There are many ways to think about partnering

[LWS]

The End Game:

The NDA has been summitted to the FDA, with all (i's) dotted and (t's) crossed. Acceptance and approval now appear to be a formality considering successful trials, cancer disease modifications, a new EAP, and patients' immediate needs. (Ryan has the probability at 99.98%). The timeline (as always) is uncertain, but soon is the general belief.

All will be closely watching (potential partners, collaborators, doctors, investors and the most important---the patients).

[LWS]

August Revelations:

I suspect there is much more going on than any of us realize. If Imetelstat is the blockbuster medicine that we think and hope that it is, there is and will be considerable interest from all of the medical resources listed, and from the investment community going forward (perhaps led by Goldman Sachs).

August will be an interesting month, as we find out what relationships are likely, and what ones are already created.

With NDA approval, off-label opportunities arise. Apparently, Geron has a very strong package of telomerase inhibitor patents to keep the competition in check.
=========================================
Previous:

With the NDA acceptance and approval near, I made a list of organizations, that have been associated with Geron and Imetelstat one way or the other. All have been discussed on this board. Some have a continuing strong interest and others only a passing interest. In the coming months we will find out what associations, approvals, collaborations and partnerships are enhanced or newly created to manufacture, market and distribute Imetelstat.
=========================================================
USA Big Pharma
1. JNJ
2. AbbVie

USA Research and Cancer Hospitals
3. Mayo Clinic
4. MD Anderson

Ex-USA
5. Novo Nordisk (Denmark)
6. Novartis (Switzerland)
7. Bayer AG (Germany)

USA Government (Cancer Moonshot)
8. NIH/NCI

Outside Contractors
9. WEP
10. Parexel

Other Considerations
11. Incyte
12. MAIA

Approval Agencies
13. FDA (USA)
14. MHRA (UK)
15. EMA (EU)


==============================================

[LWS]

Potential of Imetelstat in combinations as a killer of cancer stem cells:

Imetelstat has much going for it. No one (on this board) doubts that the NDA will be approved, with patients' immediate needs always front and center, and the EAP recently put in place by the FDA.

Imetelstat needs a powerful, deep pocketed, partner to get through the FDA bureaucracy that seems to be part of the timeline. In addition, with disease modification and killing cancer stem cells proven, there seems to be almost unlimited opportunities for Imetelstat going forward.

The coming FDA advisory committee hearings (open to the public) should be very interesting and beneficial to Geron.
==============

Time & Timelines:

The line of evidence: Conferences (ASCO, EHA), KOLs, Webinars, MD Anderson, NDA submitted, EAP, NDA accepted, timeline (continuing question). I see no more obstacles on the medical side.

[LWS]

Four USA companies that are aware of and interested in Imetelstat:

1/ Abbvie (TELOMERE & Venetoclax)
2/ Gilead (Magrolimab)
3/ BMY (Luspatercept)
4/ JNJ (Imbruvica)

The EAP (Extended Access Program) is in place (very important), and the NDA has been accepted. It appears that Geron has had the strong support of JNJ (current staff and history) and AbbVie (TELOMERE, AML combination). Imetelstat seems to be a much better medicine than Luspatercept and Magrolimab (combinations with Imetelstat possible?). There seems to be overwhelming agreement about that. With such obvious comparisons publicly available (data, trials, etc.), the FDA has to recognize what best meets patients' needs in the here and now.

-------------------------------------------------------------------------------------

Some Material for Reference:

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 ASH2023. There are many moving parts and we still do not know how they all fit together.

The focus needs to be on getting Imetelstat approved for something, somewhere ASAP.

Note: We don't know much about JNJ-74856665 ("miracle cure"--Kmall). We believe it has been used successfully in England for AML, and is a combination with Venetoclax, likely Imbruvia, and with thoughts about Imetelstat (including oral form).
-------------------------------------------------
We are all working under the assumption that there is no misinformation about Imetelstat in the trials, including (primarily) safety and effectiveness. I believe that single-agent approvals are close, with fast-track and orphan status in place, and priority reviews possible. Then we can talk more about off-label possibilities and combination synergies. –LWS
----------------------------------------------------------------------------
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
----------------------------------------------------------------------------------------------------------------------------
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 (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. ****

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.
---------------------------------------------------------------------------------------------------------------
Combinations are in focus with JNJ still very much in the picture in ways that we do not understand. As Kmall continues to report, JNJ/Jannsen people keep finding their way to Geron. We assume, because of their special knowledge, the future for Geron and Imetelstat looks very bright to them. We do not know what discussions are taking place now about alliances, partnerships and perhaps buyouts. We also do not know the impact of fast-track and priority reviews for accelerating approvals (from FDA, EMA, MHRA (UK)). Venetoclax, Imbruvica and Imetelstat are likely key ingredients in both combinations (in unknown amounts), and all individually kill cancer cells (synergies).

What else is in these mixes?
-----------------------------------------------------------------------------------------------------------

[biopearl123]

LWS, I fail to see the strong support of the either J and J or Abbvie you cite. Individuals who previously worked at J and J have come to Geron in droves but these are individuals and do not necessarily represent what J and J management is thinking. I hope they are thinking of Geron but there does not seem to be a formal company connection. Same for Abbvie. The evidence is circumstantial and not concrete. bp

[LWS]

The evidence is circumstantial and not concrete. --from bp

The medical evidence looks solid to me (conferences, trials, KOLs, Webinars, EAP, NDA accepted, FDA public committee hearings coming). From an investment point of view, we are looking into the future with what evidence is available. John Scarlett has concealed any ongoing discussions quite well, so most of what I believe is now circumstantial evidence. There is nothing wrong with circumstantial evidence.

I believe that both JNJ and AbbVie will be an important part of Imetelstat's future (one way or the other). BMY and Gilead have medicines that seem to be inferior to Imetelstat, but both companies are active in the field of blood cancers. All four companies have very deep pockets.

I suspect there is much more going on than any of us realize. If Imetelstat is the blockbuster medicine that we think and hope that it is, there is and will be considerable interest from all of the medical resources listed, and from the investment community going forward.

[biopearl123]

LWS, there is plenty wrong with circumstantial evidence, particularly since it is speculative and not concrete. When you state this or that company has an interest in Geron that is speculation and should be labeled as such.

[LWS]

bp --- We are having two discussions:

1/ The medical evidence which appears to be very carefully gathered and proven. This is for the patients' unmet medical needs. Here we need the FDA's approval of the NDA for Imetelstat (beyond the EAP) to be viable.

2/ As investors (looking forward) it is all speculative, but (in my opinion) the circumstantial evidence is very positive.

[biopearl123]

LWS, I agree the medical data and the KOL’s presentations appear very positive. I was extremely disappointed that the FDA failed to grant priority review and continue to wonder why that occurred. Getting an NDA accepted even with standard review is an accomplishment but having a drug that can restore normal
bone marrow function seems pretty unique to me (but maybe not to the FDA)

[LWS]

--- the FDA failed to grant priority review and continue to wonder why that occurred. Getting an NDA accepted even with standard review is an accomplishment but having a drug that can restore normal
bone marrow function seems pretty unique to me (but maybe not to the FDA) -- from bp

=============================
Imetelstat (in my opinion) is a novel, breakthrough blood cancer medication with combination potential in 90% of all cancers. The EAP (Extended Access Program) is now functioning and needs to be better explained. We have advisory FDA committee hearings coming, to get to the details (open to the public). Perhaps, the FDA is being extremely cautious, since there is a whole unexplored world of oligonucleotides out there including Imetelstat and THIO. This NDA, when approved, opens the door for many innovations.

[LWS]

Oligonucleotide-Based Drugs and Therapeutics: Preclinical and Clinical Considerations for Development 1st Edition
by Nicolay Ferrari (Editor), Rosanne Seguin (Editor)

A comprehensive review of contemporary antisense oligonucleotides drugs and therapeutic principles, methods, applications, and research

Oligonucleotide-based drugs, in particular antisense oligonucleotides, are part of a growing number of pharmaceutical and biotech programs progressing to treat a wide range of indications including cancer, cardiovascular, neurodegenerative, neuromuscular, and respiratory diseases, as well as other severe and rare diseases. Reviewing fundamentals and offering guidelines for drug discovery and development, this book is a practical guide covering all key aspects of this increasingly popular area of pharmacology and biotech and pharma research, from the basic science behind antisense oligonucleotides chemistry, toxicology, manufacturing, to safety assessments, the design of therapeutic protocols, to clinical experience.

Antisense oligonucleotides are single strands of DNA or RNA that are complementary to a chosen sequence. While the idea of antisense oligonucleotides to target single genes dates back to the 1970's, most advances have taken place in recent years. The increasing number of antisense oligonucleotide programs in clinical development is a testament to the progress and understanding of pharmacologic, pharmacokinetic, and toxicologic properties as well as improvement in the delivery of oligonucleotides. This valuable book reviews the fundamentals of oligonucleotides, with a focus on antisense oligonucleotide drugs, and reports on the latest research underway worldwide.

[LWS]

Thoughts and History about JNJ and Imetelstat

There is positive support for all of these ideas, but the mystery continues:

1/ JNJ "never left the house" and has had a continuing interest in Imetelstat
2/ JNJ is fully aware of the migrating staff (JNJ & Jannsen to Geron)
3/ JNJ will be an important part of Imetelstat's future (speculation)
4/ Imetelstat is now a proven medicine (trials, KOLs, EAP, NDA near approval)
5/ Lancet and other articles leading up to ASH
6/ MD Anderson
7/ Cancer moonshot

=================================
JNJ & Imetelstat (some history, vintage 2018)

Geron’s Imetelstat Reaffirmed as a Priority for Johnson & Johnson

JNJ CEO Alex Gorsky cites hematology-related oncology among "key catalysts for growth."

07.18.2018
BY EDWARD KIM

We highlighted Geron Corporation GERN in this space in June 2018, citing the positive clinical trial results achieved so far by imetelstat, the company’s therapeutic candidate for myelofibrosis and myelodysplastic syndromes (MDS). Myelofibrosis is a rare form of blood cancer in which extensive scarring in the bone marrow disrupts the normal production of blood cells, while MDS is the most common form of blood cancer in which bone marrow cells become abnormal or malignant, thereby affecting blood cell production.

In our discussion last month, we acknowledged the risks surrounding Geron’s significant historical shareholder dilution and that it was vulnerable to an upcoming pivotal decision by Johnson and Johnson’s JNJ Janssen Pharmaceuticals unit on whether or not to continue the development program for imetelstat. We concluded that “the risk-reward of the stock at current levels merits the attention of long investors… and further, we believe that Janssen considers imetelstat to be a core part of its pipeline and view the continuation of the Geron agreement to be likely.” Based on yesterday’s comments from JNJ Chairman and CEO Alex Gorsky, we reiterate our view that Geron remains a priority for Janssen and JNJ.

Janssen reaffirms imetelstat’s potential as a billion dollar drug

In his comments during JNJ’s quarterly earnings conference call, Mr. Gorsky unambiguously referred to Geron’s therapeutic candidate when discussing Janssen’s key focus areas for growth for the remainder of 2018. If you don’t have time to listen to the entire hour and 20-minute call, we would urge you to devote just two minutes beginning at the 23:50 mark of the earnings call, when Mr. Gorsky discusses the Janssen Pharmaceutical business.

The highlights from our perspective:

Mr. Gorsky said that Janssen plans to file or launch up to 10 new drugs by 2021 (including Erleada for non-metastatic castration-resistant prostate cancer, which was launched earlier this year), each of which “has the potential for more than $1 billion of peak revenue.”

Though Mr. Gorsky didn’t mention Geron by name, the chart below, produced by Janssen, shows clearly that imetelstat is one of these 10 critical pipeline drugs he described.
Mr. Gorsky said the “key catalysts for growth” for the rest of 2018 include:

Oncology: prostate cancer and hematology
Immunology: multiple immune-mediated inflammatory diseases, moderate to severe plaque psoriasis
Pulmonary hypertension: assets acquired via the 2017 acquisition of Actelion
Neuroscience: Long-acting injectables
Cardiovascular: Xarelto
Infectious diseases: HIV portfolio

The chart below summarizes Janssen’s pipeline of new molecular entities (NMEs). We note that Janssen continues to list Geron’s imetelstat as the first oncology asset in its pipeline. Reinforcing this priority, Mr. Gorsky cited two areas of oncology—prostate cancer (for which Janssen earned an FDA approval earlier this year) and hematology (which is obviously Geron’s area of focus)—as Janssen’s principal catalysts for growth for the remainder of this year. We believe that the mentions of imetelstat at the top of the priority list in the pipeline and at the top of Mr. Gorsky’s comments on Janssen are not merely coincidental; rather, we take this as a solid indicator of Janssen’s commitment to imetelstat as a potential billion dollar therapeutic.

[LWS]

European Interest

These 3 companies have been discussed on this board as possible Geron associates or partners going forward:

Novo Nordisk (Denmark)
Novartis (Switzerland)
Bayer AG (Germany)

Novo Nordisk is becoming a very wealthy company. With extra cash to invest in oncolgy, they would be a logical choice for a Geron, Euuropean partner. There is a connection between excess weight and cancer (and other serious diseases).

"The link between obesity and cancer risk is clear. Research shows that excess body fat increases your risk for several cancers, including colorectal, post-menopausal breast, uterine, esophageal, kidney and pancreatic cancers." -- from MD Anderson

=================================================================

Obesity Drugs Will Make Billions. But They Could Break the Healthcare System in the Process. -- Barrons.com
September 21, 2023

Dow Jones Newswires

Novo Nordisk and Eli Lilly are about to start raking in tens of billions of dollars a year on their new obesity drugs, say Wall Street analysts. That's great news for the drugmakers, certainly, but it could be a disaster for the companies and government agencies set to pick up the bill.

The new medicines, known as GLP-1 receptor agonists, promise body weight reductions of as much as 20%, and may cut patients' risk of heart attack or stroke. By all appearances, they're the most effective safe weight-loss drugs in history.

No surprise, then, that the demand for these medicines is huge and projected to get even larger as more supply comes on-line and more GLP-1s win Food and Drug Administration approval for weight loss.

[LWS]

Imetelstat is now making medical news in many ways including ASH2023, Oncology ADCOM (ODAC), EAP (operational) and NDA approvals (pending). Expressions of the past are being dusted off for new considerations (examples: “Bigger than all of us”; "Tantamount to a cure”; “compelling, remarkable, durable”).

I don’t believe Geron will want to go it alone or should they. In my opinion, there will be the need for several types of partners or collaborators as Imetelstat (and other oligonucleotides) gets approved and goes into production for immediate use and additional research for various blood cancers and beyond.

Here are five current Imetelstat topics that Geron and potential partners are thinking about:

1/ Ferroptosis
2/ Telomerase & Telomeres
3/ Combinations
4/ Synergies
5/ Oral form potential


``````````````````````

Previous (for review & reference)

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

==========================================================
Synonyms & Similar Words for Tantamount:

comparable
similar
equivalent
related
like
resembling
relatable
close
consistent
conforming
approaching
substitutable
approximating

[LWS]

Some thoughts about partners:

A plan for Geron: Geron holds 51% of common stock with partners (JNJ, AbbVie, European partner as a possible combination) for the remaining 49% to be put in place after the NDA is approved. Imetelstat appears to be a very important blood cancer medicine ("remarkable, compelling, durable" ---perhaps a miracle) with immediate applications (EAP) and many possibilities going forward (combinations and oral Imetelstat).

Geron will want to stay in control, but they also will need deep-pocketed partners and collaborators for the best results in applications now and research going forward.

[LWS]

Cancer Delivery Systems and Artificial Intelligence

John Scarlett told us (fireside chat) that 2024 will be the time to think about partners and collaborators. MAIA (THIO) and Geron (Imetelstat) are covering most of the telomerase cancer ongoing opportunities from liqiud to solid. Imetelstat's early attempts at solid cancer did not go well, likely because of the delivery system. Both companies have common interests, some common history and (perhaps) some overlapping patents.

There has been progress in delivery systems which will allow for new research with interested potential partners thinking beyond blood cancers. MAIA seems to be having some successes. Imetelstat (EAP in place) is very close to NDA approval and off-label opportunities.

The future for Geron includes Oral Imetelstat, IMET2.0 and partners.
====================

nature signal transduction and targeted therapy review articles

Smart nanoparticles for cancer therapy
Download PDF
Review Article
Open access
Published: 03 November 2023

Smart nanoparticles for cancer therapy

Leming Sun, Hongmei Liu, Yanqi Ye, Yang Lei, Rehmat Islam, Sumin Tan, Rongsheng Tong, Yang-Bao Miao & Lulu Cai
Signal Transduction and Targeted Therapy volume 8, Article number: 418 (2023) Cite this article


Abstract

Smart nanoparticles, which can respond to biological cues or be guided by them, are emerging as a promising drug delivery platform for precise cancer treatment. The field of oncology, nanotechnology, and biomedicine has witnessed rapid progress, leading to innovative developments in smart nanoparticles for safer and more effective cancer therapy. In this review, we will highlight recent advancements in smart nanoparticles, including polymeric nanoparticles, dendrimers, micelles, liposomes, protein nanoparticles, cell membrane nanoparticles, mesoporous silica nanoparticles, gold nanoparticles, iron oxide nanoparticles, quantum dots, carbon nanotubes, black phosphorus, MOF nanoparticles, and others. We will focus on their classification, structures, synthesis, and intelligent features. These smart nanoparticles possess the ability to respond to various external and internal stimuli, such as enzymes, pH, temperature, optics, and magnetism, making them intelligent systems.

Additionally, this review will explore the latest studies on tumor targeting by functionalizing the surfaces of smart nanoparticles with tumor-specific ligands like antibodies, peptides, transferrin, and folic acid. We will also summarize different types of drug delivery options, including small molecules, peptides, proteins, nucleic acids, and even living cells, for their potential use in cancer therapy. While the potential of smart nanoparticles is promising, we will also acknowledge the challenges and clinical prospects associated with their use. Finally, we will propose a blueprint that involves the use of artificial intelligence-powered nanoparticles in cancer treatment applications. By harnessing the potential of smart nanoparticles, this review aims to usher in a new era of precise and personalized cancer therapy, providing patients with individualized treatment options.

[LWS]

Imetelstat for Diseases other than Cancer

With the discussion of Ferroptosis comes the discussion of Imetelstat for diseases other than cancer. This will be of interest to potential partners and collaborators.

1/ Ferroptosis (Inflammation in a variety of diseases)
2/ Telomerase & Telomeres
3/ Combinations
4/ Synergies
5/ Oral form potential
=======================

What is the link between Inflammation and Cancer? (from MD Anderson)

Myth: Inflammation is one condition.
Truth: The term inflammation actually refers to many different processes in the body.

“When the medical community talks about inflammation, we aren’t just talking about one thing, one organ or even the same type of inflammation,” Watowich says.

Inflammation is a local or systematic reaction from the cells in our immune system, but research has shown that there are different types of inflammation and that cells from other parts of the body are also involved. For example, the cells that line our blood vessels and the cells that line our skin also have inflammatory responses, so we know that it’s a more broad reaction that can involve cells throughout the body.


Myth: Inflammation is bad.
Truth: “Inflammation has a bad rap,” Watowich says. “But the truth is that we couldn’t live without it.”

But inflammation isn’t strictly good or bad. It can be either, depending on how long the inflammation lasts. Small flare-ups of inflammation are good since it’s our immune system working to heal our bodies, but chronic inflammation can be a sign of something more concerning such as rheumatoid arthritis, type 2 diabetes or even cancer.

“I encourage cancer patients to think of inflammation broadly,” Watowich says. “We have to understand inflammation in its context to understand if it’s helping or hurting.”


Myth: Inflammation always causes cancer.
Truth: Inflammation can contribute to the development of certain cancers. For example, Watowich cites the tight association of chronic inflammatory bowel diseases, such as ulcerative colitis or Crohn’s disease, and the development of colorectal cancer. But she adds that the connection hasn’t been established with other cancers and may not even exist. However, inflammation has been linked to the spread of cancer to other parts of the body.

At the same time, there are types of inflammation that help kill tumors. For example, immunotherapies can capitalize on inflammatory processes to attack and treat cancer.


Inflammation’s tie to immunotherapy

MD Anderson’s Center for Inflammation and Cancer is working to better understand cancer’s relationship with inflammation, ranging from how inflammation is involved in tumor growth to how inflammation can help fight cancer.
===================
Note: Dr. Stephanie Watowich is Professor and Deputy Chair in the Department of Immunology and the Director of the Center for Inflammation and Cancer at MD Anderson Cancer Center.

[LWS]

Now that one hurdle has been passed successfully (Transfusion Independence), there is a bright future ahead for Imetelstat, with many possibilities. Geron has never been in a better negotiation position.

It is time to think about deep pocketed partners. In the USA, JNJ and AbbVie have been very involved with Geron for a number of years. In Europe, Novartis and Novo Nordisk appear to be interested. The full potential for Imetelstat will be in combinations for cancers of all sorts, and other areas of interest such as inflammations.
================================

John Scarlett told us (fireside chat) that 2024 will be the time to think about partners and collaborators.