”Just stop and think about it. Another company completes a successful randomized controlled clinical trial in adults and gets commercial approval for the indication. They supply additional safety data and request conditional approval for paediatrics while they conduct another trial in children. The FDA says ok.”
Yes,
@whytee The FDA has made fools of themselves i my opinion by approving a highly questionable therapy for adult sr aGVHD. Not only did the original 28 day response primary endpoint fail to reflect long term mortality…it was later established that all the therapy managed to do (as evidenced by the Kaplan Meier curves ) was to extend survival by a few months relative to standard of care combined with some debilitating side effects.
As if that wasn’t bad enough, I think we may be witnessing the FDA taking a new view of Rux post some recent retrospective meta data analysis .
In the January 2024 edition of Blood ..Jan 11 Vol 143 No2 a review paper signed by a whole host of leading haematologists , from Oxford, Cambridge, UCL, etc., sent a five page letter to the Editor with some alarming conclusions about Ruxolitinib.
“ Nonmelenoma skin cancers (NMSCs) in ruxolitinib-treated patients with myeloproliferative neoplasms behave aggressively, with adverse features and high recurrence. In our cohort, mortality from metastatic NMSC exceeded that from myelofi- brosis. Vigilant skin assessment, counseling on NMSC risks, and prospective ruxolitinib-NMSC studies are crucial.”
Let me interpret the above for you. In my opinion, the chances of the FDA approving Ruxolitinib for paediatric sr aGVHD is looking pretty non existent. Many JAK Class inhibitors have already received black box warnings so no one should be surprised. The evidence has been accumulating for many years for those that are interested. The letter to the Editor references 14 different studies which highlight the facts upon which their expert opinion. I provide the link to one of the 10 year retrospective analyses. Love to hear your thoughts on the subject.
https://www.jaad.org/article/S0190-9622(21)02632-3/abstract
Now , it may surprise you that I thought your post had a semblance of truth about it.
It is true that Osiris conducted two clinical trials that did not reach clinical significance even though they showed superiority. One trail achieved a Pvalue of 0.12 (70% to 82%?)against primary endpoint from memory. However, what you fail to recognise is that Mesoblast then purchased the IP from Osiris and made
changes to the CMC (as evidenced in the ODAC meeting) and moved the lot manufacture from the US to Lonza Singapore. It is obvious from the results of GVHD001 , the EAP and the recent PAI (Pre Approval Manufacturing inspection) as well as the preceding 2 internal and external audits, not to mention 5 years of Temcell production in Japan, that batch
variability was a problem for Osiris and
not Mesoblast.
The Company appears to be being held to account for the problems faced in CMC by another company. Yes, the FDA has recommended another trial but I believe that is because, to date , Mesoblast has not been able to identify a potency assay method of proving to the FDAs satisfaction, the cause of why a meaningful proportion of Osiris production lacked potency which had a knock on effect on the efficacy of their trial results. Anyone following how MSC’s are harvested will be aware of how complicated the process is. The last explanation from the CMO in a Company webcast suggested more downstream factors such as reagents or testing kits..which suggests the fault lies with third party equipment or supplies. The fact that Silviu stated in an interview in the last week that they now have collected double the data to prove they now understand this conundrum, should not be overlooked. Of course, when the FDA recommended another trial they were not to know if any of the potency data which was collected by MSB over the last 8 years would be able to
retrospectively prove it could have identified faulty batches used by Osiris….but what IF Mesoblast can show this? I believe they can, or they would not have continued post the 2nd CRL which gave them clearer guidance of what would have to be achieved. So why didn’t Mesoblast prove this in the second submission? I would speculate , they had not backtested the data they needed at that point.
So where does this leave us ?
I speculate Mesoblast will present new data based on a potency test which must have been operational several years ago which speaks to the safety purity and potency of the cells. This new potency test must be able to retrospectively prove it could have identified the faulty batches used in the Osiris trial to avoid a recurrence of the problem.
Mesoblast are not stupid. They must have checked they could meet this requirement before submitting . Interesting times.
Personally, i think the FDA have overplayed their hand. If Mesoblast prove they were not at fault for the problems faced by Osiris, heads really should roll (I believe that the original team leader has been replaced now) . The review team had agreed the trial protocol in writing with Mesoblast .If the Company exceeded 65% efficacy as regards the primary endpoint they were assured of approval . The FDA changed their minds after statistical significance was achieved and wanted another trial. For an organisation claiming to champion new orphan treatments I believe they should hold their heads in shame..especially after they were able to see both four year survival and MAGIC biomarkers scores , the likes of which have never been equalled in a Grade C/D refractory population. OP
Please do not rely on the accuracy of any facts or opinions contained in this post. Mesoblast failed to raise all the funds it required in a recent retail offer to shareholders. The authority to place those outstanding shares I believe remains open until March 17th. Without receipt of these funds Mesoblast will probably require additional funding around the 3rd quarter of the calendar year. As a result the shares represent a very binary bet with external validation from a third party by way of partnership, or from the FDA , likely to drive extreme volatility .
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