Parsing the obnubulate Scarlett

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biopearl123
Posts: 353
Joined: Fri Jul 20, 2018 5:13 pm

Parsing the obnubulate Scarlett

Post by biopearl123 » Sun Dec 22, 2019 9:06 pm

What to make of the last press release re the EOP2 meeting with the Feds? Here we have this:"Based on feedback from the meeting, over the coming months Geron plans to submit several Phase 3 trial design proposals in relapsed/refractory MF and to have further discussions with the FDA regarding potential regulatory approval pathways. The Phase 3 trial proposals will be designed to fully characterize the efficacy, safety, and benefit-risk profile of imetelstat treatment for these patients, as well as to confirm the clinical benefit and disease-modifying potential of imetelstat in this indication."

So several is "more than two but not many". So at least three different proposals for continued study in R/R phase III. Why not just one incorporating the guidance from the FDA? Seems a little odd. What is Scarlett trying to say that he just as usual does not come out and just say? One can only speculate. First off it is clear that they do not as yet plan to pursue front line, something we all wanted to see. Each proposal is for R/R indication not front line. Why? I think it's the same problem of front line requiring a longer study time. Well that would be true if mortality were a primary end point but in this day of molecular markers and objective bone marrow findings as well as objective spleen and symptom assessment and I would think a much shorter front line study could be designed. Yet they choose R/R probably because there is no competition here. Possibly a good business decision. Now why "several" study designs? Please add your voices to this speculation but here are my thoughts. A post market P 4 would probably be large and long but allow for easy approval and allow actual sales of the drug. Thats one possibility. If the FDA did not allow a P4 study then a smaller faster PIII study design would be a fall back. But since there is no income associated with this and Geron is pouring a lot of resources into the MDS study they might not proceed. This is the "implied Scarlett threat"--if you don't give us a shot at early approval we won't develop the drug. Scarlett has made that abundantly clear and if the FDA does not support an early to market strategy, it is on them and a patient revolt would be warranted. Scarlett's iron fist in the velvet glove approach. So that's two studies. What's the third (to complete the definition of several?). This would likely be a combination study with Rux in cooperation with Incyte (my speculation only), but this makes some sense based on the recent presentation at ASH. Each of these study designs ironically would compete with each other for patient enrollment and could slow a companion study down unless it was one study with several arms perhaps including a RWD arm. In theory a RWD arm already exists and is there for the taking as long as proper statistical rules are followed. Geron has strong leadership courtesy of Janssen in this regard. To keep the studies short a surrogate end point will be needed that is acceptable to the agency. We should know more soon. Clearly the best route to market is a provisional approval and a P4 study, I hope the FDA sees it that way, but the better treatment for patients could end up being the proposed Rux/Imet combo. Not sure how Geron would get around that but we should know more soon. Best wishes to all for a happy holiday season and a prosperous New Year. The latter would certainly be a pleasant surprise. bp

rccola335
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Re: Parsing the obnubulate Scarlett

Post by rccola335 » Mon Dec 23, 2019 12:50 am

they aren't going front line because the need is met - they are going after unmet needs because they wants AA and anything less would be a disappointment

biopearl123
Posts: 353
Joined: Fri Jul 20, 2018 5:13 pm

Re: Parsing the obnubulate Scarlett

Post by biopearl123 » Mon Dec 23, 2019 3:12 am

I would submit that that need is not met. Rux is a treatment for symptoms but has not been clearly associated with disease modification. With front line there is potential to change the course of a uniformly fatal disease. I think the potential to help many more patients live longer and better is being missed.

rccola335
Posts: 38
Joined: Sat Sep 28, 2019 10:00 pm

Re: Parsing the obnubulate Scarlett

Post by rccola335 » Mon Dec 23, 2019 4:14 pm

I agree about not addressing the cause - I always think about the May 4th Ct order and what it was regarding that was so unusual about the CRO plan
-could they go for AA for R/R and
-phase 3 for combo/ single agent study - cant see doing a placebo

Secret Third Arm
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Re: Parsing the obnubulate Scarlett

Post by Secret Third Arm » Mon Dec 30, 2019 4:48 pm

Hi BP, great way of summarizing our current state and I appreciate your thoughts. I will say though that unless there is an example of a drug that has been approved in combo before being approved solo I don't think that a trial with Rux would open a path to approval. If anything, I believe that Scarlett has pretty strongly implied that the bottleneck we face is to first get Imetelstat approved as a mono therapy before it can be considered for combos.

With enrollment of the MDS trial still not at the halfway point after all these months I cannot imagine a scenario where Geron initiates any Phase 3 for r/r MF. They simply do not have the money for such trials. If we get an announcement of a partnership I might change my tune, but I believe that Scarlett has no intention of negotiating such an agreement until he is in a strong negotiating position.

This all leaves us in no-man's land for the foreseeable future. I was encouraged by the early FDA meeting but unless it results in a Phase 4 accelerated approval then I see no chance for a Phase 3. There is no surrogate endpoint for extended survival, which we all know from the MF Phase 2 that JNJ conducted. What's even worse is that now that r/r MF patients are aware of the extended survival there would be many fewer dropouts from the trial, which could move OS much further beyond 30 months. That's great for patients but terrible for approval since it means a much longer trial before data can be collected and submitted.

The fact of the matter is that without Accelerated Approval the r/r MF indication is dead for now. The financial resources do not exist to pursue that indication. As a matter of fact, I would argue that if we did have the money right now it would be better used to conduct a front line trial. So the ball is firmly in the FDA's court as far as I'm concerned.

biopearl123
Posts: 353
Joined: Fri Jul 20, 2018 5:13 pm

Re: Parsing the obnubulate Scarlett

Post by biopearl123 » Mon Dec 30, 2019 7:19 pm

STA, I agree completely with your thoughts. A combo study would probably be the slowest path, possibly requiring a PII first. I have been intrigued by this statement in the last PR: " (i) whether regulatory authorities permit the further development of imetelstat for relapsed/refractory MF before Geron’s submission of any Phase 3 clinical trial designs; " Note the timing, "before the submission of P III trial designs" , which we know are just months away. I can't help but feel that this supports your speculation that a P IV at least is on the table. Scarlett will walk away from MF (he implies) if the FDA requires an expensive PIII, lets hope reason and and the strength of reasonable data prevail. bp

Secret Third Arm
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Joined: Tue Aug 28, 2018 3:26 pm

Re: Parsing the obnubulate Scarlett

Post by Secret Third Arm » Thu Jan 02, 2020 11:22 pm

Amen to that BP. Happy New Year as well and thanks for all your work keeping this resource alive. I had hoped that the more valuable Seeking Alpha contributors would have found their way here, but I think we all have Geron fatigue. Hopefully not for too much longer though.

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