependent pain drugs like Z160 and Z944 leave nerve cells that are not actively involved in signaling pain alone. This then could well explain the low side-effect profile (which was a goal from the beginning).

      IS STATE-DEPENDENCE REAL?

      We have plenty of data from various tests both inside Zalicus and in other companies developing similar pain drugs that show it is. See Lee et al, Poster #380, American Pain Society, 32nd Annual Meeting, New Orleans, May 8-11, 2013. Also Dia et al, 2008 "A high-throughput assay for evaluating state dependence and subtype selectivity of Cav2 calcium channel inhibitors."

      IF NOT STATE-DEPENDENCE, WHAT ELSE COULD EXPLAIN THE LOW CNS SIDE-EFFECTS PROFILES WITH BOTH Z160 AND Z944?

      And this is where Mr. Napodano's sources make some alternate hypotheses--educated guesses basically. What are they, and do they hold up to scrutiny?

      MAYBE THE Z160 JUST ISN'T GETTING INTO THE BLOODSTREAM AND THAT'S WHY SIDE-EFFECTS ARE LOW.

      One source is arguing that there's just poor bioavailability here, same as with NMED160, the earlier pill version of this molecule. Little or no drug in the system, ergo low side-effects. But the bioavailability data for the new pill formulation of Z160 in human subjects exists, and it is excellent. You can see these data in Mr. Napodano's own reports titled "Meeting with Zalicus Management Confirms Z160 Potential; Big Pharma Awaiting Trial Data." The highest levels in the blood are eight times greater than before, and a measure involving concentration over time (call AUC for area under the curve) is five times better.

      So low bioavailability is not a likely explanation for the lack of side-effects with Z160. Not given all the available data in human subjects.

      (more in PART THREE)

      Sentiment: Strong Buy

      • 1 Reply to rul6t2
      • (CONTINUED FROM PART TWO)

        MAYBE THE DOSE IN THIS STUDY IS JUST TOO LOW TO BE PHYSIOLOGICALLY EFFECTIVE.

        If the dose is just too low to have any physiological effect at all, you won't get side-effects but of course you won't get pain relief either. And the idea that follows on the heels of this is important too. If you raise the dose high enough to get pain relief, then you would finally see those troubling side-effects. If this were the case, then you would have no advantage over existing pain drugs. That was the position of another of Napodano's sources.

        What do we know about how much Z160 it takes to achieve physiological effects? We look at the doses that successfully decreased pain across a range of the best animal models. We then scale them up allometrically to tell us what levels of the molecule would have the same physiological effects in man. The level at which Z160 is now getting into the blood system in man has been measured in the Phase One trial for Z160. And it does in fact reach those desired levels. To put it more simply, Zalicus has measured levels of the drug in the bloodstream and they are the levels needed to generate physiological effects.

        So here the alternate explanation for low side-effects, that the dose is just too low to have any significant pharmacodynamic effects, misses as well.

        SUMMARY

        The idea that you just can't have a pain drug that works and also has low side-effects may have been true at one time. Z944 seems to have just disproven that old saw. It does reduce pain in FDA approved human model, and the side-effects are quite low.

        The suggestions that low side-effects for Z160 might be the result of not enough drug in the bloodstream (because of low bioavailability or too low dose) doesn't well fit the available data.

        The likely explanation or the low side-effects profile is that Z160 and Z944 are state dependent. This is the only explanation that explains the all the available data and the recent success of Z944.

        END

        Sentiment: Strong Buy

 
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