Putting 6-thio-Dg into perspective

[biopearl123]

Worth continued watching, here’s a good place to start:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293221/

[biopearl123]

Here’s a report funded by MAIA, clearly not free of bias therefore. I would encourage a revisit to the question as to who controls the patent on 6-thio-Dg. Anyway we shouldn’t lose sight of the ties between MAIA, Sergei and Jerry Shay. I know I have read patent filings remotely that seemed to include 6-thio-Dg attributing the patent to Geron when Sergei was there but these MAIA patents seem to claim ownership. Anyone who can shed updated light on this would be appreciated. Did MAIA/Geron divide the world in two and Geron took the liquid tumor route and MAIA the sold one? We have discussed in remote past but with stock showing so poorly and MAIA planning stock by back, just wondered if we might discuss further. Bill our controversial Socrates has been touting this all along even in his admittedly acerbic manner. Geron very secretive about basic bench work (if any) mostly now directed by hints at oral agents. We have not seen recent presentations from the likes of Dr. Ma/Jameison or further “basic” work from Dr. Lane who is now leading the charge in AML clinically. MAIA has very strong basic scientists on board. Thoughts?

https://ml.globenewswire.com/Resource/D ... 140b86ad20

[LWS]

There is a world of oligonucleotides to be explored. We are near the beginning with Imetelstat leading the way. Both Geron and MAIA are in interesting negotiating positions, with possible (I believe likely) overlapping patents. Blood cancers are much further along with the EAP in place and NDA acceptance (ADCOM next). The solid tumors, as I understand it, require special delivery systems. MAIA seems to be making progress.

MAIA and Geron have common histories. These may come together again in ways that we can speculate about.
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by LWS » Fri Apr 28, 2023 4:10 pm
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.

[LWS]

Telomerase is under attack (present in most cancers)

Imetelstat has achieved a place of medical excellence (Nobel Prize, conferences, publications, KOLs, trials, MD Anderson, etc.) and different levels of success in treating various forms of blood cancer from ET, MDS, MF to AML. ODAC (Oncology ADCOM) is currently reviewing Geron's NDA request.

MAIA is also having successes in developing their medicine, with delivery systems for solid cancers. An NDA approval for Imetelstat, will also be a major boost for MAIA (THIO).

This is the 'tip of the iceberg' for both companies (Geron & MAIA), with years of research and progress ahead.

[LWS]

Free PMC article

2022 Oct;45(5):991-1003. doi: 10.1007/s13402-022-00702-8.
pub 2022 Aug 12
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Telomerase-targeting compounds Imetelstat and 6-thio-dG act synergistically with chemotherapy in high-risk neuroblastoma models

Janina Fischer-Mertens, Felix Otte, Andrea Roderwieser, Carolina Rosswog, Yvonne Kahlert, Lisa Werr, Anna-Maria Hellmann, Maya Berding, Bill Chiu, Christoph Bartenhagen, Matthias Fischer


Abstract

Background: The majority of high-risk neuroblastomas harbor telomerase activity, and telomerase-interacting compounds, such as 6-thio-2'-deoxyguanosine (6-thio-dG), have been found to impair the growth of telomerase-positive neuroblastoma cell lines. It has remained unclear, however, how such drugs can be combined with other compounds used in current treatment concepts for neuroblastoma patients.

Methods: Growth-inhibitory effects of varying concentrations of 6-thio-dG in combination with etoposide, doxorubicin or ceritinib were determined in eight telomerase-positive neuroblastoma cell lines with distinct genetic backgrounds. Tumor growth inhibition of subcutaneous xenografts from three different cell lines was assessed upon treatment with 6-thio-dG, the competitive telomerase inhibitor imetelstat, etoposide, or combinations of these compounds.

Results: Robust synergistic anti-tumor effects were observed for combinations of 6-thio-dG and etoposide or doxorubicin, but not for 6-thio-dG and ceritinib, in telomerase-positive neuroblastoma cell lines in vitro. Treatment of mouse xenografts with combinations of 6-thio-dG and etoposide significantly attenuated tumor growth and improved mouse survival over etoposide alone in two of three cell line models. Treatment of xenograft tumors by imetelstat monotherapy decreased telomerase activity by roughly 50% and significantly improved survival over control in all three models, whereas treatment with imetelstat plus etoposide led to enhanced survival over etoposide monotherapy in one model. Mechanistically, the synergistic effect was found to be due to both increased apoptosis and cell cycle arrest.

Conclusion: Our study indicates that telomerase is an actionable target in telomerase-positive neuroblastoma, and demonstrates that combination therapies including telomerase-interacting compounds may improve the efficacy of established cytotoxic drugs. Targeting telomerase may thus represent a therapeutic option in high-risk neuroblastoma patients.

Keywords: Animal models; Drug testing; Neuroblastoma; Pediatric cancer.

© 2022. The Author(s).

[KTArsenal]

Why are you still here?

[LWS]

KT -- I am going on the assumption that Imetelstat will be approved soon (timeline?) for this pending MDS/NDA. That will open up the possibility of all sorts of off-label uses, including, in combination, with established forms of chemotherapy. That could lessen the unpleasantness of these toxic drugs, improve the quality of life, and perhaps have other positive features, including overall survival time. We will see.
=================================================================

Conclusion: Our study indicates that telomerase is an actionable target in telomerase-positive neuroblastoma, and demonstrates that combination therapies including telomerase-interacting compounds may improve the efficacy of established cytotoxic drugs. Targeting telomerase may thus represent a therapeutic option in high-risk neuroblastoma patients

==================================
Cytotoxic means that a substance or process can damage cells or cause them to die. "Cyto" means cell and "toxic" means poison. You might hear the word when talking about chemotherapy drugs that kill cancer cells. The human immune system even has cells that are cytotoxic: T-cells kill bacteria, viruses, and cancer cells.

[pursang]

Why are you still here?

As so he can constantly state the obvious? So redundant and tiresome.
Myself I've learned so much here and for the most part stay silent.
I think my only post was thanking Bio for the effort he and others put into this site.
But this incessant repetition goes beyond the pale.

[CKTC]

Maia’s drug THIO (6-thio-2′-deoxyguanosine, aka 6-thio-dG) is a nucleoside. Geron’s imetelstat is a nucleotide, or rather, an oligonucleotide, which is a small nucleotide. Chemically, a nucleoside contains a nitrogen base and a sugar. A nucleotide contains a nitrogen base, a sugar, and a phosphate. The drugs are not chemically similar, nor do they function in similar manners. Imetelstat is designed to inhibit telomerase, which eventually results in DNA chain termination and cell death. THIO is designed to be picked up by telomerase and incorporated into telomeres resulting in immediate DNA chain termination and cell death. THIO has major advantages over imetelstat. There is no lag time, as DNA termination is immediate, and its effect is independent of telomere length. THIO is unquestionably a more elegant drug, and I doubt there would be any patent overlap between the two. Maia licensed THIO from the University of Texas.

[LWS]

Thank you CKTC for the very informative and concise biochemistry lesson. .

Imetelstat has the advantage of time, since NDA approval appears to be very close. Also, I was not aware of the role of the University of Texas. That is also the homebase of MD Anderson, who has collaborated with Geron with Imetelstat. Geron is focusing on blood cancers, and MAIA is focusing on more solid types of cancer. The ultimate beneficiaries will be the patients. I wonder what IMET2.0 will look like.

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THIO has major advantages over imetelstat. There is no lag time, as DNA termination is immediate, and its effect is independent of telomere length. THIO is unquestionably a more elegant drug, and I doubt there would be any patent overlap between the two. Maia licensed THIO from the University of Texas.

[biopearl123]

CKTC, thanks as always for posting. I do wonder if the lag time for Imetelstat is much less of an issue with AML since the cell doubling time is measured in hours. Also the “non canonical” effects of Imetelstat, now known to be related to ferroptosis effects might be at play. Of course the subtext of your note highlights what an abysmal failure Imetelstat was in solid tumors and the advantages presented by 6-thio-DG in this arena. We did have some remote discussions about the IP regarding the telomere in general in the past and there was verbiage in some of Geron’s patent filings that specifically mentioned guanine related compounds so I have always wondered if a future patent fight might loom.

[biopearl123]

https://patents.justia.com/patent/11279720

[CKTC]

biopearl123
That’s a good find! I wish I still had the mental bandwidth to research these applications. The original application was filed in 2011, and the patent was finally approved in 2022. Standard patent law provides 20-year exclusivity from the original filing date, so in this case, it is through 2031 or seven more years. Assuming Dr. Shay and the University of Texas filing doesn’t differentiate THIO sufficiently, which would be unlikely, and assuming THIO doesn’t reach the market any time before 2026, which it can’t, would Geron want to sue Maia to prevent a drug from reaching a market (solid tumors) that it’s not even pursuing itself, understanding that its patent claim would only be enforceable for a few more years anyway? Scarlett is petty enough to do that, but it would open up the debate as to why Geron didn’t develop, or license for development, a potentially valuable drug it developed over a decade ago. I do know the Federal courts take a very dim view of anyone who might try to prevent or delay a safe and effective drug from reaching the market. So, if Geron filed a claim against Mia, it would have that to contend with. I also quickly looked at Maia’s 10-Q and noticed that the 2-4% royalty it will pay the University of Texas Southwestern on THIO sales would be reduced by 50% if the compound is not covered by a valid claim (patent). So maybe Maia knew this might be an issue when it originally licensed the compound? Regardless, we’ll have to see how this all plays out. Hopefully, imetelstat will be approved in 2024, and patients can finally start receiving the benefits of a compound that seems to have been in development forever.
Merry Christmas, everyone!!!

[biopearl123]

CKTC, I was hoping this patent might get your attention. Thanks for sharing your thoughts. I can’t imagine Geron would just roll on this without attempting some agreement on royalties (or merger—time to come home Sergei?) Happy holidays to all. bp

[LWS]

I can’t imagine Geron would just roll on this without attempting some agreement on royalties (or merger—time to come home Sergei?)--- from bp

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The wait for information from ODAC to surface in some way, concerning Imetelstat, is the prime consideration now. The next very important consideration is a combination of Sergei, patents, other intellectual property and intentions about collaborations between Geron and MAIA (which can take many forms) on the 90% of cancers that are telomerase dependent. 2024 will be interesting and productive.

[LWS]

Telomerase Inhibitors for Potentially 90% of all Cancers

MD Anderson and the University of Texas medical unit are already partners. They are building the ulitmate cancer research and treatment center in Austin Texas. Both are well aware of Imetelstat and THIO. I suspect they are involved in intellectual property discussions, including overlapping patents.

Imetelstat's NDA approval (blood cancers) will also be a major victory for MAIA (solid cancers with delivery systems) for their proof of concept. It makes sense for the two companies (Geron & MAIA) to find a way to collaborate. We are talking about partial remissions, complete remissions, and, hopefully, some cures. This is just the beginning.
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History Lesson: Imetelstat (IMET has come a long way since ET). Dr. Sergei Gryaznov (Dr. G, now at MAIA), formerly Geron's (NASDAQ: GERN) Chief Scientist in Nucleic Acid Chemistry, is the named inventor of GRN163L, also known as Imetelstat