@stanjupiter,Nice analysis. You asked for some comments so I'll...

@stanjupiter,

Nice analysis. You asked for some comments so I'll make a couple of points to keep the conversation going. You said: "AA for end-stage is quite possible... and In light of... the new pressure, approval for the much larger indication of (class II/III) ischemic HF isn't out of the question."

I agree with the first part on AA. With an underline on how unique the situation is. In general, to make an approval FDA likes two large prospective ph 3 controlled trials demonstrating efficacy and safety - and that would be 2 trials on the same class of patients. Based on the April 30 PR, the company is now eligible / plans to file for a Revascor AA in end-stage CHF (ie class IV LVAD) patients and then run a confirmatory trial in class II and III patients. The pattern of an (accelerated) approval in class lV patients followed by confirmation using only class II and III patients stands out. It suggests FDA indeed accepts DREAM-HF as the additional trial needed for LVAD approval (the requirement for such a trial was announced in a PR back in 2019). Since DREAM-HF enrolled only class II and lII cases (no LVAD cases), that's a major concession. It indicates FDA is on board with the concept of using elevated inflammatory biomarkers to select patients for Revascor treatment... realizing that essentially all LVAD patients have elevated inflammatory biomarkers due to the foreign body reaction caused by the implanted assist device. And all of them are anti-coagulated. Only thing needed to move forward are resolution of CMC and potency assay issues. Mesoblast has certainly done that before.

That said, the company clearly states on April 30: "a single confirmatory trial in class II/III patients with ischemic HFrEF and inflammation will need to be completed after any accelerated approval is obtained." So, the second part of your statement above seems unlikely. Which is ok at this stage given an addressable US population of LVAD patients in the 10-20,000 range compared to class ll/lll CHF cases numbering in the millions. One step at a time - and LVAD cases represent greatest immediate need.

But academically, we might ask why class ll/lll DREAM-HF patients with elevated inflammatory biomarkers can be used to support an approval in class IV LVAD patients, but LVAD patients who all have tremendously elevated inflammatory biomarkers can't be used to support an approval in class ll/lll DREAM-HF patients... shouldn't this be a 2-way street? I believe the answer may be found at the end of Dr Perrin's paper in the European Journal of Heart Failure: the arrival of SGLT2 inhibitors. These meds were first approved for CHF by the FDA in May of 2020. Only a handful of patients, 1 or 2%, were taking them in the DREAM-HF study. They have both a mortality and a hospitalization benefit in HFrEF patients though the literature suggests benefits become more nuanced and side-effects of more concern in class IV patients. In any event, Stan, you might want to focus more research there rather than on beta blockers, statins, or Entresto imho. Any med acting on heart function has to be dose-titrated and its use individualized. I doubt anyone's opinion at the FDA will significantly impact the use of these well-established approved meds - unless they issue a black box warning or withdraw them from the market which seems highly unlikely.

For example, it would be interesting to know how many patients had to be enrolled in ph3 SGLT2i trials to get the label extension? (They were previously approved for type 2 DM). I suspect we'll see that enrollment across the LVAD trial and DREAM-HF gives us a respectable number of cases, recalling that the power/number needed is inversely proportional to potency/magnitude of effect.

You mention, "DREAM-HF didn't meet its endpoint of reducing hospitalizations..." It's important to precise "...for decompensated CHF". Which in most cases is related to fluid in the lungs. I think there's a lot of confusion on this point. The study did show a reduction in MACE hospitalizations. One might think that a patient with a failing heart who comes into the ER with blue lips gasping for breath due to a large accumulation of fluid IN the lungs (pulmonary edema) and perhaps also fluid ON the lungs (pleural effusion) might be classified as suffering from a major adverse cardiac event. But no. In most cases there's no new heart attack, it's just a case of "decompensated CHF". Patient gets admitted for IV diuretics, a tune up of electrolytes and oral meds, and a rule out of some new underlying problem. After a few days she or he gets discharged. With a bill for $$TT. Rinse and repeat (literally) weeks to months later. So, the hope was that Revascor might do something for those cases... In order for that to happen to a significant degree the heart would probably have to regenerate myocardial (muscle) tissue, the promise of RMAT / regenerative medicine.

The late Dr Arnold Caplan, "the father of MSCs", used to say, "in order to control regeneration, which should be feasible, we must first learn to control inflammation". And that latter goal - control of runaway inflammation resistant to all other treatments - has now been accomplished with Ryoncil in GvHD. And inflammation is clearly impacted by Revascor in CHF. But actual regeneration of tissue has been harder to achieve. We've seen a common pattern for most companies doing trials with MSC's - Mesoblast, Athersys and Pluri(stem) in particular. They all set high goals in their trials. For Athersys to have reached the primary end-point in its stroke trial would have required the regeneration of dead brain tissue. Based on an infusion of stem cells into the blood stream. Cells that can't cross the BBB but would somehow effect a neurologic miracle acting through the spleen - as first proposed by Galen with his humoral theory all those years ago. Galen was a smart dude, but that's maybe a long shot and it apparently didn't happen. But could a focal injection of stem cells into the myocardium lead to regeneration of surrounding cardiac muscle? That seems more feasible and the report of "increased ejection fraction" is exactly what one would hope to see if on the right track in an illness marked by "reduced ejection fraction".

Some tweaking and additional bioengineering and perhaps additional doses may get us there yet.
Happy King's Day and good luck to all, Left-e