A Few Random Thoughts re Recent Conference

[biopearl123]

Hi All! I am very impressed with the recent presentation and thought I would try to cobble together some random thoughts. First a reminder we are only a little over a year away from the first PIII top line results in MDS. So hang on!!! Dr. Platzbecker emphasized (with a soft pitch from John) that we are seeing true disease modification in some cases. Confirmed by Dr. Mascarenhas comments. The EU is favorably disposed with the prolonged TI data. Some adverse genetic markers are actually disappearing. Once OS established in MF, end points will be different in the newer studies (PFS for example so we wont have to wait forever.) The AML and lymphoma studies will be short because life expectancy is measured in months. Long ago CKTC referenced an article for me re BCL-2 inhibitors and the potential to synergize with Imetelstat. I still have that article someplace or it is buried in the annals of this board. It was fascinating and he was spot on with his observations. Finally a front line study with end points that will allow shorter studies. It appears the Dr. Lane lives!! After a long vow of silence in the monastery, it looks like the AML studies will include patients from Australia and Dr. Platzbecker gave him a shout out. We always thought his mouse experiments were amazing and the word cure was actually used in the abstract and by Dr. Mascarenhas. Speaking of, don’t know if you caught it but there was discussion of palebresib without mentioning it by name. There was also discussion of CAR-t by Dr. Iyler. Neither treatment is going to take over the universe, as it were. Re Imet 2.0. Once upon a time it was said in a conference that Geron screened over 1 million compounds, that’s right. One million. It might have been in their search for telomerase extension not suppression I just don’t remember, but clearly the search for Imet 2.0 had to be going on for more than a year. Just look at the Geron’s published patents for this implication. HI knows a lot about this. John has always deflected any discussion of Geron’s IP. You can be sure development will take a long time. To emphasize (and Geron does), the ability to selectively target the malignant clone is a remarkable and unique feature of Imetelstat. Nice to see the treatment universe expanding. Once PIII data available (if really good), and with the other multiple studies ongoing Geron will be an irresistible tender morsel for BP. Best Regards to all. What a long strange trip its been. bp

[CKTC]

From a post I made on Seeing Alpha back in March of 2017 regarding Janssen's preclinical work on combining imetelstat and venetoclax. This resulted in a patent being filed by Janssen that is now owned by Geron. https://www.freepatentsonline.com/y2018/0036336.html

"I’m not sure everyone is fully understanding the point I was trying to make. Using the ibrutinib example, there’s no synergy to be had by combining imetelstat and ibrutinib (Imbruvica). Bruton’s tyrosine kinase (BTK), the protein to which ibrutinib binds, has no known modulatory effect on telomerase, and vice-versa. So combining imetelstat with ibrutinib, while a plausible scenario, would not be synergistic but would create a combination where the two drugs act independently to create the desired result. Combining Venetoclax with imetelstat, however, is an entirely different story.

Venetoclax inhibits Bcl-2. Inhibiting Bcl-2 inhibits telomerase.
https://www.jbc.org/article/S0021-9258(19)62532-9/pdf

Imetelstat also inhibits telomerase. Combining imetelstat with Venetoclax should synergistically have a greater effect on inhibiting telomerase than either agent acting independently. And this is exactly what the Janssen study found: “Molecular analyses showed combining imetelstat with venetoclax reduced hTERT expression and telomerase activity much more strongly than either agent alone.”

Inhibiting Bcl-2 leads to apoptosis (cancer cell death). Telomerase works to prevent apoptosis when Bcl-2 is inhibited.
https://www.nature.com/articles/4401670

Venetoclax/imetelstat acting together have a much stronger impact on reducing telomerase. The less telomerase available to interfere, the more successful inhibiting Bcl-2 should be in causing apoptosis. This is exactly what the Janssen study found. “A dose-dependent synergistic activity in inducing apoptosis was observed in multiple AML cell lines when combining imetelstat with venetoclax.”

Telomerase is overexpressed in most cancers. Bcl-2 is overexpressed in many cancers. Because there is such a close relationship between telomerase and Bcl-2, the Venetoclac/imetelstat combination may have widespread potential.

Side note: From the first link I provided above: “Our findings of the modulation of telomerase activity by a widely deregulated survival factor, Bcl-2, may serve an important model to study the regulation of telomerase activity by an apoptotic pathway and could open new possibilities to develop novel strategies to control cancer cell growth by co-targeting both pathways.” This study was conducted at M.D. Anderson in 1997. So the potential for the Venetoclax/imetelstat combination has been known for a long time."

Mar 16, 2017. 08:09 AMLink
Geron: Speculative Biotech With Upcoming Catalyst - Truth Investor

[Hoosier Investor]

The US patent number cited above by CKTC is an application number (i.e. not yet granted). It was first filed by Janssen in August 2016 with the assignment (ownership) being transferred to Geron in 2019. I just checked the status of the application, and we (Geron) just received a "notice of allowance" for the application on 10/21.

The "allowed" claims are specific to the treatment of AML with the combination of Imetelstat + ABT-199 (Venetoclax). Thus, we're going to have patent protection on the use of IMET + Venetoclax as a treatment for AML until at least 8/2/2036 based on the original filing date. NOTE: Geron will attempt to gain time extensions for the patent protection, and I believe time extensions of up to 5 years are possible in some cases.

Next step....Geron can file one (or more) "Continuation" applications up to the day when the patent is formally issued. The USPTO restricts a patent grant to one specific invention, so Geron will have to pursue protection for additional indications via additional Continuation patent applications. This is common practice in the patent world, and Geron is well aware & equipped to manage the continuation process.

Based on the teachings of the original patent application, Geron can pursue patent protection for the list of disease indications shown below. As you can see, AML was first on the list. Thus, we may see a significant number of continuation applications involving the IMET + Venetoclax combination over time....especially if the upcoming IST yields promising results.

Wherein the hematological cancer is.....
acute myeloid leukemia, essential thrombocythemia, polycythemia vera, primary myelofibrosis, systemic mastocytosis, chronic myeloid leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts, type 1, refractory anemia with excess blasts, type 2, myelodysplastic syndrome (MDS) with isolated del (5q), MDS unclassifiable, chronic myelomonocytic leukemia (CML), atypical chronic myeloid leukemia, juvenile myelomonocytic leukemia, myeloproliferative/myelodysplastic syndromes—unclassifiable, B lymphoblastic leukemia/lymphoma, T lymphoblastic leukemia/lymphoma, diffuse large B-cell lymphoma, primary central nervous system lymphoma, primary mediastinal B-cell lymphoma, Burkitt lymphoma/leukemia, follicular lymphoma, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenstrim macroglobulinemia, Mantle cell lymphoma, marginal zone lymphomas, post-transplant lymphoproliferative disorders, HIV-associated lymphomas, primary effusion lymphoma, intravascular large B-cell lymphoma, primary cutaneous B-cell lymphoma, hairy cell leukemia, monoclonal gammopathy of unknown significance, smoldering multiple myeloma, and solitary plasmacytomas (solitary bone and extramedullary).

[biopearl123]

HI and CKTC, very illuminating, thank you. Why do you think myeloma (stand alone) is not mentioned? The patent dances around active myeloma e.g. plasmacytoma, smoldering myeloma, monoclonal gamopathy, etc but does not come out and state active myeloma. Given the recent resurgence of interest in the cancer stem cell (lymphoma studies under the direction of Dr. Iyer), why have we (Geron) avoided myeloma do you think? Recall the Hopkins/Univ of Md study that showed a prompt reduction of CSCs in myeloma. Just curious as to why the patent lists variants of myeloma but not actually myeloma (unless I missed it in my read of HI note.). Also, given the proximity of the issuance of the patent and the announcement of the new studies, do you think the painful delay in proceeding with the long promised AML study was related to waiting for the patent office (also known as Godot)? Anyway this all seems like good news. CKTCs observations were 4 years ago!! We have had to do some serious waiting. Thanks, bp

[Hoosier Investor]

BP,

I wondered the same thing regarding a specific callout (or lack thereof) for Multiple Myeloma. I wasn't familiar with the term "Smoldering Multiple Myeloma" which appears to be a precursor to MM (see definition below). One would think the patent application should've specifically listed all types of myeloma, but it only contained the references listed in my prior note. Thus, I don't have a good answer for you.

Definition (Smoldering Multiple Myeloma):
Smoldering multiple myeloma (SMM) is an early precursor to a rare blood cancer known as multiple myeloma, which affects plasma cells. This type of cancer produces certain proteins that can be measured in both blood and urine. These proteins show up before a person has any symptoms of cancer.

[LWS]

My thoughts go to MD Anderson and the previous successes they have had with Imetelstat. I would like to understand what they have done with Imetelstat in the past, and what they plan to do in the future. It seems to me that MD Anderson is the new Mayo Clinic for Imetelstat. They have the experience as both a research facility and as a cancer hospital to get the best results, alone or in combinations, in a wide variety of cancers from blood cancers to solid tumor cancers.

[cheng_ho]

Yes, they screened a lot of compounds looking for telomerase activators, and found the astragalus chemical that became TA-65.

However, one million is a tiny subset of the organic chemicals, and Nature herself already has activators more powerful than TA-65, e.g. Centella asiatica herb:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755196/

Why big pharma doesn't bother to use their 1000X more powerful screening labs to look for activators (or inhibitors) is a real mystery.