2023 The Final Countdown, page-1960

I seldomly have the chance these days to post anything meaningful and even less so to read all the posts that come and go each day ... but from what I do read, the situation we are in is pretty well understood by many here. There is little insight to add above what is already in these forums.

At the end of the day Ryoncil is either going to get approved in the coming weeks or it is going to get another CRL ... the risks are well understood and should not be ignored, but with the risk comes great reward.

At a high level, there are three key boxes MSB need ticked by the FDA.. one of them is ticked already with little risk attached.. and that is safety. Manufacturing and efficacy are the two with risk attached.

On manufacturing I'm feeling confident simply because a form 483 was not issued. For those who have time to burn, you can check out the FDA freedom of information reading room and look up other form 483, and establishment inspection reports for reference and what MSB mean when they talk about these reports.

https://www.fda.gov/about-fda/office-regulatory-affairs/ora-foia-electronic-reading-room

From what I've seen, establishment inspection reports (EIR) which note that no form 483 was issued (just like MSB's case), typically end up with a No Action Indicated (NAI) inspection outcome. Voluntary Action Indicated inspection outcomes are typically noted in the form 483 and resolved or at least addressed in the EIR by the applicant. And Official action indicated (OAI) are from what I can see, always in a Form 483.

So hopefully the manufacturing box is ticked, but the FDA also need to be comfortable that the CQA & MOA have a relationship to clinical outcomes.. all we've heard from the FDA on this is that they agree the CQA used by MSB in the resubmission is reasonable .. but MSB need to establish the relationship to clinical outcomes. Which MSB have said they have in hand i.e potency assays linked to survival in the phase 3 trial. We await the FDA's conclusion on this critical point.

And on efficacy I'm comfortable that the FDA have what they need to tick that box too, but it is totally up to their discretion and that is what nobody can predict where they will land. A lot of unknowns, such as the weight behind the recommendation for at least one more randomised controlled trial... but one thing is for sure, we have a 9-1 ODAC vote supporting efficacy of remestemcel-L in pediatric patients with steorid-refractory aGVHD.

So despite all the concerns raised by the FDA at the ODAC e.g. around study designs ... the FDA if they want to, have that 9-1 ODAC vote to support a tick for efficacy despite all their concerns raised. And since then, MSB have provided propensity matched post-hoc analyses and long term surivival of patients in the phase 3 trial which provide the FDA with more, not less reason to tick this box.

In my mind, the only reason why the FDA would not tick the efficacy box is that they were adamant that an RCT was required.

If that was the case, this BLA resubmission would not have been accepted. It simply would not have been considered a complete response and knocked back. The fact they accepted the BLA resubmission tells me that this was not a hard requirement and that the FDA would be willing to approve Ryoncil if the manufacturing issues were resolved. Not that they will, but would be willing to consider it.

The FDA could very well disagree on the MOA and CQA again.. they could conclude that they do not have sufficient data to approve and ask for an RCT .. these are all risks we can't ignore. But there are factors and indicators that suggest otherwise... maybe the most obvious of all being the fact that there are no safety concerns, so if Mesoblast can demonstrate they can reliably manufacture potent and consistent lots of remestemcel-l, which has long term survival benefits compared to standard of care ... then IMO they have everything to gain and nothing to lose by approving Ryoncil. IMO no form 483 is a strong sign that the if, is likely going to be a yes.

Catch you all once we find out what the outcome is known.

goodluck all