"If you look at what is being said by MSB now regarding the FDA, GVHD is GVHD (kids/adults/other) [...]."
The important part here is NOW. And MSB as well as the FDA may now have more information as they did back in 2010.
The reason there was assumed to be a difference goes back to Osiris trials, which by the way also lead to future trial designs (organ involvement, targeted recruitment etc.).
Osiris study with 260 patients, "Efficacy and Safety of Adult Human Mesenchymal Stem Cells to Treat Steroid Refractory Acute Graft Versus Host Disease (GVHD)" (https://classic.clinicaltrials.gov/ct2/show/NCT00366145), combined with the 275 patient study, "Efficacy and Safety of Prochymal® Infusion in Combination With Corticosteroids for the Treatment of Newly Diagnosed Acute Graft Versus Host Disease (GVHD)" (https://classic.clinicaltrials.gov/ct2/show/NCT00562497) - although both studies failed primary endpoints - did report the following key findings:
"* There was no statistical difference between Prochymal and placebo on the primary endpoints for either the steroid-refractory (35% vs. 30%, n=260) or thefirst-line (45% vs. 46%, n=192) GvHD trials.
* The primary endpoint for the steroid-refractory GvHD trial (durable complete response) 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 durable complete response (29% vs. 5%, p=0.046).
* Prochymal significantly improved response rates in patients with steroid-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-trials
On a side note, the following comment after the failed P3 trials may sound like something that has also been heard in recent years about the rebranded Prochymal therapy:
"We are encouraged to see Prochymal significantly improve response rates above standard of care in GvHD patients who currently have no good treatment options. We will meet with the FDA as soon as possible to discuss the most appropriate and efficient path forward for Prochymal in this life-threatening indication."
C. Randal Mills, Ph.D., President and Chief Executive Officer ofOsiris Therapeutics, 2009
Above sub-group analysis (children vs adults) was then picked up by Dr Kurtzberg and informed study, "Prochymal Expanded Access Treatment for Pediatric Patients Who Have Failed Steroids for Acute GVHD" (https://classic.clinicaltrials.gov/ct2/show/NCT00759018).
According to Dr Galipeau, "On this basis, on May 17, 2012, Health Canada issued marketing approval for Prochymal™ to treat children with acute Graft versus Host Disease (Reicin, 2012). Health Canada approved the drug via a Notice of Compliance with Conditions (NOC/c), which allows certain drugs into the market without full efficacy data. Under these terms, Health Canada subjected Osiris Therapeutics to heightened post-market surveillance. In addition to long-term monitoring, the NOC/c requirements restricted treatment to children with refractory GvHD and restricted access of Prochymal™ to physicians who have experience treating GvHD patients. As of 2018, 6 years after Health Canada approval, Osiris – or latterly Mesoblast – have not marketed Prochymal™ in Canada. Debate at the Canadian House of Commons Standing Committee on Health held on May 30, 2016 spoke to the conundrum at hand, where testimony described the case of Prochymal™, which was “probably the first truly innovative technology to be put forward for a conditional licensing approval” [in Canada], and it “went nowhere because it couldn’t get reimbursed” (Minutes of Proceedings of House of Commons (Canada) Standing Committee on Health, 2016). (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434696/)
Whilst the original Osiris trial in newly diagnosed aGvHD patients failed back in 2009, Cynata has now the advantage of further research conducted by the likes of Mount Sinai and Mesoblast, that will hopefully allow them to correctly identify the patient sub-group that will likely respond best to MSC treatment. This is however something that is yet to be seen.
In 2013 Mesoblast as we know acquired Osiris and with it the right to receive royalties from Temcel treatments in Japan (Licensing/collaborative agreement 2003:
https://www.sec.gov/Archives/edgar/data/1345099/000119312515361222/d943277dex109.htm).
Muroi (incl Murata), overseeing the clinical development of Temcell, which has been approved in Japan in 2015 for the treatment of acute graft versus host disease (aGVHD) in children and adults in Japan (https://www.pmda.go.jp/files/000215658.pdf).
In 2021 Murata et al published, "Off-the-shelf bone marrow-derived mesenchymal stem cell treatment for acute graft-versus-host disease: real-world evidence" (
https://pubmed.ncbi.nlm.nih.gov/33976381/) and the article published a few months later (Front. Immunol., 19 August 2021, https://www.frontiersin.org/articles/10.3389/fimmu.2021.724380/full):
"On multivariate analysis, liver involvement of acute GVHD and longer duration from first-line steroid therapy to second-line MSC therapy (≥14 days vs. <14 days) were associated with a lower OR rate. Older patient (18 to 49 years and ≥50 years vs. <18 years), higher grade of GVHD (III and IV vs. ≤II), higher number of GVHD therapies before MSC therapy (≥2 vs. ≤1), and non-achievement of OR on day 28 were associated with a higher NRM. OS was significantly higher in patients with an OR on day 28 than in those without an OR."
It does however refer to an article using MSC FFM, an MSC therapy using pooled starting material from 8 donors in an attempt to manufacture a more homogenous product, "Children and Adults with Refractory Acute Graft-versus-Host Disease Respond to Treatment with the Mesenchymal Stromal Cell Preparation “MSC-FFM”—Outcome Report of 92 Patients" (https://www.mdpi.com/2073-4409/8/12/1577):
"The overall response rate to MSC-FFM was 82% and 81% at first and last follow-up, respectively. Relapse of aGvHD was infrequent. First follow-up overall response was highly predictive of long-term response in that there were very few late responders thereafter, but the quality of the response improved over time, as there were 28% complete responses after first evaluation but 51% at last follow-up (see Sankey diagram in Figure 2). The probability and quality of response were largely independent of aGvHD severity and similarly good in children/adolescents vs. adults (Figure 3A).
[...]
Certain highly relevant short-comings of the data presented here should be mentioned. We could only collect high-level data and the data were not monitored. Moreover, this is not a clinical trial with defined in- and exclusion criteria and a control cohort, but in- and exclusion was solely directed by the breadth of the label of MSC-FFM as mentioned in Material and Methods. As was shown, partly contradicting several earlier reports, children and adolescents trended towards better responsiveness to MSCs than adults, but this benefit was modest and did not reach statistical significance (Figure 3A). Contributing confounders may be that the sizeable pediatric sub-group differs from the adults in that they were more heavily pre-treated, i.e., likely to represent a higher-risk group. Therefore, it is quite possible that response rates in pediatric and adult patients appear statistically similar in this case series because the children are sicker, as well as the response rates in TR-aGvHD patients are as good as it is because the TR-aGvHD patients are predominantly pediatric patients (who may be more likely to respond to MSCs, according to the literature)."
The authors also mention something that I consider highly relevant in Cynata's case:
"After steroid-treatment, lymphocytes are largely depleted, including from aGvHD target organs, so that the assumption that allo-reactivity suppressing activity of MSCs is primarily responsible may fall short. Endothelial damage accompanying aGvHD has been appreciated for many years and is currently emerging as a leading problem of steroid-refractory aGvHD [33,34,35] so that trophic (pro-angiogenic) factors emanating directly or indirectly from MSCs may be equally or even predominantly responsible for observed benefits."
This is something I want to follow-up on with the company as I recall a study in MI, "Cymerus MSCs enhanced angiogenesis without sustained engraftment or significant impact on infarct scar size" (
https://pubmed.ncbi.nlm.nih.gov/34588150/).
As I was forced to use my phone, some links may not be working properly. Also, Sci-Hub may be required to read some of the referenced articles.
(20min delay)