ImetelChat

Was anyone privy to the presentations? I'm curious how they went.

Scott, on Yahoo 'InPlay from Briefing.com' the following was published about the two AACR poster presentations:

"1. The first poster presentation described results that treating acute myeloid leukemia cell lines with imetelstat enhanced the effects of agents currently used for the treatment of AML. These data extend the rationale from prior non-clinical studies for the potential use of imetelstat in hematologic myeloid malignancies, such as AML, including in combination with standard therapies
2. The second poster presentation described results from non-clinical studies that 'provide further evidence' of potential on-target mechanisms of telomerase inhibition by imetelstat underlying the reduction in platelets observed in previously conducted imetelstat clinical trials
3. The non-clinical studies were conducted by scientists at Janssen Research & Development and academic collaborators under the terms of the exclusive worldwide imetelstat license and collaboration agreement between Geron and Janssen Biotech, a Johnson & Johnson (JNJ) subsidiary."

ad 1.
Especially the DAC + Imet highest dose combination was able to knock down OCI-AML3 and OCI-AML5 viable cell lines, to a stunning 6% and 1% reduction respectively if I am correct. The poster says: "Populations of dying and dead cells increased in a dose dependent manner for DAC and Imetelstat, with the greatest effect observed at the combination of highest DAC with the highest Imetelstat doses." It also says that after 2-4 weeks of stopping single use of DAC or AZA the AML cells returned. Especially the combination of DAC and imetelstat showed impressive reduction of AML. That seems to be a very convincing argument for conducting a follow up combination trial. The fact that JNJ researchers have contributed to this poster presentation and the preceeding study, may give us an indication of where the upcoming AML trial will be aiming at.

ad 2.
This provides further evidence about imetelstat's MOA, The poster says: "It is instead hypothesized that the thrombocytopenia associated with imetelstat may result from on-target mechanisms. Other studies of imetelstat have demonstrated potential on-target mechanism for the observed thrombocytopenia." This may imply that with this knowledge methods could be developed which are able to counter this side effect, which allows for administring higher doses thus inducing a stronger effect on the disease.

ad 3.
This is the first time that JNJ is showing publicly to be directly invovled in imetelstat studies. It shows their commitment and their expanding expertise on imetelstat. If you combine that with Dr. Scarlets most recent presentation at Needham, where he says that it is almost 100% sure that the AML trial will start this year, we can be confident that next steps in the development of imetelstat will be taken soon.

just saw something like that this morning, thanks Fisher.

would be nice if after DAC and Imetelstat the disease was cured, but at least patients would have an option on how to treat it. So would those with AML then be on a combo of DAC and Imetelstat for the rest of their lives? It would be one thing if they could take a pill, such as CLL does with gleevac, but having to go into a clinic every three weeks to get infused would be less convenient. Of course, death would be least convenient.

Anyway...exciting times...wonder when Geron becomes an inevitability? with the announcement of AML study or after preliminary results of MF or MDS?

And when prostate inflammation studies get started or brain tumors...so many applications...would be amazing to see new studies launched by JnJ/Janssen in all directions.

Thanks Fishermangents for the information and I assume your comments following the three points on the AACR poster presentations. Not being very knowledgeable on the science at this level, I was wondering if you could elaborate on what the on-target mechanisms of Imetelstat are that affect the platelets bringing on the thrombocytopenia disease. My sense would be it is again related to reducing the telomere length of the cells (on the platelets?) which is a case of the platelets being innocent bystanders in the application of imetelstat. Therefore armed with this knowledge, Jansen would devise a counter balance treatment to normalize what is happening to avoid the reduction in platelets. If I am so far off base that my question and comments makes no sense, I apologize. Maybe just point me to a source to better understand. Thank you.

I think that the full article of Baerlocher should explain it. For me it is a little too technical.

Okay, thanks. Will check out the article but will probably find it too technical as well.

The following text will explain a bit more on the thrombocytopenia issue:

Myelosuppression in patients treated with the telomerase inhibitor imetelstat is not mediated through activation of toll-like receptors

Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns to trigger innate immune responses. For example, synthetic, single-stranded oligonucleotides with certain properties characteristic of bacteria and virus genomes activate the innate immune response through TLR9 signaling. In addition, TLR activation has been associated with lipopolysaccharide-ind... thrombocytopenia in animal models.

The aim of the non-clinical study in the AACR poster was to test a recent hypothesis that the thrombocytopenia observed in patients with myeloproliferative neoplasms (MPN) treated with imetelstat might occur through off-target effects by binding to and activating TLRs, such as TLR9. Results from the study suggest that the thrombocytopenia associated with imetelstat is not likely to be driven via interactions with TLRs. First, the oligonucleotide imetelstat is shorter and lacks certain features in its sequence required to activate TLR9. Second, in an assay for TLR activity, treatment with imetelstat at clinically relevant concentrations had no stimulatory effect on the majority of TLRs tested, including TLR9. Although a small induction of TLR8 was observed in the assay, such activity was not believed to be relevant because the induction was substantially lower than the positive control used in the experiment, and TLR8 has not been reported to be associated with thrombocytopenia.

The poster also cites results from previous non-clinical studies which suggest potential on-target mechanisms of telomerase inhibition for the observed thrombocytopenia in patients treated with imetelstat. Since telomerase activity is required for the differentiation of megakaryocyte progenitors into mature platelet-producing cells, previous ex vivo studies used cells taken from MPN patients and healthy individuals to show that treatment with imetelstat decreases hTERT expression and inhibits telomerase activity, which is concurrent with blocking the terminal maturation of normal megakaryocyte precursors, reducing the number of mature megakaryocytes available to produce platelets. Other prior ex vivo studies also included in the poster showed that imetelstat selectively inhibits the proliferation of malignant megakaryocyte progenitors from patients with essential thrombocythemia compared to normal progenitors from healthy individuals, suggesting that imetelstat may regulate telomerase differently in malignant versus normal cells.

Baerlocher GM, et al. 2016 AACR