Sherlock Holmes and the QT interval

[biopearl123]

First off Happy Thanksgiving to fellow board members. This is my favorite holiday and there is much to be thankful for. I think we have a surprise at the conclusion of the MDS enrollment and it is not overtly pleasant. A new extension study to look at “ventricular repolarization” has been added. First a word about me. I have been fortunate to have had a wonderful career as a cardiac electrophysiologist . My experience has included performing over 10,000 cardiac related procedures including ablations, pacemaker implants and ICD implants. During this period I have cared for thousands of patients with arrththmias and multiple cardiac problems. I have read perhaps hundreds of thousands of ECGs and thousands of Holter monitors. I have cared for many patients with QT prolongation syndromes both inherited and acquired. Three days ago, after carefully reviewing the KOL event, I sold most of my stock holdings and bought more Geron. Last night I became aware of the “ventricular repolarization” sub study. My interpretation is that the mandatory DSMB review at the conclusion of enrollment has identified a signal of increase mortality in the study, apparently in patients with underlying cardiovascular disorders. Looking at the new study arm I suspect they are trying to hone in on the potential effect of imetelstat on ventricular repolarization, specifically the QT interval. QT interval disorders and specifically “Torsades de Pointes” are of particular interest to EPs. By using an extensive exclusion criterion that includes virtually all adult cardiovascular disorders they want to isolate any potential effect on the QT interval. I will try to explain in some detail when I get to ion channels and and potassium blocker effects on phase III of repolarization. Suffice it to say that for now, by excluding all adult cardiovascular conditions, what they are left with will be an ability to comment as to whether Imetelstat has any effect on the QT interval and its potential effects on mortality. I will continue this in the next panel…

[biopearl123]

And so to Sherlock who said something to the effect, “when you have eliminated all the possibilities, what ever you are left with, no matter how improbable must be the truth” It appears this study design is eliminating all adult cardiovascular conditions to try to isolate a potential QT adverse effect. This seems odd to me. First off the FDA has been adamant about studying QT interval effect for many years since drugs like Seldane (particularly in combination with macrolid antibiotics like erythromycin) led to QT interval prolongation and potentially lethal arrththmias. The QT issue had to be addressed with Imetelstat very early on and I mean years ago. To my knowledge there was none. Hundreds of patients have received Imetelstat at this point and each of them had to have ECGs (and some maybe signal averaged ECGs) looking for arrhythmia issues and QT prolongation which is a marker for trouble. Janssen scientists also looked and did not find if I remember correctly. On the ECG, frankly, its not hard to find. So why now? My guess it that the study ran into one of the problems of life, if you live long enough you might die from something besides the disease you are studying. Not everyone who has MDS dies from MDS, they might die from something else like congestive heart failure, hearts attacks etc. Each one of the cardiovascular exclusion factors has been associated with a potential statistical increase in morbidity or mortality. And this is why Geron has an army of statisticians. To sort out who actually dies from the disease, who dies from the drug and who dies from getting hit by a car. It’s complex. So to a brief discussion of Torsades.

[biopearl123]

Torsades de Pointes means literally a “twisting of the points”. To an EP’s eye it is a balletic ECG arrhythmia pattern that would be beautiful if it weren’t so deadly. It is typically related to antecedent QT prolongation as part of the ECG that evaluates repolarization of the heart after it finishes contracting and is related to a complex interplay of the flows of electrolytes during phase III of the repolarization process. Some drugs affect this, and particularly those that affect the potassium flux. Some of those drugs are utilized today, just very carefully so as to monitor and avoid any problems (e.g. Sotolol, some anti fungal agents etc). The conditions can be acquired via drugs, electrolyte disorders or congenital. Sudden death and cardiovascular collapse can ensue. It’s dramatic and definitely has the attention of the FDA. To my knowledge it was never an issue with Imetelstat and may still not be. Hence the extension study. A lot is known about the natural history of various cardiovascular disorders. I have little doubt that many patients with hematological problems also have concurrent cardiovascular issues. If the FDA allowed RWD perhaps the study would not be required. I don’t know. In any case the new extension study appears to be taking a Sherlockian approach. Have a wonderful TG. Perhaps Dr. Scarlett and Dr. Rizo will address this new arm of the study in their post ASH comments or preferably with a PR now, a little reassurance would be welcome. Regards to all, bp

[LWS]

(from Biopearl)-----"Hundreds of patients have received Imetelstat at this point and each of them had to have ECGs (and some maybe signal averaged ECGs) looking for arrhythmia issues and QT prolongation which is a marker for trouble. Janssen scientists also looked and did not find if I remember correctly. On the ECG, frankly, its not hard to find. So why now? My guess it that the study ran into one of the problems of life, if you live long enough you might die from something besides the disease you are studying. Not everyone who has MDS dies from MDS, they might die from something else like congestive heart failure, hearts attacks etc. "
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If I read this correctly, you are saying that many survivors, using Imetelstat (IMET), have significantly exceeded their life expectancy (OS data), but eventually die of something else (heart failure for example). Since IMET is "remarkable, compelling, etc.", dying primarily from something other than MDS would be a positive outcome, emphasizing the immediate need for this medicine.

[ashah]

Andrew
Thank you as always for wonderful analysis.
Quick question or rather feedback on an hypothesis.

Any possibility that ventricular repolarization is mandated for ILAP? Drug Candidate effectiveness can be acceptable when considering - RWD and phase 2 days. P3 days cannot be unblinded early for obvious reasons. Likely mortality among trial patients is disease or cardiovascular events... and this arm COULD answer the Cardiovascular Safety sufficiently to green light conditional approval per ILAP.

[biopearl123]

Hi Ashah, Hmmmm possible but QT effects usually assessed very early in clinical studies so should already be done. Might be something specific to ILAP I suppose. Given the time it would take to draw up a study modification and have FDA approval one would think this was in the works well befor ILAP announcement or KOL meeting so it could be pro forma as you suggest. Modification of a flagship study should qualify as a material event so I would think we should hear an explanation soon. Yours would be the most benign explanation.

[FC4364]

No announcement from company, then IMO, not a material event. Now, not to say one is not forthcoming, but for now, no and if there is one to be made, it would need to be made soon, very, very soon, like tomorrow. Pawns in the game are constantly being moved around and this could be just another step for early or conditional approval. Jakafi (Ruxolitinib) was approved and it provides limited relief for patients at best. Imetelstat provides an unheard of level of OS and in some cases clearing of bone marrow. As stated above, patients may actually be succumbing by other means and unless there is an announcement, then this could be a very positive step in the journey for approval for Imetelstat. In My Opinion, of course.

[FC4364]

No announcement from company, then not a material event. Now, not to say one is not forthcoming, but for now, no and if there is one to be made, it would need to be made soon, very, very soon, like tomorrow. Pawns in the game are constantly being moved around and this could be just another step for early or conditional approval. Jakafi (Ruxolitinib) was approved and it provides limited relief for patients at best. Imetelstat provides an unheard of level of OS and in some cases clearing of bone marrow. As stated above, patients may actually be succumbing by other means and unless there is an announcement, then this could be a very positive step in the journey for approval for Imetelstat. In My Opinion, of course.

[CKTC]

There are dozens of marketed drugs that affect the QT interval on the ECG. The change from baseline in QTc interval was added to the IMerge trial as a secondary outcome measure in September of 2017. So they must have picked up a signal they didn’t like, and thus the reason for the Ventricular Repolarization sub-study. They’re going to enroll approximately 45 patients (with all types of cardiac exclusions) in the sub-study. Geron needs to advise how long this will be anticipated to delay things.

[kmall]

Happy Thanksgiving board.......any chance we can get a link for the Ventricular Repolarization sub-study extension of 45 patients? Didn't see anything posted on the company website. Not considering this exactly "unpleasant" news just yet. Thanks. -Kmall

[biopearl123]

Hi Kmall, it’s outlined in detail in clinical trials.gov site. Let us know what you think. CKTC, have experience with many meds that can prolong QT interval. And yes they are in active use but must be utilizing very carefully with close monitoring. I remember the 2017 mention in clinical trials end point section and thought the issue was over and done. It’s just not that hard to measure a QT interval. Regards, bp

[CKTC]

https://clinicaltrials.gov/ct2/show/NCT02598661
Trial update posted 11/24/21

Study Description
Detailed Description, paragraph 4

In a separate Ventricular Repolarization substudy of Part 2, approximately 45 participants will be enrolled and randomized 2:1 to receive either imetelstat or placebo. If after a minimum of 2 treatment cycles in the Ventricular Repolarization substudy, a participant has no significant change to pRBC transfusion burden or evidence of clinical benefit per Investigator, after discussion with the Sponsor the participant may be unblinded. If the participant was on placebo treatment, he/she may be permitted to start treatment with imetelstat.

[kmall]

Thanks Andrew and CKTC. I have to agree that it seems odd in that P2 should have addressed this concern. Looks like a minimum of 8 weeks additional time, so hopefully not more than 4 - 6 months delay?

I suspect that Andrew is correct in that many of these patients have underlying issues and for the sake of ruling out Imetelstat as being a cause, additional data is needed. If cleared of being an issue then this delay is nothing more than a minor inconvenience. Thanks for the update and link! -Kmall

[Hoosier Investor]

BP,

In your professional opinion, how long will they need to monitor patients after they start IMET treatment? I’d guess it will take around 6 months to enroll the extra 45 patients, but I have no idea how long they’ll need to monitor the patients.

Thank you for sharing the info & interpretations.

[Hoosier Investor]

The answer to the “delay” question may be best answered by checking to see if Geron changed the trial’s estimated completion date(s).

Even if it takes 6 months to enroll the extra patients, they may be able to absorb the activities (without having to extend the trial completion date) if the QT question can be answered in short order.

[biopearl123]

HI, the primary completion date appears essentially unchanged and is Jan 15th 2023. Once enrolled, the QT effect should be obvious after a few doses (once pharmacologic steady state is reached-this should be 5 half lives of the drug, unless there is some as yet unrecognized cumulative repolarization effect which seems unlikely. There will have to be clarity provided at the very least by the end of ASH if not before. bp

[ashah]

Any stats expert on the forum?
Would be very interesting to postulate the P value of the additional cohort if/ when/as data is unblinded - and assuming the Phase 2 efficacy is replicated.

[biopearl123]

Ashah, to your comment that the P3 data can not be unblinded yet, while this is true the DMSB does review the data periodically. Thus far we have been told “no new safety signals have been identified”. Let’s hope remains the case. bp

[FC4364]

DDD on YMB, points out that ----

From EU clinical site "Protocol Amendment: 31 August 2017 Attachment 11: Ventricular Repolarization Substudy at Selected Sites Study Objectives To evaluate the effect of imetelstat on ventricular repolarization in a subset of subjects in Part 2 from selected clinical sites:"

If this is the case, and this study was not previously completed, and it appears it has not been. Then I Believe this is nothing more than a cleaning up the ledger exercise to get the paperwork in order. All the T's crossed and all the I's dotted. In my opinion, of course.

[biopearl123]

FC4364, yes that the protocol was added in 2017, is not in dispute. But look at how long it took to recruit the 170 patients for part two of the MDS study. Now we are facing the burden of recruiting an additional 45 (in the face of new COVID varients to boot). And while these additional patients may strengthen the statistical weight of the main study, the sub study could have been performed on existing patients, as sub groups can be defined and studied as things go. That what substudies do, they look at groups split out from a given study with certain characteristics. If in 2017 there was interest in the QT interval great, study it. There was never an inkling that a sub study was part of the protocol once enrollment for the main study was complete. This is new and may as noted by others on this board conceivably prolong the entire study unless the sub study will be of very short duration and designed to answer a specific question (this does appear to be the case) and recruitment goes rapidly. To say this was conceived of in 2017 and was planned to start once enrollment in the main study was complete seems murky at best. Quick enrollment and a short study time may not interfere with the overall timeline as this study appears designed to answer a specific question and effects on QT should be apparent before or on the way to reaching steady state so the study will likely be short and judging from the clinical trials site update not affect target read out of top line data for mid Jan 2023. My understanding of a sub study is that it is an “add on study designed to ask a separate research question and which includes new data collection of some or all of the trial participants participating in the main protocol.” However in this case there are new enrollments required. So it may well be that this was “planned” in some way and could only start after initial data was collected but it does not appear to involve patients already involved in the main study so I will continue to seek clarification. Best Regards, bp