One-liner: Assessment of Repair Biotechnologies, a preclinical-stage biotech company developing a first-in-class universal cell therapy for atherosclerosis.

This proposal is based on the supporting documents provided by Repair Bio, 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

Longevity Dealflow WG team

Scientific and business evaluation: Diane Seimetz, Sebastian Brunemeier, Tuan Dinh, Eli Mo, Paolo Binetti, Anonymous Professor

Shepherd: Laurence Ion

Other squad members: Eli Mo, Paolo Binetti

Simple Summary

Repair Biotechnologies is developing a new atherosclerosis therapy that could reduce the risk of cardiovascular events, such as heart attack and stroke, improving on current drugs.

Their patented technology modifies cells to safely break down excess cholesterol and can be delivered as a gene therapy or cell therapy. The present focus is on the development of a universal cell therapy with enhanced macrophages derived from induced pluripotent stem cells and engineered to express a protein capable of degrading excess cholesterol. First tests in cell lines and mice were encouraging. With cardiovascular diseases as the worldwide leading cause of death (27% of all global deaths), the market potential is significant. The company is already supported by a number of investors, including venture capital firms. The current raise aims at finalizing the candidate therapy and getting approval for phase 1/2 clinical trials.

Problem

Atherosclerosis is the main cause of cardiovascular disease (CVD), an age-related disease ranking as the number 1 killer in the world, responsible for a quarter of all deaths according to recent World Health Organization data**.**

In atherosclerosis, plaques that are mainly made up of cholesterol build up over time in the walls of arteries, restricting or even blocking the flow of oxygen-rich blood to organs and other parts of the body.

Atherosclerosis can occur in arteries anywhere in the body but is most serious when affecting the heart or the brain. If it occurs in one of the two main coronary arteries that supply blood to the heart, it results in a heart attack. In the brain, it can cause a stroke.

In arteries, cholesterol is carried by low-density lipoproteins or LDLs. Some of this ends up in artery walls. In young individuals, macrophages, a type of immune cell, help clear excess LDL-delivered cholesterol from artery walls by ingesting it and then attaching it to smaller high-density lipoproteins, or HDL, which return to the liver for excretion. Unfortunately, with aging, macrophages become overwhelmed by excessive localized deposits of cholesterol for a variety of reasons.

To date, no therapy can reduce plaque size. Current medical treatments for atherosclerosis, like statins, which are inhibitors of cholesterol production, can only slow its accumulation in plaques. Statins do reduce cardiovascular events by about 25%, which is already a huge achievement, but do not cure atherosclerosis.

Solution

Repair Bio aims to solve macrophage dysfunction with their “Cholesterol-Degrading Platform” (CDP), a novel allogeneic cell therapy. Concretely, the idea is to produce macrophage cells engineered to have better LDL disposal capabilities and deliver them to patients.

Repair manufactures these enhanced macrophages in a series of steps (see figure below):

1. First they obtain induced pluripotent stem cells (iPSC, a cell that can be converted into any other type of cell) from healthy donors
2. Then they modify these cells so that they are not recognized and attacked as foreign by patients’ immune systems, in other words, they make them universal
3. At this point they add proprietary genetic instructions for the cells to produce an LDL-degrading protein in a tightly controlled way, to avoid tampering with the cholesterol normally required by cell membranes
4. Finally they convert the cells into macrophages

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In-vitro tests of these enhanced macrophages have shown that they can break down excess ingested cholesterol into safe catabolites. Encouraging results were also obtained in vivo in a strain of mice used for studying cardiovascular disease: in this proof of concept (POC) study, mice on a high-fat diet were treated with a gene therapy implementation of Repair’s approach. The treated mice exhibited a rapid halving of atherosclerotic plaque lipids, an outcome needing only a one-month period following a single treatment, with no identified side effects.

The next steps are:

• End 2023: out of preclinical studies
• Mid 2024: clinical studies start (IND enabling)
• Beginning 2024: GMP manufacturing
• End 2024: phase 1/2a

Opportunity

The atherosclerosis subpopulation market is worth about 20 B$. However, initially, Repair will address the smaller market of familial hypercholesterolemia, an orphan indication with an easier approval process.

Because Repair’s therapy is based on universal cells, it should be relatively cheap, of the order of 10 k$, thus ensuring accessibility by a large number of people.

A startup developing a comparable therapy, Verve Therapeutics, was acquired for 1.5bn.

Finally, it has to be noted that Repair’s platform to enhance macrophages could also be applied to other cell types to address different indications.

Intellectual Property

• Exclusive license of core technology patent from the University of Alabama covering Repair cholesterol-degrading mechanisms in cells (No cash milestones, 2% royalty)
• Patent filed for use of cofactors/modifiers
• Patent in progress for use of repair technology to treat hypercholesterolemias

Team

Executive team

• Reason, CEO and cofounder: active angel investor in the longevity industry since its earliest days, he is also the founder and writer of Fight Aging!, a noted news and commentary website
• Mourad Topors, PhD, Chief Scientific Officer: experienced manager in translational medical research with a focus in cardiovascular disease. Formerly, Dr. Topors was Principal Investigator and faculty at Harvard Medical School and served as team leader of a drug development program at Pfizer’s Center for Therapeutic Innovations
• Bobby Khan, MD, PhD, Chief Medical Officer: he is a cardiologist and clinical investigator, professor of medicine at the University of Central Florida School of Medicine. He co-founded Carmel Biosciences, which got its first drug approved by the FDA in 2018. Dr. Khan was the principal investigator for several clinical trials.

Scientific Advisory Board

• Richard Honkanen, PhD: inventor of Repair’s CDP platform technology. He is a professor in the Department of Biochemistry & Molecular Biology in the College of Medicine, University of South Alabama
• Graham Pawelec, PhD: professor of experimental immunology in the Department of Immunology, University of Tübingen
• Andrew Zhu, MD, PhD: director of Jiahui International Cancer Center, director emeritus of Liver Cancer Research at Massachusetts General Hospital Cancer Center, and professor of medicine at Harvard Medical School

Financing

Since its incorporation in 2018, the company raised more than 2.7 M$ pre-seed and seed funding from angel investors, Grapeseed, Methuselah Foundation, SENS Research Foundation, Jim Mellon (Juvenescence Ltd), Thynk Capital, Emerging Longevity Ventures, Longevitytech.fund, Bioverge, and Healthspan Capital.

Now raising 5M$ in a SAFE (Simple agreement for future equity), with a 50M$ post-money valuation.

Next raising Series A $20M by end of the year to fund preclinical dev and a phase 1 and 2a

Additional information

Long-form presentation: https://www.youtube.com/watch?v=zA11QbXczYA

Press: https://longevity.technology/repair-bios-novel-platform-and-exclusive-from-ceo/

Publications:

• “Development of a Synthetic 3-ketosteroid Δ1-dehydrogenase for the Generation of a Novel Catabolic Pathway Enabling Cholesterol Degradation in Human Cells”, Brandon M. D’Arcy, Mark R. Swingle, Lindsay Schambeau, Lewis Pannell, Aishwarya Prakash & Richard E. Honkanen, Scientific Reports, 2019

The author in bold is a member of Repair’s scientific advisory board

Further Q&A: https://drive.google.com/file/d/1BvLLdBi63Dytnb10AiqHJg4PO-vwMtBw/view?usp=drivesdk

Highlights

• Targeting the deadliest aging-related diseases, a multi-billion $ market
• Encouraging results of human in-vitro and mice in-vivo proofs of concept
• Comprehensive and recent intellectual property protection
• Solid team with drug development and clinical trial knowledge

Risks

• Early stage
• Approval of iPSC-based therapy
• Potential side effects of allogeneic cell therapy: immune reaction, cancer, …
• Complex manufacturing process

Longevity WG scientific evaluation digest:

4/4 senior reviewers have expressed a vote in support of this assessment. Here is the digest:

Quantitative reviews:

To quantify the level of conviction, they have provided a score on a scale of 1-5 (with 5 being the highest).

The average score was 3.75/5

Brief qualitative review summaries:

1)

Macrophage engineering is very exciting, and atherosclerosis is the leading cause of death. I've known the management team for a few years and they are strongly aligned to the longevity mission.

2)

Compared to approved atherosclerosis products Repair Bio’s macrophages have the potential to breakdown cholesterol in macrophages and thereby ameliorate the fundamental cause of atherosclerosis rather than lowering the cholesterol content and slowing of plaque build-up. Furthermore, a synergistic effect may be achieved by the M2 phenotype of the macrophages which is known for anti-inflammatory and regenerative properties. Available in vitro and in vivo data, albeit limited, support the mechanism of action of the concept with the caveat that the final cell-based product was not used, nor was a comparison to approved products performed.

With the experienced team and the potential to make an important difference in the field of longevity, I support this project.

3)

Highlights: Published data seems to show strong effects They have a strong executive team with a lot of drug development experience for CVD They are open to licensing deals The macrophage engineering approach can be applied to the broader longevity space The first indication of familial hypercholesterolemias makes sense as data demonstrates that statins and other cholesterol lowering drugs are less effective for this group The inventor has strong credibility in the AS/macrophage field

Risks: Very cutting edge - not much is known about safety and FDA approval risk Only ApoE mouse model data is available - Would love to see more data Manufacturing of cells is expensive - could lead to tens of thousand dollars for therapies -> much more expensive to generic statins No discussion on how the macrophages will be delivered to the site of action. Very high valuation for limited data

Overall: Rather high risk but maybe a sweet spot for VitaDAO

4)

Overall: I like the idea, think the cell therapy approach is novel and distinct (particularly from what we have in the DAO pipeline), and see an obvious path to IP. While there is strong POC for the gene platform, the lack of POC for the cell therapy approach in animals is a limitation. Given that the hurdle to clinical trials and proving efficacy is quite challenging, the project is obviously one of those high risk - high reward things. Finally, I like the team, as they seem thoughtful and committed to the approach and tackling this important health issue.

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