CKTC

[biopearl123]

First off, your posts have been incredible and really helped to make sense of a what amounts to a very surprising FDA position paper. I can understand that the FDA would want to look at the negatives carefully. In this case however using criterion for HI that are almost 20 year old and are no longer considered relevant by the heme community at large, seems purposeful. The shortcomings of this older classification have been recognized and refined by panels of experts over time as the nuances of a disease that does have natural fluctuations is recognized. Better tools to assess treatment efficacies were sought and the prescience of these expert panels anticipated future treatments that would actually lead to disease modification and realized they would need tools to assess the efficacy of these new modalities. I was just sitting back and imagining the medicine of 20 years ago. I was still taking defibrillators out of abdomens because they had been too huge to put in chests. Now pacemakers can be made small enough to fit within the heart itself. The evolution in medicine over the past 20 years has been remarkable! So to the question, what could possibly be behind the FDA using an outdated, outmoded classification system to evaluate a new therapy? Was the use of this system what allowed them to conclude that the placebo group had such odd incomprehensible numbers, numbers none of us had seen before? Could the FDA actually believe that this latter analysis was correct, relevant and accurate? Perhaps there is another explanation. I am sure Geron will address this tomorrow. Again thanks for your very valuation lead in the discussion. bp

[Hoosier Investor]

FYI....The initial (agreed upon) trial design did NOT specify which criteria was to be used for HI-E. Thus, it seems fair & reasonable (and proper) for Geron to use the updated 2018 IWG criteria....which is designed to distinguish a statistical difference at ~4 months (16 wks) instead of ~2 months (8 wks).

The exact language (from clinicaltrials.gov) for HI is shown below.....

Secondary Outcome Measures
Percentage of Participants with Hematologic Improvement [ Time Frame: During study (approximately 2 years) ]

[biopearl123]

Yup, I think you have hit on an important point. The first patient was enrolled in 2015 in part 1, obviously before the 2018 criterion were adopted. Will the FDA require the 2006 criterion to obtain because of that? We are talking about a study start to top line (not yet even at final completion date) of 11 years. Will the FDA be able to acknowledge evolving progress in the field that occurred during the study (e.g. recognition that new guidelines were needed by an expert panel) or will they require the 2006 IWG guidelines which are clearly outdated to apply. I don’t remember if part 2 started enrollment after the newer guidelines were adopted or not and if the FDA might be able to update their thinking. I think the experts will made the case for an evolving and more complete understanding of the disease that should be taken into consideration when evaluating the data. We will see if the FDA is stuck in 2006 mud or whether they will acknowledge progress and promise. Well, promise is too much to ask, but they should acknowledge data. An almost 20 year old year yardstick is just obsolete.

[CKTC]

The FDA notes that the p-value of HI-E, according to the 2006 guidelines, is p=0.112. They didn’t come up with this themselves. The likely scenario is that Geron provided the numbers for the 2006 and 2018 guidelines and then made the case for why the 2018 numbers should be used. The trial protocol didn’t stipulate which version of the guideline to use, but when the trial was designed, only the 2006 guideline existed, and the FDA could make the argument, however unreasonable we may find it, that the trial should be judged under the guidelines in existence when the statistical protocol was initially written. Geron did refer to the 2006 guidelines when it published the Phase 2 IMerge results. It looks like Phase 3 started recruiting in July of 2019. Could they have updated the trial protocol and statistical plan to reflect the 2018 guidelines? Would that have been necessary? I have no idea.

Regardless, I expected the FDA briefing docs to have a negative bias, but only towards safety, not efficacy. But with Geron, as we all know, nothing comes easy, and it seems like the FDA is not in the mood to be generous with interpretations.

[LWS]

Common sense should prevail favoring the newer 2018 guidelines. ODAC and the FDA are composed of some very smart people.

[biopearl123]

Well, if the 2018 guidelines are used the results look stellar and include a strong endorsement for HI. If this end point is excluded by using earlier, older guidelines we still have 1. Primary endpoint reached. 2. Key secondary endpoint reached. 3. Caveats re cytopenias etc. Points 1 and 2 are factual and probably will not be contested regardless of which guideline is applied. Point 3 will be discussed and the committee will vote on benefit/risk at the conclusion of the meeting but weighting the benefit will have to include data re HI patients as well. Every member of that committee will know about the 2006 vs 2018 guideline issue which doesn’t really impact point 3 but will certainly adds more weight to the benefit side of the scale if positive HI data is included when evaluating risk. Expert members of the panel will know this. I suspect the FDA will maintain a strict interpretation, perhaps based on when the study was first approved, they are the FDA after all and will probably (perhaps with silent regret) maintain the highest of evaluative standard, that’s their reputation. But the advisory committee is a different story. They are not held to an FDA decision that was made in the years before the newer guidelines came to be. They are there to advise the FDA after considering all that will be laid before them. Some on this committee are in active practice and have very sick patients. I think they will not allow for intellectual inflexibility bound by the chains of a 2006 consensus. I think they will evaluate the sum of the data to answer the fundamental question of benefit vs. risk after considering as much information as can be brought to them and they will see a vote for approval or denial through the lens of their own patients, their families and their knowledge base. Their knowledge base will include the 2006 guidelines, the FDA will see to that, as well as the 2018 guidelines, Geron will see to that as will expert published and reviewed established heme/onc consensus. The FDA as we know is not bound by their recommendation but they wouldn’t be asking if it weren’t essential.

[Hoosier Investor]

For full consideration, we also have.....
* A relatively sick (sicker) patient population (transfusion burden) than prior/competitive studies.
* A subset of patients who have been transfusion free for 1+ years.
* FDA has already allowed imetelstat to be available for this indication via EAP.....with no cited issues.
* Pre-clinical and clinical data involving other Heme indications (e.g. ET, MF, AML).

[KTArsenal]

I'd like to inject this entire thread directly into my veins.

Thanks for everything, even if we come up short. Cheers

[biopearl123]

KT, well tomorrow is a seminal event for sure. My thanks to everyone who has contributed to furthering our understanding of this drug and the studies that support it (or don’t), guess its who you ask…:)