Dr. Patnaik, editorial comment in Lancet

[biopearl123]

Like every major featured article in a top tier medical journal, a prominent physician is asked to comment. I did "buy" 24 hour access to the comments by Dr. Patnaik of the Mayo in Rochester. I am sure I had to agree not to reproduce it so I will just summarize a few points. Dr. Patnaik summarized the studies leading up to the current Platzbecker article. He emphasizes the neutropenia and thrombocytopenia as potential problems. Our KOL's have met this head on and reassured that they have plenty of experience handling these issues and of course they do as Dr. Patnaik well knows. (The subtext is will the community oncologist be able to do the same--probably a little patronizing to the very excellent heme/oncs in private practice) He also took issue with the IV administration every four weeks which to me sure beats getting tons of transfusions. He also says further study is needed to see if different ethnic groups respond differently, fair enough. Another issue is diseases that are inherently associated with short telomere might have adverse affects, like dyskeratosis congenita which by the way are very rare. All this seems like a reach. Further, he points out the ease of treatment with Luspatercept and ESAs and the importance of knowing if patients who have been treated with Luspatercept respond to Imetelstat (we already know the answer to that.) There is nothing in this editorial about disease modification and nothing about the extraordinary durability of therapy or the effect on the malignant clone or improvement in symptoms. Instead, it is a very conservative view and focuses on the primary endpoint which ongoing studies clearly have moved beyond. He is happy about the use of biomarkers. There were no drug related deaths but he thinks supportive care measures will be required for cytopenias unlike Luspatercept or ESAs. He says that "the advent of Imetelstat is truly an important milestone." But then cautions: "Given that all our patients already endure, the appropriate and safe use of this drug is paramount in ensuring that we do not make the treatment of the disease more grievous than the endurance of the same." 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.

[kmall]

Bp - Thanks for the synopsis on this editorial, great insight!

Going waaaayyy back to April 2019 and the Needham Healthcare Conference, where Dr. Rizo was publicly introduced, Dr. Scarlett mentioned side effects and in particular:

"They understand how to manage the drug in regards in cytopenias"

Direct quote.

At another point he addressed any other side effects; neutropenia and thrombocytopenia as "manageable and reversible"

How is it that 4+ years later this is even an issue going into the final leg of approval?

And even if it were, wouldn't Geron's Medical Affairs dept. be forwarding guidance to physicians on the "management" of these side effects if they were considering Imetelstat as a possible pathway for treatment?

Thanks in advance for any clarification here. -Kmall

[huntingonthebluffs]

Yes, great summary biopearl123. And to pile on kmall’s post, there is clearly something not right about the aim of Dr. Patnaik’s comments. I would suggest ulterior motives or just inept, could be both. I don’t think I’m paranoid here but I just find it hard to trust anyone or entity that continues at this point to stand in the way or misleads in ways that could delay or prevent the commercialization of Imetelstat.

[ross929]

Well, now at least it seems obvious what the drug is up against in terms of approval/ADCOM. GERN will have to demonstrate that the drug’s potential side effects and management thereof are worth the potential benefit. I’m not sophisticated enough to know what that management entails; we know they are “manageable” but does anyone here know the complexity of that management? I know it’s dose reduction and other things, but are those other things difficult to administer/assess? It definitely feels like he is throwing a little shade at the drug…first time I’ve ever had a real concern based on feedback from a top clinician. Would love more perspective from the better educated group here.

[Ryan]

Like every major featured article in a top tier medical journal, a prominent physician is asked to comment. I did "buy" 24 hour access to the comments by Dr. Patnaik of the Mayo in Rochester. I am sure I had to agree not to reproduce it so I will just summarize a few points. Dr. Patnaik summarized the studies leading up to the current Platzbecker article. He emphasizes the neutropenia and thrombocytopenia as potential problems. Our KOL's have met this head on and reassured that they have plenty of experience handling these issues and of course they do as Dr. Patnaik well knows. (The subtext is will the community oncologist be able to do the same--probably a little patronizing to the very excellent heme/oncs in private practice) He also took issue with the IV administration every four weeks which to me sure beats getting tons of transfusions. He also says further study is needed to see if different ethnic groups respond differently, fair enough. Another issue is diseases that are inherently associated with short telomere might have adverse affects, like dyskeratosis congenita which by the way are very rare. All this seems like a reach. Further, he points out the ease of treatment with Luspatercept and ESAs and the importance of knowing if patients who have been treated with Luspatercept respond to Imetelstat (we already know the answer to that.) There is nothing in this editorial about disease modification and nothing about the extraordinary durability of therapy or the effect on the malignant clone or improvement in symptoms. Instead, it is a very conservative view and focuses on the primary endpoint which ongoing studies clearly have moved beyond. He is happy about the use of biomarkers. There were no drug related deaths but he thinks supportive care measures will be required for cytopenias unlike Luspatercept or ESAs. He says that "the advent of Imetelstat is truly an important milestone." But then cautions: "Given that all our patients already endure, the appropriate and safe use of this drug is paramount in ensuring that we do not make the treatment of the disease more grievous than the endurance of the same." 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.

Excellent summation. Thankful. I’m not quite as worried about stressing the understanding of treating neutropenias as well as understanding the dosing schedule. I don’t find these points to be sinister.?This would be a medical practitioner prodding at a new drug, as this is his/her’s role. If the drug is going to become widespread in clinics, it would be factor to not only know how to reverse side effects but also have a protocol to follow. And if there may be a better dosing schedules to make the patients burden less, this discovery should be a priority.

I’ve been calling out the importance of biomarkers for years, and I’m glad the doctor is also calling out the necessity / promise of assessing patient biomarkers before treating a patient with Imetelstat, as well as patient/family expectations.

The editorial is indeed not meant to be a full throated endorsement of a new drug. Sounds like in many ways the endorsement is implicit. It is a helpful guide to work to improve patient outcomes, in the near and distant futures upon marketing authorization.

All systems go right now. Hurry up and wait for it.

[jayfish101]

As a former citizen of Rochester, MN. I often found Mayo Clinic to have some peculiar "conservative" responses to issues. They know lots about lots, but some fringe and compromised folks seem to reside there also. Is that libelous? That's the kind of fear Mayo can engender.

[biopearl123]

Jay you are not wrong. There are plenty of fruitcakes that hide in academic institutions. And also masquerade as knowing physicians in academics and in the community. The best way to find and avoid them is to ask a nurse. They will tell you who the good guys are. To be clear I am not suggesting this comment applies to Dr. P. Or Dr. T for that matter, but my personal opinion is the for the latter, the adage "When you have a hammer, everything is a nail", applies, or did as recently as a decade ago.

[KTArsenal]

Yes, this is from 2yrs ago. Yes, Dr. Patnaik was one of many medical doctors involved with this trial, data collection, and authorship.

Scroll down to the bottom to see the usual suspects in paying for expenses, travel, and consulting fees:

BMS, Celgene, Incyte.

Also, Dr. Patnaik himself is listed as having a potential conflict of interest.

I detest conspiracies. I just wanted to post this link for others to decide for themselves.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8791814/

[biopearl123]

KT, I am defending no one but just making an observation. Dr. P has 52 pages of article cited on Pub Med going back over 20 years. It’s hard to find a prominent physician especially in academics that doesn’t have some tie to industry. After all that’s (with the exception of pure funding from foundations and some places like NIH) where the funding comes from. When I was a young naive physician I rebelled at the unholy alliance between medicine and industry and felt docs should keep themselves “pure” when they prescribed drugs or did research. For a period of time the medical profession also took a careful look the this relationship. I remember one year when a medical meeting was held in Massachusetts when visiting booths sponsored by different companies you could hear “what, no coffee? What, no pens or golf balls?” etc. I eventually made peace with this especially when asked myself by companies to assist in evaluating new devices and techniques. The fact is they went for docs with experience and good outcomes. I hoped I could maintain my impartiality. In fact bias is impossible to discern because we don’t even see it ourselves. The truth is there would be no medical progress if the private sector wasn’t picking up the bill. It’s just a fact. One hopes integrity carries the day and high standards of ethics are upheld. Nonetheless, when you look around any major medical meeting you will see big money sponsoring speakers, symposia, honoraria, travel for speakers, research projects etc. At least with the sunshine act this info should be public.

[KTArsenal]

BP, you're the smartest guy in the room when it comes to medical science. Without question.

Allegiance to a certain company(s) can be developed if your first class plane ticket is always paid in full beforehand.

Dr. Patnaik hasn't authored objective imetelstat data in a long time. Not since 2020, I believe.

Subjective reasoning alert: Dr. Patnaik hasn't been greased enough to speak highly of imetelstat, and The Lancet allowed one MDs opinion to almost discredit compiled CT safety data.

The smartest people in the room can also sometimes be the most gullible.

Happy holidays, imetelchatters.

As always, thanks for having me.

[biopearl123]

KT, thanks for your comments. I am actually ok with Dr. P’s editorial. He is after all an expert and was chosen perhaps because of the ties of the early Imet clinical heme studies to Mayo and Dr. T but undoubtedly also because of his experience, expertise and familiarity with Imetelstat (Mayo probably having some of the longest experience of any institution with Imetelstat, excluding of course the dismal solid tumor trials that predate Dr. Scarlett). I think its ok and perhaps desirable to urge caution with any new drug especially a completely new class of drug such as Imetelstat until a wide range of patients are treated and physicians have the opportunity to acquaint themselves with the goods and the bads. I do not see any nefarious conflicts here. In medicine there are always early adopters of new meds and technologies and those that hang back and learn from others experience (and mistakes.) With apologies to the politically correct, it is said you can always tell the pioneer because he is the one with the arrows in his back. With that said, I was an enthusiastic early adopter, eager to get experience with, and to offer the newest and best, to my patients. I was asked to to perform clinical trials on devices the screwed into heart muscle, plugged areas where clots might form, place thimble sized pacemakers directly into cardiac chambers, threat tiny catheters into tiny veins to try to get near nerves that controlled respiration, try new cardiac drugs, you get the idea. For each of these programs I had to present protocols to either our local IRB (Institutional Review Board), the state IRB or the regional IRB (for big studies). For some reason my presentations (sometimes sent back for clarifications) were always approved. IRBs are usually composed of physicians, pharmacists, nurses, clergy (very helpful when ethical issues arose) and community non medical personnel. I realized that most of the people on the board could never really understand the presentation, for example what a new device did, how a new algorithm worked, what the side effects of a particular meds ramifications could mean to a patient. Yet they approved the protocols. I realized why and the reason was humbling, they trusted me. Just as the patients for whom I might recommend something new and different in the approach to their disease did. So why all this? I think we would be wise to trust Dr. P and his cautious approach. Wider utilizing of Imetelstat will come if it is warranted, as its reputation spreads as patient testimonials are heard, as physicians get more experience. I do not expect every doc to be an early adopter. No one wants that arrow but some will take it if they think it will really help their patients. We will need to see physician endorsements and guidance from experts (like everywhere there is a hierarchy in medicine—we have our own gods we worship and seek guidance from, as we continue to learn and get better at what we do or in my case, did.) Some asked me to fill that roll and I can only hope I did it well and with humility, no one has all the answers. Anyway, I am ok with Dr. P’s editorial and will be interested to see what his colleagues have to say about it over time.