Basis for Approval....

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Hoosier Investor
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Joined: Thu Jun 18, 2020 5:48 pm

Basis for Approval....

Post by Hoosier Investor » Wed May 22, 2024 5:13 am

A summary of my thoughts/observations as we head into the home stretch. Based on the clinical trial results & treatment considerations, it seems likely the FDA will approve Imetelstat as a treatment for LR-MDS patients who are post-ESA treatment.

* FDA granted Fast Track Designation (2017) for LR-MDS
* P2 Trial results were promising
* P3 Trial design was approved by FDA
* P3 Trial results mirrored the P2 trial results
    - Primary & Secondary Outcomes were met (per 2018 IWG)
    - Significant hemoglobin increases in 8-wk TI patients (3.6 g/dL)
    - SAEs are manageable and mostly reversible
- ~80% of patients had a transfusion burden > 4 units / 8 weeks
* FDA granted EAP status following P3 Trial
    - EAP resulted in Speakers #3 and #9 (both had failed Luspatercept)
* ODAC vote of 12-2 in favor of Imetelstat Benefit > Risk
    - Including 100% of heme physicians 
    - Including the patient advocate 
* There are multiple P3 patients who have been TI for > 1 year
* There's at least one P3 patient who has been TI for ~4 years
* Institutional ownership up to 76%
* Short percentage is at ~10% 
    - Short % was >40% going into the 2018 continuation decision
* Unmet Need Remains in LR-MDS
    - Luspatercept hasn't resolved the treatment need
    - Imetelstat may be superior to Luspatercept albeit with more SAEs
- Imetelstat and Luspatercept are both needed for LR-MDS market
* Geron has been in discussions with FDA since the ODAC
* Geron continues to hire in preparation for FDA approval & commercial launch
* Geron filled key sales positions quickly with experienced staff

biopearl123
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Re: Basis for Approval....

Post by biopearl123 » Wed May 22, 2024 7:53 am

Great summary HI, thank you.

kmall
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Re: Basis for Approval....

Post by kmall » Wed May 22, 2024 1:53 pm

Great post Hoosier......but what a complete joke Fast Track Designation is......we're going on SEVEN years.....good thing they "designated" the fast lane on this one.....seems like we were duped into the breakdown lane. -Kmall

huntingonthebluffs
Posts: 260
Joined: Wed Feb 24, 2016 12:00 am

Re: Basis for Approval....

Post by huntingonthebluffs » Wed May 22, 2024 8:30 pm

Great summary Hoosier Investor of reasons the FDA should approve.

For those of us who still suffer from positive confirmation bias and have outsized expectations and investments, I think it would be appropriate if we also had a reference summary of reasons the FDA won’t approve.

I personally am struggling to see how the FDA can just disregard their logic and rationale used in their ODAC presentations. While to most of us, the FDA appears to be totally out of touch with how to interpret facts and statistics and to some of us, likely dishonest in their judgment and intent, they are still the FDA and they will decide not the ODAC voters.

In addition, while this board may not be the appropriate place, if anyone has suggestions on how one could / should hedge outsized stock positions, I think some of us would find it useful to review alternatives other members find helpful, given concerns as we roll towards June 16th.

lacour_98
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Re: Basis for Approval....

Post by lacour_98 » Wed May 22, 2024 8:46 pm

One way may to buy Protective Put Options to limit your losses should the FDA not approve or takes action the investment community views unfavorably. You pay the premium and have the right to sell the stock at the strike price. Should the stock price fall below the strike price, you exercise your option to sell the stock. If the stock price increases because of FDA approval, you let the Options expire and you're only out the premium you paid. Get with your broker to review this possibility and maybe others.

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

Re: Basis for Approval....

Post by biopearl123 » Wed May 22, 2024 11:13 pm

Hunt and Lacour, (and others), implicit in your comments in the indelible memory of the serious twisting of the shorts (sartorial shorts that is) that occurred in 2018. The memory of the scramble to get emergency loans not to mention emergency therapy feels like yesterday so I can’t blame you for wanting to hedge your bets, and also to consider what negatives might temper approval, it’s probably sensible. But there are a few differences to consider, and allow me append a few comments to HI excellent summary. The Janssen debacle was a failed partnership with one company. I think looking at what has changed in the last 6 years helps with perspective. For one thing Geron has spent a whole lot more money, but they were able to raise it because investors still believed. That money went into development of impressive data, development of a first tier management team, development of a manufacturing pipeline, development of a substantial sales force (I think that’s where the last cloaked incentives went), that was just not present six years ago. And yes a whole lot more risk for a stand alone company with no partner, for a potential much bigger return. JS said it best, fortune favors the bold (actually it was said by an ancient philosopher, oh wait he is one!.) We are looking at an entirely new drug class. An exciting one. We saw overwhelming support from experts and patients that just can not be ignored (except by the two under informed luddites that voted against.) Yes the all powerful FDA is capable of wreaking destruction on Geron and dashing the hopeful expectations of the thousands of patients who can benefit. The FDA can manufacture reasons to not approve but if they do it will only underscore their failure to understand the reasons for the cytopenias and the appropriate management of such. I would only show a disregard and disrespect for those experts who know the most and have the most experience. It could happen. But it won’t. We have to give the FDA some credit here. They have put Geron and Imetelstat through a long exacting evaluation and we have to have some faith in this institution. It’s no about a failed partnership anymore. It’s about what will be the first step in an approval process that makes this drug available world wide. Geron is saving their PR for EHA. There will certainly be internet conferences on the day of or day after approval. The stock will react accordingly, black box or no. Forgive Janssen, forget Janssen, f…oh,( I can’t say that here, it will never get past the moderator.) Maybe they will be back, who needs them? Best wishes to all, keep the faith. Shalom. bp

lacour_98
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Re: Basis for Approval....

Post by lacour_98 » Wed May 22, 2024 11:30 pm

BP, I whole-heartedly agree with your assessment. I've been following Geron too long to abandon ship now as I've always believed in the expanding opportunities for IMET to treat blood cancer disorders. So, I'm not going anywhere, just looking forward to June 14 or maybe earlier.

Ryan
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Re: Basis for Approval....

Post by Ryan » Fri May 24, 2024 5:18 am

Three weeks to go. It’s almost unbelievable. Soon we’ll be able to count the days on our fingers and toes. Unbelievable.

Quote of the year, or maybe the decade, buried in BPs paragraph up there:
“It (FDA rejection of marketing authorization) could happen. But it won’t.”

LWS
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Re: Basis for Approval....

Post by LWS » Fri May 24, 2024 4:02 pm

Fear of a Confused FDA

The FDA is the problem. Has the FDA been corrupted in some way? That has been the #1 worry every since the ODAC meeting (March 14th), where they took the "devil's advocates" approach to Imetelstat as the first speakers (refuted by the ODAC committee (12 yes votes) and other blood cancer experts). Medically, Imetelstat needs to be approved (patients' needs now and a building block for better treatments going forward).

===================
Quote of the year, or maybe the decade, buried in BPs paragraph up there:
“It (FDA rejection of marketing authorization) could happen. But it won’t.”
--- from Ryan

huntingonthebluffs
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Re: Basis for Approval....

Post by huntingonthebluffs » Fri May 24, 2024 7:31 pm

I, in no way agree with the validity or importance of these points and were refuted by various ODAC members. I do believe we will see approval, agree with the reasons above and I remain heavily invested.

However I believe these points were included in the FDA presentation and could impact approval unless their internal assessment process changes how they interpret the data. IMO all one needs to do to understand the correct interpretation of the data is to review the Geron presentation.

Here is a list of some of the FDA points I remember:

1. Inadequate population in P3 sourced from the US (8/178).

2. High percentage of patients with grade 3-4 cytopenias (75%+). Presents a challenging treatment regimen for both doctors and patients.

3. 60% of patients did not achieve 8 weeks TI but still had to experience grade 3-4 cytopenias of Imetelstat.

4. Medical events average higher for patients treated with Imetelstat. Questionable benefit vs cost ratio.

5. No available bio markers to identify the 40% of patients who are likely to achieve TI.

6. On average across all 118 patients treated with Imetelstat, hemoglobin improvement of 1.5 was similar to patients receiving placebo.

7. Can not confirm disease modification potential of Imetelstat, OS improvement and no CR/PRS.

biopearl123
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Re: Basis for Approval....

Post by biopearl123 » Fri May 24, 2024 9:07 pm

Hunt without trying to rebut or refute point by point, the FDA written presentation was posted prior to Geron’s responses which we have discussed in detail previously. I think its worth revisiting whether you think understanding the drug and the data is a process or can only be seen through the rigid lens of what in part was shown skillfully to the FDA by Geron and world class experts, to be based on misunderstanding and interpretation and the use of outdated obsolete standards. The fact is the FDA did not use updated IWG standards in their initial written and oral presentation. Geron and Geron experts were able to refute and perhaps even enlighten the FDA. It is worth asking if the self same position paper the FDA submitted at the beginning of this process, pre ODAC meeting would look the same afterwards. The purpose of the FDA convocation of the ODAC was to do precisely that, to look at each objection carefully with the charge to recommend whether the benefits outweighed the risks. If one only had the FDA pre meeting notes they probably would have run for the hills. (And those that did, probably did.) If one had studied the data and the presentations as we and you yourself have here, they at least would have said wait for the counter arguments, something is not right with the FDA position paper. CKTC really helped provide stability by making the point about using the updated IWG criterion. Geron made their points by making true experts familiar with the disease and the drug available to the FDA for the purpose of educating them. I have been an “expert witness” in some legal cases. My role was simple: to educate. Education is a process by which we understand a subject in a different, hopefully more complete and layered, nuanced manner. To say the FDA is immovable and the initial stance could not possibly take into consideration the recommendation of the ODAC negates the value of the ODAC in the first place. I just don’t think that will happen at this point. This is my opinion alone but I believe education is a process that requires looking all all arguments, all data from as many vantage points as possible. It requires asking for advice from experts. The FDA did that, you have to credit them that. Where they end up will surely not be where they started and it could be argued that the points you have made here (for the purposes of discussion) is exactly where they started. Keep the faith. bp

Hoosier Investor
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Re: Basis for Approval....

Post by Hoosier Investor » Sat May 25, 2024 12:03 am

I can’t point you to the exact time stamp, but there was a point during the ODAC when Dr. Feller clarified that the P3 trial allowed for the use of the 2018 IWG criteria. The statement was crystal clear, and there was no rebuttal from the FDA personnel. The statement came across as gospel based on the clarity & confidence of Dr. Feller’s statement. The FDA’s silence seemed to either be in acknowledgment of, or in surprise to new information they weren’t aware about.

Either way, I have no doubt (based on her statement) that the P3 trial allowed for the use of the 2018 criteria.

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

Re: Basis for Approval....

Post by Ryan » Sat May 25, 2024 12:34 am

Again I ask, why is this #1 ?

Inadequate population in P3 sourced from the US (8/178).

It’s a bigoted argument I believe. The days of eugenics are over.

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

Re: Basis for Approval....

Post by biopearl123 » Sat May 25, 2024 1:18 am

HI, I think that was an Aha! Moment even for the FDA, especially when it was part of a pre specified protocol, I think they missed it thinking it was not and may have even been a little embarrassed. Hence the awkward moment that followed. Geron graciously did not rub their nose in it (wisely). Where the importance comes in, is that even though the focus is on the very high bar of extended TI which Geron has reached in a substantial number of patients, using the most recent IWG criterion (and leading the way to further modification of the IWG criterion), the astounding hemodynamic improvement (HI) comes into the spotlight. While HI patients did not necessarily reach TI they did have a substantial improvement in hemoglobin, something like 65-70% of patients. So if your transfusion requirement halved, you save a lot of transfusions but might not reach transfusion independence. An important moment in the presentation to the FDA to be sure. Thanks for highlighting it. bp

Hoosier Investor
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Re: Basis for Approval....

Post by Hoosier Investor » Sat May 25, 2024 2:06 am

Use of the 2018 IWG is the only way we get any extra (deserved) credit for enrolling a sicker patient population.

I’m not 100 percent sure, but I believe the Luspatercept trial allowed patients down to 2 units per 8 week period. Our trial started at 4 units/ 8 weeks, and we enrolled multiple patients over 8 units. Our highest patient was 14 units as I recall.

No chance in hell a 14 unit patient is going to reach TI status within 8 weeks. Should we be penalized when they come down to a more reasonable number, but don’t make it to zero? That’s how the 2006 criteria would score it (my understanding).

Imagine what our TI rate would’ve been if we had steered the enrollment to patients in the 2-6 units/ 8 week range.

LWS
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Joined: Thu Jul 14, 2016 2:00 am

Re: Basis for Approval....

Post by LWS » Sat May 25, 2024 6:46 pm


Perhaps this Special Report will add some clarity to the IWG's (International Working Group) efforts. I see some familiar names.


https://ashpublications.org/blood/artic ... atological
==================
SPECIAL REPORT| MARCH 7, 2019

Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials
Clinical Trials & Observations

U. Platzbecker,
P. Fenaux, L. Adès, A. Giagounidis, V. Santini, A. A. van de Loosdrecht, D. Bowen, T. de Witte, G. Garcia-Manero, E. Hellström-Lindberg, U. Germing, R. Stauder, L. Malcovati, Mikkael A. Sekeres, David P. Steensma, S. Gloaguen

Proposals for revised IWG 2018 hematological response criteria in patients with MDS included in clinical trials | Blood | American Society of Hematology (ashpublications.org)

Abstract

The heterogeneity of myelodysplastic syndromes (MDSs) has made evaluating patient response to treatment challenging. In 2006, the International Working Group (IWG) proposed a revision to previously published standardized response criteria (IWG 2000) for uniformly evaluating clinical responses in MDSs. These IWG 2006 criteria have been used prospectively in many clinical trials in MDSs, but proved challenging in several of them, especially for the evaluation of erythroid response. In this report, we provide rationale for modifications (IWG 2018) of these recommendations, mainly for “hematological improvement” criteria used for lower-risk MDSs, based on recent practical and reported experience in clinical trials. Most suggestions relate to erythroid response assessment, which are refined in an overall more stringent manner. Two major proposed changes are the differentiation between “procedures” and “criteria” for hematologic improvement–erythroid assessment and a new categorization of transfusion-burden subgroups.



huntingonthebluffs
Posts: 260
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Re: Basis for Approval....

Post by huntingonthebluffs » Mon May 27, 2024 1:48 am

Thanks biopearl123 for all you do and contribute to this board. Including,of course, always being the adult and taking the high road and having substantial insight and understanding of these processes to balance our rants.

You are right regarding the mark 9/2018 made on many of us. At this juncture, we carry it like more of a badge of honor to go along with our PTSD. I personally have not hedged any thing to the upside or downside. Not sure there is an effective way to do that for outsized positions other than selling enough to recoup our costs and just play with house money or maybe consider a set of option strategies but at potentially significant cost.

Anyway all things considered, I believe the FDA has repeatedly acted dishonorably at a minimum. While a lot has changed at Geron and in regard to CTs over the last 6 years as you noted, I personally still believe the FDA continues to act dishonorably as demonstrated at the ODAC. I do agree that understanding the drug and the data is a process, however hasn’t the FDA has had the same ten years we have had for the process of education and analysis to update their thinking? Why do we get it along with Geron, the KOLs and the patients while the FDA continues to miss it. Maybe the ODAC will finally be the straw that breaks the camel’s back? I hope so, it is time!

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