Here’s maybe why we didn’t get priority

[biopearl123]

rccola makes a strong point. All along Geron has made the point that Imetelstat could be used in the R/S negative population (75%) while Luspatercept was not effective. Anil’s presentations emphasized the same points. But here we see priority review for Luspatercept on trial for all MDS subtypes. Where effective hemoglobin rises to 1.5 gm (contrast with Imetelstat 3.6) and perhaps much less durability but if applicable would take Luspatercept to front line where we would also like to see Imetelstat. Imetelstat of course is directed to the heart of the problem, the stem cell and malignant clone and has a totally different MOA. The MOA suggests that perhaps avoiding transformation and enhancing longevity might favor Imetelstat but that is conjecture without more data. In any case one of Imetelstats strongest argument may have a dent put in it if Luspatercept is approved for all L/R MDS subtypes. Please share your thoughts.

https://ascopost.com/issues/june-10-202 ... %20alfa%2C

[kmall]

Bp - Perhaps our answer lies within one of Geron's latest hires, who has left Bristol Meyers Oncology and is now representing Geron and Imetelstat. -Kmall

[biopearl123]

I think as the dust settles and we start to get clarity, Luspatercept will probably start as first line therapy, not really a surprise, eventually therapy will fail and patients will move on to Imetelstat. They might even be used in combination, or intermittently after treatment “vacations” no data to support but Lus failures have been looked at in Geron studies. No tree grows to heaven and Lus will probably not show the durability of Imetelstat. Also intriguing is the MOA for Imetelstat which I am hoping will demonstrate a true change in the natural history of the disease. As to those on YMB talking about black boxes, the history of chemotherapy is harsh. In this case since therapy is directed toward the stem and progenitor cells, and the bone marrow is full of them of course cytopenias follow as those cells die. The good news of course is that the bone marrow (unlike from many chemo agents) is not irreversibly fried. After the malignant cells undergo apoptosis, repopulation with cells appears possible. Every hematology expert we have heard from seems to emphasize this and make the point that they know how to handle this with dose adjustments which of course is why we have heme onc specialists in the first place. Nothing is with out side effects, not even water. We have not even started to understand what is coming in AML and MF for Geron. The MDS story is but one chapter in a very long book. Very long. Very long. bp

[biopearl123]

Kmall, interesting. Durability has always been emphasized by Geron as they “differentiate” from the competition.

[rccola335]

the placebo arm showed a rise of .8 Hgb - so luspats 1.6 is not much to write home about - and it did not show efficacy in the RS- group - when Uwe Plazbecker was asked what he would use for RS- he said Luspat unless high transfusion burden patients (if I had MDS I would like a medication that could modify the disease rather than letting it smolder but that is just me) - the FDA / Big Pharma is corrupt but this goes for anything where billions and billions of dollars are involved - someone from the FDA leaked that imetelstat was not getting a priority review last week and that is why the stock price tumbled - BMY wants to delay imetelstat at long as possible to try and establish a foothold and prove itself before imetelstat can show what it has - JNJ thought imetelstat was going to be useful for AML induction ineligible back in 2018 when hiring a pricing manager - this should of had priority review and if JNJ or another BP had filed the NDA it would be getting approval this fall - someone should be ashamed of themselves

[bucbeard]

spot on rccola. thanks for sharing this.

also, side note, trying to dig around the various threads on here with no luck, but i recall someone saying that JS alluded recently (maybe at quarterly earnings call) that he was asking for patience and to understand that there are legit reasons for some cloudy things, and to essentially keep the faith.

it struck me as both cryptic and interesting.

Does any one else recall this?

[CKTC]

@biopearl123

Luspatercept received FDA priority review for its recent supplemental BLA for anemia as a first-line treatment vs. ESA’s in low/intermediate risk MDS. It did not receive priority review for its original BLA in MDS patients failing ESA’s. It did receive orphan drug and fast track designation in the initial review. So, I wouldn’t read anything negative into Geron not receiving a priority review for imetelstat in its first potential indication.

However, I would caution anyone in minimizing the potential for luspatercept to treat ring sideroblast-negative patients. The recent Phase 3 COMMANDS study showed luspatecept to be not inferior to ESA’s when treating ring sideroblast negative patients (41.0% vs 46.3%). Moreover, patients receiving luspatercept enjoyed longer response durations regardless of ring sideroblast status.

According to Dr. Garcia-Manero in the above-linked study, ring sideroblast is the more commonly occurring phenotype, not ring sideroblast negative.

[biopearl123]

CKTC, great to see you posting again. It always gives me some measure of reassurance to read and think about your thoughts. A couple of points you brought up worth revisiting. As you point out, COMMANDS 3 and IMerge are not equivalent studies, the former head to head with ESA’s the latter in patients who had failed ESA’s (and luspatercept). As to the preponderance of R/S + patients in the study, this reflects patient selection as pointed out by the author and does not apparently reflect the general distribution of subtypes in untreated patients. The hematologic effect in R/S neg patients was pretty minimial 41% vs 46% with better durability in the Lus group but still not an overwhelming effect. But your point is well taken that it should not be discounted especially if application for the additional use in R/S neg patients is what got it in front of the FDA with priority review. It was not inferior (but not stated as superior, with the disclaimer that the study was not powered to answer that question.) So to my read, even though R/S neg patients will very likely receive Luspatercept early in the treatment algorithm, the effect may turn out to be minimal. Also no evidence that Lus affects the molecular signature as Imetelstat does in many patients. So although there was non inferiority compared to ESA’s and maybe some positive effect, I am underwhelmed (except for improved durability) re Luspatercept’s effect in R/S neg patients. I agree that Luspatercept review by the FDA started out as standard and only now has received priority review. I suppose it would have take a head to head study comparison of Imetelstat and Luspatercept for it to be otherwise. What Luspatercept’s sponsors really want is to kick ESA’s off the front line and their study was designed to do that. Best Wishes, bp

[LWS]

How flexible is the timeline?

The interest in Imetelstat has never been higher, and patients' needs have never been greater. All can see this, including the FDA, EMA and MHRA.

We will hear much more about the timeline going forward. Imetelstat is a proven, unique blood cancer medicine that is effective, safe and needed now.
======================
Previous for Review:

Geron has the strong support of JNJ (staff and history) and AbbVie (TELOMERE), I believe. Imetelstat is a much better medicine than luspatercept. There seems to be overwhelming agreement about that. With such obvious comparisons publicly available (data, trials, etc.), the FDA has to recognize what best meets patients' needs in the here and now.

Imetelstat has much going for it at this point in time. The FDA cannot and will not (IMO) hide from the obvious.

The line: Conferences (ASCO, EHA), KOLs, Webinars, MD Anderson, NDA submitted, EAP, NDA accepted, timeline (continuing question). I see no more obstacles on the medical side.
========================

REMEMBER the EAP (Extended & Expanded Access Program with compassionate care). That is an interim approval to give all MDS victims (and perhaps others) access to Imetelstat before formal approval. That is now a program in motion as patients' needs are being met.

[biopearl123]

Yes, but unless the FDA chooses to approve sooner (not likely), Geron is forced to carry a very heavy financial load that will not be offset by much from EAP

[kmall]

Bp - The fact that this potentially drags out for an additional 8-10months is really misfortunate for retail investors, many of whom have endured so much up until this point. Expect another massive round of dilution for payroll, additional hiring and both ongoing and developing Clinical Trials. Disappointment doesn't begin to scratch the surface. -Kmall

[LWS]

Timeline:

This is Geron. There have been constant surprises and false starts. I don't believe the timeline is set in stone, with patients' needs the #1 priority and Imetelstat proven and ready to go. Certainly, if the plan is to dislodge long-term, retail investors, that objective probably has been met.

The questions again become:

1. Is Imetelstat as good of a blood cancer medicine as we tend to believe?
2. Is Imetelstat needed now?
3. Where are the EMA and MHRA (compared to the FDA)?
4. How flexible can the timeline be?
5. What is John Scarlett's thinking (partners, buyout, etc.)?
==================

From bp --- Yes, but unless the FDA chooses to approve sooner (not likely), Geron is forced to carry a very heavy financial load that will not be offset by much from EAP
=================
The line of evidence: Conferences (ASCO, EHA), KOLs, Webinars, MD Anderson, NDA submitted, EAP, NDA accepted, timeline (continuing question). I see no more obstacles on the medical side.
========================
REMEMBER the EAP (Extended & Expanded Access Program with compassionate care). That is an interim approval to give all MDS victims (and perhaps others) access to Imetelstat before formal approval. That is now a program in motion as patients' needs are being met.
========================

[biopearl123]

Kmall, I have to agree. I quick look back to as recently as the June presentation did not guide the delay in MF study (but we knew it anyway and so did they) and also guided something like “ready for launch” in early 2024. These two misrepresentations alone are barf worthy. If they are really planning to be ready for launch in early 2024 they should be selling drug the day after approval in June 2024. Perhaps the FDA with have a “road to Damascus” moment once they see the R/S negative data from Luspatercept. But unless they approve Imetelstat before June 2024 it will be clear the scales have not fallen from their eyes. This places enormous financial burden on Geron and will as you speculate likely lead to additional delays. There will certainly be dilution in spite of the optimistic guidance. We have seen that before. Another misrepresentation. (We have enough money to last into the universe and beyond!!”) The FDA places such a terrible burden on this small biotech and then everyone wonders why investors are trying to reclaim their losses as company debt piles up. Totally unnecessary. I bet the FDA has all the information necessary to approve or disapprove right now with the exception of the ADCOM. The application is complete, the data is there. Just sitting there. You can be sure the experts that would sit on the ADCOM would be on a plane today for an FDA meeting if it would bring this agent to their patients sooner. The FDA bureaucracy makes this impossible. Imagine approval is now almost another year away. That’s a lot of horses in the Geron starting gate just pawing the ground ready to run (and drawing a paycheck). Dr. Scarlett indicated the the view from inside the FDA was favorable and they wanted to approve the drug. But standard review (regardless of the fact that Luspatercept also got a standard review—so what?) conveys a message that this drug goes on a shelf with lots of other available treatments and does not show the distinct advantage that priority review conveys. If the FDA wishes to convey that message then it is at variance with that of Geron. One of them is wrong, right? bp

[kmall]

Bp - It does raise concerns that Geron has been in constant communication with the FDA over the past several years, and up until the most recent company projections Geron was expecting approval by the end of 2023, or there abouts. How did they miscalculate this event while periodically reviewing and submitting data with the FDA for as long as they have claimed to be doing so? And as in typical Geron fashion, yet another company blunder shrouded in mystery??? -Kmall

[LWS]

Timeline---standard, priority, flexible:

The line of evidence: Conferences (ASCO, EHA), KOLs, Webinars, MD Anderson, NDA submitted, EAP, NDA accepted, timeline (continuing question). I see no more obstacles on the medical side.

=============================================================================
Kmall---The timeline has always been a question and now seems to be the final hurdle. With completed trials, Geron's carefulness, EAP supplementary results (coming), the data seems overwhelmingly positive. I do not know what the FDA (or the EMA and the UK group) are thinking. I see no reason for rejection, and every reason for approval of the NDA, post-haste.

Patients' lives do matter. The FDA is suppose to put patients' unmet needs first. Perhaps they want to see the EAP results on a full range of patients from the sickest to those with early symptoms.

Strong, deep-pocketed, partners in the wings?

[kmall]

LWS - Actually the "timeline" for expected approval has been forecasted by Geron the past 2yrs or so in company conference calls and events as being the end of 2023, the latest in the first quarter of 2024. And that last part I'm fairly certain I'm incorrect about, I'm just being conservative. Pretty certain they were hanging their hat on commercial rollout by Q1 2024. Having constant dialogue with the FDA these past 3-4yrs, this shouldn't have been an unforseen circumstance during latest company projections. As investors we were led to believe everything was on track as expected. Once again in Geron fashion, pushing those goal posts out even further. -Kmall

[LWS]

Kmall --- I will try to answer my own questions.

1. That is what the FDA is trying to determine. They do not want to make any mistakes with a unique medicine that has vast potential.
2. Yes
3. Hopefully up to speed.
4. Seems to me that the FDA can choose any timeline that seems appropriate. Couple with EAP.
5. I believe there will be important partners soon.

======================
Previous:

The questions again become:

1. Is Imetelstat as good of a blood cancer medicine as we tend to believe?
2. Is Imetelstat needed now?
3. Where are the EMA and MHRA (compared to the FDA)?
4. How flexible can the timeline be?
5. What is John Scarlett's thinking (partners, buyout, etc.)?
==================

[jayfish101]

I still have some hope (irrational?) that the Advisory Committee will recommend priorty or quick approval process. Just maybe FDA needs more support from the troops to help them do what is right.
I noticed that a second Oncology Advisory committee meeting now appears in the agenda, about a week after the first. Still no mention of Geron thoug. So, I guess they can meet more often than four times a year.

[kmall]

LWS and Jayfish - In theory, the FDA can do whatever ever they want...... anyone here remember COVID and all of the vaccinations rubber-stamped over night?

I'd love to think this may be the case here as well, but with Geron's history, expect a decision sometime next June. -Kmall

[LWS]

Time & Timelines:

The line of evidence: Conferences (ASCO, EHA), KOLs, Webinars, MD Anderson, NDA submitted, EAP, NDA accepted, timeline (continuing question). I see no more obstacles on the medical side.

==========================================================================
Time is of the essence, when it comes to patients' lives. As I see it, it is a matter of time before Geron's NDA is approved for Imetelstat. I understand Kmall's pessimism (this is Geron with a history). However, IMO, the COVID example is more likely to apply (rubber-stamped over night).

I believe that the data is overwhelming. Imetelstat is already a proven, effective, good blood cancer medicine. The question in my mind is: Will further testing and trials change "good" to "outstanding" or, hopefully, to miracle?

Patients' unmet medical needs are the most important factors here. The FDA knows that, as well as the EMA and MHRA in the UK.

==========================================================================

LWS and Jayfish - In theory, the FDA can do whatever ever they want...... anyone here remember COVID and all of the vaccinations rubber-stamped over night?

I'd love to think this may be the case here as well, but with Geron's history, expect a decision sometime next June. -Kmall