MSB 2022 - The road to commercialisation, page-1404

Although this post got few ticks its still the area of MSB that is most interesting to me and around which most of my research (or speculating and thinking about MSB) has gone.

My current working hypothesis is that MSB has had an anti-body problem relating to its TNFR1 expression (which has been the potency assay (as part of the matrix approach) since donor cell banks were made 2008 to 2009) at passage 2.

To do either flow cytometry (or FACs) or ELISA work involving the measurement of TNFR1 expression anti-bodies capable of selecting TNFR1 are needed. But sometimes anti-bodies are not specific enough. The failure of antibodies to specifically identify and select what they are supposed to have selected caused a lot of problems (not just with Mesoblast but generally with reproducibility of many science papers).

MSB(and prior to them)/Osiris did release testing at passage 2 when the donor cell banks went into vials and at passage 5 when drug product is made at a different location (Lonza Singapore rather than Lonza Walkerville).

MSB does its TNFR1 expression level measuring at the batch level - I think at some stage, possibly when they moved production of the second phase to Singapore they changed their antibody supplier. Perhaps they even went for a theoretically better antibody. (But if the antibody used at p2 is not the same as what is used at p5 (years later in some cases - the original donor cell banks would have been release tested into storage with antibodies available at the time) then you have potentially confounding variables. Recombinant mono clonal antibodies, if validated, should be better than antibodies from hybrid lines which is older technology.

IF MSB's p2 TNFR1 expression measurements and correlations use an older hybrid derived anti-body and their p5 TNFR1 expression measurements from the 54 patient GVHD001 trial used a different antibody then you could have problems with your potency assay not doing what you'd expect it to do (because you'd inadvertently introduced a variable - an antibody that either better or worse than what you had previously used - but in any case was giving different results).

This could make sense of "reverting" to a previous assay as stated by Dr Rose. New batches that didn't show correlations as expected and as noted by the FDA at ODAC time could be retested with old antibody from former suppliers.

I think MSB is going to go back to the FDA at resubmssion time with a story (possibly true) about an antibody problem with the potency assays. And just as they offered an explanation about changing trypsinization times improving the product (which I found plausible by the way) I think they are going to offer an explanation to the FDA about changing antibodies explaining lack of correlations (also plausible) and so ask the FDA to unpack the totality of the data that MSB wants to present the FDA which show what it has done to explain the lack of correlations before.

But I don't think MSB is going to be able to do it. I don't think there is going to be enough data going all the way through to successful patient outcomes in the already completed phase 3 trial. I suspect (this is just a theory I hold currently) MSB knows that they may not be deemed to have enough data by the FDA to avoid doing a new trial. I suspect MSB may be positioning itself for the possibility that the FDA may reject their BLA resubmission within 14 days of getting it or sometimes within six months if they don't summarily reject - so they need money to survive that.

-This was in reply to my own previous post in this thread.