Hey there
@Fastback6666I feel the frustration, but this is the FDA we are dealing with... they make the TGA look like putt-putt vs the PGA tour / FDA. The FDA is notoriously difficult to deal with, and many simply give up. Just look at SPL, they were issued a CRL back on 27Dec18 .. for a BV gel and haven't done anything since or updated their shareholders on the path forward. The disclosure we are getting from Mesoblast, whilst frustrating is actually significantly better than peers on the ASX. I mean SPL haven't even publicly mentioned the word CRL, and have given no update on the process it is taking to address the issues raised by the FDA.. its been 3 years! Anyway I digress, but I believe comparing one ASX company against another, in how they disclose information gives you a much better appreciation of the quality of disclosure/comms... because if we compare what we get from MSB, vs what we want as retail shareholders.. then we'll never be satisfied.
But to answer your question (and others have done so already I can see), the FDA meetings take place on a particular date, but the official minutes from that meeting are not provided to the company until 30 days after the meeting. A lot of shareholders here figured out that the OTAT meeting took place on the 30th Nov (right after the AGM), as Silviu said in an interview that the OTAT meeting would take place in November.. and at the AGM (29th Nov), they still said they were due to meet with OTAT.. so there was only one day left in November... being the 30th.
As such, the FDA was not due to provide minutes for that OTAT meeting on the 30th Nov until 30th Dec (US time), which was overnight for us.. so the FDA would have sent those minutes after the US markets closed, but before the AU markets opened.
So Mesoblast actually informated the market as soon as they received the OTAT minutes, and met the expectation that we would receive an update on the approval pathway for CLBP, CHF and SR-aGVHD in Q4 2021.
But having said that, the FDA is a tough nut to crack. But if you do crack into the US markets through the FDA, then anyone who wants to follow in your footsteps as a potential competitor has to also go through the same difficult journey. What we refer to as a MOAT. And the harder it is to get approval, the bigger the MOAT. Right now its looking massive.
Mesoblast are aiming to be the first to bring MSCs to the US market, which means the FDA knows that anything they say and do with Mesoblast will become the benchmark for future applications... so the bar is being set for the first time, and they are ensuring that it is done by the rule book and will not accept anything less. Not even Mesoblast's attempt to save children's lives by not subjecting them to weakened Rem-:L doses, just to demonstrate potency to the FDA, was a good enough excuse. The doesn't want our cells being compared to children in a database (like the MAGIC database), or past trials / compassionate use data... they want the cells to demonstrate efficacy and the potency assays to be demonstrated in the successful phase 3 trial run by MSB.
So I'm going to hone in on what the CRL said first... namely the points raised in that CRL were:
1. FDA recommended that Mesoblast conduct at least one additional randomized, controlled study in adults and/or children to provide further evidence of the effectiveness of remestemcel-L for SR-aGHVD;
2. FDA identified a need for further scientific rationale to demosntrate the relationship of potency measurements to the product's biologic activity.
And for the first time, Mesoblast said this "by demonstrating the relevance of the in vitro potency assay to clinical outcomes, Mesoblast believes it will be able to show that the remestemcel-L product used in the Phase 3 trial in pediatric SR-aGVHD was standardised as to identify, strength, quality, purity and dosage form, and that this will address OTAT's recommendation for an additional adequate and well-conrolled study".
So what I didn't know is that the first point being raised (to run another trial) was not solely to address efficacy (which has been demonstrated by the single arm successful trial + the 9-1 ODAC vote), but instead both those two points in the CRL were from OTAT, and stemmed from the concern that OTAT raised on the proposed Mechanism of Action (MOA) using a matrix potency assay presented in the initial BLA i.e. TNFR1 levels (quantitative i.e. measurable in Rem-L), and inhibition of IL-2Ra (qualitative i.e. impact of Rem-L on biomarker IL-2Ra) was not demontrated in vivo, and more specifically not demonstrated in the Phase 3 trial.
But back to the issue at hand... OTAT said this at the ODAC "In vitro immunomodulatory activity was demonstrated for remestemcel-L, but this MOA has not been demonstrated in vivo".
So basically the FDA tore Mesoblast's initial potency assays and MOA to shreds at the ODAC and said that none of it translated to the phase 3 patients. If you look at the ODAC notes, they said:
a) No differences in mean TNFR1 levels in product lots received by responders and non-responders in the Phase 3 trial
b) No association between mean TNFR1 levels in lots received and survival on Day 100 in the phase 3 trial.
c) No association with the D28 Overall Response primary outcome
d) Pooled data from the three clinical studies (the failed one a decade ago, EAP and phase 3 trial) found statistically significant association between TNFR1 reulsts and survival on Day 100 post-treatmnet, however different study populations and concomitant medications, and significance not observed in the stand-alone phase 3 trial.
Compare OTAT's position at the ODAC (above) vs today through today's announcement:
In today's announcement, it said this... "OTAT indicated that the
in vitro immunomodulatory activity Mesoblast intends to measure for potency is a reasonable critical quality attribute (CQA) for the product,
and the relevance of this activity to clinical outcomes should be established."And...
"Mesoblast has now generated substantial new data that it believes establish the relevance of the proposed in vitro immunomodulatory activity of remetsemcel-L to the in vivo clinical effect of the product in the Phase 3 trial in children with SR-aGVHD, including survival and biomarkers of in vivo activity".
And here is the key thing to note from today's announcement in relation to the SR-aGVHD BLA:
First of all, to appreciate the significance we need to understand that the Mechanism of Action of any product is like the foundation of the entire BLA. If you don't establish that foundation, the FDA cannot rely on the data you generate in a clinical trial because you can't reasonably demonstrate that the product you used was the reason why the clinical benefit was seen in patients. So it didn't matter the ODAC voted 9-1 for efficacy... because if Mesoblast can't establish the foundation of the BLA i.e. MOA, then they can't take credit for any benefits seen in the trial. So with that out of the way...
The position at the ODAC was that OTAT did not believe the MOA proposed by Mesoblast was demonstrated in the phase 3 trial data, and they made it clear that they wanted to see the MOA and potency assays correlate with data in the phase 3 trial and no other trial or EAP program data. That's the treasure I was talking about before... Mesoblast now knows the FDA only care about the phase 3 trial data. With this, they can plan their strategy to approval.
So for our initial BLA, essentially OTAT didn't recognise any of the clinical benefit in the Phase 3 trial, because Mesoblast couldn't demonstrate the link between rem-L and the clinical benefit seen in patients. Hence in the CRL they recommended another trial, so that if they wanted to maintain that initial MOA and potency assays (TNFR1 and inhibition of IL-2Ra)... then another trial would be needed to demonstrate that their proposed MOA was in fact reasonable for the clinical benefit / efficacy.
Since then, CBER were presented with the in vitro data for the new MOA. They said it was reasonable, but OTAT needed to verify it i.e. through in vivo data. That is, when establishing a Mechanism of Action, whilst it is demonstrated in vitro ... for the FDA to accept the potency assays and CQA, it must be demonstrated in vivo i.e. in humans. Once you can do that, then the FDA can rely on the in vitro MOA i.e. they now know it doesn't just work in a petri dish, it also translates into humans.
Now OTAT were presented with an updated MOA and potency assays which included new quantative and qualitative attributes i.e. on top of the two used in the initial BLA being TNFR1a and inhibition of IL-2Ra, which they needed to validate by observing that the in vitro MOA and potency assays could be translated in-vivo. That was the new data Mesoblast spent almost US$10m on generating. So what Mesoblast succesfully did was introduce a new MOA, and have demonstrated that with new in-vivo generated data, that it was in fact reasonable. That was a massive task and one that was not guaranteed to succeed.. but we got confirmation today that OTAT have now agreed the new MOA/potency assays/CQA....
Why is this important? In case you missed the punch line... now Mesoblast are able to reanalyse the phase 3 data using the new MOA/potency assays/CQA to demonstrate that the product (rem-l) was in fact responsible for the clinical benefit seen in patients. This is the ultimate objective and hurdle set by the FDA from the outset... they blew up at Mesoblast at the ODAC because they didn't think Mesoblast demonstrated that rem-L was responsible for the clinical benefit seen in the successful phase 3 trial... as there was no link between the MOA/potency assays/CQAs and clinical outcomes in the phase 3 trial... so what has Mesoblast now been able to do?
From today's announcement again.... "Mesoblast has now generated substantial new data that it believes establish the relevance of the proposed in vitro immunomodulatory activity of remetsemcel-L to the in vivo clinical effect of the product in the Phase 3 trial in children with SR-aGVHD, including survival and biomarkers of in vivo activity".
This is quite momentus, and explains why Mesoblast believe that by addressing the potency assay.. they will also address the need for another trial, because by successfully demonstrating the link between rem-l used in that phase 3 trial and the clinical outcomes, they then allow the FDA and OTAT to rely on the clinical outcomes observed in the phase 3 trial and as such not need another trial to demonstrate efficacy as the efficacy demonstrated in the phase 3 trial already submitted is now linked to the agreed MOA with the FDA.
It's a game of chess, and I think Mesoblast knew exactly what they were doing.. because they were basically able to generated substantial new data using the newly established MOA so soon after the OTAT meeting... it's almost as if they knew exactly what to do next, if OTAT agreed the new MOA was reasonable...
Now what Mesoblast have disclosed today shows very promising progress, but probably not the final blow we all hoped for. And it appears that Mesoblast never quite aimed for, as they first needed to agree they could reanalyse the phase 3 data using a new MOA, and pivot away from the originally submitted MOA. And right now, the only piece left is to use the new MOA/potency assays/CQAs to draw that link between rem-l used in the phase 3 trial, and the phase 3 trial outcomes.. which were spectacular.
So it appears to me that Mesoblast have everything in place to close out the resubmission of the BLA after the next OTAT meeting... which I feel is needed because OTAT need to be comfortable that there is a correlation between the new MOA and clinical outcomes before they will tell CBER that the need for a new trial is no longer required. And if OTAT tell CBER that Mesoblast have demonstrated that link.. then all the CRL points have essentially been addressed, and the new re-submission should be accepted by the FDA, as the FDA can reject a BLA if it believes it is incomplete i.e. if they believe any remaining CRL items have not been adequately addressed.
I mean what would have sent the share price soaring is if OTAT agreed that Mesoblast had done everything it needed to address the CRL points raised, and that they could re-submit the BLA. But it appears what retail shareholders want is not how the FDA works... things need to be done in a particular order and Mesoblast are working through this process methodically and appear to be on top of it.
I think many were thinking that Novartis terminated their collaboration with Mesoblast because they must have received a bad OTAT outcome, which puts into jeopordy not only the Ryoncil BLA for SR-aGVHD, but the proposed COVID-19 ARDS trial which could lead to an EUA. So the fact Mesoblast actually made progress with OTAT, with the Ryoncil BLA still very much on track and what I believe to be a successful outcome for the upcoming COVID-19 ARDS trial... that is all a far cry from the disaster the market may have been bracing for coming out of this meeting. The market reaction may have been a little dissapointing for some, but in my view the company has just avoided what could have been a terrible outcome if the assumption that Novartis terminated because of a bad OTAT outcome was true... but we now know that it clearly was not true.
So that now should put back into focus all of Mesoblast's other programs, which are all set to announce some very price sensitive developments in early 2022. CLBP has all it needs to start the second phase 3 trial, with the only missing piece a partner ... or if it feels it can afford the trial, then they may go it alone, but I feel that this may be an opportune time to partner up and take away some of the financial stress. Novartis terminating enforces this sentiment.
CHF is going up for a follow-up FDA meeting, where the Q4 meeting confirmed that our first phase 3 trial was a success, whereby the primary endpoing of 3 point MACE (stroke, heart attack and cardiac death) was confirmed to be acceptable for approval by the FDA. The follow up meeting appears to be the FDA considering if the second trial is needed, or if they will approve Revascor on a single trial based on ethical grounds. Worst case here is Mesoblast get the green light to run another trial, which means they will partner up shortly... and that's a big big partnership. Or there is a slim chance the FDA may approve Revascor on a single trial, in which case... we will have lift off.
And the second COVID-19 ARDS trial could not start until the potency assays were agreed with the FDA, and because OTAT just confirmed the CQA / potency assays they would accept to demonstrate quality, purity and potency of Rem-L, that IMO just unlocked the COVID-19 ARDS trial... Mesoblast can now piggy back of this successful OTAT meeting, and use the newly established MOA for the COVID 19 ARDS trial. So once Mesoblast meet with the FDA to confirm that, then that second trial will be up and running (assuming funding is provided by the NIH or a partner).
Anyway this is my last post for 2021... time to enjoy the NYE celebrations and fireworks.
Happy new year everyone, stay safe...calm and don't flinch. We got this!!
(20min delay)
