Pharmacokinetics, safety, and efficacy of cedirogant from phase I studies in healthy participants and patients with chronic plaque psoriasis

Abstract

Cedirogant is an inverse agonist of retinoic acid‐related orphan receptor gamma thymus (RORγt) developed for the treatment of moderate to severe chronic plaque psoriasis. Here, we report the results from two phase I studies in which the pharmacokinetics (PK), safety, and efficacy of cedirogant in healthy participants and patients with moderate to severe chronic plaque psoriasis were evaluated. The studies consisted of single (20–750 mg) and multiple (75–375 mg once‐daily [q.d.]) ascending dose designs, with effect of food and itraconazole on cedirogant exposure also evaluated. Safety and PK were evaluated for both healthy participants and psoriasis patients, and efficacy was assessed in psoriasis patients. Following single and multiple doses, cedirogant mean terminal half‐life ranged from 16 to 28 h and median time to reach maximum plasma concentration ranged from 2 to 5 h across both populations. Cedirogant plasma exposures were dose‐proportional after single doses and less than dose‐proportional from 75 to 375 mg q.d. doses. Steady‐state concentrations were achieved within 12 days. Accumulation ratios ranged from approximately 1.2 to 1.8 across tested doses. Food had minimal effect and itraconazole had limited impact on cedirogant exposure. No discontinuations or serious adverse events due to cedirogant were recorded. Psoriasis Area and Severity Index (PASI) and Self‐Assessment of Psoriasis Symptoms (SAPS) assessments demonstrated numerical improvement with treatment of cedirogant 375 mg q.d. compared with placebo. The PK, safety, and efficacy profiles of cedirogant supported advancing it to phase II clinical trial in psoriasis patients.

Cedirogant Population Pharmacokinetics and Pharmacodynamic Analyses of Interleukin‐17A Inhibition in Two Phase 1 Studies in Healthy Participants and Participants with Moderate to Severe Psoriasis

“…Details of the design and eligibility criteria for the 2 Phase 1 studies (Studies 1 and 2) have been previously described. 7 Briefly, Study 1 consisted of 2 substudies (Study 1A and 1B). Study 1A was a randomized, double-blind, placebo-controlled study in healthy participants to assess the pharmacokinetics, safety, and tolerability after single ascending oral doses of cedirogant ranging from 20 to 750 mg. Doses were administered orally under fasting conditions.…”

“…7 The median time to maximum observed plasma concentration was reached within 2-5 hours, with a harmonic mean terminal phase elimination half-life at steady state of 26-28 hours. 7 Cedirogant plasma exposures were dose proportional over the single-dose range of 20-750 mg. After multiple daily administrations, cedirogant steadystate plasma exposures were less than dose proportional from 75 to 225 mg once daily but were dose proportional between 225 and 375 mg once daily. Steady-state concentrations were reached within 12 days of dosing.…”

“…In Phase 1 studies, the pharmacokinetics of cedirogant were evaluated following the administration of single doses up to 395 mg in healthy men and 750 mg in healthy women. 7 Cedirogant pharmacokinetics were also evaluated following the administration of multiple once-daily doses up to 375 mg for 14 days in healthy men and women, and for 28 days in both male and female participants with PsO. 7 The median time to maximum observed plasma concentration was reached within 2-5 hours, with a harmonic mean terminal phase elimination half-life at steady state of 26-28 hours.…”

“…7 Cedirogant pharmacokinetics were also evaluated following the administration of multiple once-daily doses up to 375 mg for 14 days in healthy men and women, and for 28 days in both male and female participants with PsO. 7 The median time to maximum observed plasma concentration was reached within 2-5 hours, with a harmonic mean terminal phase elimination half-life at steady state of 26-28 hours. 7 Cedirogant plasma exposures were dose proportional over the single-dose range of 20-750 mg. After multiple daily administrations, cedirogant steadystate plasma exposures were less than dose proportional from 75 to 225 mg once daily but were dose proportional between 225 and 375 mg once daily.…”

“…Renal elimination has negligible contribution to cedirogant clearance. 7 To evaluate target engagement of cedirogant, drug plasma concentrations and ex vivo IL-17A concentration measurements from healthy participants and participants with moderate to severe PsO from 2 Phase I studies were analyzed in a population pharmacokinetic and pharmacodynamic modeling framework, and the results are reported herein. The objectives of these analyses were (1) to characterize the population pharmacokinetics of cedirogant following single and multiple doses in healthy participants and participants with PsO and (2) to assess ex vivo IL-17A inhibition in relation to exposure of cedirogant in healthy participants and participants with PsO.…”