Imetelstat Franchise

[mistergern]

Agreed HB - One of his best conference calls/chats. I especially enjoyed the heavy emphasis he placed on creating shareholder value. He also conveyed clearly that the only significant potential side effect was cytopenias which he stated were resolved quickly. Overall it was good to get confirmation that we're on track.

[LWS]

From the fireside chat (Needham with JS), all Imetelstat considerations appear to be on track, and Scarlett appears to be very confident. Geron will be in existence for awhile to benefit from the vast potential in combinations and cancer vaccines. The Imetelstat franchise is intact.
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#1 on everyone's agenda is the modular NDA (completion, review, acceptance, approval) --absolutely necessary for single-agent, combinations and off label uses. Then partners can be chosen in both the USA and Europe. Will Geron be the controlling force in any new partnership, collaboration arrangement? I don't believe that there will be a buyout anytime soon. Telomere/telomerase are fundamental to blood cancer treatments and possible cures (and beyond to solid cancers).

[LWS]

Geron seems to have the patents, the successful trials, and the data now for most important blood cancers. MAIA is taking an important shot at some solid-cancers, where the delivery system may be the critical factor. This is another reason why Geron needs to focus on its NDA to seek rapid approvals from the FDA and other regulatory bodies. Then they can move on to various off-label opportunities beyond blood cancers.

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Two names: John Scarlett & Sergei Gryzanov.

I don't pretend to understand all of this. Geron and MAIA are working on cancers, but at the opposite end of the spectrum (blood cancers and single-agents vs. solid cancers and combinations). Imetelstat was invented at Geron by a scientist that is now with MAIA. They must be in communications, especially since there appears to be overlapping patents. Now that the Imetelstat NDA is well underway, and surely will be accepted, I am thinking about what is coming. The successes of Geron will certainly spill over to MAIA.
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Some Reference Material for Discussion:

History Reviewed --- Geron & MAIA---Overlapping Patents

Dr. Shay and Sergei Gryzanov's new telomerase inhibitor showing promise.The inventor of imetelstat moved on to the MAIA startup some years ago.

Geron has patents that apply to MAIA's 6-thio-dG. At minimum GERN patents apply to 6-thio-dG if it is used in MF, MDS, or AML. Dr. Shay and Sergei Gryzanov's new telomerase inhibitor is showing promise.

It seems to me that both Geron and MAIA are going down separate telomerase paths. I wonder if these two companies are on good terms and could combine their initiatives at some point in time. Geron has blood cancers well in hand, but MAIA is going down other paths that Geron will want to and need to explore (solid cancers).

Dr. Sergei Gryaznov, formerly Geron's (NASDAQ: GERN) Chief Scientist in Nucleic Acid Chemistry, is the named inventor of GRN163L, also known as Imetelstat. He said that Geron should go back to developing Imetelstat for ET/PV
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About THIO

THIO (6-thio-dG or 6-thio-2’-deoxyguanosine) is a telomere-targeting agent currently in clinical development to evaluate its activity in non-small cell lung cancer (NSCLC), in sequential administration with LIBTAYO® (cemiplimab) an anti-PD1 therapy, developed and commercialized by Regeneron. Telomeres play a fundamental role in the survival of cancer cells and their resistance to current therapies. THIO is being developed as a second or higher line of treatment for NSCLC for patients that have progressed beyond the standard-of-care regimen of existing checkpoint inhibitors.

About MAIA Biotechnology, Inc.

MAIA is a clinical-stage biopharmaceutical company developing targeted immunotherapies for cancer. The Company’s lead program is THIO, a potential first-in-class cancer telomere targeting agent in clinical development for the treatment of patients with telomerase-positive cancers. For more information, please visit www.maiabiotech.com.

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Imetelstat (development code GRN163L) is an experimental anticancer drug.[1] The first telomerase inhibitor to enter clinical trials,[2] As of early 2023, it was in Phase 2/3 trials for various cancer types.[which?][2]
Chemically, imetelstat is a synthetic conjugate consisting of three parts: GRN163, a thio phosphoramide oligonucleotide, and a palmitoyl lipid group.[2] GRN163 is the pharmacological component with telomerase inhibition. The palmitic acid moiety is conjugated via a phosphothioate linkage to the backbone of the antisense oligonucleotide. Telomere shortening and lower cell viability are observed after inhibition of telomerase activity in vitro. IC50 values ranged from 50 to 200nM for 10 different pancreatic cell lines. [3]

Oligonucleotides are short DNA or RNA molecules, oligomers, that have a wide range of applications in genetic testing, research, and forensics. Commonly made in the laboratory by solid-phase chemical synthesis,[1] these small bits of nucleic acids can be manufactured as single-stranded molecules with any user-specified sequence, and so are vital for artificial gene synthesis, polymerase chain reaction (PCR), DNA sequencing, molecular cloning and as molecular probes. In nature, oligonucleotides are usually found as small RNA molecules that function in the regulation of gene expression (e.g. microRNA),[2] or are degradation intermediates derived from the breakdown of larger nucleic acid molecules.

Oligonucleotides are characterized by the sequence of nucleotide residues that make up the entire molecule. The length of the oligonucleotide is usually denoted by "-mer" (from Greek meros, "part"). For example, an oligonucleotide of six nucleotides (nt) is a hexamer, while one of 25 nt would usually be called a "25-mer". Oligonucleotides readily bind, in a sequence-specific manner, to their respective complementary oligonucleotides, DNA, or RNA to form duplexes or, less often, hybrids of a higher order. This basic property serves as a foundation for the use of oligonucleotides as probes for detecting specific sequences of DNA or RNA. Examples of procedures that use oligonucleotides include DNA microarrays, Southern blots, ASO analysis,[3] fluorescent in situ hybridization (FISH), PCR, and the synthesis of artificial genes.

Oligonucleotides are composed of 2'-deoxyribonucleotides (oligodeoxyribonucleotides), which can be modified at the backbone or on the 2’ sugar position to achieve different pharmacological effects. These modifications give new properties to the oligonucleotides and make them a key element in antisense therapy.[4][5]

Main article: oligonucleotide synthesis

Oligonucleotides are chemically synthesized using building blocks, protected phosphoramidites of natural or chemically modified nucleosides or, to a lesser extent, of non-nucleosidic compounds. The oligonucleotide chain assembly proceeds in the 3' to 5' direction by following a routine procedure referred to as a "synthetic cycle". Completion of a single synthetic cycle results in the addition of one nucleotide residue to the growing chain. A less than 100% yield of each synthetic step and the occurrence of side reactions set practical limits of the efficiency of the process. In general, oligonucleotide sequences are usually short (13-25 nucleotides long).[6] The maximum length of synthetic oligonucleotides hardly exceeds 200 nucleotide residues. HPLC and other methods can be used to isolate products with the desired sequence.

[LWS]

Abstracts in May:

We know that there will be an important IMerge presentation at ASCO, with the abstract on May 25th, in early June. We also know that the EHA is having their annual conference in Frankfurt, Germany in June, with abstracts on May 11. We do not know what Imetelstat updates (if any) will be presented then. These conferences appear to be part of the hoped-for "Miracle in May". May 1 is Monday.

With parts of the modular, rolling NDA under review and near completion, and no negatives in sight (especially no new safety problems), Imetelstat's blood cancer future looks very bright. Nothing is a 'sure-thing' until it happens, but I would be very surprised if the NDA is not approved (fast-track & orphan status in place with patients' needs high).

Both the Needham chat and the Stifel chat (with John Scarlett) were very upbeat with JS in rare form. I believe positive surprises are coming in May and June. We will soon find out.

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Details for the oral presentation are as follows:

Title: IMerge: Results from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Imetelstat in Patients (pts) With Heavily Transfusion Dependent (TD) Non-Del(5q) Lower-Risk Myelodysplastic Syndromes (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESA).

Presenter: Amer Methqal Zeidan, Yale School of Medicine

Abstract number: 7004

Date: Friday, June 2, 2023

Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant

[LWS]

With parts of the modular, rolling NDA under review and near completion, and no negatives in sight (especially no new safety problems), Imetelstat's blood cancer future looks very bright.

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The next important date is May 11 (EHA abstracts). All indicators, that I am aware of, point to a successful and approved NDA including : trials, data, patients' needs, uniqueness, disease modification, survival time, transfusion independence, Needham chat, Stifel chat.

There are many important subjects to be presented.

[LWS]

Dates to Watch:

June 2 (ASCO)
June 8-11 (EHA)
June 14 (KOL and Company participants)

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For Reference

The next important date is May 11 (EHA abstracts). All indicators, that I am aware of, point to a successful and approved NDA including : trials, data, patients' needs, uniqueness, disease modification, survival time, transfusion independence, Needham chat, Stifel chat
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ASCO (Chicago --- June 2)

Title: IMerge: Results from a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Imetelstat in Patients (pts) With Heavily Transfusion Dependent (TD) Non-Del(5q) Lower-Risk Myelodysplastic Syndromes (LR-MDS) Relapsed/Refractory (R/R) to Erythropoiesis Stimulating Agents (ESA).

Presenter: Amer Methqal Zeidan, Yale School of Medicine

Abstract number: 7004

Date: Friday, June 2, 2023

Session: Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
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EHA (Frankfurt, Germany June 8-11) 5 papers

1/ Longer follow-up data for 1-year transfusion independence (TI) in IMerge Phase 3, which demonstrated statistically significant and clinically meaningful continuous, durable efficacy

2/ Strong correlation of reduction in MDS-associated mutations with clinical benefits, including TI duration, provides compelling evidence for the potential of disease modification

3/ Based on PRO data, imetelstat-treated patients were more likely to have sustained meaningful improvement in fatigue, as well as experience such improvement more quickly

4/ Data support NDA submission which is on track for June 2023 to support potential U.S. commercial launch in first half of 2024

5/ Virtual Geron-hosted investor event featuring KOL and Company participants planned for June 14 from 8:00-9:30am Eastern Time
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[LWS]

Dates to Watch:

June 2 (ASCO) --- Chicago, USA
June 8-11 (EHA) --- Frankfurt, Germany
June 14 (KOL and Company participants)

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Key Opinion Leaders (KOL) will be from all over the world. Geron's top collaborator is MD Anderson. I suspect they will be a very important factor on June 14. "Everything is coming up roses".
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To be evaluated based upon May 11, 2023 information

Mayo Clinic (Tantamount to a cure)
JS (Bigger than all of us)
Dr. Rizo (Remarkable and compelling)
MD Anderson (Numerous positive remarks)

[LWS]

Key Opinion Leaders (KOL)

The most important date (so far) for Geron and Imetelstat will be June 14 or KOL Day. We will hear from experts from all over the world about Imetelstat's accomplishments and potential alone and in combinations. We should also get a better understanding of the NDA timeline and potential collaborators and partners. The names that stand out now are: JNJ, AbbVie, MD Anderson.

[LWS]

While we all wait for June presentations (ASCO, EHA, KOL), all leading to an accepted and approved NDA, I want to reflect on the path of future research in this time of budding AI (Artificial Intelligence).

Cancer research and life science research are closely connected. I believe this is what John Scarlett meant with his thought, "Bigger than all of us". These levels of research are just getting off of the ground, and no one knows where they will lead us by the end of this century. I hope to be around for awhile, and see how some of this plays out.

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For Reference

Telomeres, Telomerase, Immortal cells, cancer, long life are all connected in ways that we are only beginning to understand.

Some thoughts (for future research): It is beginning to look like that there is an important relation between too much telomere (cancer), and not enough (cell death). Is there some place in the 'middle' that prolongs life, without causing cancer?
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Length

This enzyme, telomerase, is responsible for maintaining the length of telomeres. Without telomerase, telomeres progressively shorten until they die or cease functioning. However, by activating telomerase, it is possible to actively restore telomeres and allow for many future cell divisions

[LWS]

The Franchise is looking strong both medically and financially:

1/ In June---ASCO (June 2), EHA (June 8-11), KOL (June 14)
2/ Combinations in Trials including TELOMERE for AML
3/ Continuing strong interest by AbbVie and JNJ
4/ NDA (modular, rolling) nearing acceptance and approval
5/ Debt Ceiling resolved allowing for strong stock markets

"June is Busting Out All Over"

[LWS]

The words Paradigm shift say quite a bit about Imetelstat, its successes and potential. ASCO (June 2) will be the start of this chain of events (ASCO, EHA, KOL).
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For Reference:

Asco 2023 – Commands leaves the door open for Geron

Jacob Plieth

Full data from Reblozyl’s Commands study show limited activity in MDS patients without ringed sideroblasts – a boon for Geron.

Paradigm shift

The recently intensifying battle in myelodysplastic syndromes between Bristol Myers Squibb’s Reblozyl and Geron’s imetelstat appears to have turned in favour of the latter’s underdog: presentation of the front-line Commands trial at Asco has confirmed Reblozyl’s limited activity in patients without ringed sideroblasts.

Reblozyl is already approved for post-ESA use in low-risk MDS, though only in ringed sideroblast (RS) positive patients – a fact that apparently does not preclude some off-label prescribing in RS-negative MDS. Full data from Imerge will be presented alongside the Commands results at an Asco session on 2 June.

[LWS]

The "Imetelstat Franchise" will be reenforced by ASCO today, EHA and KOL (June 14).

NEXT -- TELOMERE trial for AML (Geron & AbbVie combine medicines) providing new synergies and new treatments for AML, with cures a possibility. After the single-agent NDA approval, AML combinations are the next hurtle to jump over. The preclinical results were very good.

[LWS]

The "Imetelstat Franchise" and the NDA approval are almost identical.

Remember that the NDA is fast-tracked, modular and rolling. Apparently, it has already been partially submitted with an ongoing review by the FDA. The NDA will be completed by the end of June. The KOL (June 14) will put everything in proper perspective for the NDA acceptance and approval.

The KOL (Key Opinion Leaders) will be experts in various aspects of blood cancers.
I wonder who they will be, and when we will know.