ImetelChat

Hi Kmall, have been thinking about your potential timeline to MA in Europe of 67 days. The problem I have is how that could possibly reconcile with enrollment in the ongoing PIII in MDS? If early MA were granted (in my view this is a stretch), the MDS study would not be fully enrolled and patients would lose any incentive to be part of the ongoing study. At this point the study is not even enrolled at the halfway point, meaning that approximately less than half of the 55 control patients would be enrolled at this point. Given the option of receiving an approved drug or risking enrollment in the control arm, it seems that most or all patients would opt for the former. While this might be a nice problem for Geron to face, it would mean enrollment would only continue in the US (or non EU sites), a contradiction to the added international study sites. For this reason alone I somehow think MA would have to follow full study enrollment and at that, still risk patient drop out once the drug were approved to ensure that they actually received drug. CKTC has made a strong point that we will be waiting for top line data in 2022 with little or no chance for earlier status change, at least in the US. I had hoped that perhaps a data safety monitoring committee might insist on earlier analysis if the data warranted but there does not seem to be a provision for an early look the way there is in the proposed MF study. Maybe the EU feels that already have adequate data from the PII study for MA but if so this does not appear to be reflected in the additional study sites added by Geron (unless they are exclusively outside of the EU which I suppose could be possible.) All thoughts welcome and this area seems worth exploring further. Best Regards, bp

67 days for MA is after it is recommended which I think they have around 200 days after applying for it for the committee to recommend

also they state before they do MA they consult with the FDA and the Japanese regulatory commission - "in some cases for example when a medicine is intended to treat a life threatening disease for which there is no satisfactory treatment or if the disease targeted is very rare, EMA can recommend Market Authorization on the basis of less complete or limited evidence on the medicine , provided that further evidence is provided at a later stage" this is from the EMA website - they will consult experts in the field to help with the decision - European docs are different cats - they are the type to like telomerase inhibition and may push for its open use - the added sites are likely due to interest from docs wanting to use after seeing the stellar data
-do I think we are getting early MA? possible but not in 67 days - it doesn't take long for subjects to ring the bell at 8 weeks TI - the year long TI is fantastic but I think they can turn it loose with good 8 week numbers and follow it from there

Completely agree that, while it presents an interesting line of thought, it is just conjecture and highly unlikely at best.

Here is what the company states - data from MDS PIII in 2022. And yes they added sites to meet the timing goal, which is good news, as their “Covid update” pointed to potential delays in data release.

I’ll presume that those who want to believe in this hypothesis are looking for stock appreciation to suspend their disbelief - I’ll say that the stock can certainly appreciate, and appreciate substantially, during the ‘data desert’ of a Phase III. Using the metaphor, there are many different types of desert - just in CA there is the splendor of Joshua Tree just 100 miles or so from the completely baron Death Valley - and a Phase II data desert is much different than a Phase III.
- I’ll take the top-of-the-line institutional investors who just plowed more than nine-figures into Geron a as supporting info for that statement.

biopearI123, think this is a very good discussion to have. I really like and appreciate this thread. This could also be expanded into other considerations given an MA from any entity not just the EMA although it seems obvious that the regulatory agencies work together and try to stay in sync and probably have some protocol / precedent for letting the FDA lead the way for a USA company.

kmall has again provoked some serious thought by stringing together the information provided by JS/Geron over the last year and change along with KOL’s, regulators, competition etc. I do think rccola335 has made some interesting counters on the schedule impact of the 67 days to MA being “after it is recommended” as well as the possibility of differences in the EU vs USA doctor perspective playing into the MA decisions. I also think the opportunity to reduce RBC transfusion demands could play a more significant role in the EU’s desire for MA as hopefully they are able to overcome “some” of the political/competitive FDA baggage toted in the US. Regardless, JS and Geron are committed to the top line in 2022, however much data is available and will be added to over the several months ahead and plans can change. And to Ryan’s point, I think we all know that JS is preparing for many exciting possibilities that have decent probabilities of happening prior to 2022 as this plays out.

To the discussion of MA and the CT cohabitating, I have some but very limited experience on how most patients might respond to MA drug availability versus choosing the ongoing P3 MDS CT. However, if Geron needed, could and wanted to stay focused on both ramping up MA as well as continuing the CT in the EU, I would think there would be patient interest and availability in CT participation even with the possibility of the patient drawing the short straw and being given a placebo.

In the US at least, cost is a major issue for patients and insurance does not come close to mitigating the Impact to patient financial challenges. I think generally, drug costs for patients participating in a CT are minimal, please explain if I am missing something there. Given that reduced costs are key for many patients, once the drug is MA’ed, or the CT ends, patients with limited financial means do need to stop that treatment so where is the risk of getting drawn for a placebo. I have no idea how that works in the EU but I doubt socialized medicine eliminates the cost issue entirely. Maybe someone could and would be interested in explaining how that might play out in the EU.

In addition, if a medical institution is focused on both treatment and research, I believe their doctors will offer the CT (albeit on a more selective basis) as an option for patients wanting more focused / expanded access to medical care and Imetelstat. However, again I believe the matter of being selected to receive a placebo would need to have an option to switch over to Imetelstat in a reasonably short period based on results as a patient incentive for some to join the CT versus choosing the MA’ed drug option assuming patient finances are not an issue.

Also, if a doctor, not part of a medical institution participating in the CT, understands the personal side issues for a patient including cost, etc., I believe they would consider recommending the CT as a means to receive treatment.

Lastly, participating in a CT appears to have advantages associated with more focused / expanded care and treatment for the patient and less liability for the doctor. I realize liability comes in many sizes and flavors given our expansive legal system but that spreads across several entities in a CT. In many cases, I think these considerations could be of interest to patients, doctors and their associated medical facilities even with the placebo being a possibility.

the main reason i am willing to consider MA a possibility is because one thing I have learned is the system is totally corrupt - when this article came out I scratched my head - you know the only way GERN will surpass 10.00 a share by January 2021 is some type of approval - then when the accouncement for OD came out which has the small possibility of MA it made sense
https://finance.yahoo.com/news/implied- ... 12401.html

so the European commission met on June 18th (where they decided to recommend OD) which was released to the public on June 25 and a Geron PR on July 1 - June 19th yahoo writes an article that on the 19th there was a surge in 10 dollar call options for Jan 15th
-we aren't stupid - someone got inside info which gave them the impression that there was a possibility of approval before the end of the year and bought all those options

Thank you all for a very intriguing thread. The initial post which the link for the 67 day EMA OD to approval or MA (Market Authorization) appeared, centered on my thoughts concerning the CD J&J/Geron breakdown and how I believed it was a business rift between the two rather than J&J having only a partial snapshot on the science or efficiency of Imet up until that point as many believe. Lining up events leading up to that decision and those since I tried to lay out a thesis as to why I felt business was more to blame. The IMbark P2 CT patients enrolled on a “rolling basis” seemed more in line with what I had envisioned – and thankfully more precisely described by Bp in a reply to that hypothesis. A mere months’ time appeared razor thin in the scope of things and the chain of events to follow felt more in line with a deal gone sour. In the end I know as much as anyone else on these boards, and you know what they say about opinions.

While researching the EMA OD to approval timeline I came across this link-

https://www.ema.europa.eu/en/from-lab-t ... #read-more

“Who grants EU-wide marketing authorisation?

EMA is a scientific body with the expertise required to assess the benefits and risks of medicines. However, under EU law it has no authority to actually permit marketing in the different EU countries. The role of EMA is to make a recommendation to the European Commission which then takes a final legally binding decision on whether the medicine can be marketed in the EU. This decision is issued within 67 days of receipt of EMA’s recommendation. The Commission is thus the authorising body for all centrally-authorised products.
Commission decisions are published in the Union Register of medicinal products for human use.”

The investor in me would be ecstatic if 67 days was a possibility. As a realist, it’s a very long shot. rccola335 had pointed out the 200-day application post recommendation and this link is confirmation –

https://en.wikipedia.org/wiki/European_Medicines_Agency

“Comparison with other regulatory agencies -
The EMA is roughly parallel to the drug part of the U.S. Food and Drug Administration (FDA),[31] but without centralisation.[32] The timetable for product approval via the EMA's centralised procedure of 210 days compares well with the average of 500 days taken by the FDA to evaluate a product.”[33]

BTW rccola335 excellent points on the EMA approval process in general and nice work on the Jan 15, 2021 $10.00 calls being tied to a “leak” around June 18, 2020. It seems as if it’s safe to say that this ongoing info leak is from under the Geron roof. Another post altogether. Love to read some thoughts and timelines on that topic.

The CT / MA patient contrast points with regards to financial burden, insurance, etc; placed on patients by Huntingonthebluffs were eye opening and an entirely new angle on the situation with regards to those enrolled in CT’s. A thread like this just goes to show how invaluable this board is. One thought or idea has the capability of spawning many more. I for one feel fortunate by being able to contribute with those whose enthusiasm and knowledge seek a positive path forward for this drug and company.

Expounding on some points in Huntingonthebluffs reply, hopefully the European Commission takes into consideration –

- Subsidized Healthcare – most EU nations would benefit from cost/patient with regards to Ti burden reductions

- Covid strain on Global Blood Supply – Andrew-bp has pointed out on numerous occasions in MDS patients alone how Imetelstat would help alleviate an already stressed supply

- Unmet need / rare disease – OD already in place and should weigh in favor here

- Increasing patient population – several factors come into play, including: overall aging population, pollution, unregistered and misdiagnosed amongst them

- Lower median patient age in less developed countries – although not as drastic as other parts of the world (Asia / Africa / S. America), Eastern Europe has seen a dramatic rise in MDS patients with a lower median age


One more link I found of interest is this Oct 2019 abstract that highlights the differences in FDA vs EMA Cancer Orphan Drug Designation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797305/

“Application of orphan drug designation to cancer treatments (2008–2017): a comprehensive and comparative analysis of the USA and EU”
Kerstin Noëlle Vokinger 1,2,3 and Aaron S Kesselheim3

Good News –

- “The FDA approved 135 cancer drugs with orphan indications that met our inclusion criteria, of which 101 (75%) were also approved by the EMA. 80/101 (79%) were first approved in the USA. Only 41/101 (41%) also received orphan designation by the EMA.”

- “Drugs receiving designations in both settings were more likely to focus on truly rare cancers, such as multiple myeloma or follicular lymphoma.”

- “out of those approved cancer drugs that received orphan designation by both agencies, 20% (8/41) were indicated for solid, and 80% (33/41) for non-solid tumours.”

- “For non-solid tumours, multiple myeloma (eight indications), chronic lymphocytic lymphoma (eight indications) and acute lymphocytic lymphoma (four indications) were the most frequently approved cancer drug indications with orphan designation (figure 4).”

- “Among the 101 cancer indications that were designated with orphan drug status by the FDA and also approved by the EMA, 46 were approved for first-line therapy while 55 were indicated for second-line, third-line or fourth-line therapy.”

- “Less than 50% of cancer drugs with orphan designation by the FDA received such status in the EMA. Our results are consistent with other studies showing that the USA has more orphan drug designations in general and specifically for oncology drugs compared with the EU.21 27 28


- "One important reason for the different application of ‘orphan status’ in the USA and the EU could be the different legal prerequisites for orphan designation. The demonstration of ‘significant benefit’ is mandatory for drugs to be designated with orphan status by the EMA compared with those drugs already on the market targeting the same disease.15 34 36 ‘Significant benefit’ means that a drug has a clinically relevant advantage or makes a major contribution to patients’ care, compared with existing drugs already on the market that target the same condition.33 37 Significant benefit is a higher standard than the positive benefit-risk assessment that must be demonstrated by the sponsor in the marketing approval process, which does not involve an obligation to show that such a drug is more beneficial than all other methods for treating the same condition.19 Significant benefit is required at the time of orphan designation, when it can be supported by preclinical studies, and at the time of marketing approval, when clinical data are needed.36"

- “global spending on orphan-designated drugs will reach $178 billion per year by 2020, much of which will also be drugs for cancer patients.8”

Not so Good News –

- “Orphan designation was intended to encourage drug development for rare conditions. This study shows that the FDA approves more cancer drugs with such designations compared with the EMA, especially for subgroups of more prevalent cancers. One reason for the difference could be that the European Union requires demonstration of significant benefit for drugs that target the same indication as a drug already on the market to earn the orphan designation.”

With regards to posting on this company and drug I liken it to wildly swinging at a piñata while blindfolded…….usually you’re swinging at air; but every once and a while you get a good crack at that sucker and the candy comes raining down. Shout out metaphor for you Ryan! Thanks again to all who make this forum what it is. All the best. -Kmall

^ I do like that analogy!

Today is a very small microcosm of what I mean about stock appreciation in a Phase III data desert - in this case, the 'news' (more of a factoid) is that big institutions have shown their cards with filings - and the stock moves. I expect many more of these 'non-news' surges over the next 2 years...

Kmall, your not so good news scenario might not be so bad. We know for sure the FDA is not going to approve until they see PIII data. (Their recommendation for yet another low dose arm in the MF study is infuriating and suggests they haven't been paying attention.) But we don't know about the EU. Its still not impossible that the EU might give the PII data in either or both studies careful evaluation in light of the glaring unmet medical need. Dr. Scarlett's emphasis on manufacturing with an eye toward commercialization remains intriguing. If the timeline is really 2023 for US approval does it really take three years for commercial validation? This especially for a drug that already had its manufacturing methods subjected to the quality control of the likes of Janssen. We know much of the supply line and manufacturing facilities Janssen established and standardized carried over to Geron when they took over. So I have to ask is three years from now a little generous in setting up and validating an already established manufacturing process.?

"Kmall, your not so good news scenario might not be so bad. We know for sure the FDA is not going to approve until they see PIII data. (Their recommendation for yet another low dose arm in the MF study is infuriating and suggests they haven't been paying attention.)"

Another theory - please review the following and advise.
Hypothesis: FDA likes what they see, and they may be internally thinking of conditional approval based on comprehensive P2 data + RWD. However, they want confirmatory trial in P3 and given that there is more time available for the confirmatory trial, they want to explore one more dose. After all, given the approval, there is less pressure on timelines, and the new arm recommended by the FDA will have the drug being given to the patients anyway.

Thoughts? Of course, I am not an expert on FDA regulatory options.

Hi Ashah, Geron has already and correctly I think, rejected the FDA suggestion for a low dose arm as part of the PIII MF study as redundant, unnecessarily costly and of little contributory value in light of what is already known. This is especially relevant since the experts have a good handle on how to deal with dose related side effects so the 9.4 mg/kg dose should be set up to show the maximum OS effect the study is designed for with out the distraction of a lower dose that would likely show a present but lesser effect on MOS and to what end? I think Geron realized whoever was on the other end of this well meaning but pointless suggestion was a bureaucrat straight from the good hearts that reside at the department of redundancy department. It would cost money and lead to the conclusion that the higher dose arm was the right way to go. With regard to the FDA Suddenly moving toward conditional approval, CKTC and made a very convincing argument that based on the guidance from the last end of PII study meeting that its all about PIII and nothing happens until there is new data. This is spite of my nudging toward hoping the FDA would take a more conditional approach The studies are strictly outlined and it does not look like much could break them open except prearranged data analysis point. These will not be approached in a frivilous manner, just too much riding on the data. So at least for me, I have come to accept data in MDS as guided for early 2023 and the potential for a "early look" at the MF data as outlined depending on death rates in the control arm. In any case "conditional approval from the FDA is probably impossible but the EU has yet to speak and does look favorable on a small number of orphan drugs that unmet medical need. Even with Lus approved, this drug only addresses some 15 % of lower risk patients +RS mostly, these patients are a small fraction of the potentially treatable patients so the orphan restrictions raised by Kmall should not apply. I might have to edit this in the AM, eyes at half mast. Ashah, in short even thought we would like it to be othewise the FDA will make Geron run out the clock with a fully enrolled set of studies. (But a provision for an early look in MF--still takes us to 2024. Since the EU has not yet to made a definitive statement re MA we should wait and hope and be prepared for disappointment should it come. So many of the influential KOLs are from Europe, lets hope they can make a convincing case. Be well, bp

Hi Andrew,
This is one of those threads that seems to snowball into an avalanche of thoughts and queries, many of which are far out of my realm of understanding ( approval, regulatory and clinical trial process, etc. ) so many thanks to all of those contributing here.

With regards to my last posting in this thread and the "Not so good news" excerpt, on reflection I do agree that it actually bodes well for our current situation. The not so good part I was originally contemplating was that the "FDA approves more cancer drugs with such designations compared with the EMA" - as you know for the last several months I have honed in on EMA approval being Gerons primary target at this point, especially given the hiring of Sharon McBain and the constant wording of Ex-Us partnership for commercialization in many of their PR's over the course of the past 18 months or so. However, that last bit of that excerpt - "One reason for the difference could be that the European Union requires demonstration of SIGNIFICANT BENEFIT for drugs that target the SAME indication as a drug ALREADY on the market to earn the orphan designation."
- may as you pointed out be one of the strongest points for an EMA approval - and perhaps an expedited one at that. As we all know Imetelstats most recent data outshines BAT ( JAK-afi and Luspat ) in 2 indications ( MF & MDS ) by 2-3x in OS and Ti. Significant benefit - same indication - as a drug ALREADY on the market - seems to be a clear cut case across the board for expedited approval.

Maybe I'm focusing too hard on the details, but sometimes those things matter most. All the best. Kmall

Hi Andrew,
This is one of those threads that seems to snowball into an avalanche of thoughts and queries, many of which are far out of my realm of understanding ( approval, regulatory and clinical trial process, etc. ) so many thanks to all of those contributing here.

With regards to my last posting in this thread and the "Not so good news" excerpt, on reflection I do agree that it actually bodes well for our current situation. The not so good part I was originally contemplating was that the "FDA approves more cancer drugs with such designations compared with the EMA" - as you know for the last several months I have honed in on EMA approval being Gerons primary target at this point, especially given the hiring of Sharon McBain and the constant wording of Ex-Us partnership for commercialization in many of their PR's over the course of the past 18 months or so. However, that last bit of that excerpt - "One reason for the difference could be that the European Union requires demonstration of SIGNIFICANT BENEFIT for drugs that target the SAME indication as a drug ALREADY on the market to earn the orphan designation."
- may as you pointed out be one of the strongest points for an EMA approval - and perhaps an expedited one at that. As we all know Imetelstats most recent data outshines BAT ( JAK-afi and Luspat ) in 2 indications ( MF & MDS ) by 2-3x in OS and Ti. Significant benefit - same indication - as a drug ALREADY on the market - seems to be a clear cut case across the board for expedited approval.

Maybe I'm focusing too hard on the details, but sometimes those things matter most. All the best. Kmall

Exactamente, Lus label is for RS positive, a fraction of the MDS population. Imetelstat has much to offer across the board. Will the EU see it that way? I don't know. The real question all along is whether the EU will value the PII data in both indications enough to allow for MA. It is a stretch because, well, both studies are small PII and neither has a classic control arm (RWD not withstanding). But if the EU acknowledges that further ongoing studies are in progress and that they have a provision to pull approval if the PIII studies do not yield supportive data, ...well maybe it's possible, after all the data so far in both studies is unprecedented, peer reviewed and the product of first class medical institutions. EU please listen to your physician leaders who are asking for this drug to be made available to their patients. Our own FDA has failed these patients and will continue to fail them for at least two years. Perhaps the EU will show more compassionate and enlightened thinking. bp