Imetelstat treatment for CML (pipeline expansion opportunity)

[Hoosier Investor]

We know SF3B1 is the primary somatic mutation associated with MDS, and (as we hoped) our recent TLR data indicated a significant benefit to patients with the SF3B1 mutation. The below language is taken directly from our recent press release.

"Clinical and molecular evidence supporting the potential for MDS disease modification with imetelstat included a one-year median TI duration for imetelstat 8-week TI responders, a median rise of 3.6 g/dL in hemoglobin levels in those same patients and >50% variant allele frequency decreases in SF3B1, TET2, DNMT3A and ASXL1 mutations."

As I noted the other day, I was surprised to see the ASXL1 mutation mentioned alongside the SF3B1 mutation. The ASXL1 mutation is associated with poor patient prognosis in MF, so I was pleasantly surprised by the ASXL1 improvements. These ASXL1 improvements offer further evidence of disease modification in MDS, and they may enable further treatment options in other heme diseases.

A little research (link below) highlights the presence of ASXL1 mutations in CML patients.
" ASXL1 mutations are common and associated with disease progression in myeloid malignancies including MDS, acute myeloid leukemia, and similarly in CML. In MDS, ASXL1 mutations have been associated with poor prognosis; however, the impact of ASXL1 mutations in CML has not been well described."
https://www.karger.com/Article/FullText ... 0described.

Further research on CML mutations also highlighted the presence of TET2 and DNMT3A mutations. Thus, with our recent TLR showing significant improvements with ASXL1, TET2, and DNMT3A mutations, it seems reasonable to assume that Imetelstat may benefit some CML patients.

CML patients are typically treated with tyrosine kinase inhibitor (TKI) compounds. I'm not very familiar with TKI inhibition treatment, but I believe there are multiple TKI inhibitor drugs that generally represent good treatment options for CML patients. Thus, there may not be as significant of an "unmet need" in CML as we have in MF and MDS. This may explain why CML hasn't been prioritized yet.

However, given the significant population of CML patients, there may be a sufficient (future) business case. Thus, we may see future comments, preclinical studies, and/or clinical trial plans involving CML patients. The most likely path would seem to be either A) In combination with TKI inhibitors, or B) CML patients who are deemed to be R/R to TKI inhibitors.

[Hoosier Investor]

More Evidence......

Telomerase Inhibition with Imetelstat Eradicates β-Catenin Activated Blast Crisis Chronic Myeloid Leukemia Stem Cells
https://ashpublications.org/blood/artic ... Eradicates

https://www.geron.com/wp-content/upload ... H-2016.pdf

[biopearl123]

Great post HI, thank you. It is worth noting what lab the study you cite comes from (Katriona Jamieson). Dr Ma as lead author has done some very elegant preclinical work, see also ref to ADAR-1. Also, although we didn’t discuss it much, Dr. Jamieson gave a lecture which is referenced on Imetelchat several months ago in a post entitled “Dr. Jameison saves the best for last”. I had to listen to it at slower speed since the auditory quality is very poor but her closing slides are phenomenal and speak specifically to Imetelstat work in her lab. Very exciting stuff. Also note that Dr. Jamieson did prior work on magrolimab (Forty Seven biopharma acquired by Gilead for 4.9B. Many dots to connect here. Thanks again for the post. As a footnote, many years ago there was some research to suggest that Imetelstat reduced CSCs in myeloma but that research seemed to go nowhere.

[rccola335]

I think they will expand across the entire spectrum of blood cancers - may be what the funding was for and that is what their new website says - doesn’t say for MDS or MF , says for blood cancers

[kmall]

Hoosier - not much to add to the clinical aspect of your post, but the patient population you had mentioned, is indeed quite significant. Next to Non-Hodgkins Lymphoma (NHL) the second largest of possible Lymphoid Malignancies which Geron/Imetelstat could potentially target in the future, to the tune of over 34,000 new patients/yr globally, and almost 9,000 new patients/yr here in the US alone:

*Chronic Myeloid Leukemia (CML) – 8,930 patients/yr in the US……200,000+ people in the US living with CML - 34,179 patients/yr Globally

https://www.google.com/amp/s/amp.cancer ... kemia.html

https://www.google.com/amp/s/amp.cancer ... stics.html

https://www.prnewswire.com/news-release ... 33689.html

https://www.globaldata.com/store/report ... -analysis/

https://ascopubs.org/doi/full/10.1200/OP.20.00143


For more detail on additional Lymphoid Malignancy indications, global patient population estimates and future global revenues of, look no further than the post titled: A Purple Squirrel & Venetoclax Combo - AML & Lymphoid Market Potential** - Nov 27, 2021........

http://imetelchat.imetelstat.eu/viewtop ... f=1&t=1242

*The five links provided here are updated from the original "A Purple Squirrel & Venetoclax...."** post.
Yearly updates of many of these findings in turn make prior links absent/not found. When/if possible I will try to revise, however, it has been my experience that most of these projections/figures do not fluctuate significantly from original forecasted estimates. -Kmall

[kmall]

Important to remember as well that Dr. Aleksandra Rizo was the Global Clinical Leader for the ibrutinib (IMBRUVICA) cell mantle lymphoma (MCL) program at Janssen.

"Previously, Dr. Rizo was Global Clinical Leader for the ibrutinib mantle cell lymphoma (MCL) program and was responsible for all MCL studies led by Janssen."

https://ir.geron.com/investors/press-re ... fault.aspx

Ibrutinib (IMBRUVICA) has been used in combination with imatinib to treat patients with CML, although it is primarily used to target CLL.

"Imatinib and ibrutinib are oral kinase inhibitors that, respectively, target the BCR‐ABL1 fusion protein in chronic myelogenous leukemia (CML) and the Bruton's tyrosine kinase (BTK) in chronic lymphocytic leukemia (CLL)."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5458012/

Dr. Aleksandra Rizo is currently employed by Geron as a Senior Medical and Regulatory Advisor.

https://ir.geron.com/investors/press-re ... fault.aspx

Dr. Aleksandra Rizo has vast experience and understanding of myeloid assets, and was Global Clinical Leader for all late-stage myeloid assets while at Janssen, including Imetelstat from 2014-2018. -Kmall

[Hoosier Investor]

Based on the available data & evidence, it seems reasonable for CML to be part of the Imetelstat discussion and/or list of future (target) indications. Adding CML to our pipeline list may benefit the value proposition of our ex-US license rights.

BTW, We should start a separate discussion on the "potential value of our ex-US license rights". I've been of the opinion we could be garner an upfront payment of $500M (or more) as Imetelstat's business case becomes A) less risky with respect to approvals, and B) more known in terms of potential indications & value. Of course, the value will depend heavily on whether the rights agreement covers all future indications, or just the current late-stage indications (R/R MF, LR MDS).

One basis for my high upfront estimate is the values often associated with the so-called Bio-Buck agreements. In such agreements, there's typically an upfront payment along with additional payments for milestone achievements. In total, those types of agreements sometimes approach the $1B amount. For example, I believe Incyte got $150M upfront plus an immediate $60M milestone payment. Thus, $210M upfront with additional payments due upon achievement of certain milestones (e.g. NDA submission, FDA approval, etc).

FYI....I'm not saying we need a "Bio-Buck" agreement at this point. I'm only highlighting that we may be able to expect similar (or higher) values retroactively as part of the forthcoming ex-US licensing rights negotiations.

[rccola335]

I have often wondered if they haven't taken on a partner making Geron more attractive for a buyer - I think it is getting down to the time they will need to involve a partner and the stock price is nowhere near where a buyout can be considered
Why the QT repolarization study was added was never addressed - we were told there were no triggering events and it wasn't required by the FDA - I suspect it was done to alleviate the fears of potential buyers who are kicking the tires
I saved some of the documents from 2018 - compassionate use list of Janssen, pricing manager for Imbruvica and Imetelstat (no MF just MDS and induction ineligible AML) and the Janssen employee who listed imetelstat launch team on his LinkedIn (he finally moved to another company but had imetelstat launch team on his profile even when he updated it for a few years - good luck to all - better days are ahead