CEO Itescu needs to go, page-453

• Mesoblast successfully met the pre-specified primary endpoint in their phase 3 trial, which was prospectively agreed with the FDA.

However, apart from some other points that have already been mentioned on these threads, the way MSB proposed how the cells will have proven effectiveness of the therapy did not satisfy the FDA:



(page 80)
https://web.archive.org/web/20210305082200/https://www.fda.gov/media/143337/download

That's the FDA highlighting the potency issue (which is still based on Danilkovitch's work at Osiris) since TNFR1 levels forms part of matrix approach:
"FDA also identified a need for further scientific rationale to demonstrate the relationship of potency measurements to the product’s biologic activity. Assays measuring the potency of remestemcel-L will continue to be refined to provide further scientific rationale for its use in severe inflammatory diseases with high mortality risk, such as SR-aGVHD and COVID-19 ARDS."
https://investorsmedia.mesoblast.com/static-files/71f7b715-a029-47dc-af8e-8c8f09a4a96f

@JB1975 discussed this in multiple posts like this one here:


https://hotcopper.com.au/threads/ann-mesoblast-completes-resubmission-of-bla-to-fda-for-sr-agvhd.7206622/page-710?post_id=66362915

New data had been requested by the FDA to do that.

• The drug Jakafi was approved with the same trial design and worse results, although they did have a larger sample size.

Whilst both REACH1 and GVHD0001 are both open-label, prospective, multicenter studies, one obvious difference is adults vs. children:
"Since then, some of the best empirical insights on patient selection for MSCs therapy of GvHD have been obtained from the large number of GvHD patients having received MSCs either through clinical trials in the US, Europe, or through hospital exemption in Europe. In GvHD, it has been observed that children respond better to allogeneic MSCs than do adults overall (Kurtzberg et al., 2010) [...]"
Galipeau et al, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434696/

Although Murata et al somewhat questions the conclusions drawn from that study above:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417106/

And in addition to that the FDA also had some other issues with the trial design in this particular case:

https://web.archive.org/web/20210310192904/https://www.fda.gov/media/141131/download

Abd remember, that sample size had to be reduced even further as paert of the post-hoc analysis, which was intended to provide the additional evidence requested by the FDA - instead of conducting a further trial.

• The FDA appointed an Oncology Drug Advisory Committee in September 2020, where the committee voted 9:1 in favour of the therapy's efficacy.

Agreed, they did.

• Mesoblast had met with the FDA following the previous CRL, and established that if they resolved the CMC/quality aspects then CBER would re-review the BLA in full.

And they did re-review the BLA in full and still weren't satisfied with the newly generated data via post-hoc analysis. They recommended a clinical study to eliminate any confounding factors.

• The therapy was acknowledged as having a clean safety profile.

Agreed.

• The therapy has been made available to over 250 children through a compassionate use program/early access protocol (EAP) in the past 3 years (which is a non-insignificant proportion of the estimated annual total patient population of 750 within the US).

Protocol 275 has been made available to children between 2007-2014 according to Mesoblast's November 2017 presentation:


https://announcements.asx.com.au/asxpdf/20171115/pdf/43p7fmgkh7cb1d.pdf

That means, it very likely included therapies before and after the manufacturing improvements undertaken by Mesoblast.

• Within the EAP, day 100 survival has been demonstrated to be 74% within 275 patients.

I take it that you are referring to the same protocol 275 EAP, that treated 241 children, the day 100 survival "was 66.9% (n = 160 of 239). Importantly, survival through day +100 was significantly greater in subjects who achieved a day +28 OR compared with nonresponders (82.1% versus 38.6%; P < .001, log-rank test)."
https://pubmed.ncbi.nlm.nih.gov/32044400/

Murata et al also noted:


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8417106/

It is also important to note what the FDA mentioned about the comparability of that study during the August 2020 Clinical Evidence Presentation by Kristin Baird, FDA Clinical Reviewer, CBER/OTAT/DCEPT/CHB given that the trial design Null Rate was chosen based on study Protocol 275 and 280:


(check REACH1)


https://web.archive.org/web/20210310192904/https://www.fda.gov/media/141131/download


And as Murata et all said, "the efficacy of remestemcel-L alone has not been prospectively compared with other immunosuppressive drugs in the treatment of acute GVHD." MSB, you know what you have to do, now do it!