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Investigational Topical Agent Targets Dormant Follicles in Androgenetic Alopecia
In early clinical research, a novel topical agent under development for
androgenetic alopecia (AGA) delivered hair density increases greater than 20% for about one third of patients with a higher degree of hair loss 1 month posttreatment. The ability of the small-molecule mitochondrial pyruvate carrier (MPC) inhibitor known as PP405 to reactivate dormant follicles signals a potential paradigm shift in hair restoration, according to the product’s lead investigator.
Qing Yu Christina Weng, MD
Researchers led by dermatologist
Qing Yu Christina Weng, MD, chief medical officer of Pelage Pharmaceuticals, Los Angeles, which is developing PP405, randomly assigned 78 men and women with AGA and diverse skin types and hair textures to once-daily application of either PP405 or placebo for 4 weeks, followed by 8 weeks’ observation.
At week 8, 31% of the men in the study with moderate and moderate-to-severe hair loss achieved greater than a 20% increase in hair density with treatment compared with none in the placebo group with the same degree of hair loss, according to a June 17
press release from the company announcing the results. Treatment was well tolerated, with no systemic absorption detected at any time during dosing, the release said.
Phase 2a results also show that PP405 worked in areas that were previously bald. “And the hair that is growing is thick, mature, terminal hair,” Weng said, “not vellus ‘baby hair.’” PP405 has been engineered to penetrate the skin 1000-fold more effectively than the blood, a property that is critical for both efficacy and safety, she added.
Previous research has shown that hair follicle stem cells (HFSCs) in people with hair loss are
not dead but dormant. Researchers from the University of California, Los Angeles, who later cofounded Pelage, discovered that inhibiting MPC increases pyruvate levels, which drives up lactate dehydrogenase and activates HFSCs to spur new hair growth, said Weng.
Cautious Optimism
Hair-loss experts interviewed by
Medscape Dermatology met Pelage’s announcement with cautious optimism. “A completely novel mechanism” as a potential treatment option for hair loss “is very exciting,” said Glynis Ablon, MD, associate clinical professor of dermatology at the University of California, Los Angeles, who practices in Manhattan Beach, California. “The phase 1 and 2 data are quite promising,” added Ablon, who was not involved with the study.
Brett King, MD, PhD
Brett King, MD, PhD, a Fairfield, Connecticut-based dermatologist who also was not involved with the study, said, “The technology is born of interesting science, and the early data are compelling.” However, he added, the phase 2a results, in a small number of adults treated for a very short period, have not been peer reviewed. Phase 3 clinical trials and their results are at least 3-4 years from FDA review, he said.
Pelage’s goal is to offer the first FDA-approved option for treating AGA in more than 25 years, said Weng, who is also a dermatologist at Massachusetts General Hospital and Harvard Medical School in Boston. “The treatments we can offer patients in the Xxxxxx right now are limited.” Only
finasteride and topical
minoxidil are FDA-approved for AGA, she said, and only the latter is approved for women of all ages. Both drugs provide limited efficacy and response rates, she added. Beyond these treatments, Weng said, lies a “wild West of unproven hair loss treatments” such as platelet-rich plasma, red-light therapy, lasers, and supplements.
Used off-label for AGA, Weng added that low-dose oral minoxidil can be an option for patients who prefer a pill over a topical product.
“Most of the options out there target indirect causes of hair loss and try to slow it, often through hormonal mechanisms,” Weng said. “PP405 is looking to do something different by addressing the underlying biology at the level of the stem cells and restoring biological function.”
Moderate-to-Severe Hair Loss Niche?
Treatment of AGA, the most common form of alopecia, has progressed in the past few years, said King, particularly since an August 2022
The New York Times article about oral minoxidil popularized its use.
“Oral minoxidil is very inexpensive and often effective, either alone or in combination with
spironolactone, finasteride, or
dutasteride, in people with more mild hair loss,” he added. Although King is unaware of any randomized, double-blinded, placebo-controlled trials of oral minoxidil for AGA, he said, “It is widely recognized by those of us who take care of people with hair loss disorders that it is better than everything else.”
He referred to a
retrospective case series of 64 patients with male or female pattern hair loss published in 2020, treated with low-dose sublingual minoxidil, which showed a 1.07-point reduction in the 5-point Sinclair stage at 12 months. Dosing can vary widely, King said, from
0.625 mg to 5 mg once or twice daily, according to a recent
expert consensus, depending on the dermatologist’s comfort level with oral minoxidil.
“However,” he said, “in men and women with severe hair loss — and there are many — the results of current therapies are usually inadequate.” Therefore, King said that although prescribers and patients across the AGA spectrum would welcome any effective treatment, “PP405 would have an obvious role in those with moderate-to-severe hair loss.”
Glynis Ablon, MD
Oral minoxidil is perceived as a wonder drug for hair loss, added Ablon. “But people forget that there are side effects.” Many doctors are prescribing minoxidil without discussing potential complications, most notably leg edema, hypotension, and hypertrichosis, and ensuring that they change dosing based on patient response, she said.
Ablon is an investigator in a phase 3 trial of VDPHL01, which she said is a nonhormonal oral treatment that Veradermics, the New Haven, Connecticut-based company developing the treatment, hopes will provide better efficacy and tolerability than existing AGA therapies.
Results of a
phase 2 trial of VDPHL01, which has yet to be published, were very promising, she said, and phase 3 research in men and women is ongoing, with initial data anticipated to be available in 2026. (Neither Veradermics nor Ablon has disclosed VDPHL01’s mechanism of action, although the company’s January
filing for a patent on an extended-release minoxidil formulation has prompted speculation that this is VDPHL01’s mechanism of action.)
Among other therapies, Ablon said, about 50% of patients achieve some success with topical minoxidil, 5%. Although topical minoxidil and finasteride are reasonably priced and often covered by insurance, she pointed out that finasteride can cause sexual dysfunction.
Platelet-rich plasma injections, exosomes, and laser caps may work for some patients but are expensive, Ablon added. Altogether, she said,
ethically providing appropriate treatments for hair loss requires being honest with patients about their options, including a thorough discussion of treatment prices and duration.
“I like being able to offer multiple modalities and treatment options to my patients, as the average dermatologist will want to do,” Ablon said. And if PP405 proves to be successful in phase 3, cost-effective, and low risk for patients, she said, it could be a game changer.
Next Steps
By year’s end, Pelage plans to complete a 3-month open-label safety extension of the phase 2a study involving patients originally randomized to placebo. The company anticipates initiating phase 3 studies in 2026.
Beyond AGA, Weng said, PP405 could potentially work in other nonscarring alopecias where the follicle and stem cells remain intact. Examples include hair loss caused by weight loss or weight-loss medications such as GLP-1 receptor agonists, which she said is an area of growing patient interest. One day, Weng added, PP405 could perhaps treat hair loss driven by perimenopause,
menopause, and other drugs, including chemotherapy.
However, King said that before speculating about other forms of alopecia, “Let’s first confirm the peer-reviewed results of PP405 in androgenetic alopecia, including results of treatment in larger populations.” Because different hair-loss disorders have different pathophysiologies, he said, a single drug mechanism might not be helpful across the board.
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