Ann: Mesoblast Maintains Momentum with FDA, page-95

Hi Reg,

re "how fast an approval could come for Adult SR aGVHD , given the voicing of accelerating approval processes by the new FDA Department Heads?"

based on the little I know, I consider an RR-aGVHD adult target population is still the first most likely indication to be targeted for grant & that would be under Accelerated Approval to extend the RYONCIL label for marketing into the adult SR-aGVHD population.

Why do I say this? Well, in Prof Kurzberg's case series study presented at TANDEM CIBMTR-ASCT on Feb 12 this year MSB seemed to me to be focussed quite deliberately on a treatment intake in which there were "44% having failed ruxolitinib", which to my mind also necessarily implied that Mesoblast wanted to have 56% of the case series SR-aGVHD (but not RR) as the contemporaneous control. Here's the highlighted abstract as post-printed in the journal - note how many times "Ruxolitinib", "mortality", "overall survival" and "unmet need" get a mention.

In a poster abstract. Hmm...

And that indicated to me at the time that MSB likely saw this case series as primarily indicating to FDA and clinicians in Feb 2025 an efficacy irrespective of Rux in the adult SR-aGVHD population without actually being a trial vs Rux in SR-aGVHD adults. It helps to establish an unmet need in an adult SR-aGVHD population completely unaffected by the 'Rux as proven SOC' arguments. And in doing so it elegantly highlights Ruxolitinib's often overlooked failings. So, good 'PR'. But more importantly it, bravely and compellingly IMO, measures overall survival (but only to Day 100 in February & of course we had some inkling how that would play out from RYONCIL's paediatric trial GVHD-001/2).

Of course, it might also demonstrate a likely effectiveness of RYONCIL against a Rux-treated or other 2nd-line therapy control arm in the proposed adult RCT seeking to prove either superiority or at least non-inferiority of RYONCIL. But that didn't seem to me to be the most obvious use of this case study given CIBMTR-BMT CTN's pre-existing commitment to MSB re funding a full blown RCT. For example, I'm not aware of CIBMTR saying to MSB that they'd like a case study to provide an indication of likely efficacy prior to the committed adult trial.

So, what use could MSB get out of Prof Kurtzberg's case series right now?

At that time i.e. February I thought that Mesoblast was most likely going to push hard for AA for RYONCIL in adults i.e. as the way to get RYONCIL product into the adult market without having to wait for even the speediest RCT to be run as CIBMTR-BMT CTN and MSB do intend. Yes, I'm sure MSB intends to seek a clear efficacy signal as a 2nd-line therapy in that adult population, but I think it chose to have at least 44% RR to have a clear efficacy signal as a 3rd-line therapy in the same population to demonstrate to the FDA right now an unarguably unmet need under any SOC.

OK then, so why wouldn't they just enroll all patients in the case study as RR? Well, it may be that they enrolled 56% not RR (but at least SR) so that a relatively clear and broad efficacy signal for non-paediatric use in Class III-IV SR-aGVHD could be drawn from this case series i.e. in connection with glucocorticoids and all of the currently available second-line therapies. That would be of use in connection with the large clinical trial design. And it could assist in discussions with the FDA on appropriate controls and primary efficacy indicators for that larger RCT, especially if there were discussions about AA being initiated with FDA at the same time. What I'm saying here is that it might be possible to bring on a speedy adult population AA with FDA's consent & at the same time use the process of settling the confirmatory trial design to sort out the remaining adult trial issues between MSB, BMT CTN and the FDA. It seems to me that MSB must be pretty comfortable already with the overall survival datapoints gathered so far i.e. in this case series and the earlier RCTs.

And I believe this kind of approach is exactly what CBER's new Director (Dr Prasad) wants to see to consider 'rapid approval' for rare diseases - no surrogate endpoints here. Just genuine overall survival with a demonstrated biological plausibility (according to the FDA's own correspondence) & an RCT to confirm the efficacy. Perfect from the current FDA's POV, I'd suggest.

Yes, Reg I know this had little to do with timing. But I wanted to lay out the context that makes most sense for me.

How quickly could we then hope to file a BLA for AA for the RR-aGVHD adult population? If this kind of RWE is what the FDA wants to use to demonstrate rapid approvals, then I expect it would be toward the end of this year i.e. just as Ruxolitinib's patent cliff issues start to swing into view.

Cheers
GLTALTH