In my opinion, Prof Knopfler has not done his homework properly. In a prespecified endpoint of those aged under 65 representing 60% of the enrolled patients ( before trial was stopped ) Mesoblast produced exceptional results. If he wishes to dispute Mesoblasts explanation that the over 65 patients require a higher dosage because their immune systems are less able to react… fair enough .. but I find his article misleading clickbait which adds little to the discussion. Perhaps he has not had time to look at the latest biomarker evidence which helps to further support a whole series of generally successful trials using MSCs. Indeed it is hard to find an unsuccessful trial. Even the total treated cohort in the Mesoblast trial showed a 15% reduction in a Phase 3 RCT . The trial failed of course because it was underpowered, because the standard of care, post dexamethasone being introduced , changed the goalposts in terms of percentage improvement needed to achieve statistical significance compared to the initial mortality rates of the initial outbreak for ventilated patients .
https://insight.jci.org/articles/view/148983https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6560575/In every trial thus far without exception I believe , there have been no adverse events using Mesenchymal Stromal cells . The combination of Dexamethasone and Remestemcel has a small dataset , but the quality of the data means the FDA should stop prevaricating and grant tightly controlled use with an EUA. Let’s not forget this was an NIH sponsored trial and had massive input from the FDA. They really are running out of excuses . Time to get of the fence and allow others to save lives . IMO the FDAs initial refusal to allow dexa whilst thrusting Remdesivir as the only treatment option ( when there was no improvement in mortality) just about sums them up. If it had not been for the NHS Recovery trial where 1 in 10 patients were administered Dexa the US would have lost tens of thousands of lives . People should be angry . I am sure Prof Knopler could do better . His contribution is not exactly making progress any easier . We are in a land of dinosaurs. Perhaps he could explain the remarkable string of exceptional efficacy data in advanced Class 2 patients in the Revascor trial for CHF in composite endpoints like 3 point MACE.
Any decent machine learning computer could work out these therapies work but we are stuck using frequentist or in this case Bayesian models which don’t incorporate other supporting data. I for one, am happy to approve ( like the ODAC panel for aSR GVHD ) where there is a negligible chance of a false positive and no adverse effects in an orphan indication. No more excuses FDA. Of course you need potency assays for Stem Cell consistency … but you were told that in published papers for the last ten years. To hold up therapies because you have to approve a first in class biological is a disgrace . When the true scale of lives lost from their inaction is realised … I think the public will want heads to roll! I think they should .
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1) A CRL is not a “no”… it is a “not now” … we need to resolve some issues … but I believe ,there is still a pathway to approval which the Company is pursuing. Have you ever asked yourself why there is a meeting with OTAT regarding Quality Attributes rather than a requirement to restart the whole process post a further RCT for srGVHD ? My interpretation is that as a first in class treatment using allogenic cells the greatest remaining concern is batch and product consistency… a universal standard approach to best practice need to be determined by the FDA who have to be aware of the precedent set by any new approvals .
2) with regards to the Revascor trial. I believe MESO correctly identified ischemic patients as the most likely to benefit, post the LVAD clinical results..but they did not fully appreciate the role that CRP and levels of non chronic inflammation had to play in activation of their cells. The results of the RCT , whilst failing to meet a primary endpoint, show that in a very substantial proportion of the patients receiving MSCs there is efficacy the likes of which are UNPARALLELED in the treatment of CHF … indeed for the large ischemic Grade 2 cohort a “sweet spot” has been identified which halts PROGRESSION of the disease !!! What the FDA will make of such spectacular findings we shall have to wait and see. Far from rejecting the data the FDA has yet to formally meet with MESO to formally provide the regulatory path to approval for both CHF and CLBP.
3) the results from the lower back pain trial were all the more remarkable when you consider that many physicians broke with protocol and prescribed enhanced opioid medication to the control group … which obviously prejudiced the results against Mesoblast . This is a point no one talks about …. Just like the 49% of patients being Grade D in our srGVHD trial which shows great efficacy.
4) the ARDS trial … is Silviu right ? Should we have used a higher dose in the over 65’s . On our current dosage in combo with dexamethasone for under 65’s in ventilated Covid 19 patients … our results are first in class… the data set needs to be bigger. With the FDA give EUA . Maybe? .. otherwise a month delay for a 200 ? patient confirmatory trial is in prospect . In less than a year we may have a therapy for a condition which occupies 1in 10 beds in ICU !