Regardingthe Edison Open House interview with SI, there were several points hemade that struck me in particular.
First,he said the FDA approved the design of the single-arm trial Mesoblastconducted in children with SR-aGvHD. I had heard that before, but itjust underlines FDA's current stance requiring a controlled trial inchildren (or adults) seems all the more unreasonable and may havebeen strongly influenced by “the letter” acting on a small blocof bureaucrats.
Second,his comments on the ARDS trial reinforce to me that we need to holdjudgment until we have full results. While I do like OP's analogy“set out to discover India and found America instead”, I thinkthere's still a chance we may find both - plus the northwest passage. ie to the extent the issue is one of study power due to shifts in the control group - as opposed to rem-L efficacy - we are going to be in for some surprises when the full data areunveiled, especially on secondary endpoints. SI sounded verypositive on the Novartis partnership, which I take as a good sign. But we should remember: not even management knows what the blinded data will show.
Third,regarding the heart study, one thing I heard him say for the firsttime is the plan to explore using rex-L in non-CHF indications wherethere is a high risk for ischemic events. This is a SEISMIC shift tomy mind and underlines perhaps a deeper significance of the CHF studythat few seen to have perceived: rex-L may ultimately have a greaterrole as a prophylactic than as a traditional therapeutic. I believehe is talking about patients who do not have CHF, but who presentwith some kind of ischemic event or who are at high risk for suchevents due to co-morbidities like diabetes. Obviously, more trialswould be required, but the move is to screening larger populationswith inflammatory markers and intervening with rex-L (or rem-L?) inhigh risk patients BEFORE the stroke or heart attack occurs. Prevention... as opposed to treatment. And if you think about it,that's what the CHF study really showed. We're not treating the CHFas much as we're preventing nasty complications and progression ofdisease. This mindset involves a much larger population than thealready large CHF population, but we can see the direction this isheading. It may well have an impact on the partner chosen to goforward to tackle the challenge. Key things to watch for are wherethis research gets published (a journal with the caliber of the NEJMor Lancet would be very significant, as opposed to a cardiac journal) and of course, which large pharma or large biotech partner isultimately chosen to pursue these broader indications.
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Fourth,and I believe under-appreciated is the point SI made regarding apotential pathway to rex-L approval via the end-stage CHF indicationin patients who have an LVAD. He said the FDA previously indicatedinterest in any study with rex-L showing a reduction in mortality,which they now have. Combine that with the probable ongoing datacollection in the end-stage patients. We shouldn't under-estimate theorphan indication for GI bleeding in LVAD patients. Someone on theYahoo board referred to it as “stomach” bleeding, but that makesit sound localized and mundane, like something you could get fromstomach irritation due to aspirin. This bleeding is trickier and canoccur anywhere in the gastro-intestinal tract from esophagus tostomach to intestines to colon to anal hemorrhoids. Any one spot ormultiple spots. Which means evaluation of these fragile patients isa medical nightmare and potentially very expensive. All thesepatients are taking both anti-coagulants and anti-platelet agents toprevent blood clots related to the LVAD acting as a foreign body. Itmeans the bleeding can be profuse, and typically these meds have tobe stopped in order to control the bleeding. Transfusions may beneeded. Then come invasive procedures like upper and lowerendoscopies, vascular studies to locate bleeding sites, andpotentially surgery to stop bleeding. Stopping the anti-coagulantmeds puts these patients who are bleeding at high risk of having asimultaneous stroke or heart attack from a blood clot. ie they are bleeding and clotting at the same time, literally between a rock and a very, very hard place with high mortality risk.And it's why the significant reduction in bleeding demonstrated inthe end-stage trial is... well, significant. Will the FDA "havea heart" and take action now that a second large cardiac studyagain shows an MoA related to reduction of vascular inflammation? Inpatients at high risk of death with no good therapeutic alternatives?Mesoblast will be pursuing those discussions and in my opinion wecould be in for a surprise from the FDA on this one. It just hasthat kind of feel for a situation where they'll take action (despite the decision on the children). Irecommend watching the interview again from that perspective. glta
(20min delay)