VDP-46 [Assessment]: Repair Biotechnologies

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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.
If this goes on-chain, the VITA token holders will ratify the 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: Responses to VitaDAO 05-2022 - For proposal.pdf - Google Drive

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.

Vote:

Here we’ll vote if this should go on-chain, along with the final assessment from the Senior Reviewers, and the community as a whole.

If it succeeds here, the VITA token holders will ratify the WG’s assessment (positive or negative) via a decentralized vote.

  • Agree
  • Agree with revisions (please comment)
  • Disagree
0 voters
2

Interesting idea, but too many points of failure right now.

Is the paper claiming efficacy in the mouse model published yet? A 2-fold drop over the course of a month is not very encouraging to me. The 1-month timeline is a very short time point for atherosclerosis in mice… usually you feed them the high fat diet for 12-16 weeks just to induce the phenotype. Were the cells introduced after the 16 weeks, or earlier in the process? Did they target to plaques, how long did they persist, etc?

What data support the “universality” of these cells? This claim needs extensive evidence to support.

There’s a ton of data needed on these modified macrophages, eg do they polarize like real macrophages, how do they respond to infection/inflammation, how long do they last, where else do they target? From the summary, it is unclear how well characterized these macs are.

The world of biotech fundraising is foreign to me. Are all of these unknowns and likely points of failure considered acceptable risk at this stage? Or are there data that address my concerns just not public?

Minor point: the journal name of the cited paper is Scientific Reports, not Nature Scientific Reports. This is an important distinction because Scientific Reports is a fourth tier journal in which anyone can publish. In contrast, Nature and the real Nature branded spin-off journals (eg Nature Communications) are way more exclusive and report work of greater importance. Trying to inflate the importance of Scientific Reports by calling it Nature Scientific Reports triggers warning bells to me-- if the work was revolutionary, no need to try to steal importance by conflating it with higher impact journals.

I get used car salesman vibes from this proposal.

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Very interesting project, although I think the points raised by @bowtiedshrike above are quite fair.

Judging by this proposal and other press releases by Repair Bio, it’s clear that the treatment with Cholesterol Degrading Macrophages is aimed at reversing already established plaque rather than at preventing its formation/delaying its progression. However, it’s unclear if the mentioned proof of concept study looked at prevention/delay or if the treatment was started when the plaques were already established and therefore could actually be suggesting repair. As @bowtiedshrike writes above, inducing atherosclerotic lessons in mice is difficult and takes a long time, so more clarity regarding the timing of the treatment is needed to judge how promising the study actually is.

On a related note, is there any data on how the treatment could affect plaque stability? If they’re aiming to remove/reduce already present atherosclerotic plaque, it’s important that they do it in a way that doesn’t increase the risk of plaque rupture (which is what actually causes the fatal cardiovascular events).

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There were several follow up questions to ask them, some of which may be critical, while others can give us a better idea of e.g. where they are with the SAFE.

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Including some Q&A responses that can be shared publicly: Responses to VitaDAO 05-2022 - For proposal.pdf - Google Drive

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Hi, thank you for your comments.
As for the journal name, you are right, it does not contain “Nature” even if the journal is published by Nature group: this is actually what misled me, my mistake, we have corrected it.

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Thanks for providing those responses; they are helpful

Biggest concerns for me:

  • no PoC for the cell based therapy (=timeline in OP seems overambitious)
  • AAV PoC took the mice off the high fat diet during treatment. Unclear what supporting data provided beyond ‘we got less oil red o staining of aortas’-- did the mice eat more/less, secerete more/less, differences in infiltrating cells in the plaques, gene expression, AAV-targeting, etc
  • PoC on “universality” of the cells needs more support. Xenogeneic response from one challenge isn’t enough to claim they’ve evaded the immune system. Timeline on the survival also needed, and in allogeneic organisms.
  • The M2 macrophages sound under-characterized because macrophage phenotypes all blend together to some degree, especially M2a/M2c. scRNAseq is needed to figure out what kind of macrophages they become (and plaque cellular composition in general +/- Tx assessed by scRNAseq-- this would also confirm gene function at the therapeutic site)
  • No PoC with the cell therapy which means this is extremely high risk.

Without seeing the preliminary data, they still sound weak and over-interpreted to me. If that’s the case, I would reject. If the data were stronger, this seems like R21 territory to me-- do the PoC on the cell therapy along with the scRNAseq. If it is good, then it’s worth considering more money, to de-risk the other potentially lethal concerns. if PoC fails, all the rest is moot.

The other thing dampening enthusiasm for me on this proposal is that the ideas seem sufficiently interesting that an R21 or STTR/SBIR should have no problem succeeding, if the data are compelling. I’m not clear why those routes are not being pursued, unless the data did not support the ideas very well.

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Thanks @bowtiedshrike. These are good comments. This is the chicken or egg of early stage projects. We agree this is high risk with limited PoC but it’s an interesting idea with a solid team. Going for non dilutive funding (R21/SBIR) is always a good option but it takes valuable time to apply and the funding is not much. Because ultimately one needs more money than these mechanisms allow one has to connect with investors who can get you there.

Hopefully in the future when DeSci matures, the fundraising requirements will be lessened and the whole industry will be more efficient, but Repair is just operating in the system that exists today.

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Hey Tim - I like this one as an early stage bet in principle.

To me the comp as they mentioned on their call is Saar Gill’s company Carisma. Carisma has found a path forward with CMC, would be interested to learn more about Repair’s protocol and compare/contrast. I could probe if this one looks like there is serious interest and it is worth putting time in to vet further.

CDP is not something I am familiar with - would also be interested to learn more. While mouse data is nice, human cells would be interesting to see as well. Are there receptors that are not expressed in mouse that this protein can interact with? IDK. My interest is much more to understand the safety side of the equation, the protein looks active on degradation of cholesterol.

They did not talk about dose much - this will be import to probe on or at least see that they have built into their use of proceeds a plan to flush this out in greater detail.

Lastly, my biggest question/concern is on safety side. Immunity is of course a balance and adding a high concentration of TGFB /IL10 expressing macrophage must have some effect? Crown Bio can do a full cytokine workup in mice, would be interesting to see this experiment at a few different doses.

Will also throw in as an additional risk to autoimmunity that TGFb can be pro-tumor at high dose.

Overall, I think this is interesting - but very difficult to give a real go/no-go without being able to really jump into the data and see the full use of proceeds plan.

Mike

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@scienceman I agree. Safety is my biggest concern. Injecting cells seems like it could have alot of collateral damage. We all have our own biases and I’m partial to genetic or small molecule therapies over biologics and cell therapies. However, sometimes I feel its good to zig when our brain zags. To me, this could be one of those times. Also, alot of my interest in Repair stems from our own work which shows the paramount importance of cholesterol across the top ~250 most common diseases (manuscript forthcoming). From what we can see there is no more important metabolism to target.

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I like this one as well - but probably worth it to go a bit deeper on some of these points with the team before committing. Its so early for them it is ok if they do not have the data, we just need to see a plan for generating it and that there is sufficient capital in the financing plan to run the experiments…

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If Repair can get the money, more power to them–financing in the biotech world is foreign to me, so I’m recalibrating expectations as I go. Presumably the funding agreements include required milestones to unlock more of the money? I also did not realize that VitaDAO is not investing in this, but affiliates/others might use the reviews to make their own decisions. PoC with the cell therapy and scRNAseq would be my first milestone for this, and that should be doable on similar budget to an R21.

Agree with cholesterol as one of the most important molecules out there. IIRC, cholesterol has the highest density of Nobel Prizes per molecule.

It still surprises me how well hydroxypropylcyclodextrin (small molecule that can grab cholesterol for the non-lipid people) is tolerated in people.

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Thanks, everyone, for the lovely discussion and valuable input - shared with Repair.

We’re in talks with them about a royalty agreement as well.

I think we have enough for the community to digest and vote on this assessment.

Closing this thread and opening up voting on Snapshot.

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This proposal is now live for voting on Snapshot