ImetelChat

Annie hi on the ymb recently pointed out that the MM study 2010-2014 from Hopkins and U of Md (13 patients enrolled) was updated in March of this year to reflect the addition of lenolitamide to the imetelstat regimen. I remember reading the summary of the study years ago. It did not rate a presentation at ASH or even a poster but was presented in supplemental materials related to that year's presentations. I read a statement in that presentation the said "there was no single agent activity" (despite a report that MM stem cells were effectively targets.) I was very disappointed. I see now that the MM protocol was updated in March of this year (I thought the study was over well before then) that allowed inclusion of patients on lenolitamide to be included. Hence combination therapy (which seems to be imetelstat's forte). Revisiting the statement of no SINGLE agent activity I wonder if I misinterpreted that and the bread crumb is that while there is no single agent activity (what about MM SC activity?) that perhaps combination therapy activity was implied in the authors statement and I missed it since the CT site did not seem to reflect that possibility until the most recent update. Scarlett said to watch the CT site to help us know where the company was going (obviously). We know AML is next, will a path of bread crumbs lead to a Myeloma study after? Thoughts? Regards, bp

Bio, I found this on imetelstat DOT info:

The Telomerase Inhibitor, Imetelstat, Rapidly Reduces Myeloma Cancer Stem Cells (CSCs) in a Phase II Trial
C.A. Huf et al. (2012)

MM cells are relatively resistant to a wide range of anti-myeloma agents. In preclinical models, the novel telomerase inhibitor imetelstat has been found to inhibit CSCs from a wide range of tumor types, and we reported that imetelstat reduced TA in MM CSCs resulting in the loss of self-renewal and clonogenic growth potential. ../..

These findings (editor: of this trial) demonstrate that imetelstat rapidly decreases circulating MM CSCs. In addition, several patients experienced delayed, but sustained, clinical responses as measured by standard criteria. Therefore, imetelstat may have therapeutic implications for MM and other malignancies driven by CSCs.

(Blood, ASH Annual Meeting Abstracts, 2012 120: Abstract 4898)

This link doesn't lead to the article directly anymore. Instead, you gets ome log-in screen: http://abstracts.hematologylibrary.org/ ... type=HWCIT

This change on the CT site indeed good be an indication for a next combo. I will look a bit closer into this the coming days.

I found this on the Multiple Myeloma Research Foundation website:

Additional Experimental Treatments
Phase II
Imetelstat (GRN163L) Geron Corporation
Telomerase inhibitor that induces apoptosis and inhibits myeloma cell growth; enrollment completed

Link: http://www.themmrf.org/multiple-myeloma ... reatments/

Trial seems to be ongoing.

Fish, don't think so. CT site lists trial as completed. bp

You're right.

Bio, thanks for pointing this out. So the study is complete as of November, 2014. On March 14, 2016 the study is changed to Imetelstat alone or in combination with lenalidomide standard of care maintenance therapy. Also added is a lower dosing of 7.5 mg/kg as a 2-hour intravenous infusion. It would be great to hear Dr. Scarlett make a comment on the study, at least when to expect results. There has certainly been enough time since study completion. Maybe someone will ask during the conference call.

The only slightly interesting crumb to me is the following: Certification or Request for Extension to Delay Results Receive: February 8, 2016 and ClinicalTrials.gov processed this record on May 02, 2016 (yesterday.) Could it be since patients enrolled in this trial were already receiving therapy, including Lenalidomide, they noticed some synergy with Imetelstat? Are there patients that have been on this "Combo" therapy since 2010 and still receiving benefits from it? While I doubt it based on the difficulty treating MM, but these recent changes raise a few questions?

Hoosier Investor wrote a great article on SA Jan 12, 2016 entitled "Geron:What To Expect From Imetelstat Now." It's worth reviewing because it was written before the recent changes to the MM clinical trial. Interesting because the article spends a good amount of discussion on Multiple Myeloma, referencing some hard to find data from Geron's 2012 Annual Report. The following response to a comment is also interesting:

Thanks for welcoming me back, and for confirming JNJ's focus on Multiple Myeloma. The early Geron results were difficult to locate, but they indicate promise for Imetelstat's ability to benefit MM patients. At this point, I'm not sure why MM isn't already on the board for planned trials given....etc.

JNJ made the investment in Imetelstat with not only Dr Tefferi's MF data, but also all the other panoply of data, trials, papers including the 2010-2014 MM clinical trial (John Hopkins) to which study results have not yet been made public. It would be great to get Hoosier's thoughts on the MM clinical trial with respect to the recent CT changes.

Great comment, Hiprock. As not everybody visiting this board has a SA account, I have copied the MM part of Hoosiers article here:

Multiple Myeloma (MM)

Janssen will revisit Imetelstat as a treatment for multiple myeloma based on the following:
· Imetelstat and lenalidomide appear to have similar efficacy in MDS.
· Lenalidomide sales as a multiple myeloma treatment are ~$5B per year.
· There are ~96,000 multiple myeloma patients living in the US alone.
· Janssen highlighted the need for new therapies in their May '15 investor presentation.
· The majority of multiple myeloma patients are anemic at diagnosis with the remainder becoming anemic during their disease progression.
· Multiple myeloma patients with increased marrow fibrosis have a poorer prognosis.
· Multiple myeloma is one of Janssen's core focus areas.
· Geron's prior Phase 2 trial suggests Imetelstat will benefit multiple myeloma patients.

Geron has conducted two Phase 1 clinical trials (NCT00718601, NCT00594126), and a Phase 2 clinical trial (NCT01242930) to investigate Imetelstat as a treatment for multiple myeloma. The Phase 2 trial (NCT01242930) featured Imetelstat as a single agent therapy dosing at 9.4 mg/kg on days 1 and 8 of a 28-day cycle. According to Geron's 2012 annual report, the Phase 2 multiple myeloma trial was designed as a biomarker trial and not necessarily to directly enable further development of Imetelstat in multiple myeloma. Preliminary data from the multiple myeloma trial showed a rapid and significant decrease in myeloma progenitor cells with several patients experiencing delayed, but sustained, clinical responses as measured by standard criteria. Geron concluded the Phase 2 data supported the thesis that Imetelstat has a beneficial effect on malignant progenitor cells. However, given the results of the ET trial and the potential application of Imetelstat in other hematologic myeloid malignancies, Geron chose not to pursue development of Imetelstat in lymphoid malignances at that point in time. A summary of Geron's multiple myeloma results and commentary is shown below.

====
Multiple Myeloma Phase 2 Preliminary Results (From Geron's 2012 annual report):
"We designed a Phase 2 trial of imetelstat in patients with multiple myeloma to measure the effect of imetelstat on the progenitor cells responsible for the disease. This trial was primarily designed as a biomarker trial and not necessarily to directly enable further development of imetelstat in myeloma. The preliminary data from this trial, as of July 30, 2012, have been published in an abstract in the journal, Blood (ASH Annual Meeting Abstracts) 2012 120: Abstract 4898. The published data showed a rapid and significant decrease in myeloma progenitor cells that were detected in the blood over the course of imetelstat treatment in eight out of nine patients assessed. In addition, several patients experienced delayed, but sustained, clinical responses as measured by standard criteria. We believe these data support the thesis that imetelstat has a beneficial effect on malignant progenitor cells.
As reported in the abstract, as of July 30, 2012, six patients remained on study. Four patients were discontinued from imetelstat therapy after receiving a median of seven doses of imetelstat. Of these four, two patients discontinued due to disease progression and two patients discontinued due to hematologic toxicity. Cytopenias, or reduced blood cell counts, were the most frequently reported toxicities with eight of ten patients demonstrating Grade 3-4 thrombocytopenia and neutropenia during cycle 2, which in many cases required dose reductions or holds in subsequent cycles.
This trial is no longer enrolling patients, and we expect full clinical data from all patients enrolled in the multiple myeloma trial will be available in 2013. Given the results of the ET trial and the potential application of imetelstat in other hematologic myeloid malignancies, at this time, we do not have any plans to pursue further development of imetelstat in lymphoid malignances, including multiple myeloma.
We intend to expand our directed program of investigator-sponsored trials to other hematologic myeloid malignancies, including myelodysplastic syndromes and acute myelogenous leukemia. The specific design of these trials will be informed by preliminary data from the Mayo Clinic Trial. At this time, we do not have any plans to develop imetelstat in lymphoid malignancies, including multiple myeloma."
=====

For the above reasons, Janssen is likely to revisit Imetelstat as a treatment for multiple myeloma in hopes of aiding patients and capturing a portion of Celgene's ~$5B per year of lenalidomide sales. Future trials would feature revised dosing schedules and may utilize Imetelstat in combination with Daratumumab or Velcade, both of which are approved multiple myeloma therapies that were developed by Janssen. It should be noted that Geron has patent protection involving the treatment of multiple myeloma via a combination of Imetelstat and Velcade until April 2025.

Some links as provided by Hoosier:
Cancer treatment by combined inhibition of proteasome and telomerase activities US 7998938 B2:
http://www.google.com/patents/US7998938

MM is one of JNJ focus areas:
http://files.shareholder.com/downloads/ ... _Final.pdf

Lenalidomide sales:
http://ir.celgene.com/releasedetail.cfm ... eid=923485

interesting...

how do you get around imetelstat lowering blood count, though? or would lowering the dosage and combo'ing solve that rather than Imetelstat being used as a single agent, which (seems) to be both slow acting (unraveling the existing cells) and toxic.

and the lenalidomide, Daratumumab or Velcade first wipe out the cancer and then Imetelstat is used to prevent progenitor cells from creating new cancer cells? so first poison and then maintain? is that the basic scenario?

Was wondering if anyone had listened to the Charlie Rose (Bloomberg) interview of Tom Brokaw (NBC News) last night (5-17-16)? I think he said he suffered from Multiple Myeloma beginning late 2013 and was diagnosed at the Mayo Clinic? Based on his comments, I was wondering what treatment was responsible since he said he was now in remission versus most can only hope for getting to chronic stage. I missed much of the interview up until those comments so probably missing a lot here. It was an hour long and the part I listened to was very interesting just wish I had given my full attention. I see there is a lot of info out there on his situation but not seeing Imetelstat mentioned. Probably just the "omides", etc. being used but he did mention that he did not require a stem cell transplant.

Hunting, I read he was treated with Revlimid, Velcade, and Dexamethasone.

Okay, thank you. Just wasn't looking in the right places or maybe just not paying attention. Interesting reading on the use of these drugs, dosing, combinations, cycles, etc. You probably have seen this but found this interesting: http://www.myelomabeacon.com/news/2014/ ... e-myeloma/