Basic Considerations....

[Hoosier Investor]

Q: Is there an unmet medical (treatment) need in this patient population?
Q: Did the FDA approve the trial design?
Q: Did the P3 trial meet its primary endpoint?
Q: Did the P3 trial meet one (or more) of its secondary endpoints?
Q: Acceptable safety profile? Acceptable dosage protocol to adjust/manage SAEs?
Q: KOL support?

If the answer is "yes" to the above questions, a recommendation to approve would seem to be in order. The "unmet need" associated with the indication should be a key consideration.

FYI....I'm reminded of my college (engineering) days. While it was always nice to get a 100% score on the exam, a 100% score wasn't required to pass the course.

[CKTC]

I just read the FDA briefing doc and have a lot of questions regarding the data. For example, in its presentations, Geron always uses the 2018 revised IWG criteria for HI-E response which in the trial was statistically significant in favor of imetelstat vs placebo. But the FDA refers to the 2006 IWG criteria and says there's no statistically significant difference. Plus, the FDA claims there was a transfusion reduction of ≥ 4 units/8 weeks in 50% (30/60) of placebo subjects. I’ve never seen that number before. How would that even be possible?

From the FDA briefing doc:
3.2.2 High proportion of hematologic improvement-erythroid (HI-E) in the placebo arm.

In the Phase 3 trial, there was no significant difference in the proportion of subjects who achieved an HIE response per IWG 2006 criteria, with an HI-E rate of 63.6% (75/118) for imetelstat versus 51.7% (31/60) for placebo, p=0.112. Additionally, transfusion reduction by ≥ 4 units/8 weeks (a component of the HI-E response) was achieved by 60.2% (71/118) of subjects receiving imetelstat versus 50% (30/60) of subjects receiving placebo. The high proportion of subjects who achieved an HI-E response and transfusion reduction in the placebo group is notable; these results suggest that a portion of hemoglobin rises and corresponding periods of transfusion reduction are due in part to natural fluctuations of the underlying disease, rather than a direct treatment effect.

[biopearl123]

Right you are. Geron is going to have to tread carefully not to irritate the FDA which as you point out used IWG criterion that are almost 20 years old and have been updated at least twice since then. Also the astounding HI rates in the placebo group, well, I tried to find confirmation. Just not sure what to make of it. Thank you for your usual deep dive into the data. I think Geron will make a strong case despite the naysayers. Thank you for pouring factual oil on potentially misinformed troubled waters.

[Hoosier Investor]

Geron has anticipated the question, and provided the following rationale for using the 2018 criteria....

Analysis of HI-E was also performed using the revised IWG 2018 criteria for HI-E
(Platzbecker, 2019) , which is considered more clinically relevant in MDS than the
previous IWG 2006 criteria because it emphasizes durability of response over a 16-week
interval, versus the 8-week interval used by the IWG 2006 criteria (see Appendix 11.3 for
details on the IWG 2018 criteria). This criterion is a standard of LR MDS studies to assess
responses beyond TI.

Geron's HI-E data analysis per 2018 criteria.....

HI-E per IWG 2018 criteria overall was 42.4% (50/118) in patients treated with imetelstat
versus 13.3% (8/60) patients treated with placebo ( p < 0.001; Table 7-1). Among those,
31.4% in the imetelstat group achieved ≥ 16 -week TI vs 6.7% on placebo ( p < 0.001).
For all patients, 43.2% on the imetelstat arm had reduction in the transfusion burden by
≥ 50% over 16 weeks, compared with 15.0% on placebo ( p < 0.001, per IWG 2018,
criteria overall was 42.4% in patients treated with imetelstat vs 13.3% patients treated
with placebo (p < 0.001; Table 7-1). Among those, 31.4% in the imetelstat group achieved
≥ 16-week TI vs 6.7% on placebo (p < 0.001). For all patients, 43.2% on the imetelstat
arm had ≥ 50% reduction in the transfusion burden for ≥ 16 weeks, compared with 15.0%
on placebo (p < 0.001). Additional details on transfusion burden are provided in Section
7.2.3.6.

[CKTC]

There’s a lot of negative bias in this FDA briefing doc. For example, two of the three efficacy issues the FDA raises (3.2 Efficacy Issues) make no sense to me. The first listed issue, magnitude and durability of RBC-TI vs. risk of treatment, is a legitimate question for the panel. However, the second issue, that data on specific secondary endpoints do not support disease modification is stupid. Disease modification was not an endpoint but an observation made from a post hoc analysis of the trial data. So, the fact it’s not supported would be irrelevant to approval. But the third issue raised is the worst. The FDA claims that patient-reported outcomes do not support the treatment effect because each arm experienced similar rates of deterioration in fatigue. That endpoint, like in the luspatercept MEDALIST trial, was designed to show that imetelstat patients were not more likely to experience deterioration in fatigue than placebo patients. The theory was that as imetelstat patients became TI, fatigue would worsen because they were no longer getting blood transfusions. So, the fact that imetelstat patients did not become more fatigued than placebo patients supports that endpoint’s hypothesis. But the FDA spins it the other way around.

And after all that, in the very next paragraph, the FDA states:

“Of note, FDA also examined patient-reported tolerability data from the FACT GP5 item “I am bothered by side effects of treatment” and found that patients treated with imetelstat did not report increased side effects compared to placebo. This is likely because the full side effect profile of imetelstat includes non-symptomatic AEs such as cytopenias and is further discussed in detail in Section 3.4.”

WTF? The FACT GP5 tests how a patient feels, not what a test result may show. If imetelstat patients felt as good as placebo patients, that’s good. But again, the FDA is spinning it around.

As I said, this doc has a ton of negative bias.

[Hoosier Investor]

They (FDA) do acknowledge the trial met both its Primary & Key Secondary endpoints (p.39 summary). At least we got that acknowledgement out of them.....which should be the most important consideration along with Safety.

Along the lines of your comment, it seems rather obvious the 2018 criteria would be more relevant in terms of demonstrating durable/meaningful HI-E rates between the groups. I'm glad we're arguing to use the longer-term data and not the other way around.

[earfool]

Perhaps those on the FDA board are simply not as experienced as Geron is in interpreting this data and knowing what IWG criteria applies....as the hematologic improvement-erythroid (HI-E) data analysis between the IWG 2018 and IWG 2006 criteria for the Geron study have significant differences in how response rates are evaluated and implications for the efficacy of imetelstat.

IWG 2018 Criteria (Geron's Analysis):
Overall HI-E rate was 42.4% (50/118) in patients treated with imetelstat versus 13.3% (8/60) in patients treated with placebo. This difference is statistically significant (p < 0.001).

Among these, 31.4% in the imetelstat group achieved ≥ 16-week transfusion independence (TI) compared to 6.7% on placebo (p < 0.001).
Additionally, 43.2% of patients on the imetelstat arm had a reduction in transfusion burden by ≥ 50% over 16 weeks, compared to 15.0% on placebo (p < 0.001).

Actually... the 2018 criteria include a more stringent measure of response, .... ≥ 16-week transfusion independence and ≥ 50% reduction in transfusion burden over 16 weeks. The results of these criteria show a much more pronounced effect of imetelstat compared to placebo, whereas the 2006 criteria, with a shorter duration and less stringent measures, show a smaller difference between the two groups.

.....earfool

[CKTC]

Dr. Platzbacker designed the study that led to the IWG 2018 revisions, and led the panel that incorporated the changes into practice. https://ashpublications.org/blood/artic ... atological

And as you can see from Dr. Platzbacker’s IMerge poster, imetelstat’s HI-E improvement was clearly statistically significant under the 2018 guidelines (Table C). https://www.geron.com/wp-content/upload ... bility.pdf

The question becomes whether an endpoint (HI-E) designed around the earlier guidelines should be judged by those guidelines, or judged by the updated guidelines? This is especially significant when you consider the importance of this endpoint to the trial, and the fact that “apparently” when judged under the 2006 guidelines, the endpoint was not statistically significant.

If the FDA is willing to go with the 2018 guidelines, then Geron hit statistical significance on the primary endpoint of 8-week TI, and the three most important secondary endpoints: 24-Week TI, Duration of TI, and HI-E. Then it’s just a question of justifying the AE’s. But it’s a lot easier to justify AE’s when there’s no dispute as to the drug’s efficacy.

I wish Dr. Platzbacker was on Geron’s ADCOM team.

[LWS]

Let's not forget the unique mechanism of action (MOA) based upon two methods to kill cancer stem cells (1/ Ferroptosis, 2/ Telomerase & Telomeres) that is just beginning to be recognized and understood as an important part in the treating of blood cancers and beyond. Imetelstat may not be the "perfect" medicine, but it appears to be better than any other available medicine.

[Ryan]

Numerous great / insightful comments the past 36 hours.
I would say nothing left to do but wait.

I still believe the vote will be unanimous in favor. It’s b/c of these Basic Considerations, because of (the unchanged) p values, and because of Geron’s response along with the independent experts from Vanderbilt Med Center and Moffitt Center which will be quite compelling and authoritative I am quite confident.

[pursang]

ADCOM and the FDA, all over the map ..

fiercebiotech.com/biotech/fda-goes-agai ... tudy-finds

fiercepharma.com/pharma/fda-has-approva ... tudy-shows

edited; don't know why but the links aren't working

[KTArsenal]

Links don't work.

What's your synopsis on those dead space links?

[LWS]

CDER & ODAC (parts of the FDA) are working together. Imetelstat is a top 10 new medicine for 2024
=================

CDER plans to provide a free of charge, live webcast of the upcoming advisory committee meeting (ODAC, March 14). If there are instances where the webcast transmission is not successful, staff will work to re-establish the transmission as soon as possible. Further information regarding the webcast, including the web address for the webcast, will be made available no later than two (2) business days before the meeting in the Event Materials section of this web page.

CDER plans to post archived webcasts after the meeting, however, in cases where transmission was not successful, archived webcasts will not be available.

Contact Information
LaToya Bonner, PharmD, MBA
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Avenue
WO31-2417
Silver Spring, MD 20993-0002

Phone: 301-796-2894
Email: ODAC@fda.hhs.gov
================================
FROM CDER :

NO. 10. Imetelstat (most anticipated & important new drugs of 2024)

▶ Company: Geron
▶ Indication: Lower risk myelodysplastic syndromes (MDS)
▶ Status: PDUFA date of 16 June 2024
+++++++++++++++++++++++++++++++++++++++++++++++++
The Center for Drug Evaluation and Research (CDER) is a division of the U.S. Food and Drug Administration (FDA) that regulates over-the-counter and prescription drugs, including biological therapeutics and generic drugs . CDER evaluates new drugs before they can be sold. CDER is the lead Center for regulation of human drugs that are regulated by FDA under the authority of the Federal Food Drug and Cosmetic (FD&C) Act. Biological products are covered by the Center for Biologics Evaluation and Research

[pursang]

Links don't work.

What's your synopsis on those dead space links?

The FDA went against the recommendations of AdComm 22% of the time between 2008 and 2015.

And; The ill-fated launch of Biogen’s Alzheimer’s disease treatment Aduhelm raised many questions, including this: Why did the FDA sign off on the drug after an independent advisory committee recommended against it?