The curious case of the abstracts that didn't bark

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biopearl123
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The curious case of the abstracts that didn't bark

Post by biopearl123 » Sat Nov 07, 2020 6:14 pm

First off the abstracts were released a day early. This could give unfair advantage to anyone who expected the abstract release on Nov 5th. I call foul on ASH. Remember when the Mayo abstract info was released inappropriately early? That of course was years ago. So a few curious things about this years abstracts. 10 is a big number for a little company. But when this is parsed, besides the informational abstracts re future PIII studies that contain no patient data, several of the abstracts repeat the data presented at EHA. Take for example the part I MDS data, an exciting abstract indeed that was presented at EHA. Data cut off for analysis: Feb 2020. Now the ASH abstract reviewing the same data. Data cut off of analysis: Feb 2020. Neither Dr. Scarlett or Dr. Rizo took a moment to say that data would be updated at ASH. My understanding is that in order to be acceptable for presentation at a major meeting (e.g. EHA or AHA), abstracts must contain data not previously presented or at least new data to enhance that previously presented. Another foul? Unlikely given the stringency of the meeting rules. So why would this be understated? We know patients continue to receive therapy in the MDS study (at the discretion of their physicians). Will we know the presumed TI's, HI's, bone marrow data at ASH? One hopes so. Maybe only a few patients are left on treatment or maybe the data significance falls off over time (paging a good combination for the future.) So when you count to ten remember there are presentations directly from the department of redundancy department. Unless new data is presented. Let's hope. But why didn't the astute financial analysts ask about it? After all they are the only ones allowed to ask at all. Wainright, still sticking by your analysis? There was no barking, but I did hear some very interesting stuff about disease modification...bp

biopearl123
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Re: The curious case of the abstracts that didn't bark

Post by biopearl123 » Sat Nov 07, 2020 6:18 pm

Oh I didn't mention that we were being prepared for no KOL meeting this year. I think because there is nothing new to say until there is new data from the PIIIs. Pour a drink, wear a mask and wait. We have had a lot of practice doing just that. bp

CKTC
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Re: The curious case of the abstracts that didn't bark

Post by CKTC » Sun Nov 08, 2020 4:40 pm

Speaking of KOL’s, I noted in a 6/17 post, Srdan Verstovsek (Dr. “Ruxolitinib”) of MD Anderson will be co-Principal Investigator with John Mascarenhas of Ichan School of Medicine for the upcoming Phase 3 IMpactMF trial. Dr. Verstovek was Principal Investigator for Incyte’s Phase 3 COMFORT trial that won ruxolitinib FDA approval. He has been intimately involved in all aspects of ruxolitinib trial work over the past decade. As a cancer center, MD Anderson participates in more MPN trials and treats more MPN patients than any other institution in the world. It is considered ground zero for MPN research. So getting Dr. Verstovsek involved in a primary role with the upcoming MF trial is a smart move by Geron.

Dr. Verstovsek’s colleague at MD Anderson is Dr. Ruben Mesa. Dr. Mesa co-led the research that won FDA approval for ruxolitinib in both myelofibrosis and polycythemia vera. More importantly, Dr. Mesa led the National Comprehensive Cancer Network’s (NCCN) development of the clinical practice guidelines on diagnosing and treating myelofibrosis. The NCCN guidelines are what oncologists throughout the country turn to when diagnosing and treating cancers. Dr. Mesa has now taken a role in the upcoming IMpactMF trial. He is listed as an author on ASH abstract 2194 that describes the forthcoming study. Neither IMbark nor IMerge enrolled patients at MD Anderson. Getting the world’s premier MPN institution and two of the most prominent voices in MPN research involved in IMpactMF adds instant credibility and will go a long way towards speeding recruitment.

https://ash.confex.com/ash/2020/webprog ... 38915.html

biopearl123
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Re: The curious case of the abstracts that didn't bark

Post by biopearl123 » Sun Nov 08, 2020 5:55 pm

CKTC, no question the heavyweights are on board. Thank you for emphasizing this. Would you please comment on the following observation? I've been waiting for someone else to confirm this thought but I will present it to you and the board. It was been touched on before but I really think it should be reexamined. As a starting point look at slide 16 from the KOL June 2020 meeting. This slide shows 16 patients that demonstrate at least 8 weeks of TI, some with a much longer interval. We also know that HI is extraordinary. Yet only a fraction (7 of 16 patients) remained on treatment at the time of data analysis. Yet the benefit appears to persist even when not on active treatment, in some patients for an apparently very long time! I am not sure why this effect is not emphasized by the team, or maybe they think the data should speak for itself. Perhaps I am assigning too much weight to it but I also see it in the MF trial where the patient drop out rates were high because the "end points" were not met, that is until the realization of dramatic improvements in OS dawned. Again an argument that the drug effect is realized long after it is discontinued (in the latter case perhaps discontinuing it for the "wrong" reasons.) We continue to see molecular end point data, which will probably drive the ASH presentation since there is not a lot of new clinical data to be presented other than an update on the clinical status of the MDS part I patients. I remain curious as to why this was not emphasized in the Platzbecker abstract. I am optimistic about the new administrations approach to COVID and think it could actually have an impact in a convoluted way, of ultimately improving recruitment rates. Best Regards, bp

biopearl123
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Re: The curious case of the abstracts that didn't bark

Post by biopearl123 » Sun Nov 08, 2020 6:01 pm

Also while we are on the subject of KOL's, Dr. Steensma from the Dana Farber (which also did not contribute patients to either the IMbark or IMerge studies) has taken an interest in Imetelstat. I suspect when we see new sites added to Part II of the MDS trial and perhaps also the IMpactMF we will see a strong presence there too. We are definitely looking at world class institutions and investigators taking a strong interest in Imetelstat. bp

CKTC
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Re: The curious case of the abstracts that didn't bark

Post by CKTC » Sun Nov 08, 2020 9:24 pm

@biopearl,

It is painfully apparent many patients came off imetelstat too early. Imetelstat is a potent drug whose benefits can linger long after discontinuation. If there is a conscious effort on the part of investigators to not “emphasize” those lingering benefits, it might have to do with salvage treatments. Many patients who stopped imetelstat likely took salvage treatments. While it is unlikely those treatments could have been responsible for the prolonged hematological improvements or OS attributed to imetelstat, researchers would not be able to make those claims with absolute certainty.

Early on from Dr. Tefferi’s study, we learned patients need to be kept on imetelstat for as long as tolerable. In the case of MDS, even those who achieve TI but later lose it should be maintained on imetelstat as there exists the potential to regain TI. This issue was touched upon in the Q&A session of the most recent earnings call.

Bonnie Quach (Stifel): And for the MDS patients to achieve transfusion independence but then end up requiring transfusions again, is there any evidence of the potential of achieving a durable transfusion, sort of achieving that transfusion independence again with continued treatment? Is this something you looked into?

Dr. Scarlett: So the question -- so if I understand the question, it was, so what happens in the real world if a patient has achieved transfusion independence and then they require a transfusion, are they going to just stop the drug? Or are they going to potentially continue on? Is that your question?

Dr. Scarlett: Yes. And I think just to answer the question very directly, I think if a patient, for whatever reason, requires a transfusion, these patients are used to requiring different levels of transfusion, et cetera. So if they require transfusion, I think our experience suggests that they would likely continue to give imetelstat an opportunity to keep them transfusion-free again. It goes back to the question that you asked before, what happens to patients who quit having transfusion independence. Do they then reestablish transfusion independence after getting a transfusion? Can the drug continue to work? The answer is unequivocally yes. So I think because of that, the likelihood is that investigator -- or sorry, in this case, treating physicians and patients, would have a very high incentive to continue along the drug, even if there was an interruption of their transfusion-free period of time.

biopearl123
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Re: The curious case of the abstracts that didn't bark

Post by biopearl123 » Sun Nov 08, 2020 10:09 pm

CKTC, thank you for responding. It looks like Imetelstat "knocks back" malignant clones, allowing bone marrow normalcy to recover but that the disease can smolder and later cause clinical recurrence. I was hoping for some discussion from Geron regarding assessment of MRD. Clonal selection is a problem in that the more susceptible mutations are affected by drug while more difficult to treat complex mutations may emerge later in the course of the disease and ultimately determine the final stages of disease evolution. In any case, it does appear that even after drug cessation, longer term continued benefit can be anticipated in some. bp

Hoosier Investor
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Re: The curious case of the abstracts that didn't bark

Post by Hoosier Investor » Tue Nov 10, 2020 12:49 am

Notably Present: Mascarenhas, Harrison, and Verstovsek.

VERY Notably Present: Mesa & Vannucchi**
**Dr. Vannucchi Disclosure.....AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Notably Absent: Tefferi*
* Perhaps Dr. Tefferi rubbed Geron management the wrong way when he filed his own patent application (with himself listed as the sole inventor) the day before the ASH 2013 abstracts published online. This is the one where he claimed use of Imetelstat as a treatment for MF patients with certain splicing mutations. The assignment (ownership) of the patent application was later transferred to the Mayo Clinic, and the application was still pending (not granted) the last time I checked on status. Geron IR previously told me they (we) will have a license to the patent (should it grant), but there was no mention of it being a royalty-free license.

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

Re: The curious case of the abstracts that didn't bark

Post by biopearl123 » Tue Nov 10, 2020 10:18 pm

HI, yes this apparent intellectual land grab by Dr. T probably caught Geron off guard and was not anticipated. I know you are an expert in IP so wouldn't you find this something unlikely to stand up in court? Was it legal slackness that allowed this to happen? Geron had a reputation for closely guarding its IP. Recall the stem cell IP that was kept from academic institutions, in retrospect a big mistake. Dr. T is a world renown oncologist and his NEJM article was earth shaking. That he probably slowed development of a drug that he should and could have been a torch bearer for is quite a shame. His follow on study in from line was ready for take off about 5 years ago if I recall and then was trashed when the FDA decided the drug caused LFT abnormalities, despite not meeting Hy's law and being evaluated by a panel of liver specialists. Much of Geron's IP was related to its stem cell portfolio now spun off into the cosmos. Reading some of their patent library makes me think at least in recent times that the i's are dotted and the t's crossed. Your points about the world class physicians now involved is notable. I suspect eventually Dr. T will have a pang about not being at the center of the development of an important drug that at least at the beginning he played a seminal role in investigating. bp

Hoosier Investor
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Re: The curious case of the abstracts that didn't bark

Post by Hoosier Investor » Tue Nov 10, 2020 11:00 pm

Someone should let JSAN (Jeremy Smith) know the world's leading hematologists are taking an active interest (role) in our upcoming MF Phase 3 clinical trial. That was always his main contention with Imetelstat (i.e. lack of KOL support and/or participation).

http://www.mpnresearchfoundation.org/Je ... hemia-vera

CKTC
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Re: The curious case of the abstracts that didn't bark

Post by CKTC » Wed Nov 11, 2020 4:11 am

In addition to UT running an enormous MPN research operation, Tefferi is probably one of the reasons Mesa left Mayo for UT after being at Mayo his entire career, including medical school.

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

Re: The curious case of the abstracts that didn't bark

Post by biopearl123 » Wed Nov 11, 2020 3:45 pm

HI, if Jeremy Smith owns a computer, he knows. He also probably reads this board. bp

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