Ann: Mesoblast Partners with BMT CTN on Adult SR-aGVHD Trial, page-314

I am curious Southoz, and apologies for putting you on the spot in front of an audience, funding issues and questions aside, do you consider MSB in a better place, specifically in terms of regulatory approval probabilities with the FDA on GvHD than in 2020 (that most press commentary to be fair described as "shocking", given the FDA’s unprecedented 'side-stepping' of the ODAC 9 to 1 vote) and indeed 2023? Even the most objective of remaining shareholders (some of us try to remain circumspect despite frustrations at past events) I would suggest still do - one last failure in GvHD, the fall of Silviu and possibly the company in present form - bar a white knight regulatory/partnership event - very likely. I am curious, as a coherent yet less admiring commentator of MSB, do you feel success at the third attempt in present guise more likely from purely trial/evidence/regulatory perspectives?

As you yourself pointed out in previous posts, many years ago MSB were "recommended" by the FDA to do an adult RCT - not "told" as so many falsely allege on these threads. The FDA’s AD Com 2019 briefing notes reported that during the rolling BLA MSB were advised:

“FDA recommended a new randomized trial of remestemcel-L versus standard of care for treatment of steroid-refractory acute GvHD, indicating that such a study would likely be feasible in the adult population. A randomized, controlled study in the adult population could potentially also confirm clinical benefit in the pediatric population, depending on the results.”

Now SI and many leading Physicians of course stamped their feet (as much as you dare with the FDA) and questioned the morality and necessity of a further trial and felt the wealth of standalone studies and other data (particularly the MAGIC study) on GvHD mortality would be a sufficient natural control cohort, when combined with the single arm phase 3 trial MSB-GVHD001 for the pediatric acute GVHD, as an adequate study for the purpose of demonstrating substantial evidence of effectiveness. Certainly the ODAC Committee felt the efficacy persuasive enough and it worthwhile revisiting the premise of their decision:

"The ODAC is an independent panel of experts that provides advice and appropriate recommendations to the FDA based on potential issues highlighted by the FDA during their review of the efficacy and safety of marketed and investigational products for use in the treatment of cancer. The ODAC review will comprise two separate sessions: a morning session which will discuss issues related to the characterization and critical quality attributes of remestemcel-L as they relate to clinical effectiveness, and an afternoon session which will discuss results from clinical trials included in the BLA. Although the FDA will consider the recommendation of the panel, the final decision regarding the approval of the product is made by the FDA solely, and the recommendations by the panel are non-binding."

In SI's defence, he had other irons in the fire that he probably felt would sway the FDA's overall sentiment (and certainly the ODAC vote will not have deterred that), that might have changed his and his staff's attitudes if he had been going on GvHD purely alone, but they went with the single arm study and other data/evidence in GvHD of course.

The FDA of course more recently noted what it felt was a lack of a suitable potency assay for the RYONCIL product used during the study and of course MSB is currently finalizing additional potency assay data on commercial inventory to provide to FDA in Q1 CY2024 with evidence that it believes shows the product used during pediatric Phase 3 trial MSB-GVHD001 "was standardized as to its identity, strength, quality, purity, and dosage form to give significance to the results of the investigation" (along with a meeting on with the FDA regarding potency assay data for the pediatric BLA and completion and submission to FDA of protocol for adult SR-aGVHD Phase 3 trial in partnership with BMT CTN).

As usual lots of hurdles with the FDA, but I am curious, again, trial funding questions aside, if you feel from a regulatory standpoint, objectively, MSB closer to FDA approval at the third attempt in GvHD, particularly given the forthcoming partnered trial with the BMT CN (not under-estimating MSB's own costs still therein)?

Always good to hear a different perspective - well informed ones that is.

(For those unfamiliar, SouthOz was actually a decent non-holder giving pause for thought in MSB in 2020 and not some Harry Hindsight detractor)