Firstly, may i thank
@benelong for his kind words. I do spend many hours trying to cross reference and provide links....as do so many other stalwarts and “keepers” of this “precious” thread. Sometimes, I really think it all sounds a bit Lord of the Rings....with ecoool2 as Saruman slicing though the ruffians in the Battle of Bywater...but then he buggers off, leaving old Bilbo Baggins here, to try to carry the ring. I would imagine if the real Bilbo was around right now, to fight the evil Covid, he would utter one of his immortal lines “It’s a dangerous business, Frodo, Going out the front door”
What the last two months have taught me is that Silviu has some imperfections...he is not a robot....and he is fallible like everyone else including me.
BUT, the difference between then and now...is that we know a great deal more about how fallible and how nonetheless how brilliant he truly is.
A picture is emerging...it is a complicated picture...we have not yet been provided with a “definitive” win ...not because our therapy lacks treatment effect, but largely owing to the wrong trial design. As with all “black swan events” the thing that cocks up is seldom that envisioned by any troll or true believer. I think one of the reasons this problem emerged with trial design is that our phase 2 trials were not appropriately powered and our resultant phase 3 trials were more vulnerable to surprises. Ever changing treatment protocols for both CHF and Covid ARDS and the restrictive nature of NIH run trials particularly in relation to speed of enrolment, have proved particular bugbears.
I think Silviu has underestimated the mortality impact of corticosteroids in treating ventilated patients for critical ARDS..and it is Methylprednisolone not so much dexamethasone, especially when used in combination with another agents such as Anakinra or as part of the MATH+ Protocol, which are narrowing the efficacy gap considerably ... making the 43% hurdle for powering our Covid/ARDS trial way too high in the light of advances in treatment options . Indeed even yesterday a combination therapy of an IL6 antagonist Tocilizumab and Sarilumab , which are used for rheumatoid arthritis, were proven effective as a treatment option by UK regulators following a very large clinical trial. People should not get despondent. Having looked up the potent side effects and contra indications of Anakinra or considering the large populations of people who are steroid refractory, there are plenty of reasons why I think our therapy is superior. Indeed, I must say that after months of research, I have yet to find a non mesenchymal based Covid/ARDS treatment that I believe can eclipse the likely efficaciousness of Remestemcel. I was particularly pleased to see the results of the University of Miami UC stem cells blinded trial for Covid/ARDS published this week for 24 patients. I compared the biomarkers scores for Rantes (CCL5) and IL17 (CD4+) immune pathways relative to those reported by CytoDyn’s Lereonlimab. I believe we really do have something quite exceptional and I think when the trial data becomes available late February/March we should have cause to celebrate and apply for an EUA. I do take on board the point raised by
@Sorepocket...but i would make the following observations . No one is suggesting that our therapy is offered as a first line therapy..or as a prophylaxis...you can use grading systems and biomarker scores like SOFA to very accurately identify your target population of non responders. ARDS already has existing reimbursement codes which allow a treatment coast of approx $40k...if you adjust these rates for improved mortality benefit, faster recovery and reduced ongoing rehabilitation costs , a charge of $60k would be most reasonable in the circumstances.
https://www.theguardian.com/world/2021/jan/07/covid-arthritis-drugs-could-help-save-lives-of-seriously-ill--patients-research-findshttps://www.sciencedirect.com/science/article/pii/S0091674920316213@kervio provides a logical, circumspect and sobering review of our current position. Sometimes a good splash of cold water and a resetting of timelines is desirable. I dare say that if you want to adopt a more conservative approach it is not far off....with the facts that have been presented to us thus far. We are forced to take such a prudent position because “once bitten twice shy”. Previously Silviu told me that we would almost certainly require an ODAC hearing for Ryoncil as part of the BLA process...as a totally new therapy, mesenchymal stem cells would require a very public and detailed scrutiny from a panel of experts to help alleviate and address, any concerns emanating from the FDA......wow, that turned out to be quite an understatement . I actually researched many cases of where the FDA gave approval, in spite of objections and a marginally negative vote, against a new BLA submission from its expert committee. I really knew what a frickin awful year 2020 was, when instead, for the first time since 2006, a review team at the FDA had apparently told its panel of experts that they knew better and overruled them.
I always had a nagging doubt that maybe the FDA review team for Ryoncil did know better....but regardless i thought , they are the referees and their decision stands and move on...but the more I researched ST2 biomarkers, etc., and other treatment options that had been approved for paediatric srGVHD ..and the more i understood their position..the more I believed the FDA was morally indefensible. It is ironic that we are dealing with an advisory panel (ODAC) whose view was often ignored to allow orphan designations to be approved by the FDA but on this occasion it is bizarrely the other way around. That defeats the whole object of the expert committee’s role and has put the whole system into disrepute. It is a bit like the judge ignoring the verdict of a jury in a capital crime ...only in this case the jury is made up of Supreme Court judges !
So where do we go from here for GVHD ? A good football analogy, the next Type A meeting has become a sudden death penalty shoot out in a Cup match , with the score determining the result... not the 90 minutes played which preceded it . Silviu will be pleading his case to wise old heads at CEBR, probably headed up by Peter Marks or his immediate subordinate...as part of a carefully designed dispute resolution process. I have provided specific past cases of where some of these appeals have been successful in previous posts..... so l am cautiously optimistic that this will all be resolved in late February/ March when I expect the next Type A meeting will be convened. Many appeals have also failed...but it is very rare , with an almost overwhelming ODAC approval , that a BLA like ours should ever need to go to appeal. By going back to the original review team and resubmitting an accelerated approval request, Mesoblast had already made sensible concessions and allowed the review team to set a much narrower and conditional approval terms where there was an unmet need in children under 12. So Ryoncil for acute sr GVHD is one example of where Kervio’s “base case” might prove too pessimistic.
But the real “CauseCelebre” will be whether an accommodation can be found by the FDA for an accelerated approval pathway for Revascor. It failed to meet its primary endpoint but has instead proved spectacular efficacy in gold standard cardiac mortality and MACE key secondary endpoints. There is precedent to support an approval on condition of a confirmatory trial... and I understand some industry analysts believe this may well happen. Until the Company talks informally with the FDA post a full analysis of all the data, I am sure most investors will remain cynical....but I think it will depend on how compelling the data is...so lets watch this space. The same does not apply to Mesoblast’s competition. I do not see this company as being able to stay independent if the share price stays at anyway near current levels. After all , we will only be able to partner with one global pharma for Revascor. The bunfight has probably already started . Anyone with a major cardiovascular franchise should know, that with such a massive margin of efficacy over the competition now confirmed in a large randomised controlled study ,with no notable side effects, Revascor could eat all their collective lunches.
Have a great weekend to all .
Please do not rely on any facts or opinions expressed in the above post when making an investment decision.OP
(20min delay)