Thanks for this discussion with
@stockrock I'm very interested in where it's going, as I'd like to talk about the introduction of TNFR1 as an 'upstream' factor & what the 'downstream' effects mean for new CMC analysis.
Although this is not my field, my own research indicates that demonstrating remestemcel-l consistency and potency - as those terms are used by FDA - cannot now satisfy the FDA by simply taking a quantitative measurement of supernatants of the remestemcel-l MSCs i.e. at the point of surface expression of TNFR1.
Just for clarification, you indicated in your post above your view that "
Mesoblast have always been steadfast in their view that Rem-L shows efficacy as demonstrated by the ODAC vote and that TNFR1 is the MOA, even though the FDA were/are adamant that Rem-L has multi-modality and therefore the MOA is more complex. ". I understand this as a reference to comments made by and to FDA during the ODAC presentations and discussion.
Can I just clarify for other MSB holders that the FDA's guest speaker, Dr Temple, indicated only FDA's view of some unspecified 'likely multifactorial' MOA and neither she nor any other FDA personnel provided any helpful further comment in FDA's introduction to the ODAC panel. Link
here. Temple's exact words (p.45, l10):
"
The MSC mechanism of action is likely multifactorial, so there is value in gathering wide information on the product to correlate with patient outcomes in order to define critical quality attributes. "
MSB, on the other hand, have as I see it always claimed & never denied multi-modality - quite the contrary, as I see it. It was actually CEO Itescu who in his introduction to ODAC defined and elaborated on what MSB saw as the MOA, viz. (p.53):
"
Thank you. My name is Dr. Silviu Itescu. I'm the chief executive officer of Mesoblast. Remestemcel is a novel cellular therapy for the multimodal mechanism of action. It modulates in terms of excessive immune response to foreign tissues, autoantigens, or infections, allowing resolution and recovery of healthy tissues.
Due to these characteristics, we have developed remestemcel for..... "
and again (e.g. p.61)
" Given our understanding of the multimodal mechanisms of action by which remestemcel inhibits T cell proliferation and inhibits macrophage polarization and retains the M1 phenotype, we utilized the matrix-based approach to develop our potency assays."
The point, as I'm able to understand it, that CEO Itescu sought to make to the FDA and ODAC was that MSB thought TNFR1 measurement - as the 'upstream' effector/ trigger of everything else i.e. all other modalities - would be good enough, viz. (at p.62):
" In summary, our in vitro understanding of the multimodal mechanisms of action of remestemcel has informed the selection of our potency critical quality attributes. TNFR1 is upstream of NF-kappaB signaling and secretion of immunomodulatory cytokines, and can be determined quantitatively. IL-2 receptor alpha inhibition on activated peripheral blood mononuclear cells is an early marker of T cell activation and was selected as a qualitative bioassay based on our knowledge that inhibition of T cell activation is critical to the immunomodulatory activity of remestemcel, both directly and via macrophage polarization.". (underlining, bolding & italics added for emphasis)
Would appreciate your thoughts.
(20min delay)