Developing a Drug To Reverse Heart Disease

We have spoken with Reason from Repair Biotechnologies about his company’s lead candidate, REP-0004, a drug targeting the liver to reduce excess intracellular free cholesterol. The FDA has granted Repair Bio an orphan drug indication, and the company is aiming for clinical trials by mid-2027. Our conversation also touches on the regulatory challenges and the broader implications of rejuvenation therapies.

So let’s get straight into the lead candidate. REP-0003, can you give us the quick, layman’s version on how that works?

Firstly, it’s actually REP-0004 now that is the lead candidate. We updated the sequence, but these two drugs are both very similar. They are lipid nanoparticles that encapsulate messenger RNA and then deliver it directly to the liver and nowhere else in the body. It goes to the liver via the normal mechanisms of lipid nanoparticle delivery. The particles are sized to pass through the blood vessel walls for glands like the liver, and the liver is the usual destination for things that are injected intravenously anyway.

Secondly, there’s a ligand on the surface that only interacts with receptors present on hepatocytes, so that then delivers the mRNA into the cells through the receptor-mediated endocytosis; the mRNA escapes the endosome into the cell, where it is processed into a protein. That protein is just a selection of human proteins that are not normally expressed together in any cell, and together, they very selectively, only break down excess intracellular free cholesterol. By free cholesterol, I mean unmodified cholesterol.

This then produces a variety of benefits to your liver, because free cholesterol is toxic and it serves no useful purpose if you have too much of it inside a cell. Normally, a cell will attempt to take that free cholesterol and keep just a little bit of it, and the rest of it gets esterified into lipid droplets or put into the cell membrane or handed off in some way. But, if you get fat or you get old, in both cases, this process stops working as well, and you have too much free cholesterol.

I should emphasize this really isn’t just a problem of obesity. You can have thin people with excessive free cholesterol in their liver and elsewhere in their bodies.

Now, when you reduce free cholesterol in the liver, it kicks it back into working properly, and also makes it feel like it’s in a cholesterol deficit, even if it isn’t. So, it will try to pull as much cholesterol back from the rest of the body as it can. Various mechanisms of homeostasis will dial up reverse cholesterol transport, and you drag back free cholesterol from the rest of the body to the liver, where it then gets intercepted by the protein and broken down.

You get this feedback loop that operates for the few days that the protein is present in the body as a result of an mRNA therapy, and the outcome is a draining of this excess free cholesterol everywhere, not just the liver, and that reduces inflammation. It improves tissue function throughout the body, outside the brain, at least because the brain has its own fairly distinct cholesterol metabolism.

The two outcomes of greatest interest at the moment are, firstly, you get a dramatic regression of atherosclerotic plaque very rapidly, and secondly, you get a reversal of liver disease, such as metabolic dysfunction and associated hepatitis. You also get a reduction in fibrosis. It happens very rapidly and dramatically, and that is how the drug works.

That’s quite a knock-on effect from just targeting a single organ. What about 7-Ketocholesterol (7KC), the form of oxidized cholesterol that makes up much of the soft plaques. Would it have any effect on that?

Yes, we break down most forms of cholesterol, provided they’re inside the cell. We don’t touch cholesterol directly outside the cell, or indeed, outside the liver. In the case of this particular drug, of course, we can make other drugs to deliver this to other parts of the body. We’re about to start working on neurodegenerative conditions. And there’s certainly other options for other conditions like lung disease, for example, anyway, so yes, we can break down almost all forms of modified cholesterol.

If you’re familiar with lipid biology, cholesterol is sort of in the middle of this huge chart of molecules, hundreds of them that are all vaguely similar in structure and are either cholesterol plus some stuff or cholesterol minus some stuff, or can be processed from cholesterol or to cholesterol. There’s a lot of them, and a lot of these are problematic molecules, a lot of the oxidized ones. Cells do not like them, and getting rid of them is generally a good idea.

We haven’t looked specifically at what we do to 7KC because that’s not necessary for any of the parts we take into the clinic, but we know that we do break it down. For example, one could go run studies in a dish and load up cells with your oxidized cholesterol of choice, and we’ve done this for acetylated cholesterol and oxidized LDL and other such things, and then look at the outcome. The outcome is that we get rid of this stuff, and the cell is happier as a result.

Presumably, this cholesterol that’s pulled in would then ultimately be excreted in the urine and to be safely disposed of?

In fact, the primary catabolite produced by our fusion protein as a result of its interaction with cholesterol is actually a generally recognized as safe molecule, and it stays in the body for only a short time before it’s removed.

In January last year, your company announced positive feedback from a pre-IND meeting with the FDA, potentially paving the way for future Phase 1 studies. How’s that going?

Yeah, everything between then, now, and those Phase 1 studies are roughly GMP, manufacturing, development, and IND-enabling studies and toxicity studies stuck on the end of that. We have a rather long Good Manufacturing Practice development process.

Unfortunately, there was a big Request for Proposal (RFP) at the start. For part of it, we have to do one of the lipids that’s in the lipid nanoparticles. Then we have to do the drug itself. It’s a two-stage dance and it’s going quite well, but we are sort of midway through the whole process. Really, that means we are a few months into getting the process development underway. There’s nothing revolutionary happening here, it’s just work, but it has to be done.

Lipid nanoparticles are extremely cutting-edge. They are quite different to other ways of delivering things. We saw with the RNA approach with the COVID vaccine, how effective that was and how quickly they can scale things if they need to.

Yes, let’s hope they get more receptive to rejuvenation and then we might see a catalyst where everything starts to move a bit faster. How receptive has the FDA been to this approach?

They like it. They looked at our materials for the pre-IND and said, “Yes, we agree. Go do this.” No, they didn’t note any meaningful objections, just the usual small feedback. They gave us an orphan drug indication, and they don’t hand that out like candy. That’s because they have to really be interested in what you’re doing for that to happen.

We got that mid last year, and right now we’re applying to the Rare Disease Evidence Principles (RDEP) program, which is a new next-level addition to the orphan drug designation. This is the rare disease evidence principles program, and people are applying to it and getting accepted at the moment.

The caveat here is we kind of know what they’re aiming for at the high level, because they’ve said so. If you go look at the FDA website for the rare disease evidence principles program, you’ll see their blurb for it. This was announced late last year., but right now nobody really knows, including the FDA, how this program will pan out.

Realistically, for companies that go through it, in principle, it should speed the path to approval for these rare disease therapies where it’s somewhat more difficult to organize trials than for a more common condition. The theory is they’re going to rely more on preclinical evidence and more on post-approval assessment of the drug than on trials. But nobody really knows what that means in practice yet, but we’re engaging with the FDA on that topic right now, and we’ll see what they say.

There does seem to be somewhat of a shift happening in the FDA, but also in the UK. They announced starting next month, they’re going to be looking at accepting more computer modeling and are talking about 14-day Phase 1 clinical trials for certain approaches. I’m hearing Australia is being very proactive as well. I do wonder if all these fast-track schemes are making the UK or Australia a much more tempting place to set up and start trials. Could it catalyze the FDA to modernize and catch up?

There do seem to be signs in the FDA that it’s starting and maybe happening elsewhere in the US states, such as the Montana Right to Try exercise and Florida I believe are going in the same direction. I think what we’re looking at is that there is a pressure, right? It costs some stupendous, ridiculous amount of money to put a drug through the existing process. But, equally, one can spend a tenth of that and be treating patients in the Caribbean. You can’t have a world in which these two things exist without something changing.

I certainly think that the regulators feel the pressure of the existence of these other paths, because increasing numbers of companies are taking those other paths first before they come back to later to talk to the FDA. We’re going to see some new things, I can’t tell you about, coming up in the year ahead, on the lines of people doing things outside the system that are more sophisticated and definitely more of a challenge to the regulated system in terms of getting drugs into patients.

Something has to change, but the system will obviously react very slowly and probably only incrementally, but things have to shift, because ultimately, you’re looking at a world where the cost of a plane flight is much less than the savings you get by going to do a therapy somewhere outside the US. At some point, people will figure this out, and medical tourism jumps from being a small concern at the moment, a small and disorganized concern that’s only really used by very sick people, to something that is very widely used. Therapies for aging and therapies for common age-related conditions are probably going to be the catalyst for that, because now you have certainly a sizable increase in the number of patients who might consider doing this.

I think those pressures will obviously lead to change. Ultimately, it’s just a question of how fast. On a related note, with the recent green light given by the FDA for the Life Biosciences partial cellular reprogramming trial, it seems to suggest, whilst they’re still firmly on this one disease modification or organ at a time stance versus targeting the hallmarks of aging as an endpoint, they do seem to be open to rejuvenation-style therapies. Would you agree with that?

I think that the FDA is open to anything that treats a specific condition. They are certainly more open than they have been to gene therapies, but anything that’s new is going to get a lot of attention and probably needs a wealthy group behind it to push it through that level of attention and generate the sort of pressures behind the scenes to make the FDA conform to their desires, rather than vice versa. The situation hasn’t changed with regard to age-related diseases, you still can’t put a drug through the FDA for aging per se, TAME trial or no TAME trial, you still have to pick an indication and go for it.

What would you say is the biggest barrier to the FDA accepting biological age reduction, reversal, rejuvenation, or whatever people want to call it, of organs or tissues as a valid endpoint?

The FDA specifically wants you to improve function or feeling as a result of your therapy, and they will need to see the existence of a randomized controlled trial that demonstrates that your proposed endpoint, that is not function or feeling, connects to an endpoint that is function or feeling.

The reason why nobody can go run a trial on biological age is because you can’t point to a body of work that shows that biological age connects to in a way that the FDA is happy with. I mean, epidemiology, obviously, for these clocks, is everywhere, but the FDA will say, “Sure, that’s epidemiology. Now go run me a trial that shows, in a randomized, controlled way that this does match to some function that you care about for your indication of choice”.

This is exactly the problem that we have for the ability to regress atherosclerotic plaque. The FDA does not accept regression of atherosclerotic plaque as an acceptable pivotal endpoint for approval of a drug. Nobody can regress plaque, so nobody has conducted a randomized controlled trial to show that regression of plaque will do something good, where good is something that the FDA accepts meaning measures of function or feeling.

That’s your catch-22 whenever you’re doing something new in order to get your endpoint accepted, you have to have an awful lot of very expensive trials already conducted, which is one of the reasons why, for things like atherosclerosis, nobody really tries to do anything other than hit the surrogate endpoint of lowering LDL cholesterol, because to do anything else would require you to conduct an awful lot of work before you could even start to do a clinical trial.

We have a clever way around that. For the condition we’re pursuing, there is a functional endpoint we can pursue and improve, and therefore that’s one of the reasons why we picked the particular indication we picked, because that functional endpoint of exercise tolerance is very well established in the familial hypercholesterolemia population.

But back to the point everybody who comes in with some new endpoint that isn’t obviously function or feeling, the FDA will just say “no that’s not acceptable. Pick something else or go conduct a randomized controlled trial that demonstrates that your proposed endpoint connects to a functional endpoint and then come back and resubmit”.

Do you feel that if a few of these rejuvenation approaches do pan out and are successful? Let’s say, for instance, Life Biosciences announces next year that their Phase 1 results were positive and similar to what was seen in non-human primates and their mouse work. That means that they demonstrated that it does modify the disease. Obviously, they’re going to be recording things like epigenetic clocks. Do you think that that would strengthen the case with the FDA to accept these biomarkers as valid?

Because it’s the eye, it’s just a localized therapy and it won’t affect systemic biological age in the slightest, but everybody who does something that incrementally adds to things helps. All it takes is somebody, somewhere, doing a trial, and getting some data, and then at some point, it tips over into acceptance and biological age becomes a surrogate marker. But how long will it take to reach that tipping point? Who knows?

Certainly, there are very good arguments once you’re at the point of the FDA accepting epigenetic clocks as surrogate endpoints, but that’s a whole can of worms, because some of these clocks are clearly selective about what they what they react to, some clocks are going to react very differently to different therapies.

People are shopping for clocks to show off their preclinical data now, and they very much are just waiting until the FDA accepts clocks in a sort of fairly unlimited way. I do think it’s going to happen, I think they are probably very well aware of that, and they will be very reluctant to accept that first clock.

As supporting evidence, hopefully they’ll get more comfortable with that idea, and then that will pave the way for more rejuvenation-based approaches, or cellular resilience as Altos Labs describes it.

That was what the FDA is likely going to do, from an institutional perspective, considering its motivations, that’s separate and different from what should be done to accelerate the passage of therapies into the clinic. Certainly, I am one of those people who thinks that perhaps we should all be doing things in Prospera and building a separate ecosystem for early-stage clinical medicine, because the one we have kind of sucks.

For people who are not familiar with that, that’s a longevity hub in Honduras, and it ties in with the whole idea of a system outside the current system. Medical tourism is something that may put more pressure on regulators to get with the program and modernize. Back to REP-0004, what sort of timeline do you anticipate before you begin clinical trials?

If everything goes well with fundraising this year, because we have to raise a sizable amount of money to carry through the rest of our GMP manufacturing and run the trial itself in the best of scenarios, I think mid-2027 would be time for a trial start.

We’ll see how that goes. Because the market might be drifting back to sanity in the biotech side of the world, and the biotech market has been very disconnected from the broader market in terms of its tenor for some years now, but as the biotech market drifts back to being not terrible, then we’ll see if we can do that, otherwise there will be delays, and anybody who works in the field will tell you that biotech is basically an industry built on delay.

Although I think eventually, as a specific field of rejuvenation biotechnology, we see more of these therapies arriving, getting approved, and if we get some positive results, I do see that eventually our fairly unique sort of community will probably just merge with the greater whole in the end. It’ll all be part and parcel of it in the future, which is not necessarily a bad thing if it means that more people get access.

Everybody should get access to these technologies. It’s only really a matter of when rather than if at this point.

Yes, absolutely, it’s only a matter of when, but that’s a rather crucial matter if you’re 82, right? Weirdly, I think people have entirely the wrong idea about risk profile, and by people, I mean sort of this cultural feel and certainly the way that regulators behave. They look at very aged people and think “We can’t allow these people to take any risk whatsoever because they’re in terrible shape.”

Whereas, you know, if you’re old, what have you got to lose at this point, your personal tolerance for risk is probably completely different from what the regulators are going to impose on you as tolerance for risk. This is the eternal concern, one where the existence of a government and a regulatory system that removes choice from people, versus philosophies of government suggest more individual freedom is a good thing, and thereby, in medicine, people should absolutely have the freedom to go try things.

Of course, freedom comes with the responsibility that if you do something stupid, that’s on you, and I don’t think we live in an era in which that sort of viewpoint is looked upon favorably. We live in an era in which the prevailing consensus in government is that people should be protected from themselves, and that is why we ended up with a system that is the way it is.

So a lot of modernization is needed. Hopefully, these innovations in AI and drug discovery and their acceptance into clinical trial structures could hopefully speed things up. Of course, we’ve got this OSK clinical trial coming up, which potentially might help, but we’ll see.

Hopefully, we will see. I think the most interesting event for the OSK side of the house is going to be when some people start doing this using medical tourism. That is going to be interesting, because if you thought telomerase gene therapy was risky, then this is a whole new level of risky.

But somebody is going to try. There’s all sorts of cocktails of chemicals and gene therapies that have been tried in mice and the mice did relatively okay where they balanced the doses out and got it to work. Some people somewhere are going to try this, and maybe that ends up looking like the Wild West of early stem cell years and you have people turning up with cancers and maybe you don’t.

I don’t see it staying out of medical tourism forever. Certainly that it hasn’t shown up yet is indicative that maybe the medical tourism field has actually matured over the last 20 to 30 years to the point where they are starting to consider things more like an institution. But again, we’ll see.

Yes, we certainly will. Thanks for taking the time to speak with us today and updating us on your progress.