Breezula, a clinical stage topical anti-androgen, promotes dermal papilla inductivity and reduces IL-6 secretion in balding skin samples ex vivo

Summary: Abstract Body: Male pattern hair loss (MPHL), the most prevalent form of hair loss in men, is marked by decreased anagen/catagen-telogen ratio and hair follicle (HF) miniaturization in the frontal/vertex scalp. It is primarily driven by increased androgen receptor (AR) activity in the dermal papilla (DP), impairing DP inductivity and consequently hair matrix (HM) keratinocyte proliferation. The AR antagonist Breezula® (clascoterone 5% solution) is currently being clinically tested for MPHL management. Here, we compared its efficacy ex vivo with the FDA-approved drug Minoxidil (5%). Biopsies from balding scalp of 5 MPHL patients (Hamilton-Norwood scale III-VI) were subjected to a clinically relevant testosterone concentration ex vivo. Following a 24-hour resting period, Breezula® or Minoxidil were topically applied every other day for 5 days. Microscopic hair cycle analysis confirmed the clinical MPHL diagnosis, revealing high percentages of telogen/catagen HFs and the presence of intermediate HFs. Analysing DP inductivity, versican expression remained relatively unaffected by Breezula® or Minoxidil treatment, whilst both enhanced AP activity, particularly in terminal anagen HFs. AP activity is positively correlated with Wnt pathway activation, promoting HM keratinocyte proliferation and hair growth. Consistently, we observed a significant increase in HM keratinocyte proliferation in anagen HFs from at least 2 patients following treatment with both Breezula® and Minoxidil. Additionally, Breezula® reduced the secretion of the hair growth inhibitor IL-6, reported to be up-regulated in balding DP cells, after 5 days of culture, whereas Minoxidil did not exert a clear effect. Our data suggest that Breezula® restores DP inductivity and promotes HM keratinocyte proliferation to a similar extent as Minoxidil while its effect in reducing IL-6 secretion may indicate a greater potency for promoting hair growth, warranting further investigation. Alizee Le Riche¹, Prama Pallavi¹, Mara Gerloni², Gordon Alton², Janin Edelkamp¹, Marta Bertolini¹ 1. QIMA Life Sciences, QIMA Monasterium, Münster, Germany. 2. Cosmo Pharmaceuticals NV, Dublin, Ireland. Translational Studies: Cell and Molecular Biology