ImetelChat

Hello Cheng, How are things in sunny New Hampshire? I have a serious question for you. You have worked in the Shay lab and have a science background and have essentially forecast the demise of Geron. You have said it is an old drug still looking for a home. It appears that the holders of millions of shares agree with you. I don't. When you worked with Shay et al wasn't eh focus on solid tumors? I would be interested in learning more about your time there when you have a chance. Not everyone gets to work with world class scientists like that. Ok so to my questions. Are you aware of any drug or combination of drugs that can reverse bone marrow fibrosis in MPDs? Are you aware of any drug that has reversed the need for transfusions in MDS? If you are, please share this information with us. Please frame an argument as to why the drug is essentially a failure when the recent news has been directed to defining an proper dose for MF and reassuring stock holders that MDS trial is on track. Yes Dr. T did not see as deep a response in MDS but TI is a pretty good interim goal. I did think the timing of potential presentation of the data from part one of MDS study was deliberately vague and perhaps there is a prayer for a late breaking presentation at ASH. bp

What did Dr. Tefferi tell patients at the MPN Bay Area Conference today? He's the one who knows whether imet by itself shows any signs of being approvable for blood cancers.

At the Shay lab we showed that imet works in a dish (which is nothing, even Vitamin C is a miracle treatment in a dish...if the dish doesn't have feeder layers of normal cells). And it worked to prevent colonies in agar. On solid tumors, it supposedly slowed the growth of solid tumors (So Gunnur Dikmen said, not me).

I watched the video of Tefferi in Italy, he said he "wasn't excited about any of the drugs being tested". But he did seem to indicate that it worked on a genetic subset of MF (which you would think would be exciting, given the worthlessness of other treatments...on the MPN page they link to current clinical trials, and one is for arsenic....)

I have never been "excited" about imet itself, just about the concept of telomerase inhibition COMBINED with other drugs to pick on the confused cancer cells while they are trying to divide rapidly with no telomerase. Between the FDA, the patent system, and the empty shell of a patent-trolling company with no research staff, I don't see anyone working to make an effective therapy anywhere. But maybe a miracle has happened, and imet has shown just enough activity to get approved, and then those combinations might come about.

Ask Tefferi.

Cheng: the PRs/CRs observed by Mayo seemed to be exciting enough for JnJ. So probably you are missing something here. I also must say that I am a bit suprised that you are heavily commenting on all these message boards with all kinds of strong opinions, while not being excited about imetelstat. It is nothing new that genetic profiles are a prognostic factor whether or not imetelstat works.

Imet as a therapy shows positive results in MDS and MF. You know that, Cheng! CRs have been confirmed by Mayo and NEJM. So the 'miracles' you mention obviously DID happen in a subset of patients. So I am rather puzzled by your statement that imet therapy goes nowhere.In fact I would expect better quality of comments from you.

>the PRs/CRs observed by Mayo seemed to be exciting enough

I was directly quoting Tefferi, from his Italian talk. Take it up with him... if we can. Has anyone seen anything from his talk on Saturday? There's nothing on the MPN foundation site or their FB page...

Hi bio -

A couple of quick thoughts.

1. I am glad to see some discussion that 4.7 mg was lowest dose with any activity and so I think that dose was used to randomly assign for trial design purposes with expectation patients would need more. And if patients are healthy enough to move to higher dose after 12 weeks (possible different outcome if they had taken JAK instead) this is good news. I often ask myself why no head to head trial: imet v jak? Because not head to head drugs (one is cough drop and one is penicillin). If you have MF, you want to try imet. To start at 4.7 mg imet is a little better than nothing (like stock today!). But soon you want more so roll patients over to higher 9.4 mg (known safe working dose) asap I think - as expected I think. No prior studies said 4.7 works.

2. I am glad to see discussion finally realizes safety resolved and was always muddled (decide why for yourself) and serious side effects were only a significant issue in weekly dosing. Fact - John was Mayo Arm B weekly dosing discontinued for penias and was reason he had to go to 7.5 mg to stabilize. If he had been in Arm A - no issue and would have stayed at 9.4 optimal dose I have no doubt. Small increase in liver enzymes were minor issue to us and not liver function (!) and never mind in disease that damages all organs eventually anyway starting with your life blood - so no brainer cost/benefit analysis. John has his hair, great appetite, exericises (we are going to start soul cycling), travels, golfs, swims, and chases 2.5 year old grand daughter around house. Only lifestyle change at all is 1 hour nap and drinks lots of water and takes Vitamin C. How does that compare with people you know on traditional chemo therapy for more than 3 years?

3. All should be excited the new 2016 WHO MPN diagnostic and prognostic criteria have been reviewed and pending adoption. Documents how much more we know about mutation, chromosomes, and the likely course of the disease since start of Mayo study in 2013. Maybe why Dr. T. got all those awards. You probably already analyzed while I was on my stawaycation (stay away vacation). I will assess John against the proposed 2016 WHO criteria at Mayo entry point when I have a chance. Best~

http://www.nature.com/bcj/journal/v5/n8 ... 1564a.html

I realize there is much discussion on whether or not this is a frontline trial and how fast JJ can/will roll 4.7 patients into 9.4 dose. I will add my thoughts this weekend. Have a great day.

Hi Irish, thanks for your thoughts and your new article. I did review the Tefferi Italian talk. Cheng, I doubt the recent California presentation would have anything new since they were only a week or so apart. The article certainly confirms movement toward patient specific therapies directed toward identifiable gene mutations. Maybe this is why the MDS info from the Geron presentation was received in such a lukewarm fashion (to speak to Fish's question)--they were clear in that only a subset of MDS patients were analyzed suggesting the not all were, and they are looking to confirm action against a smaller genetically defined subgroup. The market reticence may reflect Dr. T's statement to the effect that Imetelstat effect was not nearly as deep in MDS as in MF (as a single agent). Dr. T was clearly miffed that he was kept out of the loop regarding data analysis by Janssen and said he would have to find out results from Google like the rest of us but he did give advance alert to the PR release. One interesting part of his talk was a couple of Kaplan-Meir curves emphasizing that current treatments do not prolong lives. He said nothing about Imetelstat and longevity which to me would be extremely important. (John is our N=1)--not statistically valid of course. But for him life is 100%! A good statistic indeed. Dr. T seemed to pooh pooh CI like spleen response of 50% but if you are the patient I would think this would be very important. It does seem that technically we will see 40 or so patients in the 9.4 arm since the other "rolled in" patients will not fulfill criterion of never having been treated with Imetelstat. Maybe they think the first 40 will be enough. It does seem that the pilot study alone with PR and CR should justify approval since no other drug can do this. "Cure" in the cancer world--20 % is amazing so I don't get the delays. Wonder if Janssen may throw us a bone with a late breaking abstract for ASH. Continue to hope for AML study. Best wishes and regards, bp

Hi bio -

I agree with all you say regarding Dr. Tefferi. I think he must be frustrated. I also thinks he considers liver enlargement - while very uncomfortable for patient - in the same symptom category and no more/no less regarding prognosis than severe fatigue and chronic fever. I think anemia is of more concern and contributes to high risk. The 2016 WHO criteria rationale paper gives some important diagnostic, staging, and prognostic data that can put the Imbark study in some context. However, I think bone marrrow was/is key and a good target.

John is N=1. Yes. So I am now trying to compare his mutations (JAK2 V617F only) and cytogenetics to new WHO 2016 diagnostic and prognostic criteria for clue as to why imetelstat working so well.

Lastly, I was realize I was not clear enough on what I meant by "rollover" of 4.7 patients into 9.4 dosage.

I meant they will "roll over" to 9.4 dosage like the others with regard to dosage. However, from here on out, they essentially constitute a new experimental group (4.7 12 weeks/9.4 12 weeks) and still distinct from Arm A. As such, they will undergo independent intra group analysis as well as comparative analysis with Arm A. This understanding is what I meant to convey.

I was referring to "rolling over" to the higher dosage and not "rolling over" relative to trial design - no "rolling over" (merging) with regard to analysis.

When the Mayo Arm B "rolled over", they started on same dosing/dosage as Arm A. Arm B was completed emiminated. However, Arm B was always analyzed as a separate cohort as well as in comparison to (and collectively with) original Arm A patients. In Imbark, my use of "roll over" refers to rolling over to new dosage only and no rolling over that co-mingles analysis. I hope this makes some sense.

Irish and Bio, thanks for your great comments!