Population exposure–response analysis of the effect of ritlecitinib on eyebrow assessment and eyelash assessment in patients with alopecia areata

Abstract

Ritlecitinib is an orally bioavailable, small molecule that has been approved by the U.S. Food and Drug Administration (FDA) as a once-daily oral treatment option for people 12 years of age and older with severe alopecia areata. This article assessed the exposure–response (ER) relationship of eyebrow and eyelash assessment (EBA/ELA) scores on ritlecitinib and compared them to the Severity of Alopecia Tool (SALT) score (primary endpoint) ER relationship on ritlecitinib. EBA and ELA both are numeric rating scales (NRS) with four levels (0 the most severe, 3 the normal). Longitudinal ER modeling with ordinal regression was conducted to describe ritlecitinib efficacy regarding the hair regrowth in eyebrows and eyelashes separately. The average concentration in the time interval between two adjacent EBA/ELA records was used as the exposure metric. The developed models described the longitudinal EBA/ELA profile and the responder rates adequately. The ER models and the model-based simulations implied that the tested doses in the phase IIb/III clinical trial are in the ascending region, but the magnitude of loading dose effect on earlier efficacy is different across the efficacy endpoints of EBA, ELA, and SALT scores (which could be explained by the estimated $E{C}_{50}$ [concentration at half maximum effect]). The established longitudinal ER relationships supported the selection of 50 mg dose for overall Alopecia areata (AA) patients with impaired eyebrow and eyelash hairs. The presented analysis using the ordinal regression model can be utilized in any ER analysis where PD response is an ordinal categorical variable.