FDA v. Geron

[KTArsenal]

Let's skim the fat from the soup and discuss some reasons, **less conspiracies**, why the FDA could potentially deny imetelstat for approval in the US.
It's a useful topic, everyone. Our readership has increased, so let's try to constructively criticize imetelstat as if we were judges on the ADCOM panel.

I'll go first, begrudgingly:

1. FDA hasn't and may not be willing to evolve from spleen response to durable transfusion independence.

[LWS]

I cannot think in terms of the "FDA v. Geron".

The FDA (ODAC) and Geron are on the same side when it comes to patients' needs and patients' safety. Imetelstat is unique. It excels in overall survival time, disease modification, safety profile, transfusion independence, and maintaining the quality of life. I see March 14th as a time when the KOLs, patients and other experts will be heard loud and clear about Imetelstat's accomplishments, potential and unique MOA.

I have not heard about spleen considerations for a long time, and do not believe it to be a consideration at this point in time. Also, there are no creditable conspiracy theories involving Imetelstat.

[ashah]

Concur.
I don't think this is FDA vs. Geron.
Rather, I think it may be a symptom of "measure twice, cut once".
IF we go back in time, ... VEGF, Avastin, etc... the development process was very challenging.
New MoA, unknown long term effects, and potential broad spectrum use. I would suspect that once approved, Imetelstat will be used broadly in the liquid tumor settings due to its relatively manageable adverse effects, ... of course off-label risk.
Hence the careful progress...unfortunately for the patients and investors...too careful

[KTArsenal]

1a). Conspiracy theories are based on a belief(s) without supportive data.

[biopearl123]

KT, I have to agree with Ashah and LWS. The FDA clearly has a mandate and they will take steps to be sure they fulfill it, including talking with experts, families and patients. This is a totally new med. Potential reasons for denial are out there I suppose but the pluses are pretty strong in favor of approval. If you are looking for negatives though I suppose it depends how far back you want to go. I can give you a few but with the caveat that they really don’t apply to “today’s” Geron. Geron is taking this drug to the FDA for approval in LR/MDS only. So to try to answer your question with three examples: 1. about 10 years ago Dr. T gave this drug once a week to patients with AML with the best of intentions, you can look at the outcomes on clinical trials. Now looking back, that would never happen and the proper dosing is much better understood. 2. There was intracranial bleeding in children with brain tumors. 3. The recent editorial from Mayo in Lancet was a balanced critique of the IMerge study which you might want to review. Your point about spleen size really applies to MF. The FDA and Geron will be focused on hematologic improvement in LR/MDS which is quite impressive in the 60-70% range. So yes there is always a risk of not garnering approval but I think there has been great progress and pretty clear endorsements by multiple KOLs. We’ll see what happens but I think the data supports approval. bp

[jayfish101]

I was surprised to note that its not just being reviewed for low risk, but also for intermediate risk.
Agenda
The meeting presentations will be heard, viewed, captioned, and recorded through an online teleconferencing platform. The Committee will discuss new drug application (NDA) 217779 for imetelstat for injection, submitted by Geron Corporation. The proposed indication for this product is for the treatment of transfusion-dependent anemia in adult patients with low- to intermediate-1 risk myelodysplastic syndromes who have failed to respond or have lost response to or are ineligible for erythropoiesis-stimulating agents.

[biopearl123]

Jay, that’s how the study reads on clinical trials site:

“ Study to Evaluate Imetelstat (GRN163L) in Subjects With International Prognostic Scoring System (IPSS) Low or Intermediate-1 Risk Myelodysplastic Syndrome (MDS)”. Geron is seeking approval for a well defined exact indication.

[jayfish101]

You said, "The FDA and Geron will be focused on hematologic improvement in LR/MDS which is quite impressive in the 60-70% range. "
But there seems to be the inclusion of intermediate risk also.

[biopearl123]

Jay, it’s a bit semantic, IPSS seems to be periodically revised. Technically, the study also includes very low risk patients I think. The important point is that Geron is going to the FDA for approval in the exact patient populations outlined in the study. I don’t see any indication they are trying to go for some expanded use at this time. No doubt prescribing physicians will have some latitude in interpretation as each patient is individualized.

[biopearl123]

Jay, to clarify, my limited understanding of the classification system as to "risk", reflects the predictive value of determining what the risk of progression to high risk/AML is, it is not necessarily a reflection of what the transfusion burden is. The study did enroll patients in the categories you list for sure but is focused on the transfusion burdens of these patients which can still be substantial even in "lower" risk categories. I think it is reasonable to hope that progression of disease from "lower risk" to higher risk/AML" will be impacted as well but the study did not have this as a primary end point. I don't know if this gets to the point you were trying to make. If not I can take another shot at it. Regards, bp

[jayfish101]

I believe there has been some speculation that High risk and Low risk MDS were separate diseases. If so, is Intermediate risk also a separate diagnosis/disease?

[biopearl123]

Jay, they are treated differently, that's for sure but I think they are part of a spectrum of the a single disease that has to start somewhere but evolves on different timelines, perhaps driven by different factors such as associated inflammation, genetic signatures, age etc.

[LWS]

Call for Medical Negatives Concerning Imetelstat

This thread was created to list medical negatives that would reduce the chances of ODAC's positive recommendations (from March 14th Imetelstat meeting). The conclusion that I have come to is that the list has no items because none exist. There have been conspiracy theories connecting Big Phrama and members of the FDA (no evidence of that).

At this point in time, I believe that Geron and ODAC are on the same side, with "compelling, remarkable and durable" evidence of Imetelstat's important successes, its uniqueness and patients' immediate needs. NDA approval has a very-high-probability.

[LWS]

The Medical Negatives for Imetelstat Continued

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

[biopearl123]

LWS, like many things in life, this is not binary. It might be valuable to go back and review the Mayo editorial in Lancet which tries to balance a ringing endorsement with an an examination of the potential flaws in the IMerge study and the cautionary approach that must be used with any completely new drug.

[LWS]

Negatives????

I do not have access to the Mayo editorial. With any new and transitional medicine (Imetelstat) not everything can be known in the early stages. Some features will be uncovered (like 2 ways to kill cancer cells) that were not known earlier (some positive and, perhaps, some negative). This may be why "priority review" was not granted, while EAP is ongoing. I would like someone to expand the list of potential medical negatives, that are meaningful and could cause pause (ODAC March 14th).
=================

from bp --- an examination of the potential flaws in the IMerge study and the cautionary approach that must be used with any completely new drug.

[biopearl123]

The editorial written by Dr. Patniak is summarized in my Dec 5th post. You do have access if you wish, there is a modest fee to Lancet for time limited access.

[LWS]

Thank you bp for the reference

These limited criticisms of Imetelstat are characterized as a "soft endorsement". I suspect that the KOLs (March 14th ODAC meeting) will have some "strong endorsements". These are early days in the life and uses of Imetelstat. Some prefer to wait and see (very conservative and overly cautious IMHO). Others are ready to act on the information from the completed and successful trials, the uniqueness, the safety, and most of all the patients' immediate needs.

I see no negatives that will impact ODAC's positive recommendations to the FDA.

=====================
Excerpt from Dec.5 -- from bp

There it is. I read this as a very conservative soft endorsement that will have to wait for wide spread use and experience before physicians such as Dr. Patnaik fully accept this drug. We have heard the cry for drugs that lead to disease modification for years. An unequivocal statement to the effect that there is evidence for disease modification (no "potential" anymore) is in the actual article. Not sure why the importance of this unique aspect is not pounced upon by Dr. P. Probably be some significant discussion at ASH to be sure and perhaps some of the very strong positives in the article itself can emphasized. I did not buy the actual article as I was interested in the editorial and thought we were familiar enough with that information.

[LWS]

Since the list of negatives has not been added to, I am assuming that there is nothing important or credible to be added. We will hear something on Feb. 28, with the ODAC meeting (March 14) highly anticipated. We would like to know more about that meeting's structure and the KOLs (and others) that will be heard. John Scarlett indicated that the KOLs will be an excellent source of material to introduce Imetelstat to the world, and he plans to use it in that way. The EAP is ongoing, supplementing the successful and completed phase-3 trials. Imetelstat is still unique with patients' needs still unmet.

Transfusion Independence approval is the first goal of many. The promise is in the Cancer Moonshot, where Imetelstat in many cancers (from blood cancers to solid cancers) will lead to better treatments and perhaps cures. This transfusion NDA approval will be the first step in off label uses and combinations leading to many years of research.

==================

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]

The last hurdle before the finish line for Imetelstat

The ODAC meeting (March 14) and the full FDA (June 16) are in focus now. Much of the discussion on this board has been about the FDA and its supposed shortcomings. The positive features of Imetelstat appear to be overwhelmingly positive, and the negatives (toxicity, side effects, etc.) seem to be relatively minor and reversible. This is extremely important for a powerful cancer medicine that has taken 'forever' to work its way through the system.

We all expect high praises from the KOLs, strong recommendations from ODAC to approve Imetelstat's transfusion-oriented NDA, and quick acceptance by the full FDA. Every (i) has been dotted and every (t) has been crossed. What could go wrong (a government shutdown)?

=================

An examination of how the FDA does business is welcome on this board. ---from bp