ImetelChat

I was hoping for postive results from the IMPRESS study... anyone else?

I'm sure others can weigh in, but I thought this trial was all about satisfying the FDA to conduct a single agent study on HR MDS/AML fro safety before proceeding to Telemere, a combination therapy with Imetelstat and two other drugs.

Lacour, I believe you are correct in that the HR/AML study was said to be a prerequisite to assess proper dosing for the TELOMERE study. I don’t think anyone expected stellar results from this single agent study even with QIMR’s PR piece and Dr. B’s elucidation of the ferroptosis pathway as it pertains to Imetelstat. The preclinical studies from Dr. B and Dr Lane’s lab was focused on a three drug combination which would form the basis for the TELOMERE study. One hopes Geron plans to proceed along these lines, but might not say much until after the IMpress results presented at ASH.

HODL Baby HODL on YMB points out that since Imetelstat is not effective post HMA's per the CEO/CMO comments on the Stifel fireside, the IMpress trial will have very limited results.

I’m not sure of implications for the IMAGINE CT but seems Geron and FDA were going down an unproductive path with IMpress as a prerequisite for TELOMERE.

"IMpress is a Phase 2 clinical trial evaluating imetelstat as a single agent in patients with acute myeloid leukemia (AML) or high-risk MDS, who are relapsed/refractory/intolerant to hypomethylating agents, or HMAs. The objective of this trial is to evaluate the efficacy of single agent imetelstat in this patient population. The primary endpoint of this trial is overall response rate."

Hunt good points. Both Telomere and Impress are investigator sponsored. Not sure the implications. Wonder if like with MDS Imet use might eventually jump Aza in the line. Geron has always emphasized a strong point would be the allowance of normal stem cells to repopulate. There have to be some left for that to happen I would guess.

Thanks biopearl123, that certainly makes sense!

While this is all far above my pay grade, it seems to me that given the class of chemotherapy called hypomethylating agents (HMA) reduces Rytelo's efficacy and given most of Geron’s CT's and approval in LR-MDS are for patients who have already received other treatments including HMAs, Geron has a built in disadvantage out of the shoot. For years, we've wondered why Geron’s CTs weren't front line and why Geron wasn't more aggressive and why the FDA was not more supportive of frontline. This discussion re HMAs reopens that question.

Even with IMpactMF, HMAs can be used in the best available therapy (BAT) arm. However, to get into the study, prior use of chemotherapy was in the exclusion criteria, yet for anyone requesting crossover from BAT that did use HMAs, will likely have reduced efficacy. I'm having some difficulty understanding how that makes sense. And of course, how does that play into the statistical analysis of the interim and final results?

Hunt, exactly. BAT is what might inadvertently condemn a patient to failure. So might the previous requirements of the FDA to use the drug after all else failed at the end of the line, expecting some miracle. Physicians who are stuck in the concrete of algorithms will be the last to get there. Physicians who fear cytopenias will fail to recognize just how important cytopenias may be in telegraphing a successful response. We have seen this previously with a round table discussion where physicians incredulously showed a complete lack of understanding of what the drug was telling them. We have the lawyers and the insurers to thank for stifling physician intellectual creativity. Ironically we have the labs of industry to thank for bringing new tools and better treatments as they leap ahead of many of our underfunded academic labs with many of the most creative minds siphoned off to industry and many of the rest left to regulation.

Biopearl,
I wouldn’t blame the lawyers for this fiasco, I blame the physicians. Here we’ve been holding our breath for years for the outcome of these trials, when they are hopelessly defective. I hope this quandary is at the center of our presentation at ASH.

seedylemon, point taken about the lawyers, however, many physicians are reluctant to "try the new" for fear of potential legal ramifications. Look at all the extra testing that goes on the name of physician self protection, as a patient you would never know, just your insurance company might. Also look at malpractice premiums. I stand by my contention that the medical profession is forced in some ways to support the legal profession. The medical profession certainly has its share of cowboys and psychos, not saying it's perfect but medicine is certainly policed to a different standard than the legal profession and it can stifle creative thought and encourage a cookbook approach to certain problems. When a new therapy comes out the burden of education falls to industry rather than the medical profession alone. They do have to work together as we will certainly see in this case. As for attorneys the FDA employs over 150.

Biopearl,
We all know that lawyers are the devil’s spawn, but they had nothing to do with designing this Impact trial. What are we to do with its remains? I agree with Hunt: Geron has a built in disadvantage. Our possibly stellar response will be seriously diluted if placebo patients cross over. What if we refuse to consider cross overs? Let them cross if need be, but don’t count them in the final analysis. Would that work?

Seedylemon, well technically, I still think while we are on the subject of long drawn out studies, from a legal standpoint, each study center (several hundred) certainly had contracts with Geron and Geron paid them for study nurses, clinic time etc, all would circle back to fairly detailed contracts and back and forth between lawyers. In other words—delay. A minor point but yes study design probably not but I can’t imagine the legal eagles at FDA did not also review protocols in some manner. In other words delay. But I know than’t not where you are going with this and I am just venting. So to your point: Ethicists probably also contributed to the delay and the study design and probably had input into the cross over allowance (on the basis of the PII study). So how should crossovers be handled? That one is beyond me. Technically they are not deaths (yet when they cross over) but their response to Imet may as you and other posters have pointed out may be seriously modified by antecedent “BAT”. I have asked Geron just how crossovers are handled and I got in incompressible answer that it was in the hand of the statisticians and that appropriate adjustments would be made to compensate. How that keep data pure I have no idea. If I come up with anything better I will let you know. We can ask again in May. I am afraid I have little to offer here. bp