Q&A: Pelage's Novel PP405 Advances to Phase 2a for Androgenetic Alopecia

Pelage Pharmaceuticals recently announced its novel topical agent, PP405, has advanced to a phase 2a study for androgenetic alopecia, with enrollment currently underway at sites across the US.¹

Pelage also shared that the company has secured an additional $14 million in Series A-1 funding, led by GV and supported by Main Street Advisors, Visionary Ventures, and YK BioVentures. Initial funding, equivalent to $16.75 million Series A financing, was awarded earlier this year following positive phase 1 data.¹

Dermatology Times recently spoke with Qing Yu Christina Weng, MD, chief medical officer of Pelage. Weng is a physician scientist and board-certified dermatologist seeing patients at Massachusetts General Hospital and is a member of Harvard Medical School faculty. She is also on the boards of Advancing Innovation in Dermatology and Immunis, Inc.

Weng discussed the proof of mechanism of PP405, support for advancement into phase 2, and the importance of having a diverse patient pool.

Qing Yu Christina Weng, MD via Massachusetts General Hospital

Q&A

Q: In the context of the phase 1 trials, what specific proof of mechanism and target engagement was demonstrated for PP405? How do these findings support the progression to phase 2a?

A: There were 3 main takeaways from our phase 1 study. First and of course, most importantly in a novel mechanism is safety and tolerability. We showed that across all patients, the drug was safe and well-tolerated. Importantly, we were able to, from the pharmacokinetics perspective, reach the target concentration in the hair follicles, but also have no systemic absorption, no detectable drug levels in the blood. The drug was actually specifically engineered for that, for maximum penetration into the skin with minimal blood absorption.

Secondly, we demonstrated a proof of mechanism. The drug is an inhibitor of MPC, which is mitochondrial pyruvate carrier. It is a membrane transporter on mitochondria that is able to shift the aerobic, anaerobic metabolism of the cell. Essentially what this is able to do is modulate the levels of LDH within the cell, and essentially be able to shift the metabolism so that it is able to activate stem cells that are otherwise dormant within the hair follicle. Through biopsies taken in the phase 1 study of the hair follicle and subsequent biomarker analysis, we were able to show that this is indeed the mechanism by which this is working in human patients who received PP405 topically.

Then finally, we were able to show that there was statistically significant activation of Ki-67 in the hair follicle after just 7 days of treatment compared to baseline in patients who were treated with PP405. This is important because we know that not only is the drug working through the mechanism by which is expected, but it's actually able to switch on stem cell activation in a significant manner. Further, as we look at the architecture of the hair follicles on biopsy, we actually see the architecture of the hair follicles shifting from resting telogen phase into antigen growing phase, and we see that structure of the hair follicle change. Again, this is very preliminary, only 7 days of treatment, but it's very promising as we go into the phase 2 study, from both the safety perspective, but also preliminary efficacy.

Q: How do you anticipate the diverse patient pool of the phase 2 trial will impact the evaluation of PP405’s efficacy and safety?

A: We've really designed a study with including a diverse patient population top of mind from the very beginning. There's a few different ways we do this. First is including women and men in the trial. That alone is hugely important; historically, especially in hair loss studies, most of them have been either men alone or sometimes women alone. Hair loss is a field that still, there's only 2 FDA-approved drugs for hair from the 80s and 90s. There's not great precedence for those studies, and the ones that are done typically involve a more homogeneous population segment only. The other factor is that a lot of hair loss treatments are hormonal in nature, and by that mechanism, you can include only either men or women. For example, finasteride. Our mechanism is meant to activate hair follicle stem cells directly and bypass hormonal effects.

We're excited about that from both being able to have an impact on all genders, but also, you can minimize a lot the hormonal side effects that you see with drug finasteride. We are including women and men in our phase 2a study. Additionally, we are including all hair types and skin types. This is also a reflection of how we designed a study and how the technology has evolved over time.

One of the end points that we're looking at to assess is efficacy of hair growth. We're doing 3 different measures of hair growth. First, we're assessing what's visible with the naked eye. Second, we're using high-resolution photography to quantify hair growth at the single hair level. This allows us to identify changes in density in a very objective way. Third, we're collecting tissue, and we're able to assess markers of hair growth at the macroscopic level. Designing measures of hair growth across the full spectrum of microscopic to macroscopic was very intentional, and it gives us a more holistic picture.

Additionally, the imaging technology has evolved over the years. When high-resolution hair photography was first developed, it's a objective measure of quantification that works best on dark hair on lighter skin. But over the years, that technology has improved, and now we are able to provide objective quantification across all hair types and skin pigmentary types.

Q: What might be some anticipated challenges or limitations as you evaluate PP405, in phase 2a, and how do you plan to address those challenges or overcome those limitations?

A: I think the first thing to recognize, and I think this is a strength, actually, is that this is a completely novel mechanism. We have a lot of data on hair growth after treating with hormonal drugs, minoxidil, of course, even PRP. But for a completely novel mechanism that's meant to activate stem cells directly, we don't have as clear of a timeline for how long it may take to see hair growth, for example. For a study like this, where we are doing our readouts at 3 months, it is difficult to say it's going to give us a preliminary idea of how the hair is growing, but the exact timeline of how long it will take, how this drug will be used long-term, whether it's continuous dosing or not. All of that remains to be seen, but I think that's part of the exciting part of the drug with a completely novel mechanism. Of course, we are also looking to see how women like the formulation of PP405; our phase 1 study did include only men. This is the first time we'll be enrolling female subjects with longer hair considerations. We want to make sure that our formulation is like by women and men.

Q: Where do you see PP405 fitting into the existing therapeutic landscape?

A: We're very excited about this opportunity to bring something novel into a space with high unmet need. At the end of the day, almost every single person has worried about losing hair at some point in their life, and the treatments right now are really surprisingly underwhelming. There's only 2 FDA-approved therapies: minoxidil and finasteride. Minoxidil was approved in the 80s, and the efficacy is limited, and not everybody responds similarly with hormonal treatments like finasteride. The efficacy is also limited, along with a lot of side effects. Additionally, the hair loss landscape right now has a lot of options, but nothing that works that well. Frankly, we have everything from supplements to PRP, and there's a lot of variability in who responds. We don't know why some people respond better than others. I think we have a opportunity to bring really rigorous science through PP405 into a space that just has a need from both the scientific perspective and also the patient perspective.

This technology came out of 3 basic science labs at UCLA that are rooted in stem cell biology and chemical engineering. We know this pathway. There's been a lot of publications on this pathway from both the molecular perspective, the preclinical models, genetic pharmacological models. We know how this drug works, and now we're really excited to be at a clinical stage where we can be able to move this along the pathway of clinical development.

I want to reiterate how excited we are about this latest news. I think the GV A-1 financing really reflects a strong science and a strong team, and phase 1 data that's really promising as we move into phase 2a studies. The phase 2a study is currently underway and enrolling at sites across the US. For dermatologists who are reading, who may have hair loss patients who are interested in the study, we we have links in our press release for patients who might be interested, and we're just really excited to provide a option that's really rooted in strong science in an area of high unmet need.

Reference

1. Pelage Pharmaceuticals advances clinical program with first patients dosed in phase 2 study for hair loss and GV-led $14M series A-1. News release. August 13, 2024. Accessed August 15, 2024. https://www.prnewswire.com/news-releases/pelage-pharmaceuticals-advances-clinical-program-with-first-patients-dosed-in-phase-2-study-for-hair-loss-and-gv-led-14m-series-a-1-302220301.html