speaker-0: Hi, my name is Jennifer Smith Parker, Director of Insights at Biospace, and you're listening to The Natured. In this episode, you'll be hearing from Daniel Gill, CEO of Pellage Pharmaceuticals, and Francisco Ramirez Valleck, Senior Vice President of Immunology Discovery at Eli Lilly. We dive into the long-overlooked hair loss space, exploring why true innovation has lagged, how a regenerative approach aims to reactivate dormant follicles, and what early proof of concept means for patients. Hi everyone. Thank you so much for joining this episode of Denatured. Daniel and Francisco, if you can go ahead and introduce yourselves, that would be great. Daniel, why don't we start with you?

speaker-1: Sure, hi, I'm Daniel Gill, CEO of Pilates Pharmaceuticals, where we are taking a regenerative medicine approach to develop a first in class topical treatment for pattern hair loss, also known as androgenetic alopecia.

speaker-0: Perfect. Francesca?

speaker-2: Hello, I'm Francisco Ramirez Valle. I'm a dermatologist and an immunologist by training, and I lead immunology research at Ilai Lilly.

speaker-0: Wonderful. Okay, so let's go ahead and dig into this episode where we're talking to be talking about the hair loss space. So the space hasn't seen a purpose-built therapy in decades. So I'm curious, why has innovation lagged so long? And what has changed now to make it the right time for regenerative approach, but just I say generally an investment in hair loss?

speaker-1: So you're right. There's not been a new RX treatment in this space since ⁓ friends in Seinfeld were on T V. I think aesthetics has been largely considered a kind of the domain of lotions and potions without a lot of science. And ⁓ I think they're both I think what's changed is both scientific, new scientific advances as well as societal changes. So on the scientific side It's about fifteen years ago it was recognized that for for people with pattern hair loss, even when they've lost their hair, the follicles are still there. And inside those follicles, there are live stem cells, but they've gone quiescent. And so that set the groundwork for Pelage scientific founders to figure out how it could turn those stem cells back on. And then on the I think on the societal side, you know, I think over the last five to ten years have been tremendous changes with respect to social media, online meetings, where now all of us are are spending a whole par good part of our days looking at ourselves on screens, which is quite different from the way it used to be, where you maybe glanced at the mirror on your way out the door in the morning. And so we're all much more keenly aware of our appearance. You know, I worked at ⁓ Allargan, I was a VP of research there and over thirty years I had a front row seat to watching how Botox ⁓ really revolutionized the aesthetic space, driven by really strong science. And I like to think that the GLP ones for obesity are kind of Botox on steroids. They've really kind of mainstreamed scientific driven treatments. for for appearance based indications. And so I think that's laid the groundwork as well now to think about ⁓ new science driven treatments for hair loss.

speaker-2: Yeah, no, I I agree with that. I think that ⁓ the science has begun to cut to catch up. I think hair has been difficult because we haven't really understood what causes it, really. But I think that now there's a lot more understanding. The hair follicle is an organ. It has not as simple as one cell type. It's many cell types coming together to to generate this really, you know, differentiated appendage. And so understanding what causes hair loss in the different kinds of hair loss has been a challenge. And I think that the the science is finally catching up. And I think it's driven, as Dan said, by a lot of societal changes as well.

speaker-0: Yeah, that's that's quite interesting. And we're we're talking about also the standard of care. And I know I've spoken with both of you about the existing options we have, like pinoxidal and the phenasteride. And I just wondering where do these fall short? And then we'll talk about new mechanisms or what else can be done to address hair loss.

speaker-2: Yeah. Then I I can kick this off, ⁓ but love to to hear your thoughts. I think that it's it's really important to think about the different kinds of hair loss because different treatments may not work in all the different types of hair loss. And when we consider hair loss in the field, we frequently divide them into those that are inflammatory or immune-mediated and those that are not immune-mediated. Of the immune-mediated hair loss like alopecia areata, ⁓ and frontal fabrosing alopecia.

speaker-1: Maybe

speaker-2: We also divide them into scarring and non-scarring. So scarring alopecia is when the hair follicle is essentially destroyed, and non-scarring alopecia is when the hair hair follicle is preserved. Allopecia areata is a type of immunometer alopecia where the hair follicle is preserved. And this has important implications both for diagnosis and for treatment, but also for prognosis. Because if we're able to stop the immune attack in allopesia areata, we can actually have the hair regrow. Whereas in the scarring alopecias, the hair hair follicle is destroyed and replaced by a fibrous tissue, essentially a scar. And so that makes it much harder, even if you're able to control that inflammation, it makes it much harder for the hair to grow. Those are the immune-mediated alopecias. And then there's the non-immune mediated alopecias like androgenetic alopecia, which can be treated with minoxidal phenasteride because they are caused by andro androgens and hormonal changes, they can be very different between men and women, but ultimately these hormonal changes lead to this process of hair follicle minirization and shortening of the hair follicle ⁓ growth cycle. So they become smaller and smaller. And that's where minoxidal and phenasteride can work. They can prevent that cycle of shortening the hair follicle growth and the mini miniaturization. But by and large, these treatments finesteride and Aminoxidal have essentially helped delay or stabilize the hair loss, but they haven't really promoted a lot of new hair growth. And I think that this is where we're beginning to see new mechanisms really trying to not just stabilize, because that's not what patients want, right? The patients want like their hair back. They don't want their hair ⁓ loss to be stabilized. And so I think new mechanisms are beginning to really wake up those hair follicles and really bring back new hair. But I'm sure Dan has more to say on this topic.

speaker-1: Yeah, I know. And ⁓ I I would just add, I think on the on the efficacy side, totally totally agree. I think on the when also on the safety side, finasteride and monoxidol do come with issues and we're talking about a an indication where people really by and large are looking for really safe, safe drugs as well as the companies that are marketing it. You know, we we we want drugs that come with very clean safety profiles. And so the the antiandrogens ⁓ you know, have have risks of sexual and mood side effects. The monoxidil originally developed as a blood pressure drug, has potential to impact blood pressure as well as causing, if you're taking it orally in particular, causing hair growth on parts of your body that you don't want hair.

speaker-0: You did mention on Cisco, and I know I talked with you as well, Daniel, about this, about hair loss affecting men and women differently. And I think one of the most resident aspects when I see when we first talked was you were saying about when you were seeing patients come to the clinic and particularly women and the strong emotional and quality of life impact. I just how important is it in the field that better recognizes a psychological burden when evaluating and developing new therapies?

speaker-2: Yeah, no, it's super important. I remember vividly when I was a dermatology resident, we had when I had to go to the hair loss clinic, I knew that that was going to be the place where I was going to have to hold the most hands and pass out the most tissues because people were very emotional when they were relating their symptoms, which were hair loss, and hearing their diagnosis. And it's you know, especially back then where we had fewer useful treatments, especially for women, hearing this diagnosis of hair loss and that your hair might not come back or might, you know. Come back, but not completely, was very devastating for patients. So I really dreaded giving those diagnoses as I was training. ⁓ and it's not just the emotional component, it's also that time and time again, research shows that patients who have hair loss actually have higher rates of anxiety, of depression, they can socially withdraw. So it can really have a lot of effects on their personal life, on their professional life. Because here at the end of the day is how we present ourselves ourselves to the world. It's part of our identity, it's part of how people see us. And so it when I think about hair loss, I really think that it's a a more more it's more than a cosmetic ⁓ consideration.

speaker-0: I think that that's fascinating to hear you're saying the tie to anxiety and depression. And offhand I wouldn't think about that, but you're absolutely right. You're saying of how it's tied really to the emotional self worth for so many people. And Daniel, I would love to hear your thoughts.

speaker-1: We've done some consumer surveys and we see very much those same points. And what's what's quite clear also is that with the current treatments there remains a very, very high level of dissatisfaction. When we asked a question among people who are currently taking s treatments, what is their what's their level of satisfaction? Eighty to ninety percent of people were telling us that there's a great need for more effective treatments and I think Francesco made the point that people are looking not just for slowing the loss of hair, but it's really bringing back ⁓ hair where the hair has already been lost. And so I think that's one of the things Pelaj is very excited about is that our mechanism, which is is really going and we like to say, at the root of the problem in the hair root, that we are you know, we are turning back on these stem cells, which is the kind of the initial triggering event. that you need to go away from these miniaturized resting follicles and starting new hair cycle, which will grow new hair. ⁓ and that we've now seen evidence both from biopsy data that we can see that that transition occurring and early data from our phase two studies that's it that is showing that hair is sprouting ⁓ from follicles that had been had been dormant. And so that's I think what people really are looking for.

speaker-0: Yeah, that that does make sense. And now as you're talking about the findings essentially for your studies, and I'm curious for a question for both of you is whether you think the current clinical endpoints used in hair loss trials are adequate, or do the field and regulators need different measures depending on whether it's aimed at men, women, or you mentioned earlier, Francisco, specific forms of hair loss.

speaker-2: Yeah, I I think that the short answer is yes. We probably need more and better ⁓ endpoints. And I think this is in part because of that hair loss is different in different individuals, it's different in men and women. We're usually focused on the scalp, but patients lose hair in their eyebrows or their eyelashes or their beard. And so making sure that we can quantify hair gain in different scalp locations, in different body parts in you know different regions of the of the body, one size does not fit all. The hair density, the hair thickness is different in different parts of the scalp and and other body areas. And so we really need to think more about how we objectively quantify those hair changes in those in those areas. So I think that there's an opportunity for us to to do more here. Lily and working with investigators and with academicians and other other companies, eventually we were able to get A ⁓ endpoint called the Severity of Alopecia tool, really useful for alopiciariata, right? So that's that's the tool that gets used to approve almost any ⁓ alopiciariata treatment nowadays. That took a while to be able to develop it and validate it and assess it and make it routinely systematically applied in clinical trials. But that tool is great for allopiciata, is not great for other types of hair loss. And so each one eventually has to come up with their own way. And and I think Dan probably has some thoughts on on that aspect. But ⁓ I think that regeneric alopecia probably needs other types of ⁓ assessments as well. And maybe before I I hand it to Dan, I would say that the other thing that I think is important is also bring bringing in the patient voice with patient ⁓ reported outcomes, for example, because if we can objectively measure changes in hair density, But it's not meaningful to the patients, is that really going to be a successful product? So more of the patient voice I think is important as well.

speaker-1: Yeah, just to add add as Francisco said, I mean, w one always needs to be looking for endpoints that are also appropriate for the mechanism and the approach. And s ⁓ just counting hair density doesn't get at the whole story because you don't know whether the increase in hair is occurring in already active follicles or d or does it really result is it really coming from newly activated or reactivated follicles? And so we are working on an endpoint to you know really taking advantage of some of the changes in imaging technology, ⁓ to really try to capture follicle activation. And it's really rather than just a hair count, but it's really looking how many active hair follicular units are there in this area of measurement. And I don't know whether people maybe a quick word, the way the way one does these quantitative me imaging in these studies is when tattoos and point on the scalp where there's thinning hair and then using imaging technology one comes back over time to that same place on the scalp, the ⁓ imaging equipment can center on the same spot 'cause you've where you've placed the tattoo and one can quantify over time changes.

speaker-0: that's quite interesting. Okay. So that I see what you're saying about the innovation that can happen when you're looking at these endpoints, but it's it's also interesting to hear Francisco saying it it really can vary, like that alopeciariata scale is not necessarily applicable for the numerous types of hair loss conditions that are out there. I think both of you had said about the social like media aspect and and how that brings into hair loss. But I'm trying to understand that better. Is it because we have more people on Insta or TikTok with full heads of hair or is is there something else I'm I'm just missing here or I don't know, is there youth culture that's pushing to have longer last like longer lasting hair?

speaker-1: There's a tremendous amount of online discussion, whether it be Reddit forums, whether it be influencers in the maxing appearance space. And that ranges from younger people and what's certainly been very dramatic as well is whereas ten, fifteen years ago we tended to think of the beauty, the the aesthetic space being more f female driven, it's certainly now crosses into men as well. And ⁓ I think there's tremendous broad interest, but a lot of that is also driven by the frustration of not having something that's that's really working. ⁓ there's there's only about a million people today who are and that's numbers going up, but who are taking finasteride or monoxidol. ⁓ yet the number and I'm speaking of the US and Yet there's fifty to sixty or more million people ranging from twenty to sixty or ⁓ or more that are having have some degree of hair loss, right? So it just speaks to this huge unmet need. I think a lot of again, what's keeping if you look at the online chatter, a lot of the worry is finding something that that's safe. I think that's keeping a lot there's there's some people who are willing to, you know, take the deal with the side effects that of the current drugs, but I think that a lot of people on the sideline and Francisco from your physician point of view kind of love to hear your thoughts on that too. But my impression is a lot of people want really are looking for something that's safer.

speaker-2: Yeah, th those are really good points. And maybe I'll just add two quick points on on that. ⁓ Jennifer, to you to your question. I think that there's also a component of right now we we're thinking about health span, right? How can we live well in in a variety of ways, right? We want to maintain our muscle mass, we want to maintain our cognition as we age. And I think part of aging well is also looking How you remember yourself and how you think of yourself. And that's part of why I think hair is is an important component as we think about just having the best possible health span for for ourselves. ⁓ and then then I I agree with you. I think that people are looking for science driven mechanisms that that work that we can demonstrate work and they want safety, right? We we don't want to expose ourselves to things that are, you know, toxic as we aim to have the better, the best possible health span that kind of defeats the purpose of having a a full health span. ⁓ and so what you know, when I when I think about, for example, the opportunities in other types of hair loss like alopeciariata, where jack inhibitors have started to pave the way to have really much better treatments for patients, I think that there's still an opportunity to bring new mechanisms with the the pace of ⁓ research in in alopecia has accelerated. We have new mechanisms that may be safer, maybe even longer lasting. And so there's an opportunity to to improve there, but I think safety is one of the considerations as patients and physicians choose the medications that they give their patients.

speaker-0: Yeah, it's so interesting hearing about you talk about l longevity in that aspect because I did a podcast on that and that did really well. Now the final question I have for you gentlemen is that given the large market potential, what needs to change for patients to get better diagnosis, treatment, and follow-up?

speaker-2: I think, you know, technology I think can help here. ⁓ and I know AI is like, you know, everybody talks about it and is perhaps a bit over overblown in some spaces, but I do think that AI enabled imaging analysis is already beginning to help. I think as you heard from Dan, looking at these endpoints with even machine learning can can help make sure that it's objective and reproducible. So it's already beginning to help in clinical trials. Some companies are beginning to work on smartphone. approaches where you can even just video your your scalp or other body areas and and the AI can quantify the hair changes. So I think that over time there's an opportunity for patients to be able to do this from home, right? To be diagnosed at home, to be tracking their progress at home. ⁓ and and even that can also help in clinical trials because as you know, many patients who would want to be in clinical trials ca either don't have access or or are not cannot make the time to go to a clinical trial site. So I think that this is something that could potentially help over time. But I think at the end of the day, what we need is a really end-to-end process where we bring the right science, the right clinical trials, the right regulatory endpoints that really address the patient populations broadly, both men and women. And eventually we need access to this medication so that the right breakthroughs actually reach the people who need them.

speaker-1: Yeah, and the ac I think the access area as well, we should mention, of course, the hair ho loss space is also one is sort of at the forefront of telemedicine, right? And ⁓ online platforms where these these treatments are available and will be available certainly is that is the future, right? And I know Lily's certainly been one of the companies that's been pioneering in this space.

speaker-0: Perfect. Well, that is a great ending to talking about this brave new world of hair loss right now and potential treatment. So thank you so much, Danielle Francisco, for joining this podcast. It's been fascinating. And if you'd like to listen to more episodes of Denatured, please turn to biospace.com. Thank you.