FDA ODAC Meeting Material discussion analysis, page-85

So - Here are some thoughts I had on the negative FDA " Briefing notes "

From the AM session:

"FDA’s position is that the product attributes the Applicant
has identified as related to potency and activity, however, do not have a demonstrated
relationship to the clinical performance of specific DP lots, and that the product’s proposed
immunomodulatory mechanism of action has not been demonstrated in vivo in study subjects
receiving remestemcel-L. Without a demonstrated relationship with clinical effectiveness and/or
in vivo potency/activity, controlling these CQAs may not be sufficient to ensure the
manufacturing process consistently produces remestemcel-L lots of acceptable quality."

1. I think that the only way a DP lot could be claimed as having no recorded link to a reduction of inflammation, is if the trial never recorded the levels of inflammation as it progressed, or they are considering the failed trials where there was no clinically significant reduction in the results.
2. In either case - the ARDS trial has numerous secondary end points that are measuring the inflammation markers very closely before and after the cell delivery, and if the question is purely about potency / link to efficacy then the ARDS results should be able to prove that link definitively that the cells produced lower inflammation in Vivo.

• "Although these assays are consistent with the hypothesized mechanism of action of
  immunomodulatory activity, this mechanism of action has not been demonstrated in the clinical
  BLA 125706 ODAC Briefing Document Remestemcel-L: CMC7 trials submitted to support licensure.
  products have demonstrated apparent immunomodulatory effects in in vitro experiments, the
  ability of remestemcel-L to reduce inflammation as measured by inflammatory biomarkers in
  humans receiving the product has not been demonstrated"

1. Same point re-stipulated from the other end of the proof needed. If required the ARDS data secondary end point inflammatory marker measurements ( if it works ) should be all that they are missing.

• "Considering the available data, FDA’s position is that while the CQAs identified by the
  Applicant and controlled in the product by in vitro lot release assays may have some value in
  assuring a consistent manufacturing process, these CQAs do not have a demonstrated
  relationship with clinical potency, and may therefore not by themselves ensure adequate control
  of clinical effectiveness of individual lots of product.

1. Same point made yet again, that should be addressable using COVID inflammatory marker results ( if they work ) and if more is needed.

• "Product quality attributes measured for remestemcel-L are intended to ensure that key
  qualities of the DP are maintained consistently from lot to lot. Please discuss the
  adequacy of the potency assay established by the Applicant for remestemcel-L.
  (2) In addition to discussion of potency, please discuss other possible product quality
  attributes or characteristics that could be controlled to better assure the continued quality
  of remestemcel-L with regard to safety or effectiveness of the product"

1. So Mesoblast need to discuss why their potency assays are valid, and the panel needs to tell them if they are aware of any other assays that may improve batch to batch consistency.... not bad advice if you are about to launch full scale production.

From the PM Session:

• "Therefore, FDA seeks input from the committee on whether the results of Protocol MSBGVHD001, the one statistically-positive single-arm trial, in a landscape of the multiple negative
  clinical trials for the treatment of aGVHD, including randomized controlled trials, is adequate to
  allow one to conclude that remestemcel-L is effective in the treatment of SR-aGVHD in pediatric
  patients."

1. Time for MSB to get to work and justify why they didn't allow a bunch of children to die in a placebo controlled trial, and why the older trials failed - which is already covered in their data.

• "Any claim of efficacy based on MSB-GVHD001 needs to take into account all studies of
  remestemcel-L for treatment of aGVHD, including the failed trials.
  On 1/31/2020, the Applicant submitted BLA 125706 for remestemcel-L for treatment of SRaGVHD in pediatric patients with the results of Protocol MSB-GVHD001 as the sole basis of
  efficacy. "

1. FDA seem to not understand that the product is not the same, hence company will need to convince them why they are not the same product - again already covered in the MSB briefing pack.

• "Topic for Discussion #1: Protocol MSB-GVHD001 was a single-arm trial designed to determine
  if the Day-28 ORR exceeded 45% for pediatric patients with SR-aGVHD grades B-D treated
  with remestemcel-L. Although the null rate and hypothesis were prespecified in the SAP, there
  were some limitations with regard to how 45% was chosen for the null rate, and it is uncertain as
  to whether the data cited for use as historical controls are sufficient to establish the null
  hypothesis for the purposes of quantitating a treatment effect in a single-arm trial of a new
  therapy for SR-aGVHD in pediatric patients.
  Given these limitations, what are the strengths and weaknesses of the study design?"

1. Clearly the strength here is that less children died as a result of not receiving placebo, and the weakness is that they do not have a placebo statisic to use for the null hypothesis coming from within the same trial.

• "Topic for Discussion #2: The primary endpoint results in MSB-GVHD001 were statistically
  significant, the measured response was durable (median 54 days), and the study results were
  consistent across subpopulations and secondary efficacy endpoints. However, the results of
  Protocols 265 and 280, the two randomized trials, did not provide evidence of a treatment effect
  for remestemcel-L in aGVHD even when reanalyzed using the efficacy endpoint of Day-28
  ORR. In fact, a treatment effect has not been identified in any of the previous clinical trials
  conducted in various disease entities, including: type 1 diabetes mellitus, Crohn’s Disease,
  myocardial infarction, or severe chronic obstructive pulmonary disease"

1. Again the FDA is asking mesoblast about the failed trials and to convince them why they need to discount the lack of efficacy - that is covered in the data among other things by mesoblast doubling the potency in the manufacturing process and also doubling the dosage - meaning maybe the failed trials would have worked with Osiris if they used 8 times as many cells? who knows because they did not.

Good night and DYOR !