Risk vs. Benefit

[Hoosier Investor]

RISK:
* A patient who experiences a Grade 3/4 event WITHOUT realizing an improvement in their A) transfusion frequency, B) transfusion burden, or C) Hemoglobin levels.

BENEFIT:
* A patient who realizes a meaningful improvement in their A) transfusion frequency, B) transfusion burden, or C) Hemoglobin level.

Observation:
I don't recall the exact percentages, but I believe the overwhelming majority of our patient outcomes were in the later (Benefit) category.

[jayfish101]

That seems to be what I recall from Geron spokespersons. They claimed sideffects were easily ameliorated by simple treatment procedure.

[biopearl123]

I have to agree. Hematologic improvement (a reduction of 4 units every eight weeks) still amounts to a lot of transfusions saved. Having a very high bar to assess actual benefit makes the choices clear. A personal anecdote: When I started catheter based treatment for A-fib almost 20 years ago, the bar was set at going from permanent a-fib or intermittent a-fib to NO a fib, a high bar indeed. I thought that was crazy and unachievable and I would settle for just fewer and shorter episodes. And yet as it turned out many patients did have long periods where they were completely free from the plague of atrial fibrillation, but many just felt better and were grateful to have fewer and shorter episodes. And so setting the bar high with high transfusion patients would seem unattainable in MDS, yet here we are. To HI’s point we should not forget about those that just needed fewer transfusions. This of course translates to lower risks associated with iron overload but by the time they get R/R status they have received hundreds of transfusions. The total picture of OS and LE from this fact alone has yet to be elucidated. As of now from what I can tell, the FDA documents do not include testimony from patients or families or hematology experts. Having Dr. Hunter there as an expert I hope will turn out to be a plus.

[KTArsenal]

Will the panel also include patients who did not benefit from imetelstat, and will they be able to cry wolf due to lack of efficacy and cytopenias?

I feel like the FDA might have the upper hand in this Big Pharma chess game.

Let's be honest: The FDA is basically stating that Geron cooked the efficacy books along with its safety profile. If I'm wrong, tell me I'm wrong. I'd actually appreciate being wrong .

[biopearl123]

KT, yes the panel will look at everyone in the study including non responders. Right now I am looking at this as the FDA is evaluating a study that they approved and evaluated on a rolling schedule. The study met its primary end point with a strong P value. The study met a key secondary end point with a strong p value. The patient population had high transfusion burdens not helped by first line therapy. Each patient likely had something on the order of 10's if not more, transfusions( ?(probably >50, that's a guesstimate, would like to know the real number) before entering the study. No evidence for OS improvement (late in the game, lots of iron already in the system), the FDA has highlighted plenty of side effects which Geron counters are manageable in experienced hands. Recent Cell article, Dr. Najidi and Dr. Gattermann says of cytopenias,"the situation is reminiscent of CML treatment with tyrosine kinase inhibitors where successful decimation of the CML clone can cause temporary bone marrow failure before the remaining normal stem cells resume sufficient activity to rebuild the hematopoietic system." As to disease modification, the FDA doesn't think there is evidence. In the cell article: "This finding suggests that Imetelstat may establish itself as a truly disease modifying treatment for lower risk MDS. " This stated in response to the decrease in VAF. I don't think Geron will convince the FDA of disease modification on Thursday. They will be able to say that the primary end point in an FDA sanctioned study was met and that a key secondary end point was met. They will make the case that cytopenias are manageable. The Advisory Committee will decide if the benefits outweigh the risks and advise the FDA accordingly. Then the FDA will do what it wants. You can decide if Geron cooked the books. All the data is laid out and now the experts will speak to the risks and benefits.

[KTArsenal]

Which Geron experts do we expect to speak on the behalf of imetelstat?

So far, Dr. Hunter can be ASSURED he's there as an imetelstat detractor, and for me, that's plainly obvious, if he's on the ADCOM review board.

Let's hope that this committee's questions about imetelstat's safety and efficacy are the same for every new molecule that's attempting to become available for human consumption, and not just an attempt to embarrass Geron and their clinical trial data, while using this forum as an "I gotcha" moment even when they've overreached and became the ultimate safety proponents overnight.

[biopearl123]

KT pretty strong line up on the Geron side:

https://www.fda.gov/media/176961/download

As to Dr. Hunter, pretty sure he is well aware of the limitations of present day treatments.