Enrollment

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biopearl123
Posts: 458
Joined: Fri Jul 20, 2018 5:13 pm

Enrollment

Post by biopearl123 » Fri Nov 20, 2020 11:42 pm

Recall that Dr. Scarlett said (in what seems like the distant past) that we would be informed when the 50% enrollment goal had been achieved in the MDS study. So far no notification. The shareholders letter addressed the COVID issue which is certainly playing a role but another less discussed reason has to be the presence of Luspatercept as an approved drug, readily available outside of protocol, no risk of being randomized to control and a modest side effect profile. Once patients fail Lus, Imetelstat will likely be an attractive alternative even accepting the potential of being randomized to the control group (2:1) but this is probably affecting enrollment enthusiasm regardless of how Geron spins it. Perhaps there will be some discussion at the upcoming ASH meeting. As a reminder the study has been ongoing for over a year and we are not yet at the 50% mark with guidance given for complete enrollment by the end of Q2. One can hope. bp

CKTC
Posts: 17
Joined: Sun May 31, 2020 4:26 am

Re: Enrollment

Post by CKTC » Sat Nov 21, 2020 4:39 pm

Scarlett has been downplaying the competitive threat of luspatercept for years. And he’s been disingenuous in a number of ways when comparing imetelstat to luspatercept. The most glaring example is his characterization of transfusion independence durability. Scarlett likes to quote imetelstat’s median duration of RBC-TI at 88 weeks, and luspatercept’s at 31 weeks (Stifel, Nov. 2020, pg. 10).
https://s24.q4cdn.com/668523011/files/d ... -FINAL.pdf

The problem is Scarlet is comparing updated imetelstat numbers to original, non-updated luspatercept numbers. All trials have data cutoff points, and the numbers available for publication reflect the numbers available at the time of cutoff. When the IMerge numbers were originally presented at ASH in 2017 and EHA in 2018, imetelstat showed a median duration of TI of 42.9 weeks. Fast forward to the most recent clinical cutoff of Feb 2020, and the more mature numbers show a median duration of TI of 88 weeks (EHA 2020 pg. 8).
https://www.geron.com/file.cfm/53/docs/ ... 0FINAL.pdf

When the luspatercept MEDALIST trial numbers were originally published at ASH in 2018, the median duration of TI was reported at 31 weeks. But when the data cutoff was extended to July 2019, the median duration of TI improved to 79.9 weeks (ASH 2019 pg. 11).
https://acceleronpharma.com/wp-content/ ... 2019V2.pdf

Now, I know Scarlett is aware of the updated luspatercept numbers. Pierre Fenaux and Uwe Platzbecker, the DR.’s who presented the updated imetelstat numbers for Geron at EHA in 2020, are the same Dr.’s who presented the updated luspatercept numbers for Acceleron at ASH in 2019. Yet Scarlett continues to compare the updated imetelsat numbers to the original luspatercept numbers in his investor presentations. This is very misleading.

Luspatercpet has been approved by both the FDA and EMA. Bristol-Myers reported sales of $97 million in the 3rd quarter, which is quite impressive given the drug has only been available for a short time. The drug is being sold by Celgene’s hematology sales force, probably the most experienced hematology sales group in the world. I can assure you that any MDS patient in the USA and EU that might benefit from this drug is going to get access to it. And yes, this is definitely impacting the current IMerge enrollment, regardless of Scarlett’s willingness to admit it.

CKTC
Posts: 17
Joined: Sun May 31, 2020 4:26 am

Re: Enrollment

Post by CKTC » Sun Nov 22, 2020 3:38 pm

To refine my statements above and more accurately compare apples to apples, cumulative duration of TI, defined as the sum of all periods of 8 week TI during treatment, was a median of 92.3 weeks for imetelstat and 79.9 weeks for luspatercept. To be fair to Scarlett, technically, he is correct that once an imetelstat patient achieves the first TI, s/he maintains it longer than a luspatercept patient. And cumulatively, imetelstat does provide for a superior response. He fails to consider that with luspatercept, patients who lose their response often gain it back. In the MEDALIST trial, 69.9% of TI responders had two separate response periods, 38.4 % had three, and 20.5% had four. Given that tendency and luspatercept's relatively benign safety profile, doctors in the clinic will have an incentive to keep patients who lose their response to the drug on it for a longer time in the hopes of regaining the response. So if the imetelstat trial sites are waiting to enroll luspatercept failures, they might be waiting a long time.

This rant's whole point is to understand better the potential reasons IMerge is taking so long to enroll and vent some frustration, with Scarlett being an easy target.

biopearl123
Posts: 458
Joined: Fri Jul 20, 2018 5:13 pm

Re: Enrollment

Post by biopearl123 » Sun Nov 22, 2020 7:06 pm

CKTC, thanks for your observations and clarifications. It does seem a little peculiar that that Platzbecker presentation abstract has the data cut off we have noted of Feb 2000 without mention of an update. Clearly ASH provides the opportunity to up the TI data to a later data cut off date. Since this will be an oral presentation, it is hard to see this not happening. An opportunity to further differentiate Imetelstat from Luspatercept will present itself if the data allows. It does seem that patients with high transfusion burdens are likely to be targeted by Imetelstat as the "stronger" of the two. Also if one considers the basic mechanism of action, if there were to be an effect on the actual natural history of the disease, targeting the malignant clone directly should have some inherent advantages. bp

Ryan
Posts: 83
Joined: Sat Jul 08, 2017 1:41 pm

Re: Enrollment

Post by Ryan » Mon Nov 23, 2020 6:41 pm

For lack of a better word, I find this messages in this thread to be quite loquacious while missing the mark...

More to the point:

Dr. Rizo and team have stated when the MDS Phase III enrollment is expected to be completed, and this was changed slightly due to COVID and has not changed since. Dr. Rizo also stated in the most recent quarterly call that, like most Phase IIIs, enrollment starts slow and gains momentum over time, and stated that is what they are observing here.

Luspatercept *has shown quite impressive results, yet only was tested on a small subset of MDS patients, I believe around ~15% had the condition that led to enrollment. The drug may now be being prescribed 'off-label' than that subset to more patients, however is not comparable to the patient cohort that Imetelstat is honing in to treat, which is a much larger patient population, and thus, would be in competition with Lus for that small subset of patients.

I wouldn't mistake the verbose (trying another descriptor) nature to mean that conjecture is on point here. IMO much ado about nothing (factual) - study is gaining momentum with enrollment and is still on track to enroll based on the guidance of company given over the past 6+ months.

biopearl123
Posts: 458
Joined: Fri Jul 20, 2018 5:13 pm

Re: Enrollment

Post by biopearl123 » Thu Nov 26, 2020 6:06 pm

Thanks for posting, I think we have to accept that enrollment is not at the level Geron originally hoped and is due to a combination of factors, the major one probably being COVID but some contribution of the market availability and physician acceptance of Luspatercept is likely playing a role. Given the large sales numbers of Lus, I think we have to assume some bleed over into the non RS group (diagnosis criterion may not be strict or may be driven by presence of specific mutation) even if Lus is less effective there, otherwise it is hard to see numbers of this magnitude from only 15 % of potential MDS patients. The fact is that we are not yet at 50% enrollment (but I bet we are close), in a relatively small study with a relatively large number of sites coming on line. Dr. Scarlett and Dr. Rizo have made the point the that we can expect enrollment to peak toward the end of the anticipated enrollment period. All things considered, if the enrollment will indeed be complete by Q2 that will be an accomplishment in this time of COVID. Great to see the Dr. Boerlacher back. I think the MF study will probably include made of the MDS sites as well and probably enroll fast as we will have vaccine rolling out concurrently. It may be that getting the vaccine could be a requirement for enrollment, that remains to be seen, otherwise some statistical red herring could be introduced if mortality is impacted by the virus. I will open another thread to discuss the impending ASH events. Happy Thanksgiving to all and thank you for your contributions. bp

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