Absolutely fabulous comments from Dr. Jeffrey Savidge

[biopearl123]

Eloquent, heartfelt, sincere and well informed. Worth a visit to the FDA comments board to review this. Major kudos, sir.

On another note, Just a reminder that the cytopenias are not related to toxicity like many chemo agents, this drug does not destroy the bone marrow, it heals it. It’s pretty straightforward, if you kill off malignant cells that are packing the bone marrow but still contributing to (abnormal) cell production, your counts go down until more normal cells can take over. Those who keep suggesting the need for a black box warning or
the kind of monitoring and treatment only available at major academic centers do not understand this disease and how it will be approached in the community by oncologists in the community.

[kmall]

Bp - A long time ago, on a message board far, far away, there was a campaign to raise awareness for the then upcoming MDS P3 IMerge Clinical Trial called Operation Kmall. Over the course of that campaign, it was discovered that there was a strong correlation between Vietnam veterans exposed to Agent Orange who had acquired MDS from it's exposure.

https://www.aamds.org/agent-orange-unit ... -syndromes


Dr. Jeffrey Savidge mentioned this in his comments to the FDA review:

"an ex-marine who courageously put his life on the line fighting for his country in Vietnam and Cambodia. He just away passed away on 2/23/2023"

There are many of our veterans still suffering with this affliction. Hopefully this helps the FDA to finally take action? -Kmall

[biopearl123]

Operation Kmall was a Herculean undertaking and was a great success lo those many years ago. Our service men deserve the best of care, not to mention the highest respect. When I see a Gold Star family disrespected or a national hero and fine person who has served our country on so many levels like John McCain, disrespected, I can only hope we can somehow make it up to those who survive and the families of those who didn’t. Operation Kmall deserved to have achieved “mission accomplished” status many years ago. Our own president lost his son probably related to toxic exposure from a burn pit. Many sacrifices have been made for us. For those that did, their families and their friends, they deserve to know how deeply we know, respect and appreciate it.

[CKTC]

@biopearl

The analysts had several questions today about the cytopenias. Scarlett tends to brush them off, but I think the ADCOM committee will take a hard look at the issue. Whatever the source of the cytopenias (damage/healing), they have to be dealt with, one way or another. We’ve only been privy to the sanitized data on the side effects. The FDA gets the complete raw data package.

I’m confident the drug will be approved, and maybe even before the PDUFA date. Buy if imetelstat gets tagged with a black box warning, I’m not too concerned. Hundreds of drugs have them. How’s this for a scary black box warning:

WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE.

[biopearl123]

Pretty scary, that example. No doubt the analysts have financial models with and without the black box warnings and are very interested in whether one might be issued. Considering that a black box warning is conferred when there is are serious adverse reactions that “may lead to death or serious injury”, there does not seem to be a shoe that fits. Nonetheless that is a decision for the FDA and the ODAC. So far KOLs don’t seem to be leaning in that direction, at least publicly. Cytopenias are always a concern; low white fighters can lead to infections, most of which should be treatable or resolve as the white cells recover sometimes with the help of Neupogen etc and low platelets can predispose to bleeding but are fixable also. Low hematocrits of course can lead to a host of problems, but the actual reason for treatment of course is directed to fixing that too. Physicians use meds with a side effect list as long as your arm all the time as you point out but the absence of a black box warning may lead to a more ready acceptance and wider utilization, so as you suggest, Geron does not want to see that happen. I have to agree that they have been pretty circumspect regarding the actual severity of drug induced problems. I did write to them a few months ago seeking specific information about adverse reactions that resulted in a requirement for hospitalization. That information was not forthcoming but pretty pretty sure the FDA will require it and maybe it will be made public. I encouraged Geron to make that information public, but for some reason they didn’t listen to me

[CKTC]

Think about this: The first-line drug used all these years in low/intermediate risk MDS to treat anemia has a massive black-box warning. The FDA considered this drug class to be so dangerous they required a formal REMS certification for doctors who prescribed them. After being in place for almost fifteen years, the REMS requirement was finally lifted in 2017. https://ashpublications.org/ashclinical ... for-Anemia

The other drugs used historically to treat this patient population:
Lenalidomide (Black Box Warning)
Hydroxyurea (Black Box Warning)
Hypomethylating Agents (Neutropenia/Thrombocytopenia)

My point is that doctors are used to monitoring severe potential side effects when treating MDS patients. I see no reason they would be concerned about using imetelstat, especially in the second-line setting when there are few good alternatives. Luspatercept, a relatively benign treatment, sits in the sweet spot of efficacy/safety.

[biopearl123]

Point taken, a black box warning is not the end of the world for Imetelstat and would probably not impair appropriate usage of the drug. In my area, drugs like amiodarone, Sotolol, even digitalis would kill in the hands of the inexperienced. Oncologists use very strong drugs and Imetelstat would not be among the most dangerous or difficult to use. To be sure it will at least come with guidelines for dose alteration according to cell counts, side effects etc. No doubt if a black box warning is issued, the competition will be all over it and so will the analysts. Let’s hope the docs who would champion the drug for their patients are not.