Moving Beyond Boundaries: Utilization of Longitudinal Exposure-Response Model for Bounded Outcome Score to Inform...

Area of Science:

• Pharmacometrics
• Quantitative Pharmacology
• Drug Development Science

Background:

• Model-informed drug development (MIDD) accelerates therapy availability by contextualizing data and aiding decisions.
• This study exemplifies MIDD in the combined phase 2b and single pivotal trial for ritlecitinib, a JAK3/TEC family kinases inhibitor.

Purpose of the Study:

• To describe an example of MIDD application in drug development.
• To utilize longitudinal exposure-response (ER) modeling to assess ritlecitinib efficacy in alopecia areata patients.

Main Methods:

• Longitudinal exposure-response (ER) modeling was employed to characterize ritlecitinib's efficacy.
• The Severity of Alopecia Tool (SALT) score, a continuous bounded outcome (CBO), served as the primary efficacy endpoint.
• Average drug concentration within inter-SALT score intervals was the exposure metric.

Main Results:

• The CBO model accurately depicted longitudinal SALT scores and boundary data frequency.
• Tested doses were in the ascending ER region, with a loading dose impacting onset but not long-term benefit.
• Disease severity was the sole identified covariate affecting efficacy.
• Model-based simulations suggested temporary treatment interruptions (≤ 6 weeks) minimally impact efficacy.

Conclusions:

• The CBO modeling approach and simulations supported a single pivotal trial strategy for ritlecitinib's accelerated development.
• This methodology is applicable to other indications using bounded efficacy scales.