Chemotherapy-Induced Alopecia

- Potent topical MPC inhibitor, based on discovery of a metabolic switch, reawakens dormant hair follicle stem cells to stimulate hair growth - PP405 demonstrates statistically significant activation of Ki67 in the hair follicle, a well-established marker of stem cell proliferation LOS ANGELES, March 9, 2024 /PRNewswire/ -- Pelage Pharmaceuticals, a clinical-stage regenerative medicine company pioneering a new generation of treatments for hair loss, today presented positive translational and Phase 1 clinical data demonstrating the company's novel small molecule therapy PP405 reactivates dormant hair follicle stem cells to trigger hair growth. Data were presented in a late-breaking oral session of the American Academy of Dermatology (AAD) 2024 Annual Meeting in San Diego, titled Inhibition of pyruvate oxidation activates human hair follicle stem cells ex vivo. "The translational data derived from our ex vivo studies on human facelift skin have been further validated in a Phase 1 first-in-human clinical trial demonstrating PP405 effectively reactivates dormant hair follicle stem cells," said Daniel Gil, Ph.D., CEO of Pelage Pharmaceuticals. "This therapy represents an exciting new option for not only treating but reversing hair loss. We look forward to advancing PP405 to Phase 2 clinical studies this year." PP405 is a potent topical mitochondrial pyruvate carrier (MPC) inhibitor that acts on the cellular metabolic pathway to upregulate lactate dehydrogenase (LDH), which stem cells are particularly sensitive to, resulting in their activation and hair growth. Data presented at AAD showed in human facelift skin, single topical applications of 0.006% and 0.06% PP405 led to an increase in LDH activity in hair follicle stem cells within 24 hours. The LDH activity corresponded with a significant increase in Ki67 signal in the hair bulge, indicating a proliferative response of the hair follicle stem cells. The findings demonstrated proof of mechanism in human explanted skin consistent with the results in animal models. The data informed Pelage's Phase 1 clinical trial that concluded in January 2024, which demonstrated that PP405 was safe and well-tolerated, with the target pharmacokinetic profile achieved. Additionally, the Phase 1 study demonstrated proof of mechanism and target engagement in patients with androgenetic alopecia. There was a statistically significant increase in the Ki67 signal compared to baseline after just seven days of 0.05% PP405 topical treatment. Evidence of newly emerging hair germs – the hallmark of the telogen to anagen transition - was also observed. The topical molecule also received positive formulation reviews from patients. "We are incredibly excited about this data, and PP405 offers an opportunity to change the landscape of alopecia treatment through directly targeting hair follicle stem cells at the source through a clear mechanistic pathway," said Qing Yu Christina Weng, M.D., CMO of Pelage Pharmaceuticals. "The Phase 1b study of PP405 demonstrates a strong safety profile, confirms daily topical dosing with no detectable drug levels in the blood, and demonstrates proof of mechanism with statistically significant activation of hair follicle stem cells. We can also see the structural architecture of the follicle on biopsy moving through the hair cycle from resting to growing as the stem cells become activated." Pelage will begin its multi-center Phase 2a trial of PP405 in mid-2024, recruiting both men and women with androgenetic alopecia. PP405 may also have applications for other forms of alopecia, including telogen effluvium (stress-induced hair loss) and chemotherapy-induced hair loss. About Pelage Pharmaceuticals Pelage Pharmaceuticals is a clinical-stage regenerative medicine company developing novel treatments for hair loss including androgenetic alopecia and chemotherapy-induced-alopecia. With a focus on molecular and stem cell biology, Pelage is advancing a new class of treatments designed to reactivate dormant hair follicle stem cells and restore the body's ability to naturally grow hair. Its lead program, PP405, is currently in clinical trials. Through its rigorous scientific foundation, topical formulation, and novel mechanism of action, Pelage is pioneering first-in-class hair growth solutions for people of all hair types experiencing hair loss. About PP405 PP405 is a novel, non-invasive, topical small molecule designed to reactivate dormant hair follicle stem cells and restart hair growth. Through a regenerative medicine approach, the treatment focuses on addressing the metabolic processes that regulate the activation and inactivation phases of hair follicle stem cells. Early results from a Phase 1 trial show that PP405 was well-tolerated and demonstrated statistically significant activation of hair follicle stem cells. In 2018, Pelage Pharmaceuticals licensed the intellectual property to PP405 and related topical small molecules from the UCLA Technology Development Group. SOURCE Pelage Pharmaceuticals

Hair loss is not an unserved market, but it’s not a well-served one. The available drugs are older products initially developed for other indications and they don’t address hair loss’s underlying cause, says Christina Weng, a practicing dermatologist and the chief medical officer of Pelage Pharmaceuticals. Los Angeles-based Pelage takes a regenerative medicine approach to restoring hair growth, addressing a pathway that for various reasons, is turned off. In its first test in humans, the startup now has results showing that seven days of topical application of its experimental drug led to activation of hair follicle stem cells. Data from the Phase 1 study have been accepted for presentation in March as a late-breaking abstract during the American Academy of Dermatology meeting in San Diego. The company is also preparing for a larger Phase 2 clinical trial on track to start later this year that will evaluate the therapy in androgenetic alopecia (pattern baldness) and other types of alopecia including chemotherapy-induced hair loss. “What we’re able to do is go directly to the source [of hair loss], which is stem cells,” Weng said. “It’s a very clear pathway, which is well understood from many years of study in the lab.” Pelage’s technology is based on stem cell research at UCLA. The startup’s scientific co-founders were researching signaling that could turn on stem cells. That research came to focus on dormant hair follicles. Follicles become dormant for reasons that include age, environment, hormonal changes, stress, and medication. In such cases, the hair follicle is still there, but it’s just not cycling the way it used to, Weng said. Hair growth happens in a continuous natural cycle. Besides the growth phase, there are phases of regression, resting, and shedding. Signals from stem cells allow follicles to move from one phase to the next, Weng said. At the end of the resting stage, called telogen, hair falls out. Hair loss happens when follicles get stuck in the telogen stage, preventing them from proceeding to the growth phase, Weng said. Pelage’s drug candidate, code-named PP405, is a small molecule designed to inhibit mitochondrial pyruvate carrier (MPC), a protein that plays a role in various physiological processes. Pelage CEO Daniel Gil said that for hair, blocking MPC is like flipping a metabolic switch that has the effect of turning the growth cycle back on. In mouse research conducted by UCLA, blocking MPC accelerated the hair cycle, leading to the formation of normal hair follicles within 30 to 40 days of treatment. Results were published in 2017 in Nature Cell Biology. The Phase 1 study conducted last fall enrolled 20 participants, all men. The main goal was to assess the safety of PP405. Both once and twice-daily application were tested. Minoxidil, the vasodilator that won an additional approval in 1988 for male pattern baldness and reached the market branded as Rogaine, is applied twice daily. The Pelage drug was well tolerated and no adverse effects were reported in the Phase 1 study. Gil said Michael Jung, a UCLA professor of chemistry and biochemistry and one of Pelage’s scientific co-founders, designed PP405 with properties that get the molecule to stay in the scalp and not enter the bloodstream. The trial results showed the drug was successful on both marks. Results also show the molecule engaged its target, offering proof of mechanism, Weng said. The Phase 2 clinical trial will enroll about 60 participants, both men and women. Weng said it’s important to develop a drug that will work for all skin types, hair types, and genders. Finasteride, first approved in 1992 for treating symptoms of an enlarged prostate and later approved for alopecia (where it’s marketed as Propecia, among other names), works by increasing testosterone levels and cannot be used by women, Weng said. The Phase 1 test showed once-daily use of PP405 had the same effect as twice-a-day application, said Gil, whose experience includes overseeing research and early clinical development at the former aesthetics giant Allergan. The Phase 2 study will evaluate once-daily application of the drug. In addition to old medications like minoxidil and finasteride that have won additional approvals for alopecia, other therapies have found their way into the hair loss market—some without FDA review. The injection of stem cells into the scalp is one such unapproved treatment. Gil said the elegance of PP405 is that it works with a patient’s own stem cells. “You don’t have to inject stem cells in the hair follicles, the stem cells are there,” he said. “This is a wonderful regenerative medicine story.” Besides Jung, the other scientific co-founders of Pelage are UCLA professors William Lowry and Heather Christofk. Pelage spun out of the university in 2018. The following year, it reached an agreement that granted Allergan an option to acquire the startup. The agreement provided Pelage with non-dilutive financial support, Gil said. Allergan itself was acquired by AbbVie in 2020. After that deal closed, Pelage and AbbVie agreed to terminate the option. Pelage will finance the Phase 2 study with what remains from a $16.75 million Series A financing that closed in mid-2023 but was not announced until this week. Unlike pricey and lengthy cancer and gene therapy clinical trials, a hair loss clinical trial is quick to enroll and conduct, and therefore considerably less expensive. Gil said the financing is sufficient to cover both Phase 1 and Phase 2 testing. GV led the Series A round, which included participation from Main Street Advisors, Visionary Ventures, and YK BioVentures.

Affecting both men and women, androgenetic alopecia or pattern balding is responsible for more than 90% of all hair loss. Credit: zentradyi3ell / Shutterstock.com. Pelage Pharmaceuticals has secured $16.75m in a Series A financing round to further the development of PP405, a promising regenerative treatment for hair loss caused by androgenetic alopecia. GV led the funding round, with Main Street Advisors, Visionary Ventures and YK BioVentures also taking part. The capital injection will be instrumental in advancing PP405 through clinical trials. A non-invasive, topical small molecule, PP405 reactivates dormant hair follicle stem cells and stimulates hair regrowth. By targeting the metabolic processes that regulate hair follicle stem cells’ activation and inactivation phases, the treatment adopts a regenerative medicine approach to combat alopecia, including forms induced by chemotherapy. See Also: Novo Nordisk signs $1.46bn deal to develop molecular glue therapies Praxis Precision Medicines sees highest patent filings and grants during November in Q4 2023 PP405 was well-tolerated in a Phase I clinical trial and significantly activated hair follicle stem cells. A 0.05% PP405 topical treatment administered daily was found to be safe without adverse events. This data confirms the treatment’s biological activity and mechanism of action observed in preclinical studies. The intellectual property rights for PP405 and related topical small molecules were acquired by Pelage Pharmaceuticals from the UCLA Technology Development Group in 2018. Pelage Pharmaceuticals CEO Daniel Gil stated: “We are pleased to announce that we have completed a first-in-human Phase I clinical trial that demonstrated seven days of topical dosing with PP405 was safe and well-tolerated, and showed statistically significant activation of hair follicle stem cells. “With the support of GV, Main Street Advisors and other top-tier investors, we expect to advance our lead programme to a Phase IIa clinical trial in the second half of this year.” Affecting both men and women, androgenetic alopecia or pattern balding is responsible for more than 90% of all hair loss. Apart from androgenetic alopecia, the company anticipates that PP405 has applications for other hair loss types, including stress-induced hair loss or telogen effluvium and chemotherapy-induced hair loss.