FDA v. Geron

[LWS]

What are the medical negatives? Imetelstat will be approved (IMO). Let's hear what the KOLs have to say about Imetelstat's medical successes.

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Previous: The benefits clearly are important and significant. The risks are manageable and reversible.

The Positives:

1/Transfusion independence
2/ Overall Survival Time
3/ Disease modification
4/ Two ways to kill cancer cells (MOA) -- normal cells OK
5/ Off label uses (in combination --- chemotherapy and other promising combinations when approved)
6/ Very good safety profile
7/ KOLs, publications, conferences
8/ Quality of life

The Negatives:

1/ None available that appear medically important

[LWS]

I was surprised how aggressively the FDA came out of the starting gates (devil's advocate ?). In the morning (March 14th), it appeared that Imetelstat was on the ropes. However, by the afternoon it all turned around and the medicine was approved by a 12 to 2 vote by ODAC. The subject at hand was transfusion independence, but quality of life, overall survival time, and disease modification were all in the background.

There were two negative votes, one from the ODAC Chairperson, which was a surprise. However, there were several blood cancer hematologists on the board, and they were all yes votes. I understand that 97% of all positive recommendations are accepted, so FDA approval of the NDA seems ensured. (Is there an example of a positive recommendation that was not accepted?)

How is ODAC put together? How is the Chairperson chosen?

[LWS]

A question for the board:

Has an ODAC (oncology advisory) positive recommendation ever been rejected by the FDA? I cannot find one.

If yes, can you share the case? The 'black-box' issue, while interesting, is not all that important (IMO).

[LWS]

Imetelstat is an inch from being an approved medicine by the FDA and others. NO ONE can find an ODAC (Oncology Data Advisory Committee) positive recommendation (March 14th) that has ever been rejected by the FDA. Then off-label uses can be explored including new combinations.

Somewhere over the rainbow partners of various sorts are being considered.

[CKTC]

"There were 12 instances where the FDA rejected a product that an advisory committee had recommended approval. Three were reviewed by the Endocrinologic and Metabolic Drugs Advisory Committee and two each by the Oncologic Drugs Advisory Committee, Anesthetic and Analgesic Drug Products Advisory Committee and Psychopharmacologic Drugs Advisory Committee."

Advisory Committee Disagreement With US FDA On Approval Decisions An Increasingly Rare Event
https://pink.citeline.com/PS147536/Advi ... 20approval.

[rccola335]

What i would like to see is the ADCOM votes - how common is 14-0 13-1 12-2 ETC - the cases where the FDA goes against the ADCOM is that where the vote was 8-6 , 9-5 ?

[biopearl123]

RC, also important here is where all the positive votes came from (every liquid tumor doctor), including an invited specialist. That should give us some reassurance that failure to approve is unlikely.

[KTArsenal]

If 12-2 doesn't hold any weight, then the moon is made of cheese.

[Zhears]

I am preparing myself for another delay, to knock the approval back from June.
After reading the updated risk document a few days ago, which detailed numerous ways the FDA could cause a delay, and the ridiculous showing the FDA did in the first half of the odac, I fully expect some shenanigans.

I think there is no doubt it will be approved, but just incase there is a delay, the latest offering covers that cash burn, hopefully.

[CKTC]

I don’t think the FDA will deny approval. The drug benefits a subset of patients who have failed ESAs. The agency may restrict the label regarding who can use the drug and for safety reasons. However, I see another issue the FDA may want Geron to address: the lack of data on luspatercept failures. Luspatercept is now approved as front-line therapy for RS+ and RS- MDS patients. More and more of the potential market will be luspatercept failures, not ESA failures. Geron has very little evidence to provide the FDA that imetelstat works in this patient population, as only a handful of these patients participated in the Phase 3 trial. The FDA has a built-in argument against exposing these patients to imetelstat’s side effects without evidence of benefit. The agency may require Geron to conduct a post-approval trial on these patients. And Geron should, or another company will.

[LWS]

It very unlikely that the FDA would reject their ODAC's recommendation for approving Imetelstat. Still we are a bit nervous about the FDAs "devil's advocates" comments (March 14) and the (NO) vote of the chairperson. The FDA has much on its table these days, as their past and future is now being reviewed in the Supreme Court.

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Review

These were the no votes (12 yes, 2 no)

2. AC-Ravi Madan(Chair) NO
8. AC-Mark Conaway NO

As I remember some of the no reasons were:

1. Only a subset of people benefitted
2. Unnecessary disease in those that did not benefit
3. No biomarkers
4. Quality of life (feeling better) is too subjective to be considered

However, all agreed that transfusion independence was an important goal.

It was surprising that the Chair voted no. ---- from LWS

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As far as the two no votes, I believe the Chair (solid cancer oncologist) thought too many non-responsers had to go through the initial disease ( cytopenias -- that could be controlled), and there was no benefit to them. I cannot explain the other no vote (the statistician). The Chairperson was a bit out of his field of expertise (IMO).

I cannot find any example of an ODAC positive recommendation being rejected by the full FDA. A 12 to 2 vote is overwhelmingly positive, especially when the 2 no votes were from non-experts in the field of oncology hematology. -- from LWS (Note, 2 cases were found, but we do not know the circumstances -- from CKTC)

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Yes, I am troubled that two prominent members of the FDA ODAC, who were not experts in the management of MDS have the voice to impede approval and that the FDA itself did not understand some very basic aspects of how studies in MDS are done and how yardsticks such as CR and PR just do not apply. Thank you Dr. Komrokji and Dr. Savona for setting them straight, but honestly, its the FDA, shouldn’t they already know this? Well, two members of the panel didn’t and perhaps still don’t. We should just take the win and move on. --- from bp

[huntingonthebluffs]

I have watched Geron and its stock and have been an investor for a very long time. Certainly not the longest here, maybe even just average. I know there are many old timer investors here that are determined to see this through, many of us well over a decade and some even decades. Most of us know of and have seen the ravages of the MPN diseases firsthand in our relatives and friends, several of our fellow board members have passed due to these diseases and others are still with us. And now here we are again, moving towards another launch pad of sorts for at least the 3rd or 4th time since I’ve been watching.

There has been a lot of excessive confirmation bias here over the years, admittedly including myself. I have been a strong believer since my initial Geron awareness and a very strong believer since Dr. T’s CT efforts at Mayo. I could only guess of course, but I believe the road is littered with FDA (and associated corporate sponsors) shenanigans, both large and small in that time. I don’t think anyone involved in this space over the last decade plus could or would deny the probability of what IMHO is undeniable. And that is after subtracting out possibility of Geron mistakes, execution and judgement failures.

Rationale for FDA administering delays and restricting designations and accelerators might have had some minor justification at times although even then they must cruelly face down most patients who are in their 70’s and have no other options of merit. However, the other side of that coin has the obvious, much more likely intentions, which have real costs to the Geron strategies, as well as investors and obviously patients, tens of thousands that are no longer with us including many family members, friends and fellow board members. Secondary impacts like blood supply, its quality, caregiver time and costs, next tier advancements, etc. have major untold costs. And of course, delays benefit competitors and their investors via stock portfolios, revenue streams and drug pipelines as well as leverage on partnership and B/O costs and the funds to use for M&A on Geron or other pharma’s, etc.

Anyway, for all the reasons that have been mentioned now and over the years, Geron and Imetelstat IMO are finally on the cusp of greatness. Most, maybe all of us, cannot fully comprehend the potential of Imetelstat and associated IP along with combinations and future related research discoveries like malignant cell death being invoked by ferroptosis. However, each successive time we make it to the alter, I believe we have improved likelihood of approval with revenue and relief just around the corner for MDS and MF patients as well as those with other heme malignancies.

Investors are likely due for success as well this time around. And as Charlie Munger would say, most of us only get a couple opportunities in our lifetimes accumulate generational wealth. I personally think this may be one of those times. Yet I know, the possibility is there for further delays and disappointments and the last time our confirmation bias was this high was September 2018 and that didn’t end well. Of course, while I know there is more work to be done, I again think this time will be different.

[LWS]

Imetelstat is a breakthrough blood cancer medicine that works for many today, and has almost unlimited potential (kills cancer stem-cells in two ways) in combinations going forward. The 12 YES, 2 NO votes was 100% favored by the ODAC oncology hematologists.

“ While  a  significant  minority  of  patients  clearly  benefited  from  imetelstat,  a  majority  of  patients  do  not  derive  benefit. "  -Ravi Madan   ODAC  Chair

Note: Imetelstat is a life changing medicine for this significant minority, and meets the necessary safety requirements. Benefits include transfusion independence, feeling better, survival time increases, quality of life improvements and disease modification. This is the tip of the iceberg for the Cancer Moonshot (NIH), and an important building block for developing new treatments and cures for all cancers.

[biopearl123]

Ravi, Ravi, Ravi, of course they do. HI is broken out into major (Complete TI) and minor (Partial TI) the latter is described as a 50% reduction in TR over 16 weeks (but not complete TI, still impressive). These two groups compose is a majority of patients in the study (about 70 total), of course they benefit. Even if they didn’t make TI what about their substantial hemoglobin rises? To repeat Hgb up >3.5 that’s substantial. Ravi, I am perplexed. Did you mean what you said because if you did you might want to reconsider.

[LWS]

The Chair (Ravi) was not up to speed on the importance of Imetelstat to the blood cancer world as a vital 'tool' in transfusion control and well beyond (quality of life, increased survival time, disease modification, combinations, hemoglobin increases ). I suspect he is there by now.

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From March 27 (LWS)

As far as the two no votes, I believe the Chair (solid cancer oncologist) thought too many non-responsers had to go through the initial disease ( cytopenias -- that could be controlled), and there was no benefit to them. I cannot explain the other no vote (the statistician). The Chairperson was a bit out of his field of expertise (IMO).

[LWS]

In the case of ODAC (Oncology Drug Advisory Committee) when they recommend positively and overwhelmingly (12 Yes to 2) the FDA has NEVER rejected their expert advise. I know of no blood cancer oncologist that has spoken against RYTELO (Imetelstat). Many have spoken publicly on its behalf.

NOTE: Of the 61 ODAC decisions, 30 were in favor of approval (all FDA approved), 30 were against (7 approved), and there was 1 tie (FDA approved).

From: LETTER TO THE EDITOR| VOLUME 95, ISSUE 2, P424-426, FEBRUARY 2020

Oncology Drug Advisory Committee Recommendations and the US Food and Drug Administration’s Actions
Alyson Haslam, PhD
Jennifer Gill, MS
Vinay Prasad, MD, MPH

Mayo Clinic Proceedings