There are many ways to think about partnering

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LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Wed Sep 14, 2022 7:01 pm

The topic and discussion of this thread centered on JNJ-74856665 used in combination with Azacitidine or Venetoclax. Similar to the upcoming TELOMERE P1/2 Clinical Trial using Imetelstat in combination with Azacitidine or Venetoclax. Once approved, Imetelstat as a single agent off label could possibly be a more efficient and effective means of treatment. However, for certain cancers and in the case of the patient in this discussion with AML and a two month survival expectancy, certain drug combinations, or in this example, the combination of JNJ-74856665 with Azacitidine or Venetoclax, has so far proven successful as a "miracle cure" - cited in the article. -Kmall
I am trying to digest the concept of a JNJ “miracle cure” (if it proves out), without Imetelstat in the mix. However promising this JNJ medicine is, it would likely be better with Imetelstat as an addition.

AbbVie is the combination key here (Azacitidine or Venetoclax) in both JNJ-74856665 and the TELOMERE/AML trial. The common interests of Geron, AbbVie and JNJ are obvious as we move forward with new combination treatments for an assortment of blood cancers.

There are many irons in the fire, with Imetelstat becoming an important part of the ongoing Cancer Moonshot endeavor. Telomerase inhibitors, such as Imetelstat, will be part of the 'cancer-solution'. It may be too early to talk about cures, but we can talk about improved treatments, longer survival time, disease modification and killing cancer-stem-cells.

Venetoclax

Common brand names: Venclexta

OVERVIEW

This medication is used to treat certain types of cancer (chronic lymphocytic leukemia-CLL, small lymphocytic lymphoma-SLL, acute myeloid leukemia-AML).

May Treat: Acute myeloid leukemia · Chronic lymphocytic leukemia · Small lymphocytic lymphoma

Brand Names: Venclexta · Venclexta Starting Pack

Drug Class: Antineoplastic - B-cell lymphoma-2 (BCL-2) inhibitors

Availability: Prescription Required

Pregnancy: Consult your doctor. This medication may be harmful to an unborn child.

Lactation: This drug should not be given to breastfeeding mothers

What are the uses of venetoclax?


Venetoclax is also used in combination with other medicines to treat acute myeloid leukemia in adults who are 75 years or older, or who cannot use standard chemotherapy due to other medical conditions.
Azacitidine is designed to slow the production of leukemia cells and help the bone marrow produce more healthy and normal functioning cells. Venetoclax is designed to kill leukemia cells by binding to and inhibiting a protein in cancerous cells that prevents the cell from dying known as “BCL-2”
Last edited by LWS on Wed Sep 21, 2022 4:48 pm, edited 1 time in total.

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Mon Sep 19, 2022 7:12 pm

Potential partners and collaborators

The interest in Imetelstat is now universal. These seem to be the companies or groups that Geron is most actively involved with to get approvals and to advance Imetelstat’s medical uses. The timeline for some single-agent approval is still unknown. Combination trials are underway.

1/ USA companies: JNJ, AbbVie

2/ European companies: Bayer AG, Novo Nordisk

3/ Groups: MD Anderson, NIH (Cancer Moonshot)

Geron and staff will continue to surprise us based upon past experiences.

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Thu Sep 22, 2022 12:24 am

We are now talking about TELOMERE/AML trials and combinations that revolve around Imetelstat (telomerase inhibitor), Venetoclax (BCL-2 protein inhibitor), and JNJ's special brew ("miracle-cure"), as we move from preclinical to clinical results. Geron, JNJ and AbbVie appear to be working together. The preclinical trials and have been impressive. Both Imetelstat and Venetoclax kill cancer cells by totally different mechanisms-- the perfect combination.
Experimental and Molecular Therapeutics


Preclinical History for Review


Abstract 1101: Telomerase inhibitor imetelstat in combination with the BCL-2 inhibitor venetoclax enhances apoptosis in vitro and increases survival in vivo in acute myeloid leukemia


Joshua J. Rusbuldt, Leopoldo Luistro, Diana Chin, Melissa Smith, Amy Wong, Margarita Romero, Aleksandra Rizo, Jacqueline Bussolari, Fei Huang and Amy (Kate) Sasser
DOI: 10.1158/1538-7445.AM2017-1101 Published July 2017

AbbVie already a partner (Looks like an outstanding combination, preclinical)

***Results: 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. ****


There has to be considerable interest, from all, in the fact that Imetelstat can kill cancer stem cells, while leaving normal cells alone. The research opportunities in Cancer Moonshot projects are unmatched.

HOW DO B-CELL LYMPHOMA INHIBITORS WORK?


B-cell lymphoma inhibitors are a class of drugs used to treat certain types of cancers such as chronic lymphocytic leukemia (a type of cancer that begins in the white blood cells), small lymphocytic lymphoma (a type of cancer that begins in the lymph nodes), and acute myeloid leukemia (cancer of the blood and bone marrow) in people 75 years of age or older or adults who have medical conditions that prevent them from being treated with other chemotherapy medications.
The only drug that belongs to this class is “venetoclax” which works by inhibiting the anti-apoptotic protein B-cell lymphoma-2 (BCL-2; necessary regulator of anti-cell programmed death process) with potential pro-apoptotic and antineoplastic activities and plays an important role in the negative regulation of apoptosis (death of cells which occurs as a normal and controlled part of an organism's growth or development), leading to programmed cell death of tumor cells.

• B-cell lymphoma inhibitors are administered via the oral route, typically once daily with food.
• B-cell lymphoma inhibitors work by blocking the action of a protein BCL-2 in the body responsible for cancer cell survival eventually, leading to their death.
HOW ARE B-CELL LYMPHOMA INHIBITORS USED?
B-cell lymphoma inhibitors are used to treat conditions such as:
• Chronic lymphocytic leukemia (a type of cancer that begins in the white blood cells)
• Small lymphocytic lymphoma (a type of cancer that begins in the lymph nodes)
• Acute myeloid leukemia (cancer of the blood and bone marrow
)




LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Sat Oct 01, 2022 5:04 pm

Most people (that are interested) now know that Geron is still a speculative stock, with very good science, strong positive trial results (single-agent), and very promising combination trials forming (TELOMERE/AML for example). The missing ingredient (for the share price) is a single-agent approval from the USA, EU or UK. That is very likely now, but there are always possible last-minute surprises (like hurricane Ian).

Geron seems to have figured out that they can have partners (JNJ and AbbVie for example), collaborators (MD Anderson for example), allies (NIH & Cancer Moonshot for example), and European interest (Novo Nordisk, Bayer AG), and still have an independent company. Geron will be around for a while. Will they be the next Amgen?

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Sat Oct 08, 2022 4:42 pm

Synergies are the interaction of two or more medicines so that their combined effect is greater than the sum of their individual effects. Geron, AbbVie and JNJ are focused on combinations and the synergies of the combinations with Imetelstat and Venetoclax, which kill (apoptotic activity) cancer cells modestly individually, but kill cancer cells in mass (nearly 100%) in combination.

These three companies appear to be working together: Imetelstat (telomerase inhibitor), Venetoclax (BCL-2 protein inhibitor). The TELOMERE (AML) trials hold great promise on the clinical level, especially when the preclinical results are reviewed.


Reference Materia
l

***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. ****

Abstract 1101: Telomerase inhibitor imetelstat in combination with the BCL-2 inhibitor venetoclax enhances apoptosis in vitro and increases survival in vivo in acute myeloid leukemia

Joshua J. Rusbuldt, Leopoldo Luistro, Diana Chin, Melissa Smith, Amy Wong, Margarita Romero, Aleksandra Rizo, Jacqueline Bussolari, Fei Huang and Amy (Kate) Sasser
DOI: 10.1158/1538-7445.AM2017-1101 Published July 2017


We are now talking about TELOMERE/AML trials and combinations that revolve around Imetelstat (telomerase inhibitor), Venetoclax (BCL-2 protein inhibitor), and JNJ's special brew ("miracle-cure"), as we move from preclinical to clinical results. Geron, JNJ and AbbVie appear to be working together. The preclinical trials and have been impressive. Both Imetelstat and Venetoclax kill cancer cells by totally different mechanisms-- the perfect combination.

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Thu Oct 13, 2022 7:37 pm

Combination and Partner Considerations

There are four medicines and three companies to consider as clinical combination trials start around the world (AML and other blood cancer trials ----TELOMERE and JNJ-74856665 ):

1/ Imetelstat (Geron)
2/ Venetoclax (Abbvie)
3/ Azacitidine (AbbVie)
4/ Imbruvica (JNJ)

Azacitidine is designed to slow the production of leukemia cells and help the bone marrow produce more healthy and normal functioning cells. Venetoclax is designed to kill leukemia cells by binding to and inhibiting a protein in cancerous cells that prevents the cell from dying known as “BCL-2”
(From kmall--revised) ----Nishan Sengupta - Vice President, Market-Access, Pricing, Evidence Strategy, Geron Corporation

Hired August 2021: Nishan Sengupta was employed at JNJ. He had been employed at JNJ for over 17yrs.

Nishan Sengupta's title at JNJ was: Global/US Access Strategy Lead-IMBRUVICA, B-Cell, Rare Hem
Both Imetelstat and Venetoclax kill cancer cells by totally different mechanisms-- the perfect combination. [ Imetelstat (telomerase inhibitor), Venetoclax (BCL-2 protein inhibitor)]

AbbVie is the combination key here (Azacitidine or Venetoclax) in both JNJ-74856665 and the TELOMERE/AML trial. The common interests of Geron, AbbVie and JNJ are obvious as we move forward with new combination treatments for an assortment of blood cancers.

Imbruvica is a targeted medicine that works by inhibiting the enzyme Bruton tyrosine kinase (BTK), which is part of a crucial signaling pathway in certain cancers, especially B-cell leukemias and lymphomas. By blocking this pathway Imbruvica triggers the death of cancer cells.

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Wed Oct 19, 2022 9:10 pm

There are four medicines and three companies to consider as clinical combination trials start around the world (AML and other blood cancer ----TELOMERE and JNJ-74856665 ):

1/ Imetelstat (Geron)
2/ Venetoclax (Abbvie)
3/ Azacitidine (AbbVie)
4/ Imbruvica (JNJ)
These four medicines are in use or being thought about in various combinations, perhaps all four together in a combination that is purposed or already in use. JNJ's interest and AbbVie's interest in Imetelstat is unquestioned. Imetelstat's greatest promise is in combinations with synergies.
But there is always a possibility that JNJ-74856665, an orally bioavailable, potent, and selective dihydroorotate dehydrogenase (DHODH) inhibitor has another name already in a completely different form. -Kmall

The topic and discussion of this thread centered on JNJ-74856665 used in combination with Azacitidine or Venetoclax. Similar to the upcoming TELOMERE P1/2 Clinical Trial using Imetelstat in combination with Azacitidine or Venetoclax. Once approved, Imetelstat as a single agent off label could possibly be a more efficient and effective means of treatment. However, for certain cancers and in the case of the patient in this discussion with AML and a two month survival expectancy, certain drug combinations, or in this example, the combination of JNJ-74856665 with Azacitidine or Venetoclax, has so far proven successful as a "miracle cure" - cited in the article. -Kmall

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Mon Oct 24, 2022 5:01 pm


Summary--- 3 Ways to Kill Cancer Cells


Venetoclax (approved -- AbbVie), Imbruvia (approved -- JNJ ) and Imetelstat (pending approval -- Geron) all kill cancer cells by different methods. Together, in combinations, there likely will be important synergies.

1/ Imetelstat (telomerase, an enzyme, inhibitor) -- kills cancer cells,
2/ Venetoclax (BCL-2 protein inhibitor) -- kills cancer cells
3/ Imbruvica is a targeted medicine that works by inhibiting the enzyme Bruton tyrosine kinase (BTK), which is part of a crucial signaling pathway in certain cancers, especially B-cell leukemias and lymphomas. By blocking this pathway Imbruvica triggers the death of cancer cells.
-------------------------------------------------------

Reference Material



Similarities Between Enzyme and Protein


• Enzymes and proteins are two types of biomolecules found in the body.
• Both are made up of a series of amino acids.
• Also, they are expressed with the use of instructions on genes.

Difference Between Enzyme and Protein


An enzyme refers to a substance produced by a living organism which acts as a catalyst to bring about a specific biochemical reaction while a protein refers to any of a class of nitrogenous organic compounds, which have large molecules composed of one or more long chains of amino acids and are an essential part of all living organisms, especially as structural components of body tissues such as muscle, hair, etc., and as enzymes and antibodies. Hence, this explains the basic difference between enzyme and protein.

Significance


However, enzymes are a type of proteins while proteins are a type of macromolecules in the body.

Structure


Another difference between enzyme and protein is that enzymes are globular proteins while proteins are either globular or fibrous proteins.

Classification

Enzymes are classified based on their function while proteins are classified based on their chemical composition.

Function


The main function of enzymes is to catalyze biochemical reactions while proteins form structures, catalyze biochemical reactions, and regulate biological processes. This is another major difference between enzyme and protein.
---------------------------

AbbVie is the combination key here (Azacitidine or Venetoclax) in both JNJ-74856665 and the TELOMERE/AML trial. The common interests of Geron, AbbVie and JNJ are obvious as we move forward with new combination treatments for an assortment of blood cancers.
---------------------------
Azacitidine is designed to slow the production of leukemia cells and help the bone marrow produce more healthy and normal functioning cells.

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Mon Oct 31, 2022 6:43 pm

Summary---The European Connections:

1/ Bayer AG (Germany)
2/ Novo Nordisk (Denmark)
3/ Novartis (Switzerland)

These 3 companies are interested in the future development of Imetelstat. We know most about Bayer AG and its research subsidiary (Vividion). The other 2 companies have been mentioned recently in association with Geron and Imetelstat.

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.

Dr. Rizo's two very important jobs (advisor/consultant to Geron and President of Vividion/Bayer AG) are interactive and point to the bright future of Imetelstat as a very important and transformative cancer medicine.

Vividion Therapeutics, Inc. is a biotechnology company focused on transforming the future of human health through the creation of highly selective small molecule medicines that drug traditionally inaccessible targets. The company is advancing a broad, diversified pipeline of multiple, selective small molecule therapeutics for highly sought-after disease-causing target proteins in oncology and immunology. As our knowledge of druggable pockets on disease-related proteins increases, our covalent chemistry-based library of small molecules expands.

Our platform has enabled us to identify hundreds of previously unknown or cryptic functional pockets on well-validated protein targets implicated in a wide range of oncologic and immunologic diseases, while simultaneously identifying compounds from our proprietary covalent chemistry library that interact in a highly selective manner with those pockets.

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Thu Nov 10, 2022 3:30 pm

MD Anderson is Imetelstat's well-known and well-respected collaborator. There have been numerous positive trials, experiments and tests using Imetelstat. In review, I find only positive comments, with several studies now underway. MD Anderson appears to be Geron's 'secret-weapon'.
---------------------------------
The University of Texas MD Anderson Cancer Center (MD Anderson) was established by the Texas State Legislature in 1941and is a free-standing, degree-granting health institution within The University of Texas System. Mission areas include patient care, research, education, and prevention. In 1971 MD Anderson became one of the nation’s first NCI-designated comprehensive cancer centers. MD Anderson’s strength lies in its ability to rapidly translate scientific knowledge into improved cancer therapies and prevention strategies.

MD Anderson houses one of the largest, most developed cancer prevention programs in the nation, conducting research to assess and manage cancer risk through early detection, genetic counseling and clinical interventions, and implementing prevention programs that include genetic testing, chemoprevention, behavioral and nutritional counseling. Translational goals are to develop and deliver comprehensive evidence-based strategies to achieve a measurable lasting reduction in the cancer burden, especially among the underserved.

Cancer is the singular focus for MD Anderson’s workforce of more than 19,000 employees with over 1,600 full-time faculty scholars who lead the largest number of NCI-funded grant programs and clinical trials of any institution in the nation. More than 6,500 trainees take part each year in educational programs, including advanced degrees at the Graduate School of Biomedical Science covering training from Cancer Biology to Clinical and Translational Science and bachelor’s degrees in allied health disciplines. MD Anderson invested approximately $700 million in research (FY14) which is anticipated to increase with our cancer Moon Shots Program.

The multidisciplinary approach to treating cancer pioneered at MD Anderson brings together teams of experts across disciplines to collaborate on the best treatment plan for patients. A major focus is to increase access to quality cancer care worldwide. This mission is reflected by more than 122,000 patients annually from across the nation and the world who receive care in Houston and 114,000 patients receiving care through our local, national and international affiliations. The global outreach to drive science and improve care also includes academic collaborations with 30 sister institutions in 23 countries as well as the development of a decision support platform known as the MD Anderson Oncology Expert Advisor powered by cognitive computing. Advancing care for patients is also enabled by 800 interventional clinical trial protocols involving more than 12,000 patients each year, engaged in testing approximately one-third of all new FDA-approved cancer drugs. The Institute for Personalized Cancer Therapy and the immune therapy platform provide profiling for more precise patient care and innovative clinical trials.

A goal-oriented Moon Shots Program was launched in 2012 to dramatically accelerate the pace of converting scientific discoveries into clinical advances that would significantly reduce cancer deaths. The program brings together large multi-disciplinary teams focused on high-impact projects that are enabled by professionally-driven technology platforms and resources.


* This profile was provided by the University of Texas MD Anderson Cancer Center.

Updated: February 10, 2021
1

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Sat Nov 19, 2022 5:33 pm

Review

1. Synergies in combinations (to be determined clinically)
2. Survival time
3. Disease modification
4. Transfusion Improvement
5. Kills Cancer Cells


As others have said, Geron is still a very speculative investment, with much potential. It will continue to be so, until Imetelstat gets single-agent approvals (FDA, EMA or MHRA in the UK).

With several important presentations coming in December (ASH), and a release of information promised in January, all we can do is listen and wait. Geron seems to be spinning a web of combination partners, deep pocketed partners, collaborators, and moonshot partners. It appears that there will not be a buyout any time soon.
1/ Imetelstat (telomerase, an enzyme, inhibitor) -- kills cancer cells,
2/ Venetoclax (BCL-2 protein inhibitor) -- kills cancer cells
3/ Imbruvica is a targeted medicine that works by inhibiting the enzyme Bruton tyrosine kinase (BTK), which is part of a crucial signaling pathway in certain cancers, especially B-cell leukemias and lymphomas. By blocking this pathway Imbruvica triggers the death of cancer cells.

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Sun Nov 27, 2022 7:34 pm


JNJ Importance to Imetelstat (Past, Present, Future)


More than any other company JNJ has had a continuing interest in Imetelstat, from the time of their close association with Geron leading to the “walk” (2018, I believe) where JNJ said that Imetelstat would eventually get approved, to current staff with backgrounds at JNJ/Janssen and ASH 2022, to “miracle cures” such as JNJ – 74856665 and development of oral Imetelstat.

All of this is not clearly in focus, and is suitable for discussion, as we wait for ASH and the January data release. There are many moving parts and we still do not know how they all fit together.

1/ TALC – a JNJ problem that is still not resolved. JNJ is splitting into two companies.
2/ Money – As originally constructed (before walk), not a good deal for JNJ
3/ Better Bets (Imbruvica) – A JNJ fully owned drug, that is suitable for combinations
4/ Janssen and JNJ support – staff and Korean manufacturing facility
5/ JNJ deep pockets
6/ JS statement – “Bigger than all of us”
7/ Oral form of Imetelstat --- In JNJ new formulations, perhaps
8/ “miracle cure”
=============================================
Background Material
The topic and discussion of this thread centered on JNJ-74856665 used in combination with Azacitidine or Venetoclax. Similar to the upcoming TELOMERE P1/2 Clinical Trial using Imetelstat in combination with Azacitidine or Venetoclax. Once approved, Imetelstat as a single agent off label could possibly be a more efficient and effective means of treatment. However, for certain cancers and in the case of the patient in this discussion with AML and a two month survival expectancy, certain drug combinations, or in this example, the combination of JNJ-74856665 with Azacitidine or Venetoclax, has so far proven successful as a "miracle cure" - cited in the article. -Kmall
----------------------------------
Venetoclax (ABT-199) is a novel, orally bioavailable small-molecule inhibitor for selective targeting of B-cell lymphoma 2 (BCL2). Venetoclax is in clinical development and shows high efficacy and safety in particular in the treatment of chronic lymphocytic leukemia (CLL), but preliminarily also in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
----------------------------------------------
(From kmall--revised) ----Nishan Sengupta - Vice President, Market-Access, Pricing, Evidence Strategy, Geron Corporation

Hired August 2021: Nishan Sengupta was employed at JNJ. He had been employed at JNJ for over 17yrs.

Nishan Sengupta's title at JNJ was: Global/US Access Strategy Lead-IMBRUVICA, B-Cell, Rare Hem
----------------------------------------
1/ Imetelstat (telomerase, an enzyme, inhibitor) -- kills cancer cells,
2/ Venetoclax (BCL-2 protein inhibitor) -- kills cancer cells
3/ Imbruvica is a targeted medicine that works by inhibiting the enzyme Bruton tyrosine kinase (BTK), which is part of a crucial signaling pathway in certain cancers, especially B-cell leukemias and lymphomas. By blocking this pathway Imbruvica triggers the death of cancer cells

LWS
Posts: 142
Joined: Thu Jul 14, 2016 2:00 am

Re: There are many ways to think about partnering

Post by LWS » Tue Dec 06, 2022 9:26 pm

Waiting for ASH

With ASH several days away (Dec. 10 – 13), I am focused on long time alliances and combinations. The two companies to watch most closely are JNJ and AbbVie. MD Anderson is Geron’s most important collaborator. I believe single-agent approvals cannot and will not be stopped. The most important combination studies are now focusing in on AML with oral Imetelstat the latest subject of interest. News about all of these subjects appears to be positive.

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