There are many ways to think about partnering

[LWS]

Telomeres and Cancer (original paper)

Dr. Tomislav Meštrović, MD, Ph.D.
By Dr. Tomislav Meštrović, MD, Ph.D.

Telomeres are structures found at the ends of human chromosomes that contain thousands of repeats of repetitive TTAGGG DNA sequences. A ribonucleoprotein enzyme complex known as telomerase maintains telomere length in cancer cells by adding TTAGGG repeats onto the telomeric ends, compensating for the normal shortening of telomeres in all dividing cells.

The theory that telomerase is the culprit in maintaining human cancers was proposed in 1990, but the evidence just recently became persuasive enough. A majority of human cancers exhibit critically short telomeres, suggesting that tumors can arise from genetically instable cells with dysfunctional telomeres.

--------------------------
biopearl123--- Excerpt from this paper

[LWS]

I have borrowed from several contributors. Geron seems to be going in many directions at once. There is much activity now. This is an extremely interesting and exciting time. Geron seems to be spinning a ‘web of partners and collaborators’.

Imetelstat can go in many directions from single-agent to a variety of combinations, with numerous patents now in place. Disease modification, the good safety profile, and the ability to kill cancer-stem-cells (normal cells not affected), all are unique and very positive factors. Single-agent approvals are close, with the UK (MHRA) likely first.

1. Big pharma---Bayer AG/Vividion, AbbVie, JNJ/Janssen
2. People-- Dr. Rizo, Dr. Feller, Dr. Scarlett
3. Imetelstat---single-agent, blood cancers, combinations, vaccines, solid tumors, telomeres & telomerase interactions
4. Approvals--- UK, EU, USA
5. Processes-- staff, manufacturing
6.Collaborator--- MD Anderson
``````````````````````````````````````````````````````````
Combinations studies in progress, with more to come:

(With Incyte)-- IMproveMF Phase 1 study of imetelstat + ruxolitinib in frontline MF in May 2022

(With AbbVie) -- TELOMERE Phase 1/2 study of imetelstat + HMAs or venetoclax in R/R
AML in 2H 2022
``````````````````````````````````````````````````````````````
The two hats of Dr. Rizo now include Geron and Bayer AG (Vividion). Bayer is fully aware of her involvement with Imetelstat, and certainly has the deep pockets to support both Dr. Rizo and Imetelstat in any way that they wish. The possibilities are interesting.

The two hats of JNJ---Looking at Nishan Sengupta's current job title at JNJ, he is the Global/US Access Strategy Lead-IMBRUVICA.........

Remember who else worked with IMBRUVICA while at JNJ/Janssen ???
------------------------------------------------
MD Anderson---Everyone seems fixated on P3 TLR when I think that a "major" BO offer is contingent on the Pre-Clinical Lymphoid Malignancy results at MD Anderson due by the end of this year. Global patient Lymphoid Malignancy numbers are in the TENS of millions. A total game changer for Imetelstat and it's market potential. And remember that one of Dr. Rizo's "specialties" - if you will - is Lymphoid Malignancies......she was involved with several Lymphoma programs while 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. During her initial tenure with Janssen, Dr. Rizo worked on a variety of Velcade clinical trials in lymphoma and multiple myeloma."

[LWS]

(From kmall)----Nishan Sengupta - Vice President, Market-Access, Pricing, Evidence Strategy, Geron Corporation

Hired August 2021: Nishan Sengupta Is CURRENTLY employed at JNJ as well as Geron. He had been employed at JNJ for over 17yrs.

Nishan Sengupta's CURRENT title at JNJ is: Global/US Access Strategy Lead-IMBRUVICA, B-Cell, Rare Hem - August 2019 - PRESENT

This cements JNJ's never ending interest in Imetelstat. At one time, several years ago now, JNJ/Jannsen had about 10 medicines on their most likely to succeed list, including: Imbruvica and Imetelstat. For various reasons (more business than medical) JNJ chose to move forward with Imbruvica and closely watch and support Imetelstat. Imetelstat is now ready for prime time. The two medicines are a likely combination. JNJ will be part of Imetelstat's future.

[LWS]

Subcutaneous telomerase inhibitor compositions and methods for using same

Abstract

Aspects of the disclosure include telomerase inhibitor compositions formulated for subcutaneous administration. Compositions according to certain embodiments include a hyaluronidase enzyme and a telomerase inhibitor having an oligonucleotide and a lipid moiety linked to the 5' and/or 3' end of the oligonucleotide. Methods for subcutaneously administering the telomerase inhibitor compositions, such as in the treatment of a neoplasm are also described. Kits having or not having a subcutaneous injector are also provided

.

This is apparently the basis of a new and advanced form of Imetelstat that Geron has patented. The patent office, in a sense, is the 'most important partner' that protects Geron from competition for a number of years. Geron has numerous patents, which will serve them well when the investment world figures out that Imetelstat will soon be approved in several ways as a single-agent, with vast research potential in combinations for many years. Two combination trials are getting off of the ground with AbbVie and Incyte.

https://patents.google.com/patent/WO2022015935A2/en ---- link from Carlos (YMB)

[LWS]

So many projects are underway or being contemplated that it is hard to keep track. It appears that Geron is taking 5 approaches that will allow them to remain intact (if they choose to), and at the same time have several partners and collaborators.

1/ Single-agent now in 2 phase 3’s (MF, MDS) and nearing approvals
2/ Combinations: with Incyte---IMproveMF; with Abbvie---TELOMERE; possibly with JNJ (Imbruvica & JNJ’s 2’hats’)
3/MD Anderson (Pre-Clinical Lymphoid Malignancy results at MD Anderson due by the end of this year)
4/ NIH & Cancer Moonshot
5/ Possible projects with Bayer AG (Dr. Rizo’s ‘2 hats’)

[LWS]

There has been considerable European interest in Imetelstat. Many believe that the first approvals and partners will be European.

1/ Imetelstat and HIF inhibitors evolving use in MDS
Valeria Santini University of Florence, Florence, Italy

2/ Bayer AG (Germany) and Dr. Rizo's two jobs as President of a Bayer subsidiary ( Vividion) and as a senior consultant/advisor to Geron

3/ The interest of the MHRA (Medicines and Healthcare products Regulatory Agency) in England

4/ EMA (European Medicines Agency) fast track and orphan drug approvals

5/ Janssens (JNJ) Belgium origins

6/ Novartis interest

[LWS]

The AbbVie trial & connection:

TELOMERE is a Phase 1/2 clinical trial evaluating imetelstat in patients with relapsed/refractory acute myeloid leukemia, or AML. The trial is designed to test two distinct combinations of imetelstat and venetoclax or imetelstat and azacitidine. The primary objective of the Phase 1 portion is to identify a safe dose of each of the combinations. The primary objective of the Phase 2 portion of the study is overall response rate for each of the combination regimens. The study is expected to be open for patient enrollment in the second half of 2022.


***Results (preclinical): A dose-dependent synergistic activity in inducing apoptosis was observed in multiple AML cell lines when combining imetelstat with venetoclax. In the MOLM-13 cell line, single-agent imetelstat and venetoclax had modest apoptotic activity after 48 hours (22% and 30% respectively), but the combination achieved 88% at 48 hours and nearly 100% at 96 hours. **

This potential combination cure is made more likely by the recent AML evidence that Imetelstat kills cancer-stem-cells.

I have high hopes that Imetelstat will be approved in the near future for single-agent use based upon its trial data, safety profile, orphan status and fast track. I am focused on the preclinical work combining Imetelstat and Venetoclax that achieved "nearly 100%" apoptotic activity in 96 hours. This combination, if successful at the clinical level, is breakthrough territory establishing the importance of Imetelstat cancer combinations. I suspect that AbbVie and Geron have done substantial additional testing in the last few years and are very confident about the outcome. This is likely to be an enduring relationship.

[LWS]

JNJ has been part of Geron's past. JNJ will likely be involved in Geron's future.

The Lymphoid Malignancy studies at MD Anderson will add quite a bit to that answer. As will P3 IMerge TLR in January and hopefully FDA NDA to follow.

If some Big Pharma doesn't step up to the plate soon, this could easily be out of their reach in the very near future. Just my take on how I see things these days. -Kmall

(From kmall)----Nishan Sengupta - Vice President, Market-Access, Pricing, Evidence Strategy, Geron Corporation

Hired August 2021: Nishan Sengupta Is CURRENTLY employed at JNJ as well as Geron. He had been employed at JNJ for over 17yrs.

Nishan Sengupta's CURRENT title at JNJ is: Global/US Access Strategy Lead-IMBRUVICA, B-Cell, Rare Hem - August 2019 - PRESENT

JNJ's continuing interest plus MD Anderson's ongoing research is now in focus. Imbruvica is a JNJ approved medicine and would seem to be a logical combination with Imetelstat. JNJ has been the 'mystery-man' for a very long time.

What is IMBRUVICA® (ibrutinib)?

IMBRUVICA® (ibrutinib) is a prescription medicine used to treat adults with:
• Mantle cell lymphoma (MCL) who have received at least one prior treatment
• Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
• Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL) with 17p deletion
• Waldenström’s macroglobulinemia (WM)
• Marginal zone lymphoma (MZL) who require a medicine by mouth or injection (systemic therapy) and have received a certain type of prior treatment
• Chronic graft versus host disease (cGVHD) after failure of 1 or more lines of systemic therapy

MD Anderson---Everyone seems fixated on P3 TLR when I think that a "major" BO offer is contingent on the Pre-Clinical Lymphoid Malignancy results at MD Anderson due by the end of this year. Global patient Lymphoid Malignancy numbers are in the TENS of millions. A total game changer for Imetelstat and it's market potential. And remember that one of Dr. Rizo's "specialties" - if you will - is Lymphoid Malignancies......she was involved with several Lymphoma programs while 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. During her initial tenure with Janssen, Dr. Rizo worked on a variety of Velcade clinical trials in lymphoma and multiple myeloma."

[LWS]

NIH, the Cancer Moonshot, Imetelstat

Is telomerase active in cancer cells?

Telomerase is silenced in most normal cells but is active in an estimated 85% to 95% of human cancer cells. As a result, cancer cells essentially become immortal. For this reason, some have called telomerase the “immortality enzyme.” Nevertheless, the telomeres in cancer cells are generally shorter than telomeres in normal cells

It is likely that NIH is closely following the TELOMERE trial (AbbVie combination with Imetelstat) for AML. Imetelstat kills cancer-stem-cells (Pediatric AML, preclinical in mice and sponsored by NIH among others). That clinical trial is just getting off the ground.

Imetelstat, in combinations, has vast potential in most cancers. It is ideally suited for the Cancer Moonshot.
++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++++

NIH*****1-800-4-CANCER Live Chat Publications Dictionary

• CANCER MOONSHOT℠
o Progress
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Cancer Moonshot℠

Cancer Moonshot Reignited in 2022

On February 2, 2022, President Biden announced plans to reignite the Cancer Moonshot to end cancer as we know it.

As Vice President, in 2016, Joe Biden launched the Cancer Moonshot with the mission to accelerate the rate of progress against cancer. The cancer and patient community and medical researchers responded with tremendous energy and ingenuity.

At its launch, the Cancer Moonshot set forth three ambitious goals: to accelerate scientific discovery in cancer, foster greater collaboration, and improve the sharing of data.

On February 2, 2022, President Biden announced a reignition of the Cancer Moonshot, highlighting new goals: to reduce the death rate from cancer by at least 50 percent over the next 25 years and improve the experience of people and their families living with and surviving cancer—and, by doing these and more, to end cancer as we know it today.

By focusing on areas of cancer research that are most likely to benefit patients as a result of new investment, the Cancer Moonshot has brought together a large community of investigators and clinicians who are dedicated to expediting research to improve the lives of people with cancer and their loved ones.

Congress passed the 21st Century Cures Act in December 2016, authorizing $1.8 billion in funding for the Cancer Moonshot over 7 years. The funding must be appropriated each fiscal year (FY) over those 7 years. Congress appropriated $300 million to NCI for FY 2017, $300 million for FY 2018, $400 million for FY 2019, $195 million for FY 2020, and $195 million for FY 2021.

[biopearl123]

LWS, you have made two assertions as fact. One, that the NIH is closely following the TELOMERE study and the other that the NIH is sponsoring preclinical AML studies with Imetelstat. While this might be the case unless you know these statements to be true they must be presented as your opinion. You have made these statements as fact. Please substantiate. If rather these are your opinions, you should state them as such. This is a place for discussion but fact and opinion are not the same. It would not be good if someone made an investment decision or a patient chose to participate in a study based on a post they thought were factual but was not. I will allow you 24 hours to amend your post otherwise I will be forced to take it down. You (and every poster) owe it to fellow board members as well as the patients who read this board to be clear in separating fact from opinion. bp

[LWS]

biopearl123--- I believe all that I have said to be true and is supported by fact. Please tell me which comments need to be modified.
==============================

What is a patient-derived xenograft (PDX) model? Patient-derived xenografts (PDX) are models of cancer where the tissue or cells from a patient’s tumor are implanted into an immunedeficient or humanized mouse.

NIGMS Home - National Institute of General Medical …
https://www.nigms.nih.gov

The National Institute of General Medical Sciences (NIGMS) supports basic research that increases understanding of biological processes and lays the foundation for advances in …

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45 Center Dr, Bethesda, MD 20892 · (301) 496-7301

Grant support
unnumbered/Geron (United States)
unnumbered/Lisa Dean Moseley Foundation
unnumbered/Leukemia Research Foundation of Delaware
P20GM103446/GM/NIGMS NIH HHS/United States
unnumbered/Andrew McDonough B+ Foundation
unnumbered/Nemours Foundation

. 2022 Mar 30;11(7):1923.
doi: 10.3390/jcm11071923.

Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts

Sonali P Barwe 1, Fei Huang 2, Edward Anders Kolb 1, Anilkumar Gopalakrishnapillai 1

Abstract
Acute myeloid leukemia (AML) in children remains deadly, despite the use of maximally intensive therapy. Because leukemia stem cells (LSCs) significantly contribute to chemoresistance and relapse, therapies that specifically target the LSCs are likely to be more beneficial in improving outcome. LSCs are known to have high telomerase activity and telomerase activity is negatively correlated with survival in pediatric AML. We evaluated the preclinical efficacy of imetelstat, an oligonucleotide inhibitor of telomerase activity in patient-derived xenograft (PDX) lines of pediatric AML. Imetelstat treatment significantly increased apoptosis/death of the LSC population in a dose-dependent manner in six pediatric AML PDX lines ex vivo, while it had limited activity on the stem cell population in normal bone marrow specimens. These results were validated in vivo in two distinct PDX models wherein imetelstat as single agent or in combination with chemotherapy greatly reduced the LSC percentage and prolonged median survival. Imetelstat combination with DNA hypomethylating agent azacitidine was also beneficial in extending survival. Secondary transplantation experiments showed delayed engraftment and improved survival of mice receiving imetelstat-treated cells, confirming the diminished LSC population. Thus, our data suggest that imetelstat represents an effective therapeutic strategy for pediatric AML.

Keywords: imetelstat; leukemia stem cells; patient-derived xenograft models; pediatric acute myeloid leukemia; telomerase.

[biopearl123]

LWS, firstly there is no reason to think the NIH is giving more or less attention to the TELOMERE study than any of the other hundreds of studies they over see. Secondly, here is what the article really says under funding:

“ Funding: This project was supported by grants from Geron Corporation, Lisa Dean Moseley Foun- dation, Leukemia Research Foundation of Delaware, Andrew McDonough B+ Foundation, the Cell Science Core (Delaware-INBRE P20GM103446), and the Nemours Foundation.”

There is no mention of direct sponsorship by the NIH for the AML study you cite.

[LWS]

“ Funding: This project was supported by grants from Geron Corporation, Lisa Dean Moseley Foun- dation, Leukemia Research Foundation of Delaware, Andrew McDonough B+ Foundation, the Cell Science Core (Delaware-INBRE P20GM103446), and the Nemours Foundation.”---From biopearl123

I have made one edit and will make others if you wish (please identify). NIH certainly appears to be interested. On further examination there is a significant interest from Delaware, the President's home state. The President also is the founder of "The Cancer Moonshot" project. This could be a coincidence.

Anyway, for what it is worth, commonsense tells me that NIH is aware of the forming TELOMERE trial and is following that trial. I have no 'inside-information'.

[biopearl123]

I give credit to your enthusiasm but not your imagination. Please keep it factual and if something you post is your opinion please make that plain. Thanks

[LWS]

Excerpt from Abstract--These results were validated in vivo in two distinct PDX models wherein imetelstat as single agent or in combination with chemotherapy greatly reduced the LSC percentage and prolonged median survival. Imetelstat combination with DNA hypomethylating agent azacitidine was also beneficial in extending survival. Secondary transplantation experiments showed delayed engraftment and improved survival of mice receiving imetelstat-treated cells, confirming the diminished LSC population. Thus, our data suggest that imetelstat represents an effective therapeutic strategy for pediatric AML.

Keywords: imetelstat; leukemia stem cells; patient-derived xenograft models; pediatric acute myeloid leukemia; telomerase.

I am "enthusiastic" based upon the data and the trial results to date. I do not understand why you believe that NIH is not highly interested in the TELOMERE new trial. AML is certainly the focus of the abstract. It appears that you are trying to minimize the excitement. This combination trial, if successful, opens the door to many new combination trials.

[biopearl123]

LWS, the fact is, hematologic malignancies AML included are very difficult diseases to treat. Even if remission is achieved, leave a few hidden cells behind (MRD) then the disease can come roaring back. You have to get them all. Life expectancy is short under the best of circumstances. Take a look at how long the best median survival over control in the lab animals actually was (less than 2 weeks) and you will understand why I am not cracking open the champagne yet and am cautioning against irrational exuberance. It’s progress sure. But I am charged with being sure we present credible information on this board. If you want to be enthusiastic go right ahead, just be up front about what is real and what is not, and hope for better combination studies and better results in the future. Dr. Lane’s mice with adult AML cells did much better. That’s what Geron is working toward. bp

[LWS]

***Results (preclinical): A dose-dependent synergistic activity in inducing apoptosis was observed in multiple AML cell lines when combining imetelstat with venetoclax. In the MOLM-13 cell line, single-agent imetelstat and venetoclax had modest apoptotic activity after 48 hours (22% and 30% respectively), but the combination achieved 88% at 48 hours and nearly 100% at 96 hours. ***

I agree that we should not get ahead of the clinical results. We are still waiting for some single-agent approvals, which appears very likely, but one never knows until it happens. The preclinical results, that we know about, look very promising. I wonder if there have been some 'under-the-radar' experiments on the clinical level.

Controlling telomerase appears to be an important step in better understanding and treating blood cancers and perhaps beyond. The Cancer Moonshot has been hidden behind all of the other news, but it is real with a number of projects in motion. Imetelstat, in my opinion, will be an important part of advanced cancer research in this decade. Killing cancer-stem-cells appears to be an unique and significant advance with many implications.

Simple Summary

About 20% of children with acute myeloid leukemia (AML) experience refractory disease or relapse, despite receiving intensive therapy. Leukemia stem cells (LSC) have the ability to evade chemotherapy and propagate the disease leading to chemoresistance and relapse. Therefore, treatment options that are able to eliminate LSCs are likely to be more effective in prolonging disease-free survival. We have tested the effect of imetelstat, a potent inhibitor of telomerase activity that specifically kills LSCs, on pediatric AML cells in culture and in mouse models. Imetelstat was effective in specifically killing LSCs and extended animal survival when used as a single agent or in combination with chemotherapy or epigenetic drug azacitidine.--- (from YMB, man1)

[biopearl123]

Totally agree. The study you cite did suggest CURE in four mice.Targeting the malignant clone and cancer stem cell may be unique to Imetelstat so far.

[LWS]

More details on Human-Cancer-Stem-Cell Death from young patients (the Nemours Children’s Hospital )

Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts - PMC (nih.gov)


J Clin Med. 2022 Apr; 11(7): 1923.
Published online 2022 Mar 30. doi: 10.3390/jcm11071923
PMCID: PMC8999576
PMID: 35407531

Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts
Sonali P. Barwe,1 Fei Huang,2 Edward Anders Kolb,1 and Anilkumar Gopalakrishnapillai1,*

2.2. Pediatric Samples
We have developed and characterized disseminated PDX models of pediatric AML with varying cytogenetic profiles using AML cells from patients treated at the Nemours Children’s Hospital [18,19]. The mouse passaged pediatric AML PDX lines used in this study (n = 6) were generated using primary patient samples. Patient characteristics and demographics of patients aged 1–14 years are provided in Table 1. The normal bone marrow samples (n = 4) were collected under IRB approved protocol #1345366 and consisted of diagnostic bone marrow specimens that were later identified to not have leukemia (Table 1).

Imetelstat Induces Leukemia Stem Cell Death in Pediatric Acute Myeloid Leukemia Patient-Derived Xenografts - PMC (nih.gov)

[biopearl123]

LWS, reading and understanding papers of this sort can be confusing. You will see the last four cell lines were normal at the beginning of the study and served to confirm lack of toxicity. They never had pediatric AML.