Imetelstat Update: Some Thoughts

[irishtrader52]

Some "post-update" thoughts I would share prompted by reading SA posts and many in response to fish posts:

1. Blood improvement and other symptom response is subsequent to bone marrow fibrosis response. And blood response decreases symptoms. Like a marrow transplant - eventually new marrow makes better blood - and better blood makes bad blood symptoms go away. This makes sense. Once marrow is healthier, healthier blood is produced and circulated. Once marrow is healthier, liver stops making so much bad blood and gorging itself and/or platelets stop breaking themselves up to create millions of artery clogging bits of bad blood all in futile attempt to make up for marrow failure, and/or other good results: symptoms subside. When LDH goes down, WBC and RBC and Hb go up, and more good results. Concurrently, symptoms begin to subside. Liver size increase is only one symptom of MF and not prognostic. Anemia is another symptom and more prognostic. (At some point I will list all the blood work done every 3 weeks - in fact John is drawing blood at Mayo as I write this today). When fibrosis clears, blast cancer cells in circulation are decreased or eliminated and symptoms start to subside. The more fibrosis clears, the better blood response - the more your symptoms go away so you feel better and quality of life improves.

In the imet process - in our experience - symptom relief occurs secondary to disease modification especially ine marrow clearing because most/all symptoms come from bad cancerous blood as a result of failing marrow circulating that is damaging all organs at varying rates in varying order. So when marrow clears, blood counts improve and symptoms diminish (symptoms such as enlarged liver, bone pain, fatigue, night sweats, inflammation, etc.). Not all MF patients have same symptoms. So reaching Imbark 2nd endpoints could technically "precede" reaching primary endpoints because imet does not target temporary symptom relief. I think Imbark study design can be confusing because primary end points are symptom relief and that in our experience is not sustainable without underlying disease modification. In Imbark, disease modification indicators are secondary endpoints. Go figure. I think imet might not always work in the same order as the trial design created.

2. 12 week mark could be 1st assessment point for two reasons not readily apparent: 1) If 4.7 not working as well as 9.4 at 12 weeks (should have been expected since Mayo results were at 9.4 and Tefferi reported he was confident in that dose), one would assume the ethical requirement is to review and get dying patients on 9.4 ASAP as soon as (e.g. 12 weeks) it is proven that it works better against 4.7 (duh). If John had been in the Imbark 4.7 group and I read prior Mayo research and then 'heard' 9.4 group doing better, I would be screaming for dose change to 9.4 at earliest possible interval. 2) Based on Jakafi research, Jakafi typically fails at 12 weeks on average so if Imbark 4.7 patients are still well enough to double their imet dose to 9.4 , then they are doing better than Jakafi at 12 weeks and probably expect to do even better on 9.4. As of today, in this group of patients, imet is more effective than Jakafi at 12 weeks if only because their treatment is not halted (like Jakafi) - and their imet dose is now doubled![/b] Magic's point is also well taken. The FDA could have insisted on the 4.7 dose as pre-requisite to address alleged (bogus) safety issue. However, given the reams of dosage/dosing schedule data generated by Dr. T. in ET and the Mayo studies, was it really necessary? I think it only served to delay (like the FDA hold.) So that is not my primary speculation for trial design with 4.7 dosing arm.

3. Remember: deep response in Mayo patients. Disease modifying. Morphological and molecular change. Look it up. John had improvement at the chromosomal level. So symptom relief is just window dressing.

4. If 4.7 arm patients rolled into 9.4 arm study, no new time consuming patient recruitment and processing is needed. Statistical significance in single arm criterion referenced study against end points can be achieved with the 90-100 existing Imbark patients in the study (N=100 creates sufficient statistical power and 90 close enough). So I tend to agree with posters who suggest this action could speed up process although never fast enough for those with life (and treasure) at risk. More so on this long, strange journey.

5. For heaven's sake, suspending enrollment and suspending study are 2 different things. When there were serious side effects in Mayo 9.4 weekly dosing in Arm B and Arm B was suspended and rolled into Arm A at 9.4 mg with 3-week dosing: the trial and John went on. When ridiculous FDA hold was imposed, new enrollment was suspended (and higher benefit criteria imposed to continue): the trial and John went on. That Mayo trial my friends is still not over. Neither is Imbark as some would like to spin it. These are positive trial design adjustments. The questionable interpretation of the interim data report by some persons seems like just more manipulation - and I am sure in some cases honest misunderstandings of very complex subject. I could be misunderstanding, too. However, I agree with others that this market "adjustment" may well presage good news to come.

Dr. Tefferi has a recent article on bone marrow fibrosis as predictor of MF prognosis. Not sure if board dissected that article already but it might be good background reading before his talk.

I am not a physician or biological scientist and these are my own deductions/speculations only. Do not invest on my speculation - do your own due diligence. My posts are primarily intended to provide information to patients from my perspective.

[Fishermangents]

Great post, great info! Thanks for that! Question: which Tefferi article do you mean? Do you have title/link?

Primary vs secondary end-points: it is quite intriguing that all the talk is about the co-primary end-points, while the real story is being told in the secondary end-points. And that is exactly where Dr.Scarlet doesn't want to talk about. That leaves us with putting remarks such as "encouraging trends" in the perspective of the secondary end-points, which appear as an indicator earlier in the process. I must say that is a rather complicated way of looking at things, but necessary in order to connect the dots.

"Are investors that dumb?": GERN is my first biotech investment (and probably my single and last). What I see happening with pps is uncomprehensible for me, not being an expert in the games that investment funds, hedge funds and the like are playing. I think there is massive manipulation, but that seems to be business as usual on WS. In any case, the last CC proves that Geron is an ideal candidate for manipulation. Especially with this cryptic way of interpreting results. Scarlet's perofrmance didn't help either. Did you notice that short interest went down with almost 5%? Manipulation or not, this lowered shorts interest does indicate that sentiment may be changing, despite the horrific 30% drop we have seen yesterday. With this negative interpretation of the latest cc shorts have found a way to cover, which they obviously did. So maybe (and probably) investors on the level that they have an impact on pps are not so dumb at all.

[Rajorgensen]

Excellent analysis, irishtrader!

It appears to me that the market completely misread the results and actions by Janssen, with hands giving profits to shorts and a buying opportunity to longs. Now that so many weak hands are gone, it's conceivable that a bottoming process is underway, possibly leading up to a surprise in December or a likely positive outcome in q2.

[irishtrader52]

Thanks Fish, Laughing. No, you are correct, investors are very smart in this manipulated game and I should have not used the word "dumb". I have great respect for that skill if not always some of the ethics.

I actually edited (I love that edit function!) before your comment realizing that what I posted did not accurately reflect what I meant to say. Too much frustration at manipulation and not enough analysis.

And, yes, this is complicated at every level and in every way so even seasoned investors, scientists, and smart people have a hard time figuring it out. Imagine the poor patients...thankfully the good Dr. T. will be talking to them this week.

And, yes, the PR and presentation did not help. I repeat that I am always available to review press releases and give Dr. Scarlett some pointers. Laughing again.

No, I did not notice the short interest drop - this could suggest that this event may be one of last events that can be spun sufficiently to enable short interest to cover. I promised myself if I posted again, I would stick to the imetelstat story only - but it is hard not to be drawn into the conversation about the fascinating dark machinations and manipulations of WS especially after this stunning (and unwarranted) drop.

I cannot thank you enough for a "safe" place to post. That does not mean that I think no one should disagree with me - even vehemently. As posters learned on the YMB, I can take it! And, I am first to say, I am no expert on biotech or investing by any means or measure (far from it) and this is my first venture into the biotech pharmaceutical world, too. I was drafted into it - and many faithful are 1st timers, too, I know. There are also many involved with GERON for a very long time and have the very best interest of science (and patients) at heart. In the end, I think that is why we will all eventually prosper in the broadest sense of the word.

I originally posted to thank the investors who stayed with Geron and imetelstat through thick and thin all these years so that it could develop to the stage that it saved John's life. My sentiment has not changed in that regard and never will. At this hard juncture, thank you again.

Am J Hematol. 2016 Jun 24. doi: 10.1002/ajh.24458. [Epub ahead of print]
The prognostic impact of bone marrow fibrosis in primary myelofibrosis.
Elliott MA1, Tefferi A1. http://www.ncbi.nlm.nih.gov/pubmed/27342701

[biopearl]

Irish, great collection of thoughts and observations. I agree with you on all counts. I thinks it important to review what we really do know. 1. The drug works for a subset of patients with MF and a subset of patients with MDS. Janssen/Geron knows that analysis of the 90 or so patients in the 9.4 dose arm will provide proof of success or failure. They don't need anymore patients enrolled at least not yet. It appears that many people have totally misinterpreted Scarlett's recent remarks. Irish thank you for your support and encouragement. You are the reason many here have continued to believe in Imetelstat and support its development. Fish, I couldn't find Irish article provided by the link, is part of the posted info on your board? Regards bp

[sargasso]

An interesting post from the YMB. Are the observations made in this post valid? Are the below claims more or less correct?

"In melancholy tone, CEO Scarlett stated that, "In the 9.4 mg/kg dosing arm, even though at the week 12 data assessment an insufficient number of patients met the protocol defined interim criteria..."

Balderdash I say!!!

CEO Scarlett knows full well Mayo Clinic's Ayalew Tefferi, M.D. already established that MF recovery just begins to start at week 12, and it is optimal only when patients reach the week 24 mark. Suggesting any information about efficacy before this throws imetelstat under the bus.

So why did CEO Scarlett showcase the 12 week data as a failure when he knows that CR's are established to occur only at the 24 week mark? Was he trying to feed Adam Feuerstein false information so Adam could shoot down imetelstat at 9.4 mg/kg and call it a failure?

I think Adam knows very well the CRs identified by Mayo Clinic's Ayalew Tefferi, M.D. are real. Adam was just trying to shoot down imetelstat because it only saves the lives of 20-30% of patients and has to be respected properly for toxicity like all chemo.

For proof of the 24 week time point requirement, go to video "Current Developments in Myelofibrosis Treatment", start at minute 22, go to graphs of the two CR patients presented. It is very clear that MF recovery only begins at week 12 and is optimal ONLY AT THE 24 WEEK MARK.

The questions asked during the conference call were sophomoric at best. No one challenged CEO Scarlett about how legitimate his comments about efficacy at 12 week were light of the established Mayo data proving 24 weeks is the proper time frame. None of the callers asked about Geron's viability and the JNJ collaboration if myelodysplastic syndromes (MDS) succeeded alone.

Finally, Janssen's absence is an outrage. Imetelstat is very much a medicine meant to be paired with a subpopulation of patients using biomarkers associate with efficacy. Instead, Janssen is trying to apply the "one size fits all cut-off rules" of the past when we know the mystery is why only a subpop. benefits"

http://finance.yahoo.com/quote/GERN/community?p=GERN

[biopearl]

Sargasso, its not about PR or CRs which actually did occur in some Mayo patients within the first 12 weeks (see Geron investor presentation post ASH 2014 slide 19 I think), it was about some secret predetermined measurements that Geron and Janssen baked into the study to perhaps be a go/no go determinant. We don't know what it is but it probably is not the primary end points (spleen, symptoms) for the reasons Irish and others have delineated. Scarlett is just being honest. The 9.5 arm didn't have enough patients reach this marker, but presumably some did. So I have to ask, what if they had? Would the study have been terminated and approval sought on the basis of the interim finding? (Probably some molecular marker the FDA said was important--we know they value molecular markers as a surrogate). We may never know. But they didn't stop the study in spite of this "failure". Why is the big question. It could be that they realized they set the bar too high at the start of the study. The fact is that even the Mayo pilot study does not exactly mirror the patients in the Janssen MF trial because all had to be JAK2 failures in the later. We already know the drug produces fibrosis reversal but I am not sure if all the patients in the pilot study failed Jakafi first, in fact I think it was not a requirement. The Janssen group probably had concrete for bone marrow by the time they got into the current study. In short they were on the tail end of a desperate disease. People out there seem to think the study was halted or the 9.5 arm failed. All Scarlett said was the 9.5 dose regimen goes forward and the 4.7 dose stops and of course, more time is needed for evaluation of patients. (Not to mention that the MDS data reflects the Mayo study's findings.) I think its a good thing that the study no longer requires 200 patients and that answers should come with half that amount. That speaks to me as indicating a strong signal of expectation. If the median life expectancy is 6 months, way more than half the patients will be gone by a May or June analysis failing some effect on improving life expectancy. They didn't stop the study even though this mysterious marker was not achieved. Is it because patients on treatment are living longer? Were there more deaths at three months in the low dose group? Was some other non predetermined marker emerging? I would not look to Dr. T's upcoming presentation for any answers. I would like to know how many patients from the original pilot study remain on treatment. This is not Scarlett's fault and his presentation was fine. Some idiot shareholder have already sued and I am sure he is walking on egg shells and being very careful not to create any unreasonable expectations. Hope this helps, but I sure don't have any idea about anything more than anyone else, (except maybe Irish, who lives it every day with John.) bp

[irishtrader52]

Bio - Excellet concise summary. What you say we know - we know. Based on update - no more and no less.

I did want to add 2 cents on comparing Mayo and Imbark MF populations as is much discussed on SA. More severe forms of MF - degree of disease and prognosis - is either intermediate high risk or high risk based on standard diagnostic criteria. Within that population, there are other prognostic indicators including mutation and chromosomal damage profiles that can somewhat predict severity of symptoms, prognosis, likely AML transformation, and more.

You are not sicker based on the medication you took or did not take or because it worked or didn't - though you are definitely more desperate. Refractory simply means a drug is not working or stopped working. All Mayo patients were refractory to something and had no other good treatment options. Note the Imbark trial design does not use the word refractory - it says the disease progresses (you get sicker) while taking the drug (e.g. blood counts, blasts, symptoms).

Slightly more than 1/2 of Mayo patients were refractory to Jakafi which makes sense because that is only approved MF drug so prescribed to most patients. And, Jakafi stops working in many patients sometimes as soon as 12 weeks or is halted for side effects. It is not giving symptom relief any longer. Those patients then try something else.

The other half (approximately) at Mayo had not been treated with Jakafi previously and instead were treated with something else (e.g. Hydrea, Interferon) for many reasons and not based on severity of their disease. When it stopped working or was halted due to side effects, they also needed to then try something else to treat their symptoms. Jakafi may not have been that something else for the non-Jakafi patients just as SCT is not good option for many.

John would have met all Imbark trial enrollment criteria except he was refractory to Hydrea instead of Jakafi. So thank heavens choice of prior best treatment option was not a barrier to Mayo study or he would be dead. I don't know if Imbark population is sicker they took Jakafi or Mayo less sick because they did not. Whatever they were taking, it was not working and no other drug was a good option for them.

Mayo and Imbark trial enrollment criteria same except for prior Jakafi treatment required. All patients enrolled in both Mayo and Imbark patients were either staged as intermediate 2 or high risk MF.

I would like to know how many Imbark intermediate high risk and how many high risk. I would like to know their genetic mutations, their cytogenetic profiles, their % of marrow fibrosis, cellularity, their blood count levels, and more - not just the status of their symptoms like enlarged spleen and fatigue.This would give me better idea of their disease status and stage/severity of disease so to speak. I guess that is for JJ to know and us to wait to find out.

Results on the 9.4 dosage every three weeks in 90 high risk (?) MF patients who halted Jakafi at 24 week interval is definitely our "ride or die" as my college students say.

Please do your own due diligence. Lots of research articles to read on this topic.

Update: Not sure there is a 'mysterious' endpoint not reached, bp. I speculate (that means I do not know so don't bet on it anyone) that the primary liver shrinkage endpoint was not significant at 12 week in 3-week 9.4 arm. I speculate this is because I think imet targets the underlying causes first/sooner (e.g marrow fibrosis) and improvement in underlying cause results in symptom change second/later (eg. liver shrinkage).

In other words, liver shrinks faster on Jakafi because that is all it does. Palliative. Imet may take longer to shrink liver because it modifies disease that subsequently reduces symptoms (shrinks liver). Cough drops soothe your throat but do not treat your sore throat.

All Imbark primary endpoints report symptom decrease. Mayo primary endpoints reported disease modification with ensuing symptom relief.

John back from Mayo. All good. We estimate he has had about 59 imet infusions (have to count when I have time). So routine now. He said geron needs an infusion.

[Fishermangents]

bio: the article needs to purchased, which I haven't done (yet). Maybe I will ask a medical friend if he has access to it.

[sargasso]

BP,

Thanks for your excellent reply to my post. Your post was very informative. Note to Irish: your posts are most appreciated.

[usedcarjon]

Irish, Your posts are one of the few chances that many have to understand what
Is really happening. Your insights are more appreciated than you know. I was so glad to hear
That John and you are doing well. Between you and bio pearl this is the best explanations
One could hope for. Keep up the good fight for your sake and John's. Money is one thing but
Life and death issues are what this is all about. If I prayed I would say a prayer for John and you.
But all I can do is send my best energies your way.
Good luck and hang tough-
Ucj

[irishtrader52]

Thank you used car. Thank you for the good energy, too. This reminds me of the terrible, horrible, very bad FDA hold. The hold was resolved sooner rather than later. 9.4 mg at 24 weeks is our ride or die. Good luck and I hope you can get a new car soon!