Targeting the Root Cause: Are we closer to a cure for age-related hair loss?

Over the coming season, we’ll be taking an exclusive look at some of the most exciting advancements in medicine. Today, I’m joined by Dr Jon Edelson, Chairman, CEO, and President of Eirion Therapeutics Inc., a biopharmaceutical company focusing on next-generation products for aesthetic dermatology. Today, we’re going to be discussing the science and latest advancements in targeting hair follicle stem cells to treat androgenetic alopecia.

Hello, Jon. Welcome to our podcast.

Dr Edelson: Hello, Gina. Thanks for having me on.

Gina: It’s an absolute pleasure. Before we explore the role of the hair follicle stem cell and the efforts to target them for more effective treatments, I thought we’d start right at the beginning. Androgenetic alopecia, also known as male pattern baldness and female pattern hair loss, is a widespread condition. How do current available treatments tackle it, and where do they fall short?

Dr Edelson: Sure. It’s a big problem. I mean, in the United States, it’s estimated about 80 million people have hair loss related to, we’ll say, age — about fifty million men and about thirty million women. There is actually a wide variety of treatments that are available, but the bottom line is they all fall short. So people are really looking for something better. If you start in the area of drugs, you have drugs like minoxidil, recently known as Rogaine, which was approved decades ago and eventually made it to over the counter. There’s topical, and topical does result in some hair growth. A lot of the hair growth is the thin type of hair that’s hard to see, called vellus hair, but it does result in some of the thicker normal hair called non-vellus hair. But the increase is on the order of ten percent from where you are at baseline. You also have an oral form or pill form of the drug, which they started out treating with one to two milligrams per day. Some physicians are now comfortable going up to five milligrams per day, and that is more effective than the topical. But with it also comes more side effects. Topical, you have probably about five percent of people who have a lot of scalp irritation from the topical administration. If you look at the oral form of the drug, it works better. So instead of ten percent, you’re probably in the order of twenty percent on average — some people a little bit less, some people more. But with it, you have more side effects. Some people have unwanted hair growth — in fact, on other parts of the body. They want it on their head; they don’t want it elsewhere. And in oral, it’s been reported up to half the people report unwanted hair growth. We still have some of that even with topical, maybe about a quarter of people. But with the oral, the incidence of headaches goes up, and a very few percent of people have swelling in their lower legs, which certainly nobody wants. So you have another drug, which is also in the form of a pill. It is an androgen or testosterone-blocking drug or inhibitor.

Gina: So these are ones that target the hormones responsible for some cause of androgenetic alopecia.

Dr Edelson: That’s right.

There, you have a couple of drugs. One is approved in the United States called finasteride, and that approval was about twenty years ago. So we’re in sore need of some new treatments.
That drug is also effective, the same order of magnitude as the oral minoxidil. But with that, you also have side effects, and they can be quite significant. Because you’re blocking testosterone, a lot of men particularly experience sexual dysfunction. And in some cases, they also have psychological dysfunction, with a few percent of men reporting depression. This drug has very recently become much more popular because the telemedicine companies are now promoting it actively. And, unfortunately, it seems like a lot of the men who are getting the drug don’t realize the potential side effects. In fact, there was an article in the Wall Street Journal this past weekend just about this phenomenon — about men who get the medicine through telehealth and then are surprised. All of a sudden things don’t work, or they start feeling poorly, and they go to the doctor, and the doctor says, “Well, this is the drug, and it’s a serious drug, and it does have these side effects.” And they say, “Oh, I didn’t know.” There have been reports that following men who stopped taking the drug, it may take them many months, in fact, to fully recover from those side effects — months, even years. So it’s a serious problem, and it seems like not all men who take this drug are fully informed of the effects and the long-term effects of the drug.

Gina: So for those who decide not to take the drug or those who can’t, what kind of alternatives are typically offered?

Dr Edelson: There are other, I’ll call them, non-drug approaches, all of which I would describe as somewhat to minimally effective. So there is a process, and these involve injections called mesotherapy where you inject some of these very same drugs right into the scalp. And it involves a series of many injections, which are very uncomfortable, but basically using the same drugs but delivering it locally. Sometimes people put in vitamins into that mixture. You also have a process where they inject something called PRP, which stands for platelet-enriched plasma, which is thought to, in essence, inject growth factors associated with the platelets that enrich the microenvironment around the hair follicle. And then local interventions — you have actually light therapy where there are different sorts of devices that emit light. Some of them are lasers; some of them are LED, which also, it seems, do a little. And then finally, the big solution is a surgical one, which is a hair transplant, where you basically take hair from one part of your body and put it onto the part that is lost, and that’s very uncomfortable, time-consuming, and expensive. But short of that, you know, getting a solution where you, quote, want to see a full head of hair regrown — that really doesn’t exist in today’s world.

Gina: I suppose, as you mentioned, all these treatments aren’t getting to the root cause of the issue, are they? They’re just kind of managing the actual hair loss rather than reversing it or preventing it. And I suppose that’s where Eirion are hoping to change this.

So you’re currently investigating the potential of a topical small molecule, ET-O2, and that’s designed to target hair follicle stem cells and potentially the root cause of this type of baldness. What role are hair follicle stem cells thought to play in this type of alopecia, and why target them?

Dr Edelson: Hair follicle stem cells have been understood for, I would say, at least a couple of decades to be the master control switch for hair growth. They’re one of two types of stem cells that work every day in the body. The other is in the bone marrow that creates your red and white blood cells. Stem cells in most other organ systems are dormant and are only brought into action if there’s an ’emergency’. But the hair follicle stem cell works every day. And I would say alongside of it is the melanocyte stem cell, which is responsible for actually hair colour. So you’ve got hair growth, you’ve got hair colour. And they reside in the scalp right next to where the hair follicles are.

About fourteen years ago, it was discovered, much to the scientists’ surprise, that when they looked at the scalps of men who had androgenetic alopecia, the main type we’re talking about, they found that there was actually an abundant number of these hair follicle stem cells in the scalp, but they were quiescent. I would call them deactivated. You could think of them as inactive.
Whatever the term was, they were sitting there, but they weren’t doing what they were supposed to do. And it was not understood at the time of discovery why they were in an inactive state, and this has remained a mystery for many years. We believe we’ve actually discovered how they became deactivated. And understanding that, we’ve created a drug that will allow them to become reactivated.

There is a molecular chain of events that starts either with the testosterone process, where you have elevations in something called dihydrotestosterone that leads to elevations in testosterone. There’s a chain of events that ultimately leads to an increase in the expression of something called TGF.

Gina: So that’s transforming growth factor?

Dr Edelson: That’s right. There’s another pathway, which is related to aging, that is testosterone-independent, which also causes an increase in what’s called reactive oxygen species, which also leads to this increase in TGF. But up until now, it’s really not been understood how increases in TGF lead to hair loss. We believe we’ve actually put together the molecular chain of events that lead to the inactivation of the stem cell, and our drug basically targets the last molecular step in this process and inhibits it. And by inhibiting it, it prevents the stem cell from being deactivated. Or in the case where the stem cell is already inactivated, it allows that molecular brake to come off, and the stem cell can again start functioning normally. And I would say that what’s interesting, and I think amazing about this approach, is we’re not actually stimulating stem cells. We’re actually just returning them to normal structure and function. And so in theory, this is a very safe approach to turning a tissue back to normal and should have few side effects.

Gina: So there’s no side effects because it’s not actually affecting any kind of hormonal balance in the body at all, and it’s just restoring those follicle stem cells to make thicker and stronger hair and the same type of hair that was there before. So how is ET- O2 thought to — you’ve talked about how you thought it restores stem cell function — but can you describe its chemical structure and how that contributes to its mechanism?

Dr Edelson: Well, the chemical structure is a molecular inhibitor, and it basically inhibits the factor that is causing the stem cells to become deactivated. It’s a very specific deactivator. It only deactivates that molecule. It took years to develop it, and it seems to be very capable in its job from our observations.

I want to go back into the comments about mechanisms of action. So you have one class of products that is today focused on stimulating the hair follicle itself. It has nothing to do with the stem cells. So minoxidil is thought, for example, to enrich the environment, the microenvironment around that. The same with the action of, for example, light therapy. Other drugs like finasteride are trying to dampen the testosterone pathway, and they are, by design, not fully effective. If you completely shut down testosterone in the body, it makes for a lot of illnesses, particularly for men, and you see some of those side effects. So it’s a partial damper.

None of the drugs really tackle the separate aging pathway that deals with oxidative metabolism. So by doing what we’re doing, we have a very specific solution that is tackling exactly the problem that needs to be addressed — not what I would call peripheral matters, which can be supportive. And I would add that most interestingly lately, some companies or some scientists are trying to stimulate the hair follicle stem cell, which is, as we described, inactive in many of these folks, but they are not addressing the cause of why it’s inactive. And so, in theory, they can stimulate and stimulate, but you have in the background a natural process that’s trying to dampen or put to sleep those same stem cells they’re trying to stimulate.

So we think putting this all together, it’s a solution — and one that could potentially, and I stress in theory, result in a cure. And it’s also one that, by its mechanism of action, could also prevent this problem. Or, I would say also, we believe it can address hair greying, because we think the same process is going on with the melanocyte stem cell being deactivated and then not producing hair colour.

Gina: So you mentioned that obviously it’s got potential and it’s promising, but there have been some clinical data released around the treatment, haven’t there? If we go back to the preclinical trials that were conducted, can you tell us what the findings were there?

Dr Edelson: Yes. So an experiment was done where tissue was biopsied from men who have androgenetic alopecia, like myself, right at the edge of where the loss is occurring. And these are the same type of men who are enrolled in clinical trials for products like minoxidil. And these little plugs of hair were then embedded in mice that were genetically designed to accept the hair. And once the hair had been fully taken root, if you will, and was healed and in place, then you could actually treat the mice and see what the effect was on that human tissue in the mouse. And, by the way, that model was originally developed for cancer care. So this is actually standing on that work and allowing us now to look at how this works with hair loss. So in this experiment, there were about 60 grafts from men, and 30 of them were control, and they got a topical vehicle applied to them — which is the drug without the active drug, so it has all the cream and liquid components to it. And then you had ET-O2 applied to the other half of mice, and the investigators did not know which of the two they were — it was what’s called double-blinded. And we saw over a 4-month period a remarkable amount of hair growth in the human hair, compared to the control. And when we looked at this in a separate experiment that was done to benchmark how minoxidil works in the system, we saw in the fourth month that we were getting four times the amount of hair growth as minoxidil in that month. And that, you know, is obviously a remarkable finding, since that’s sort of the gold standard treatment.

At the end of the experiment, the tissue — the human tissue — was removed from the mice and it was examined under the microscope — it’s called histologically — to see how the hair follicles looked. And what was found was that in the control group, the hair follicles had abnormalities that are typically seen with men who have androgenetic alopecia. But in the active group that got ET-O2, all those abnormalities were corrected. And the hair follicles looked completely normal in terms of both structure, function, and hair colour. So this to us was compelling data that this is a treatment that could work — and that seemed to work much better than the existing best treatment or gold standard. And we were then, of course, extremely interested to move this forward from a preclinical setting into clinical trials, which we did.

Gina: And indeed that was quite recently you started recording some results from that first-in-human trial. Can you walk us through the findings you found on that? I know safety and tolerability are very important, as well as obviously the efficacy of what you saw.

Dr Edelson: Absolutely.

So this was a first-in-man study, and it was recently completed. It was done in the United States at three clinical investigation sites. The study had 24 subjects in it. Eight subjects were control and got the vehicle placebo. Eight subjects got a 1% solution of ET-O2, and 8 subjects got 5% of ET-O2.

The first thing I’d comment on was safety, which is absolutely the most important thing when you start studying a drug. And we looked for all sorts of signals that might indicate a safety problem. And the short answer to that is that we found none. The investigators looked for whether there was any sign of skin irritation, skin itching, flaking, redness. There was none of that. They also drew blood samples from the subjects looking for any sort of significant blood abnormalities. There was none of that. And finally, they even did EKGs on the subjects to detect any potential cardiovascular problems — and again, all good. So if you look at the profile, the investigators were asked if they saw any sort of adverse reactions, did they judge that the adverse reaction was due to the drug itself? And there were none of those either. So we were extremely happy with the safety profile that emerged. And, obviously, you need to study many more subjects, which we will, to finally know the safety profile. But this was probably as good as it gets if you start this type of study.

Gina: Indeed. So then it came to efficacy — were there any surprises or exciting takeaways from that?

Dr Edelson: There are definitely exciting takeaways from that. The first I’ll start with is called dose response, which is as you go up on a dose, you expect to see a certain amount of increase in effect. And, eventually, of course, you reach a peak effect. But we did actually see what’s called dose response, which is that the placebo basically had minimal effect. The 1% of our drug had a similar minimal effect, but the 5% had a remarkable effect. So we did find that as we increased the dose, we got more effect.

In terms of measuring how much the effect was, the clinical trials that are done in hair loss look for as their primary endpoint or main endpoint an increase in normal hair. And that’s, as I mentioned, called non-vellus hair. And we saw in the active arm — and we compared the 5% to a combination of the placebo and the one percent, since they were similar, basically all acting as a placebo — we found that there was six times the amount of hair growth in the active arm compared to the placebo. So a very clear drug effect.

And when we looked to compare how good that drug effect was — and this was after four weeks of treatment, and we called the patients back after the fifth week for a final observation — we saw more hair growth after four weeks of treatment than you see in topical minoxidil after sixteen weeks, as judged by their separate clinical trials. And point of fact, that was so remarkable, we showed the results to a very noted clinical investigator and expert in hair loss, Dr Jerry Shapiro at New York University, who’s literally written the books on hair loss and how to treat it. And he said that these results were unprecedented, and he’s never seen so much hair growth in such a brief period of time.

So we think it’s fair to say that there is the potential for this drug to be a true breakthrough in the field.

Gina: Yes. I’m sure the comparative question is one everyone listening is asking about. But in terms of results, we’ve got a top line there. When do you expect them to be published?

Dr Edelson: We’re actually submitting an abstract for this paper to be presented this year, and we’re very hopeful that we will have the opportunity to present this at a large scientific meeting that will give it its appropriate audience and provide all the details.

Gina: Brilliant. And you’ve already mentioned the fact that you’re going to obviously test in a larger population of patients to look at the safety. But what other next steps do you have in mind for realizing the potential of this treatment?

Dr Edelson: Yeah. So the next steps are basically to extend the period of treatment. As I mentioned, we studied humans through these clinical trials for a four-week period of time. We would like to extend that to actually a six-month period of time to show the full potential of this drug. And we believe, based on the preclinical data where we saw continued growth through four months — and even at the end of the fourth month the trajectory was still going up — so we do think that over six months we will see continued and remarkable hair growth. We’d like to demonstrate that.

In order for us to do that, we need to do additional animal safety studies. So we need to expose two different species of animals — and this is an FDA regulation — to the product topically, demonstrating its safety. And once we’ve done that, then we can proceed to a clinical trial that would have a treatment of commensurate length. And our plan, if all goes well, is to do those studies this year and have our next study — which is called a phase II study, it’s a mid-stage study — commenced before the end of the year.

Gina: I suppose investigator were looking also at other effects, when you mentioned before with minoxidil, the systemic effects. I suppose you’d be looking for those as well with your molecule?

Dr Edelson: Absolutely. In fact, we did look for that in our initial study. And as I said, there were no systemic effects that were identified as adverse effects of the drug. And so we think with that starting safety profile, we’re off to a great start. But that’s the whole point of doing larger studies — to get more subjects and to see if anything emerges.

Gina: And do you see the treatment sitting as a stand-alone treatment, or are you investigating whether it could be combined with others, potentially putting two different pathways together?

Dr Edelson: Yes. That’s a very logical thought. I think the first thing we’d like to do, though, is see what can this drug do by itself. You know, in medicine, simpler is always better. The more drugs, the more the potential for more side effects, more interactions. Certainly more inconvenience for the patient. It’s more expensive. So I think the first step is to really understand what the drug can do by itself, and then see if there’s the potential to enhance that by combining it with one of these other drugs. So we’ll see. But I think first, let’s look at the data, let’s see what the drug can do by itself, and then ultimately patients and investigators and physicians can consider what they might want in terms of combination treatments.

Gina: Part of doing kind of where it’s going to fit — if it all goes well, is it going to be something that’s prescribed, or is it going to be something over the counter? And who’s going to be delivering it? Will it be general clinicians or dermatologists at aesthetic clinics?

Dr Edelson: So it will be a prescription product. Just like Rogaine when it started out, it gets prescribed. It would be approved by the FDA and regulated by the FDA. The physician would prescribe treatment. Let’s say there would be a bottle with a thirty-day supply of the topical. It’s a once-a-day treatment, also contrasting with minoxidil, which is twice a day. So we think not only it will be better, but it will be more convenient for the patient. But it’ll basically be a prescription drug.

Who will prescribe it? I think that likely the initial prescribers are going to be dermatologists because hair loss is kind of their medical purview, and I expect that they would be the initial ones to prescribe it. But there’s absolutely nothing to prohibit other physicians from prescribing it as well, and I would expect over time this could be primary care. I mean, this is a very common problem — 80 million people in the U.S. have it. They’re seeing more primary care doctors than they’re seeing dermatologists. So I would expect, ultimately, this is a product that could be prescribed by any doctor in the U.S.

Gina: As you mentioned, there’s so many people affected by this — men and women. At the moment, you’re just looking at male pattern baldness with the trials you’re doing. Is there any chance of you looking at female hair loss too?

Dr Edelson: One hundred percent. We absolutely will look at female hair loss. We do believe, based on the mechanism of action, that it could be effective, but again, we need to demonstrate that. So I think the areas for us to look at in the future are, first, longer duration of treatment. Second, does it work in women? And then third, does it prevent hair loss? And I’ll go to fourth — does it also work in hair greying, both treatment and prevention? So there are a lot of studies to be done. Some of these may actually work in combination — like, you could envision potentially a trial with both men and women in a row, or it may be better to do separate trials. We’re actually actively considering what’s the best scientific approach to address each of these questions.

Gina: The hair loss market in general is evolving rapidly, with loads of novel therapies coming up. There’s JAK inhibitors, there’s even gene therapy and different types of regenerative medicine. Where do you see a product that tackles the stem cell really fitting in with this landscape?

Dr Edelson: I think the important thing is that this is here now. It’s in clinical trials. I think there is a lot of exciting work being done in regenerative medicine and gene therapy. I think, in a way, you could actually characterize this as regenerative therapy because we’re taking a stem cell which is inactive and we’re, quote, regenerating it — making it active again. So in that sense, it is regenerative medicine. I think gene therapy is, you know, a step further, and it’s much more complex. You have to know what genes are specifically responsible, and you have to know how to manipulate them safely. So I think it’s a much more complex, longer-term solution.

So I see this as a nearer-term opportunity — and one that will fit into the very interesting and promising work that’s being done in this field.

Gina: So in terms of where you see the field in the immediate future, the stem cells are probably going to be it. And beyond that, in the next 10 years, where do you see the field being?

Dr Edelson: Well, I think if everything goes well, I’d see a product being approved. I mean, that’s obviously the first step to actually having the treatment implemented. I would like to see the advances you talked about in regenerative medicine and gene therapy. I think a lot of those efforts are currently focused on life-threatening medical conditions — as I think they should be. I think they will, at some point, focus on problems like hair loss. While making many people unhappy, you know, everyone can live with hair loss. Cancer? No. Another terrible disease like diabetes and cardiovascular disease? No. So I think that a lot of the work will actually be initially — and appropriately — focused on those life-threatening diseases. But I do think that people in those expertises will focus on opportunities that relate to aesthetic medicine. Certainly, people want to retain their hair. They want to retain their hair colour. So I think it will come in time, but while having optimism about it, I can’t really predict what the timeframe is.

Gina: So for those working in the field — not just clinicians and researchers — I’m sure it’s pretty exciting to hear that there is something in the potentially near future on the brink of real change. I mean, we seem to be moving in the right way — not just slowing hair loss, but regenerating it and maybe making it treatable, and as you say, possibly a reversible condition.

Dr Edelson: Yeah. And I — you know, people do talk a lot about AI, and I think AI has its role in these fields as well. One of the things that is key to these fields is looking at massive amounts of data. There are absolutely enormous databases looking at many genes, many molecules, many proteins, and trying to understand their interactions. And that is truly beyond the mind of a single person. You need a computer to do that, and the methods in AI are figuring out, in an accelerating fashion, how to sort through remarkably large data sets. This is to single out the most important factors to study. And that could be a receptor that causes disease, or it could be a drug that fits in that receptor that could cure that disease.

So I think AI does have a role here to play — and an exciting one — in terms of accelerating just the sort of discoveries you’re talking about.

Gina: Indeed. AI in medicine’s a big topic, isn’t it? It’s huge. It’s going to make a big, big difference.

Well, that’s it for today. A big thank you to you, Dr Edelson. It’s been a pleasure having you on the show.

Dr Edelson: Thank you. Thank you for having me.