@LeftYahoo if you want to stand by your post, may i at least point out the following
1) I think you should use the primary endpoint for GVHD001 for the basis of calculation not one of the secondary endpoints
2) Apply the binomial distribution method rather than your chi square analysis which is was part of the SAP registered at the Clinical Trials Registry.
Then later we can have a proper debate about the null hypothesis rate of 45%..and the comparative studies used by the FDA to justify their opposition to using that rate. Eventually, you will may come to the conclusion, that you can only find validity in a control arm trial if it is possible to find one which is properly matched ! I believe the FDA lack the volume of clinical data in severe grades of this patient population to make this analysis.
Afterwards, we can deal with the post hoc analysis using propensity matched controls from MAGIC which were already very weighted against the Remestemcel cohort to emphasise their conservatism.
Consider this , the propensity matched cohort provided by Magic at baseline as a controls population had 56% classified as high risk according to Minnesota High Risk compared to 76% in the Remestemcel arm. It is hardly surprising that the clinical response after 28 days did not quite reach statistical significance (0.08) as there was a 20% difference in the high risk group between the two cohorts. Let’s remember the Minnesota grading system is far more accurate than the previous grading system used in the FDA authorised trial GVHD001.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012472/
Randomised controlled clinical studies are the gold standard…everyone excepts that….but the FDA has used surrogate endpoints (day 28 response ) which have validity in determining short term rather than long term durability of response, NRM, follow on incidence of chronic GVHD ,etc etc,
Anyone examining the latest research into M2 macrophages role in acute GVHD will be aware of the damage to the GI crypt …the multiple immune pathways responsible for enabling complete remission go way beyond the scope of the IDO pathway on which many of the FDA members have published research. By all means ask for more trials . The FDA is understandably frustrated that not all the numbers are joined up….but it insults the good names of the expert practitioners who have used it on such a large refractory population in EAP275 to suggest that this safe and efficacious treatment is not approvable right now.
I challenge Peter Marks to look at the comparability used at ODAC to justify FDA opposition to the null hypothesis used by Mesoblast . If the FDA wants to be useful perhaps it can ask itself….why did we authorise a Statistical Analysis Plan powered to archive a minimum 20% improvement with 55 patients if we were not prepared to accept the result afterwards.
I am not a medical practitioner….but I can read……the survival, of grade D patients which formed 50% at baseline of the Phase 3 enrolment is dismal ….89% of GVHD001 patients were Grade C/D …and the FDA criticised our null hypothesis assumptions. Unfricken Believable !
I will accept that
@JB1975 made a good call about the number of actual samples which could be used to validate the potency assay not being sufficient in the eyes of the FDA. That of course is treading on new ground since I am not aware of any precedents here…nor are we aware that the FDA has made any stipulations about what quantum was required for single cell analysis ( they are making it up as they go along). Many of his other posts may have been sincere but incorrect , such as his in depth analysis of TNFR on the misguided assumption that it represented the upgraded potency assay linking in vitro to in vivo outcomes. Not to worry, the Magic Consortium has found improved accuracy using TNFR if it is combined with other biomarkers but thats for another time . Cynata has pivoted to using a primary endpoint reflective of severe disease. I think educating Cynata shareholders further about our proprietary potency assays is not a good use of my time. I will let him bathe in his glory as I have substantial wounds to lick.
Lastly, Mesoblast will have to restructure the cost base substantially to conserve cash resources . It will have to comply with the FDA’s need for another trial in adult or child and it MUST be more honest with its shareholders…I am sure Silviu would argue that full disclosure about trial restrictions post the first CRL would have endangered the very survival of the business…but this is the main reason I have lost so much money in the stock ..because the timelines were never likely to be met.
Don’t get me wrong, the technology , in my opinion is first class and Silviu is a very talented and charismatic scientist, but in order to fund yourself you need the trust of your investors. Valued on a “going concern” basis I think Mesoblast deserves a valuation of at least a billion US dollars currently but we have no idea what level of dilution existing shareholders will be subject to over the next 12 months to put the balance sheet on a level footing. I have no doubt that as the CEO is personally invested, he will avoid unnecessary dilution at all costs…but any carve out deals will probably need the full support of Oaktree…as the primary secured lender.
Post the next Type A meeting, there is always a chance of Mesoblast refiling under the encouragement of the FDA ,for accelerated approval and Silviu will emerge from the ashes like Daenerys in Game of Thrones, but hopefully fully clothed ! Nothing surprises me in this stock anymore…but for the time being I will try to limit any further share purchases to actual news and not the premature speculation we have had to put up with for years. Don’t get me wrong i still think Mesoblast has unbelievable potential as a first in class therapy , but these days anything with a cash burn seems to get slaughtered. In truth, Mesoblast should probably move its main listing to the US and even then it is doubtful if it should be on the public markets…while it is loss making. Why the exchanges allow shorting of smaller companies needing growth capital …is subject for another debate at another time. OP
Please do not rely on the facts or opinions contained in the above post when making an investment decision. I am not medically qualified . Do our own research.
(20min delay)