Disclaimer: these are just "ramblings of a soccer fan. That also avoids non-standard unscientific abbreviations like mio*, whatever that means". I also don't hold any MSB shares, which in addition to point one and two are likely making my post not worthwhile reading. If you go ahead anyway, please do so at your own risk.
I generally don't post on this thread for multiple reasons, however, with all the panic selling going on it is pretty obvious that all these new "DYOR" "investors" jumped on a hype without having done any research at all, and are now in a state of panic and/or have jumped ship already.
Ryoncil aka Remestemcel-L (formerly known as Prochymal) has had a long history of "failed" P3 clinical trials, which is what the briefing papers (amongst other things) are discussing:
'Therefore, it is unclear how to interpret the results of one statistically-positive single-arm trial in a landscape of multiple negative clinical trials, including several randomized, controlled trials that failed to show a treatment effect."
https://www.fda.gov/media/140986/downloadFact is: remestemcel-L is well and truly a first generation product, MSB says it themselves
https://www.asx.com.au/asxpdf/20191029/pdf/44b07cdc8tfg28.pdfHaving said that, SI has used the historical data to design a trial that was focused on the strengths it has shown over the years. I quoted Jacques Galipeau in a previous post on the other thread the following:
"Since then, some of the best empirical insights into patient selection for MSCs therapy of GvHD have been obtained from the large number of GvHD patients having received MSCs either through clinical trials in the United States or Europe or through hospital exemption in Europe. In GvHD, it has been observed that children respond better to allogeneic MSCs than adults overall (Kurtzberg et al., 2010) and that treating patients early on is better than delaying therapy after onset of acute GvHD (Ball et al., 2013). Gut and liver GvHD are more responsive than skin GvHD. In the absence of robust predictive biomarkers, these observations provide guidance in clinical trial designbiased toward subject selection likely to be responders. These data likely informed an adaptive clinical trial design for NCT02336230, where identical MSC products and dosing schemes in both studies were maintained but the definition of response, age of inclusion, severity of disease, and exclusion of skin-only GvHD as well as a more aggressive start time for MSC transfusion were implemented (Table 2). The latter Mesoblast-sponsored study of marrow MSCs in pediatric GvHD completed recruitment in December 2017."
https://www.cell.com/cell-stem-cell/pdfExtended/S1934-5909(18)30222-4What is he saying?Basically, in the original, "failed" P3 (Osiris) trial, enrolment wasn't limited to certain sub-groups of GvHD sufferer, it also didn't differentiate between adults and children, result:"There was no statistical difference between Prochymal and placebo on theprimary endpoints for either the steroid-refractory (35% vs. 30%, n=260) or thefirst-line (45% vs. 46%, n=192) GvHD trials."I believe that is the %@Sectorwas referring to after reading the latest CYP announcement.Prochymal did however:"* The primary endpoint for the steroid-refractory GvHD trial (durable completeresponse) for the per-protocol population approached statistical significance(40% vs. 28%, p=0.087, n=179).* In patients with steroid-refractory liver GvHD, treatment with Prochymal significantly improved response (76% vs. 47%, p=0.026, n=61) and durablecomplete response (29% vs. 5%, p=0.046).* Prochymal significantly improved response rates in patients withsteroid-refractory gastrointestinal GvHD (88% vs. 64%, p=0.018, n=71).* In pediatric patients, Prochymal showed a strong trend of improvement inresponse rates (86% vs. 57%, p=0.094, n=28)."https://www.fiercebiotech.com/biotech/osiris-therapeutics-announces-preliminary-results-for-prochymal-phase-iii-gvhd-trialsBy knowing that, MSB then designed their clinical trials in a way to focus on the sub-groups where Prochymal has already and consistently proven to be most effective. Whilst the FDA back then was not flexible enough to acknowledge the success in these subgroups, based on the latest successful P3 trials I can't see how they would not approve remestemcel-L.A very good comment on that can be found herehttps://www.cellmedicine.com/osiris-patient-subsets/.Unlike Osiris a decade ago, MSB is not looking at the whole "pie" anymore, instead taking it slice by slice. I'd also like to mention that these slices are not all the same size either. The slice they are looking at is the largest possible one in the pediatrics section as it targets the largest subgroup.
The FDA is well aware of that and of the success remestemcel-L in that subgroup, for which there is currently no treatment available.
The points raised in the briefing papers are also not exactly new from a manufacturing point of view, especially the batch-to-batch consistency issue.
When JCR filed for approval of TEMCELL in Japan, the PMDA noted the following:
The PMDA was then satisfied with the measures put in place to control the risk associated with variations:
https://www.pmda.go.jp/files/000215658.pdfThat is in adults I may add.
Based on the above, I am still very confident that Ryoncil will get approved. There may be further testing required, they may even recommend to narrow it down to certain subgroups, but given the lack of an alternative on market, I think they will do the same as the PMDA 5 years ago and approve it.
The manufacturing issue still exists, but MSB is aware that Ryoncil is a true first generation product. They have improvements ready to be applied plus they have a whole other, more advanced platform for their other products.
Anyways, just a few of my thoughts, which could of course be completely wrong, simply because I'm a soccer fan and I choose (!) to not use standard scientific abbreviations on a peer-reviewed medical discussion form (yes, I'm talking about HotCopper...).
Good luck to all holders!