VDP-80 [Assessment]: ImmuneAGE

One liner: The first drug discovery platform for immune system rejuvenation, founded by a serial entrepreneur in longevity. ImmuneAGE's lead compound targets the hematopoietic stem cells (HSCs) of the bone marrow, and the screening platform is based on a new method of >1000x expansion of HSCs for bone marrow transplant.

Longevity Dealflow WG Team

Reviewers: two scientists, a venture capitalist, and a business expert Shepherd: Paolo Binetti Other squad members: Laurence Ion Sourced by: Tyler Golato

This proposal is based on the supporting documents provided by ImmuneAGE, as well as questions and answers to their team, and senior reviews. The VITA token holders can ratify the Longevity-Dealflow WG’s assessment via a decentralized vote

Project lead: Sebastian Brunemeier

Simple Summary

ImmuneAGE Pharma is the first platform company focused on immune system rejuvenation. They are targeting immune aging at the source — the hematopoietic stem cells (HSCs) of the bone marrow. The company's lead program, IA101, is a non-toxic small molecule that rejuvenates aged HSCs and aged animal immune function (oral administration) better than any molecule previously published. The company is seeking funding to support the further optimization and preclinical development of the IA101 program. The company is willing to execute an IP-NFT.

Problem

Immune aging and chronic inflammation drives the major killers and age-related diseases: infectious disease (e.g., COVID), cardiovascular disease, neurodegeneration, metabolic syndrome, chronic inflammatory conditions and autoimmunity, and tumor immunosurveillance in oncology, etc. COVID has underscored the importance of immune aging — the factor most determinative of death and disability was biological age. Today, lung infection by other pathogens remains the 4th leading cause of death globally. Furthermore, tumors can exist and spread only when the immune system fails to control them. And yet, there has never been a systematic effort to find drugs that rejuvenate the immune system at the source: HSCs.

Opportunity

Harnessing the immune system is an extremely powerful approach in oncology — the immune-oncology (I/O) revolution, which yielded a Nobel Prize in 2018 — is the hottest area of biopharma today. These methods (checkpoint blockade, T and NK cell therapy, pro-inflammatory cytokines) tend to be “blunt instruments,” revving up the immune systems of patients whose immune systems have already failed (allowing cancer to emerge in the first place).

Despite this evidence for the efficacy of immunotherapy, there are few companies seeking to rejuvenate the entire immune system at the source: the bone marrow and hematopoietic stem cells. The hematopoietic stem cells (HSCs) of the bone marrow are the most powerful stem cells in the body (aside from the embryonic stem cells during development) — with the highest replicative capacity of any cell type (producing 200 billion red blood cells per day and 10 billion white blood cells). HSCs produce all the blood cells, and when rejuvenated in the lab, can extend the healthy lifespan of lab animals up to 30%.

Solution

ImmuneAGE’s lead program, IA101, is a non-toxic small molecule that rejuvenates aged HSCs and aged animal immune function (oral administration) better than any molecule previously published (to be published in Nature Aging later this year). A less potent natural product analog of IA101 has shown efficacy and safety in multiple human clinical trials, de-risking clinical development.

IA101 was discovered in scientific co-founder, Prof Nicola Vannini’s lab. Dr. Vannini has developed a unique assay for profiling metabolic function of HSCs and other immune cells. This platform enables the high throughput screening of compounds that reprogram immunometabolism. He has identified several molecules that enhance immune function, in vivo and ex vivo, and this platform is able to identify many more at scale. The Vannini lab has shown that metabolic reprogramming agents can enhance HSC function in vivo, as a first proof of concept for the platform. This compound is not drug-like, but Prof Vannini has since found other active scaffolds in vitro and in vivo, including an analog of our lead program, IA101 (Nature Aging, in revision).

Plan and IP roadmap

With proceeds from VitaDAO, ImmuneAGE will develop new IA101 analogs in order to strengthen their IP, enhance potency and drug-likeness, and identify the molecular target. With ImmuneAGE’s unique screening platform, they will be able to quickly iterate the new candidates to select a final pre-clinical candidate to move towards IND.

ImmuneAge will file intellectual property around the optimized IA101 derivatives discovered from the funding of this project.

Financing and cost breakdown

The current financing, future financing commitments, combined with potential funding from the VitaDAO community, would cover the following activities:

• HTS for HSC rejuvenator compounds with University collaboration - 200k
• Medical Chemistry to synthesize novel derivatives of IA101 - 250k
• Validation of top compounds in HSC transplant mouse models - 200k
• Target ID studies for IA101 and related molecules - 150k

The primary costs are with medicinal chemistry in collaboration with WuXi and medicinal chemist consulting budget.

Team

• Sebastian Brunemeier, CEO and Founder: Sebastian A. Brunemeier is a biotech VC and company builder focused on longevity & regenerative medicine. He is a co-Founder and General Partner of Healthspan Capital. Over the last 5 years, he has co-founded 4 longevity biotech (“LongBio”) companies with a total equity value of >$600M. He was Co-Founder and Chief Investment Officer at Cambrian Biopharma, Co-Founder and COO of Samsara Therapeutics, and Principal at Apollo Health Ventures (the first and largest aging-focused venture capital fund in the world with $200M AUM). Altogether, these organizations have raised ±$400M in the last 4 years. He was a Fulbright Fellow on the biology of aging, a Skaggs-Oxford Scholar at the Scripps Research Institute, and a SENS Foundation Scholar at the Buck Institute for Research on Aging. His education includes dropping out of DPhil (PhD) training in biochemistry of aging at the University of Oxford as a Clarendon Scholar, a Master’s in Life Science Business Management and Molecular Neuroscience from the University of Amsterdam as an Amsterdam Excellence Scholar.

• Nicola Vannini, PhD, Scientific Co-founder is a Professor of Immune Metabolism at the University of Lausanne, Switzerland. Previously at EPFL Dr. Vannini is a leader in stem cell and cancer metabolism, and is funded by Ludwig Cancer Institute.

• Stephan Emmrich, PhD, Director of Immunology is senior scientist with 12 years experience working on hemapoietic stem cell aging and leukemias. Stephan pioneered naked mole rat immunology as a postdoc in the Gorbunova lab. He completed his PhD and Postdoc in the Klusmann lab working on RNA in leukemia performing >1000 stem cell transplantations. He has an h-index of 16 with >1100 citations. He is also an On Deck Longevity Biotech (ODLB) Fellow 2022.

• Ryan Spangler, Director of Operations is a biomedical scientist and operator with greater than 8 years experience in drug development. He was previously the Director of Operations at Cogentis Therapeutics and a researcher at both the Broad Institute of MIT and Harvard and Mark Mattson’s Lab at the National Institute on Aging. He has a Bachelors of Science in Biology and is an On Deck Longevity Biotech Fellow.

Additional team members and SAB members are listed in the pitch deck.

Slide Deck

Use this link: Slide Deck

Publications

1. Chiang & Vannini et al. (2022) Induction of mitophagy reverts age-associated decline of the hematopoietic and immune systems. Nature Aging (in revision).
2. Dorshkind et al. (2009) The ageing immune system: is it ever too old to become young again? Nature Reviews Immunology.
3. Bajaj et al. (2021) Aging, Immunity, and COVID-19: How Age Influences the Host Immune Response to Coronavirus Infections? Frontiers in Physiology
4. Granot & Storb. (2020) History of hematopoietic cell transplantation: challenges and progress. Haematologica
5. Girotra & Vannini et al. (2019) Measurement of Mitochondrial Mass and Membrane Potential in Hematopoietic Stem Cells and T-cells by Flow Cytometry. JoVE
6. Vannini et al. (2019) The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance. Cell Stem Cell.
7. Vannini et al. (2016) Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nature Communications.

Senior reviewer evaluation

This proposal has been evaluated by two scientists, a venture capitalist, and a business expert, obtaining an average score of 4/5.

Highlights

• ImmuneAGE is the first LongBio company to focus exclusively on immune aging drug discovery
• The lead asset, IA101, already has proof of concept data in-vivo, outperforming all other HSC immune compounds in the literature.
• The lead asset is based on the same scaffold of a natural compound with a strong safety profile and significant median and maximum life extension data in mice
• Founder is a prominent founder and VC in the longevity space with >600M equity value in co-founded companies in the last 5 years. Team has >100+ years collective experience in drug development, immunology, venture capital, and pharma/biotech.
• Prestigious investor base at such an early stage.

Risks

• Immune rejuvenation is uncharted territory
• The company still needs to prioritize the clinical strategy in order to focus on the right indication
• The target of IA-101 is still unknown, although the company has plans to identify it
• Life extension in mice might not translate in humans, as any other candidate longevity intervention
• Early-stage company, faces financing risk if market conditions weaken (although their pre-seed round was heavily oversubscribed and raised quickly in <1 month).