Recent Nature letter

[biopearl]

I couldn't help but note that the recent Nature letter seemed a rehash of the already presented data in NEJM and was looking for a reason for the redundancy. Also Dr. T et al alluded to the relative "meager" response of MDS to Imet compared to MF. "Damned with faint praise!!" Here we have the potential for transfusion independence but clearly some sense that disease remission a more elusive goal compared to MF. So I read this as a strong statement in support of MF and an unclear statement re MDS. Perhaps it sets the stage for a combo approach to MDS much as we anticipate with AML. What are your thoughts? Regards, bp

[Fishermangents]

Transfusion independence in MDS is a bit like reversal of fibrosis in MF. It says that there are two possible explanations for the relative meager depth of response: different disease biology or suboptimal drug dose. For the first they need to do further screening of mutational status in order to select those who will respond. For the second they will need to do further testing with different dosing regimens. Let's see what the doctors will decide to do next. In my opinion - for what it is worth - there is a good chance that they will do further testing with a stronger selection of patients based on disease biology.

[biopearl]

<<Transfusion independence in MDS is a bit like reversal of fibrosis in MF.>> Perhaps. But the study notably omitted any bone marrow findings in MDS and there seems to be no correlate to CR and PR status. So the implication is palliation and avoidance of hemochromatosis rather than reversal of disease process in my mind. In spite of your point re transfusion independence, Dr T clearly feels this is a "meager" response to the drug and perhaps expected more? Nonetheless he emphasizes the strength of response in MF and confirms the poor showing of Incyte's drug. This is good but the MDS data thus far may be less strong. I do think the data on ET may set the stage for some intervention here too. Otherwise I agree with you on all points. bp

[Fishermangents]

Bio, I meant is that what is fibrosis reversal as a marker for efficacy, is transfusion independence for MDS. But I agree, transfusion independence seems to be a less deep response than fibrosis reversal.

[biopearl]

Agreed, we'd need to see normalization of the bone marrow. No bone marrow data presented for MDS. bp

[scottmayhew]

...Also Dr. T et al alluded to the relative "meager" response of MDS to Imet compared to MF. "Damned with faint praise!!" Here we have the potential for transfusion independence but clearly some sense that disease remission a more elusive goal compared to MF. So I read this as a strong statement in support of MF and an unclear statement re MDS. Perhaps it sets the stage for a combo approach to MDS much as we anticipate with AML. What are your thoughts? Regards, bp

Hi -- I'm far removed from being a scientist...just casual investor and interest in curing cancer...so some of my questions may be remedial for those more well versed in medicine...should I be worried MDS response has been meager? There was talk of Imetelstat being a platform drug -- curing everything from an inflamed prostate to brain tumors with the immediate attention on blood. Is this not still the case, that is, Imetelstat being a platform drug?

If "reactivation of telomerase is observed in approximately 90% of human tumours" then why doesn't Imetelstat work in 90% of all cancers? Why wouldn't it be just as effective in MDS as it purportedly is in MF? Why only certain genetic markers? Is it that there are other mechanisms at work in cancer in conjunction with telomerase or is there something about Imetelstat where the MOA may be affecting the cells differently than we think? I know the later has been asked before, namely in the NEJM article's discussion, but this worries me...possibly unnecessarily? Just seems like if it's asprin, then it should cure 90% of headaches, no matter who the person is or what caused it.

[biopearl]

Scotty, I fear you have an oversimplified view of a very complex biocellular world. First <<should I be worried MDS response has been meager? >>
Answer: (my view), yes. But it might be the best thing yet for MDS, not the magic bullet you want. As for platform, we have seen little re combo therapy in heme malignancies (more now seems to be coming with AML) so it could be a platform to build on. Take the MM data, no single agent activity (but CSCs reduced), maybe J and J will build on this. Regarding why doesn't it just work for 90% of cancers? Well it might but perhaps toxicity is a limiting factor as could be development of resistance as could be the requirement for multiple cell divisions to get apoptosis and so it just takes too long or perhaps a thousand other reasons. The take home message is that if it were easy it would be easy. For a drug that's been studied for over a decade progress has been painfully slow and hope perhaps inflated at least early on. The former president of Geron, Tom Okarma called imetelstat in CLL a slam dunk. It wasn't. He oversimplified,overstated and overpromised, and so did the staff that designed the solid tumor studies. I don't think Janssen will. bp

[scottmayhew]

Hi Pearly,

thanks for the in-depth response! Really appreciate that.

Could you tell me where Dr.T mentioned MDS response was meager? I'd like to read up on that for myself.

Thanks,
Scott

[biopearl]

Scotty, from recent Blood Journal, kindly referenced by Fisher

<<The current study suggests drug activity in imetelstat-treated patients with RARS or RARS-T. The meager depth of response in the current study, compared with the aforementioned report in myelofibrosis,1 might reflect either different disease biology or suboptimal drug dose. Further investigation on the therapeutic benefit of imetelstat in RARS/RARS-T is warranted>>

[scottmayhew]

One other thing, why would Janssen undertake an MDS study if Dr.T, whom they undoubtedly talked to, described the response as meager?

[Fishermangents]

Very good point, that's what I was thinking too. My conclusion is that they must see a way of improving the results. The Mayo study plays an important role in that, I believe. Dr.T. for sure is sharing detailed info on the Mayo study with JnJ.

[biopearl]

Fisher and Scotty, if meager gets you transfusion independence, that's pretty important and still valuable. Nonetheless, Fishers point about combo therapy suggests Janssen has just begun to fight. bp

[scottmayhew]

I don't think I'd ever consider transfusion independence a meager response...not after reading what those patients have to go through. More over, transfusions are a stop gap treatment with deminishing returns...prolongs life but doesn't work beyond a few years...from what I understand, anyway.

[earfool]

Hello all. There are several studies that suggest patients remaining red blood cell transfusion-dependent have important implications in hematological disorders because it strongly-correlated with decreased survival. Conversely, any drug that is shown to help subjects become RBC-transfusion-independent or even diminishing the number of RBC-transfusions are reported as improvements in many disease- and/or therapy-setting. Many state that there is a correlation in becoming red blood cell transfusion-dependent with improved survival but this is still widely debated.

….earfool

[biopearl]

Earfool, nice to see you here. Scotty, I suspect the reason Dr. T considered the MDS response meager was that he was comparing it to the response in MF (so a strong endorsement of Rx in MF). Reading between the lines there was probably no bone marrow reversal (they certainly didn't mention bone marrow morphology if I remember correctly) or CR/PR equivalent. Regards.bp

[scottmayhew]

Could be...meager being relative to MF response. If so, as you said, that would really say a lot about the MF response.

[scottmayhew]

Meant to ask you, Pearl, about Geron's history with CLL. My nephew, who is only 12, has CLL and it's one of the reasons I follow cancer drug treatments. Can you educate me on what happened with Geron, CLL and why it wasn't a slam dunk after all? thanks in advance.

[Fishermangents]

We can start a new topic on this CLL history.

[scottmayhew]

that would be great...or on other leukemia indications in general

[Nicky Paul]

Agreed, we'd need to see normalization of the bone marrow. No bone marrow data presented for MDS