Keeping up with MAIA

[biopearl123]

This should make Stig happy:

https://www.businesswire.com/news/home/ ... Inhibition

[LWS]

MAIA Intends to initiate its second Phase 2 go-to-market trial – THIO-102 - evaluating THIO with atezolizumab, pembrolizubmab and other checkpoint inhibitors in multiple tumor types, including small cell lung cancer, liver cancer and colorectal cancer

bp---- 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.

Geron & Imetelstat have competition. There also is some history here for review.

[LWS]

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.

[huntingonthebluffs]

Given telomerase is up regulated by 90% of cancers, the MAIA CEO saying "We have 10 shots on goal!” can get attention for sure, and not overly challenging to put together in early CTs. However, IMO, maybe wrongly, making that statement at their current level of development is the CEO going fishing for a buyout.

Dr. Scarlett knows what Geron has and could easily put up many more "shots on goal" in their future plans but I think he is entirely focused on hemo and wants to get Imetelstat commercialized in that space first. All though not doing it might say something about his interest in the possibility of a BO. That said, I do think Dr. Scarlett alluding to significantly increasing the shots on goal after initial commercialization could have a positive effect bringing some needed attention without being sued. Also, indirectly, that statement coming from MAIA, by itself, can also bring positive attention to Geron and Imetelstat given their leadership in TI science and CTs.

[LWS]

Telomerase---Common Interests and Overlapping Patents--- Back to the Future

Dr. Sergei Gryaznov (at MAIA), 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

No one knows more about telomerase inhibitors than Dr. Gryaznov. I suspect that his attempts at "solid cancer tumors in combinations" treatments are developing some important science and meaningful progress. The patents are likely such that MAIA and Geron will have to work together. Perhaps, they are already.

Telomerase is a factor in about 90% of all cancers. We have no idea how far MAIA has progressed with suitable delivery-systems for a variety of solid cancers. The world of blood cancers belongs to Geron. The world of solid cancers is the ultimate challenge, with MAIA very much in the game.

The Future--The ultimate big prize (solid cancer tumors in combinations with IMET). The main problem, as I understand it, is a suitable delivery system. There have been some papers recently that look hopeful.
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Imetelstat, a 13-base oligonucleotide (5'-TAGGGTTAGACAA-3'), is a potent, investigational telomerase inhibitor in clinical development for the treatment of hematologic myeloid malignancies.
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Delivery Systems Research---Nano Delivery Systems

Mol Pharm. 2021 Apr 5; 18(4): 1491–1506.
Published online 2021 Mar 18. doi: 10.1021/acs.molpharmaceut.0c01238

Advances in the Design of (Nano)Formulations for Delivery of Antisense Oligonucleotides and Small Interfering RNA: Focus on the Central Nervous System
Monique C. P. Mendonça,† Ayse Kont,† Maria Rodriguez Aburto,‡§ John F. Cryan,‡§ and Caitriona M. O’Driscoll*†

[LWS]

This appears to be true:

1/ Telomerase inhibition is an important factor is treating most cancers, and in combinations has the potential for cures.
2/ Blood cancers are easier to treat than solid cancers when telomerase inhibitors are the issue.
3/ MAIA gives Geron the competition and incentive that they need to move much faster to get their NDA in the hands of the FDA for fast-track approvals and off-label uses.
4/ The Cancer Moonshot considers telomerase inhibitors important in almost all cancers (about 90%)
5/ Geron and MAIA have to be considered together and complement each other.
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Question: How many shares of Geron stock does Dr. Gryaznov own (if any)? The common interest between Geron and MAIA may be closer than we realize.
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Dr. Sergei Gryaznov (at MAIA), 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.

[LWS]

Geron should control the blood cancer markets, but they now see the very real competition and have to act quickly (NDA & approvals).

MAIA already has a partner (Regeneron) with deep pockets and is working on solid cancer combinations (small cell lung cancer & colorectal cancer). They are in early phase 2 trials. There is always the possibility that MAIA gets some approval (FDA, EMA, MHRA/UK) before Geron with some breakthrough data and a priority review. That would not be good news for Geron and would open-up off-label possibilities for MAIA.

That is why Geron has to focus sharply on the NDA now and approvals now. If MAIA somehow gets to the finish line first, then they are in the driver's seat for all telomerase related cancers, including blood cancers. We do not know the patent situation and how much that protects Geron. Perhaps, Geron has received a wakeup call, loud and clear.

[LWS]

This appears to be true:

1/ Telomerase inhibition is an important factor is treating most cancers, and in combinations has the potential for cures.
2/ Blood cancers are easier to treat than solid cancers when telomerase inhibitors are the issue.
3/ MAIA gives Geron the competition and incentive that they need to move much faster to get their NDA in the hands of the FDA for fast-track approvals and off-label uses.
4/ The Cancer Moonshot considers telomerase inhibitors important in almost all cancers (about 90%)
5/ Geron and MAIA have to be considered together and complement each other.
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dr. Sergei Gryaznov (now at MAIA), 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.

As we all patiently await NDA acceptances and approvals for assorted blood cancer uses, Dr. Gryaznov's continued interest in solid cancers combination treatments also speaks volumes (positively) about Imetelstat for blood cancers. Looking back (20/20 hindsight) Geron could have taken the easy path (ET/PV) for FDA and EMA approvals, and could have pursued their current studies and trials with an approved medicine, that also would have had off-label applications. I believe there were some financial considerations about a limited market.

I wonder if Dr. Scarlett and Dr. Gryaznov are in contact with each other about joint projects and shared patents.

[LWS]

Patent Considerations

Imetelstat and THIO are apparently very similar medicines. The importance of the telomeres and telomerase has been firmly established by Geron in a variety of blood cancers with their modular Imetelstat NDA under review and nearing completion for acceptance and approval.

Patent overlapping for both blood cancers and solid cancers is very important and will likely form new collaborations and partnerships. Both Geron (blood cancers) and MAIA (solid cancers) have closely connected histories.

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For Reference

Review Mol Carcinog
. 2019 Sep;58(9):1581-1588. doi: 10.1002/mc.23035. Epub 2019 May 6.

In perspective: An update on telomere targeting in cancer
Eric T Sugarman 1, Gao Zhang 2, Jerry W Shay 3

Affiliations expand
PMID: 31062416 PMCID: PMC6692182 DOI: 10.1002/mc.23035

Abstract

Engaging a telomere maintenance mechanism during DNA replication is essential for almost all advanced cancers. The conversion from normal and premalignant somatic cells to advanced malignant cells often results (85%-90%) from the reactivation of the functional ribonucleoprotein holoenzyme complex, referred to as telomerase. Modulation of the human telomerase reverse transcriptase (hTERT) appears to be rate limiting to produce functional telomerase and engage a telomere maintenance mechanism. The remaining 10% to 15% of cancers overcome progressively shortened telomeres by activating an alternative lengthening of telomeres (ALT) maintenance mechanism, through a DNA recombination pathway. Exploration into the specific mechanisms of telomere maintenance in cancer have led to the development of drugs such as Imetelstat (GRN163L), BIBR1532, 6-thio-dG, VE-822, and NVP-BEZ235 being investigated as therapeutic approaches for treating telomerase and ALT tumors. The successful use of 6-thio-dG (a nucleoside preferentially recognized by telomerase) that targets and uncaps telomeres in telomerase positive but not normal telomerase silent cells has recently shown impressive effects on multiple types of cancer. For example, 6-thio-dG overcomes therapy-resistant cancers in a fast-acting mechanism potentially providing an alternative or additional route of treatment for patients with cancer. In this perspective, we provide a synopsis of the current landscape of telomeres and telomerase processing in cancer development and how this new knowledge may improve outcomes for patients with cancer.

Keywords: 6-thio-dG; ALT; BRAF; hTERC; hTERT; melanoma; telomerase.

© 2019 Wiley Periodicals, Inc.

[biopearl123]

I don’t think a patent court would agree with you. They are far from similar medicines. Geron and Sergei knew that a long time ago and there is wording in old patents that seems to cover 6-TG as a way to attack rampant proliferation. Dr. Scarlett would not comment on this when I asked about years ago and I doubt he (or Sergei) will comment on it now. MAIA is clearly perusing a path in solid tumors and Geron as we know is not.

[LWS]

More about Imetelstat, THIO their Similarities and their Differences

bp --- Imetelstat is an oligonucleotide and so is THIO. How different or how similar they are is far beyond my knowledge of chemistry. Also, I have no idea what is covered and what is not in the patents. I suspect that there are overlapping features that may bring these two companies closer together.

I am suggesting that Geron and MAIA have common agendas at opposite ends of the spectrum (blood cancers vs. solid tumors) that involve about 90% of all cancers (telomere and telomerase interactions).

I do not know the answers, so, in my opinion, this is an interesting subject to pursue for information and better understanding of the two medicines (Imetelstat & THIO).

Note: There was considerable talk about patents at the ends of both the Needham chat and the Stifel chat including patent extensions and orphan drugs.

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Material for Reference

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.