VDP-80 [Assessment]: ImmuneAGE

[Paolo]

One liner: An early-stage therapeutic biotech funded by a serial entrepreneur in longevity, focusing on immune system rejuvenation, with a lead compound targeting the hematopoietic stem cells (HSCs) of the bone marrow

Longevity Dealflow WG Team

Reviewers: 2 scientists and 2 business experts
Shepherd: Paolo Binetti
Other squad members: Laurence Ion
Sourced by: Tyler Golato

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. Girota & 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. Measurement of Mitochondrial Mass and Membrane Potential in Hematopoietic Stem Cells and T-cells by Flow Cytometry. JoVE
6. The NAD-Booster Nicotinamide Riboside Potently Stimulates Hematopoiesis through Increased Mitochondrial Clearance. Cell Stem Cell.
7. Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nature Communications.

Senior expert 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).

• Agree
• Revisions Requested (Details in Comments)
• Disagree

[timrpeterson]

I like the project but think we need more discussion on how the IPNFT interfaces with the equity. The 101 asset may not prove to be the focus, which could leave us vulnerable. Also the 101 is in well known chemical space which could pose challenges in freedom to operate.

Also we are now in general aiming for $100K tickets for projects, so $250K is too much.

[bowtiedshrike]

Slide deck is behind a sign-in page.

Idea is interesting, but it’s not clear what the data show. Sounds like ‘you get more immune cells in vitro’ and maybe ‘in vivo’.

Did they show improvement in immune functions in aged mice? If so, which functions? Is it all ex vivo, or did they show increased survival following something like flu? Or just ‘the mice live longer in an SPF colony’?

Usually for Nature, you need some idea of mechanism, too. I’m surprised that it’s listed as unknown.

If the seed round was over-subscribed, will that present challenges for IP-NFTs down the road?

[timrpeterson]

@Paolo

better than any molecule previously published

There’s some hyperbole that would be better removed. No doubt ImmunAge is not the first company focused on immune system rejuvenation. There is a contradiction too then 101 is better than all other molecules published. If it’s the first, how can it be better?

In general, I’d like to see this proposal toned down to not include exaggerations and over the top language. “Extremely powerful”. It detracts from the credibility.

[SB23]

It’s actually not hyperbolic – we reviewed the entire HSC rejuvenation literature and made a list of >100 interventions. This compound works better than all of them, and we have asked our team of immunologists whether they’ve seen anything comparable, and the answer was that this was the best they’ve seen. That’s why it’s our lead program.

Please see some of the key data attached. IA101 also enhances the aged immune response to various pathogen epitopes and improves myeloid/lymphoid skewing, one of the hallmarks of immune aging.

It’s factually true that, in our review of the literature and according to our SAB, they’ve never seen anything this good. See some of these team members below.

[SB23]

Feel free to message me on LinkedIn to receive the deck and I’m happy to walk you through the data. Appreciate your feedback as usual

The MoA is enhanced mitophagy, mitochondrial membrane potential, and mitochondrial biogenesis. The exact target we suspect we know but need to confirm definitively using biophysical methods. The paper is in revision at Nature Aging.

There is some sort of metabolic reprogramming event occurring in HSCs, T cells, and other cell types that this lead compound has been tested on. There are data from many other groups (at NUS, Buck Institute, ETH Zurich) on an analog that shows activity in many disparate animal models of disease. A group at the Buck recently found 18% median lifespan extension with a close analog.

I have shown some of this data to Prof Richard Miller, who runs the NIA ITP program, the gold standard for lifespan studies. He was enthusiastic and requested that we submit the molecule to his program. He is usually quite critical of everything.

[SB23]

I have also attached a few slides on the core of ImmuneAGE, which is our drug discovery platform.

I’ve also included a slide on “Project Theseus” which is the long term vision of an immune system refresh / reboot:

1. isolate HSCs from peripheral blood or a fine needle aspiration (15 min outpatient procedure).
2. Rejuvenate with proprietary cocktails
3. Expand with proprietary methods
4. Re-infuse into patient – HSCs home in to bone marrow and restore immune function without the need for myeloablation.

When a similar young-to-old bone marrow transplant (BMT) was performed in animals, 15-30% median lifespan extension was achieved by other groups. These were non-optimized protocols, and we believe there is room for even higher lifespan extension with optimized protocols. For reference, the gold standard for lifespan extension, rapamycin, achieves ±11% median lifespan extension when dosed to aged mice. The magnitude of this effect size is significant – as you would rightfully expect from a cell therapy that restores immune function versus a single small molecule that mimics caloric restriction (mTOR1/2i).

Some of these slides were produced by our director of immunology, hat tip to him for the cool art!

With the platform, we can assess mitochondrial function, stemness (division symmetry/polarity), epigenetic age, and functional readouts such as colony formation assays, limiting dilution assays, bone marrow transplant chimerism, myeloid-lymphoid skew, and response to pathogens and cancer.

The beauty of the ex vivo dosing approach is that it mitigates toxicity, obviates pharmacokinetic issues, and offers a rapid path to the clinic because of regulatory advantages.

The publicly listed company Gamida Cell has paved the path for us from a regulatory perspective, and their lead program recently received Breakthrough Status from FDA, even though the effect size is modest and the therapy is simply a B vitamin derivative. This indicates that regulators are extremely supportive of advances in the bone marrow transplant field, because it’s an area that big pharma does not pay attention to – despite the enormous potential to restore immune function and address many age-related diseases simultaneously.

[Ferreyros]

It is slightly confusing if the co-IP is for IA101 analog(s) or their unique screening platform to identify compounds. Also, many of the references are literature reviews. Girota et al., which seems to be the starting point of this project, is in revision with Nature Aging, but no data is presented here (possibly I missed it on the TLDR website as I am new here). I would want to know more about their HTS strategy (criteria and methods), characterization of IA101 treated cells (telomeres, methylation, differentiation capacity), will the HSC transplant be a humanized xenograft, can transplantations be performed without irradiation (ie Sial Lewis X glycosylation) for engraftment?

[Paolo]

Hi, I have just shared the deck with you.

[consigli3re]

What’s the status of this proposal?

[Paolo]

The poll can be closed and the proposal will go on chain. I am on it.

[scienceman]

Hi Sebastian - looks super interesting- what would be the primary indication in a clinical study?

Would also be interesting to progress from ex-vivo to in-vivo if this turns out to work as ph2 of the program. Lots of work going on trying to enable in-vivo HSC delivery, primarily for SCD atm.

[SB23]

For IA101, lead indications include: enhancement of vaccine efficacy in elderly (confirmed interest from Hal Barron when he was at GSK), prevention of colds and flu in elderly (similar design to the Novartis/ResTORBio trials – the former CMO, Joan Mannick recently joined Cambrian).

Of course, the oral compound(s) can be used for many diseases of immune senescence.

For the HSC ex vivo expansion and banking, we are planning to pursue post-chemotherapy restoration of BM clonal diversity. Solid tumor patient HSCs will be isolated pre-chemo, re-infused between chemo cycles, and a larger bolus dose post-chemo. Endpoints include anemia, neutropenia, infection incidence, and – the holy grail – tumor relapse. This indication was supported by one of our investors and SAB members who is the former CEO of Novartis.

We are also keen on the ex vivo turbocharging of cell therapies (e.g. T cell therapy), which could allow some of the myriad players in this field to be differentiated from the competition with some secret sauce. We believe this product may be regulated under a DMF.

We are early stage, and there is room to pivot indications in line with the data. We have a lot of degrees of freedom, since there is little innovation in the field of immune rejuvenation.

[scienceman]

Thanks! Looks like there is a clear path to clinical validation.