FDA, your randomised clinical trials can be manipulated by...

FDA, your randomised clinical trials can be manipulated by choosing 28 day primary endpoints which are now proven not to reflect long term survival in sicker patients .
The candidate for sr aGVHD the FDA has actually approved, turned out to have large numbers of patients suffering side effects such as haemorrhage, sepsis and anemia, etc. Real world experience from Ruxolitinib regularly show poor duration of response in severe grades . Meanwhile Mesoblast had fantastic long term survival results and was ready to prove efficacy using properly validated Biomarkers, which are now widely accepted in position papers as the leading science.. Our four year survival data was exceptional in comparison to Ruxolitinib’s over two years !

Re the ludicrous arguments the FDA put forward to inform the null hypothesis , bear this in mind :
https://www.nature.com/articles/s41409-018-0204-7.

“ Several studies have shown a lack of adherence to recommendations and inconsistencies in GvHD evaluation [2,3,4,5,6,7,8,9]. Weisdorf et al. showed in one multi-center study that acute GvHD (aGvHD) grading at HCT centers significantly underestimated disease severity compared to a central, expert review board, with inaccurate evaluation of grade III GvHD in 18% of cases [7]. In a recent chronic GvHD (cGvHD) intervention trial, up to 10% of patients entered by GvHD Consortium centers were excluded from study analysis post hoc due to failure to meet diagnostic criteria at the time of inclusion [8].”

Very disappointing day. The FDA continue to have their head up their a$$es.

Let’s for one minute accept their need for more data at face value. The guidance notes explicitly guide, not to accept BLA submissions if they believe that the applicant would not be able to gain approval in a time period of less than 12 months….but they accepted the Mesoblast BLA. Why ? The cost and delays of this failure will cost many their lives . This is unacceptable.

What happened to our priority review designated application when OTAT/OTP was given the document four months ahead of official BLA submission, so they could review and comment on any major deficiencies in the application. Absolutely sweet F.A. We are talking about an unmet need here in an ultra orphan indication . Meanwhile, Peter Marks approved the first cellular therapy to treat type one diabetes a few weeks ago after 11 patients out of 30 patients showed a treatment benefit lasting for a number of years. Congratulations to Lantidra. Probably a shrewd move, but as there was only 10 “bloods” to take for long term data , how did they get approved when our application was rejected with 8 times the enrolled patients in the EAP in more critically ill children .




Notice the mechanism of action for Lantindra is not elucidated , approval was based on two tiny single arm trials !

Remember, although the Mesoblast EAP was not in the form of an RCT , it treated refractory acute sr GVHD patients who had received an average of three different therapies including biologics. Remember also that Ibrutinib in chronic and Ruxolitinib in acute, were also approved with similar sized Phase 3 trials which were not randomised controlled studies . The lack of consistency from reviewers in different teams screams out at you.


I suspect the mistake Silviu made was in going for a full approval. It was obvious that the FDA are now luxuriating in their newly acquired controls given to them by Congress over the accelerated approval pathway (now able to withdraw approval at a minutes notice if necessary) …and he may have gained approval has he applied on this basis. Indeed if you look back to the previous CRL SIlviu said that would be his next move. Once the adult trial starts I suspect he is hoping to request accelerated approval for paediatrics….which may be forthcoming ….but i would not rely on it )

So are we back at square one? . In my opinion we have moved forward considerably. Those that questioned our CMC capabilities have been put well in their box and we passed the manufacturing inspection with flying colours…which is not easy on your first BLA (see comments from Gamida Cell CEO on the subject). It is clear however that Silviu has underestimated the resolve of the FDA to follow like lemmings a deeply flawed process. I have looked at clinical trials data for numerous studies of meta data for sr aGVHD. When Kurtzberg had such incredible success in her EAP with salvage therapy patients there cannot be any other explanation for the results achieved in non responders. The simple fact is that diagnosis of GVHD is subjective in terms of clinical grading ,and allowing complete responses times before day 28 as a primary endpoint allows better results for milder patient grade B which can distort the final data in favour of Ruxolitinib trial results
As far as I am aware there was no issue with the key quality attributes proposed and there was no mention of Interferon gamma from the CRL ! Assuming our potency assay has been accepted we can now do a comparability study in a straightforward way.

My disappointment in the latest CRL , is magnified, not just by my own personal losses which run into seven figures, but also by the thought that many of my close personal friends and family will have suffered heavy losses today. I must apologise to all of you for not anticipating the whims of an FDA review team which is heavily conflicted by papers they have co authored and published on the subject. I take comfort that my views on approval for Remestemcel are validated by the ODAC advisory panel , Philip Krause (who is one of the foremost experts on BLA submissions ) Joanne Kurtzberg, the Japanese Ministry of Health Labour and Welfare, etc etc.

Silviu must be apopletic right now. Two CRLs will probably make him an easy target for a scapegoat…especially as the issue of another RCT was highlighted previously. In view of the situation he is facing, he has pivoted well and has a number of cards to play. I don't think any of us were aware of the recent clinical data he has on adult sr aGVHD which has allowed him to choose a primary endpoint for an adult trial for GVHD with confidence. The FDA should be delighted to accept this protocol design as there will be no treatment options effectively left by the time the patient receives Remestemcel. By electing to choose a treatment refractory population for a small adult trial …he will be exposing the poor performance of other therapies and play to the strength of ours in terms of grade stratification. His comments on getting academic institutions to fund the adult GVHD trial would be very helpful to manage cash flow. All the same he will have to cull overheads quickly to reassure on cash burn. Lucky the Novaquest facilty rolls up until GVHD is approved and there are no principal repayments on the Oaktree facilty for over a year …he has limited breathing room. If i was Silviu , i would not want to pass the hat round again to shareholders so soon . It will be a shame if Mesoblast has to sell off valuable IP to provide the cash needed before approval .. but we only need one partnering or royalty deal from CLBP, Heart , ARDS , GVHD to fund the gap. .
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