@RickyHSo, RickyH, you are right in that cadaver donors have been used on many occasions....in fact there were only two cell donors used in the LVAD clinical study...a fact which is revealed in the appendices of the trial. The FDA, will i believe, specify a minimum number of donors to be used in the Mesoblast master cell bank. I am not sure, however, that heterogeneity of cell type is the holy grail. The important point you might wish to consider, is that the
genomics and
condition of the
recipientsimmunesystem plays a vital part in
efficacy. Part of this puzzle was solved over the last twenty years of clinical trials. Emerson Perrin has gone to great lengths to lecture about the faliures of using autologous stem cells, because of donor variability....particularly in relation to the age of the patient.
The key point to realise is that there are “responders” and “non responders” to all therapies used to treat acute sr GVHD. That applies as much to IL6 antagonists as it does mesenchymal stem cell therapies. DId the FDA ask Incyte to explain why it had such poor response rates using Ruxolitinib in Grade 3 and 4 gut and liver sr aGVHD ? When a mechanism of action has yet to be fully understood it is imperative to have well designed clinical trials to prevent the risk of false positives. Where the FDA stretched this requirement to the point of absurdity (in my view) is by ignoring the accompanying body of evidence from the Expanded Access Programme. Instead they waffled on about the technicial niceties of what null hypothesis should be used as a control, despite the overwhelming use of Grade D (49%) and Grade C patients by Mesoblast in almost all of their clinical trials. The reason the ODAC panel were in agreement with Mesoblast, is that Ryoncil is inherently safe and addresses and unmet clinical need . I would guess that virtually every one of the people in that CEBR group would have used Ryoncil over Ruxolitinib , (for all but Grade 1 skin sr aGVHD) if it would have been their child suffering from this horrific condition.
The FDA have a chance to redeem themselves at the Type A meeting. Their is a weight of clinical evidence emerging which supports the use of mesenchymal cell therapies... which is now supplemented by Prof Kurtzberg’s latest study and the breaking revelations from the Duke University Team, continuing to show the direction of travel. Then there is the other elephant in the room. The results of the 45% interim analysis for the ARDS trial...a huge new body of clinical evidence is there for examination which i believe will finally sway CEBR to give accelerated approval...assuming of course, they are interested in saving lives. Whilst the DSMB is fiercely independent , the Secretary of the Committee is often a representative of the FDA. By the way, if you research clinical biomarkers ,as I have , you will realise that TNFR1 expression has historically been widely recognised as one of the most accurate predictors of potency. I appreciate that recent research also vindicates other methods, such as IDO measurement but you have to present consistent data bewteen trials or the information cannot be correlated as easily. Owing to genomics you will always get less correlation in vivo as opposed to potency assays ex vivo, but that applies to virtually every therapy for obvious reasons. There has been some recent improvements in our understanding of proteomics and Quality Potency Attributes. I provide some bedtime reading below.
https://pubmed.ncbi.nlm.nih.gov/28194439/https://ashpublications.org/blood/article/131/25/2846/37158Mesoblast has led us a merry dance. The timelines for revealing the results of phase 3 clinical trials, are often out of date, just weeks after their disclosure...but we are all aware of the risks of relying on forward looking statements. This is intensely frustrating period for shareholders . I believe and trust in the decisions of the management . Many have conjectured, that management want to prioritise the Ryoncil approval above all else, which would allow them to seek parallel approval for the use of Remestemcel-L in the treatment of Covid 19 related ARDS. Whilst they are entitled to delay and prioritise, they need to be wary of creating a false market in the shares , particularly in relation to time sensitive traded options. Some analysts seem to be very perceptive about timings and changes to timings. SO much so , I always wanted to ask, if they use the services of a clairvoyant ? Enough said.
Leaving the delays to one side. I still believe that patient shareholders will finally get to benefit from a revolutionary therapy for the treatment of many severe inflammatory disorders. Yes, Silviu teases us , “momentous” news may well be ahead .....but it does not appear to be either, in a “couple of months, in “short course” ,or “imminent” . Let us not forget the mitigating circumstances. Silviu and his team, may not only have discovered treatments for CHF and Chronic Lower Back Pain , but may have as an encore , potentially saved hundred of thousands of patients, who are otherwise destined to die from ARDS ,in this brutal pandemic.
I would also argue that it is the unprecedented ruling by the FDA post the ODAC meeting which must have caused many of the other delays. Mesoblast outsources its statistical analysis to independent specialists, so internal management bandwidth is not really a good excuse for delays...but i do not think that they want three pivotal clinical trials landing on their desk for disclosure within 24 hours, at the same time ! There are many goods reasons for wanting to manage the timing of news flow. For example , in relation to optimising marketing impact, timing of milestone payments, partner negotiations, agreement of disbursements , timing of cash flow,etc.etc.
I do not doubt, that Silviu and his team are playing by the rules. They will remain totally blinded so that they are not forced to disclose results within a 24 hour period, but it is one of the great mysteries of biotech, how clinical trial results never seem to arrive on the run up to the Christmas break !
Enough said again.
Lastly, even the mighty ecoool2 has seen his timelines dismantled time and time again ...so I feel in good company when I look at some of my incorrect pontifications. However, if I may be so presumptuous, I would guess, that he would also agree with me , when I say, I believe the delay will be worth waiting for . Remember, Silviu is a rock star. He may be late on stage but we all think his performance will be worth the wait. GLA
Please do not rely on the accuracy of any facts or opinions expressed in the above post when making an investment decision . OP
(20min delay)