Some very enthusiastic commentators have recently been ventingtheir frustrations at the Company. In doing so they have failed to recognise some very important issues affecting regulatory discussions.
Some have suggested that Silviu should have commenced a second trial for steroid refractory acute GVHD. So let’s just consider that old chestnut . Apart from making the obvious observations that the original trial protocol wasagreed with the FDA before the case reviewer subsequently moved the goal posts and requested a secondtrial even whenthe primary endpoint for GVHD001 was met…or that there were many competing clinical trials which could have crossed the line in the intervening period which had the potential to gain approval at shareholders expense (including prophylaxis treatments)
How about if i told you that the use of 28 day primary endpoints makes it almost impossible for Mesoblast to show clinical significance against Ruxolitinib (RUX)in Grade II/B patients which is the largest segment. Why is this the case ? because according to Bonig et al ,
“an early response isnot accurately correlated to survival outcomes but does help determine initial responders to this JAK 1/2 pathwayinhibitor.
This is where the FDA have in my opinion have lost the plot . If your child was diagnosed with sr aGVHD would you be more concerned about long term mortality or a 28 day primary endpoint ? As the chart for overall survival illustrates, Rux showed virtually no difference in survival outcomes over 12 months despite the investigator choosing therapies which had been shown to have very limited efficacy. To show how poor the efficacy was for the other therapies i enclose a link to a Nature review of competing treatments available at the time.
https://www.nature.com/articles/s41375-020-0804-2#:~:text=The%20weighted%20average%206%2Dmonth,to%20steroid%20treatment%20%5B10%5D.
The NEJM article referenced a phase 2 trial for ruxolitinib (Reach 1 ) which enrolled patients with primarilygrade III or IVacute GVHD (48% and 20%of the patients, respectively), the response was 54.9% at day 28.”
To be fair, very few therapies available at the time wereable to achieve much better but the choice of Best available therapies included two pretty well know failures which brought down the control response comparisons considerably. Despite this fact, 12 month survival was almost identical between the two cohorts.
Reach 2 was a Phase 3 pivotal trial for Ruxolitinib whose results were published in the prestigious New England Journal of Medicine on April 22nd 2020
https://www.nejm.org/doi/full/10.1056/NEJMoa1917635
According to Bonig et al, in the Journal of Translational Medicine
“Objective overall response rates (ORR, i.e., complete or partial response) of 50% or greater have been reported across multiple studies of Rux, even in high-grade SR-aGvHD, withrates exceeding 80%in Grade II disease Patients who respond do so quite promptly (i.e., by Day 28); however,an early response was not correlated to survival.With regards to safety,ruxolitinib suppresses haematopoiesis and adaptive immune responses”
https://link.springer.com/article/10.1186/s12967-023-04731-1
“A proportion of patients do not respond to or do not tolerate ruxolitinib (herein referred to as ruxolitinib-refractory aGvHD [RR-aGvHD]). In the pivotal REACH2 trial, non-response was observed in 38% of patients at Day 28 and60% by Day 56, and another11% of patients had discontinued ruxolitinibby Day 28 due to adverse events.Non-response was especially high in patients with Grade III or IV disease (44% and 47%, respectively”
Unlike Mesoblast who excluded lower riskStage 1&2 skin only patients in their Phase 3 trial, the supplementary appendix shows that the trial investigator Robert Zeiserin Reach 2, happily enrolled almost two thirds of baseline skin patients in the lattercategories. A chart below from the NEJM article reviewing Reach2 data(against best available therapy) does not specify the percentage of patients with multi organs disease ( which may increase overall clinical grade), but it impliesthat complete response rates were likely to have been affected by these milder risk baseline characteristics (I should point out that only Grade 4 skin is considered “high risk” for the widely usedMinnesota high risk stratification) .
Despite the encouraging 28 days reported responses in Reach 2, the trial confirmed significant adverse events and ultimately, there was minuscule differences in 12 month survival compared to BAT.
The whole premise of using surrogate endpoints originally was that they are supposed to be correlated with survival outcomes. In aGVHD there is the additional consideration of being able to analyse overall responses and consider further treatment options for both steroid refractory and dependent patients. The latest research from the MAGIC Consortium is actually calling for 14 day endpoints because of the horrendous mortality rates associated with non responders.
https://www.astctjournal.org/article/S2666-6367(24)00176-3/fulltext
So , while the FDA has been sitting on their backsides pontificating on the method of action of MSCS , the outcomes for patients with Ruxolitinib refractory aGVHD are generally dismal. Ruxolitinib resistance or intolerance has been reported on 21% of adults and28-55% of children… no doubt with much higher percentages for more severe grades.
I believe it is inexcusable after so many years post the results of GVHD001 , which was a well controlled , multi centre Phase 3 trial , the FDA is still presiding so many avoidable deaths on its watch. Not one is denying that potency can be improved or that further work is required to ensure consistency, reproducibility and traceability of donor lots, but if Mesoblast was able to pass a FDA PAI manufacturing inspection in Singapore ,they have more of less proven a potent reproducible product.Remember, the MOA of MSCS is such that you can put identical doses into two human beings and you can get totally different patient responses from their immune systems.
In areal world study of 64 Ruxolitinib refractory patients receiving a range of different and mostly off label therapies including ECP, etanercept, MMF or budesonide, (given with or without Rux,) median survival was just 28 days !!! (21 days for refractory and 50 days for Rux intolerance). Overall survival was approximately 20%, 16%, and 10%at 6, 12 and 24 months respectively.
Mr Marks compare that with peer reviewed four year mortality for hundreds of patients receiving Ryoncil . Your organisation has deluded itself that you understand the mechanism of action for this disease more than the validated MAGIC biomarker algorithms and you have sided withtheincomplete scientific assessments of your colleagues, against the experience of clinicians of your ODAC Advisory Panel who plainly understood the above outcomes.
I pray that this time common sense will prevail. In Nicole Verdun we have to trust . OP
Please do not rely on the rants and opinions of this disaffected shareholder when making an investment decision .All opinions given by a non medically qualified individual in good faith . OP
(20min delay)