Risankizumab: Mechanism of action, clinical and translational science

Abstract Risankizumab is a high‐affinity neutralizing anti‐interleukin (IL)‐23 monoclonal antibody marketed in over 40 countries across the globe to treat several inflammatory diseases, such as plaque psoriasis (PsO), psoriatic arthritis (PsA), and Crohn's disease (CD). This paper reviews the regulatory approval, mechanism of action, pharmacokinetics (PKs)/pharmacodynamics, immunogenicity, and clinical efficacy and safety data for risankizumab, focusing on the three main approved indications. Risankizumab binds to the p19 subunit of IL‐23 and inhibits IL‐23 from interacting with the IL‐23 receptor and subsequent signaling. Biomarker data obtained following treatment with risankizumab in multiple indications provided supportive evidence for downstream blockade of IL‐23 signaling associated with disease pathology. The PKs of risankizumab is linear and time‐independent, consistent with typical IgG1 monoclonal antibodies, across all evaluated indications. Risankizumab exhibited positive exposure‐response relationships for efficacy with no apparent exposure‐dependent worsening in safety. Immunogenicity to risankizumab had no major clinical consequences for either efficacy or safety. Efficacy and safety of risankizumab have been established in PsO, PsA, and CD in the pivotal clinical trials where superior benefit/risk profiles were demonstrated compared to placebo and/or active comparators. Moreover, safety evaluations in open‐label extension studies following long‐term treatment with risankizumab showed stable and favorable safety profiles consistent with shorter‐term studies. These data formed the foundation for risankizumab's marketing approvals to treat multiple inflammatory diseases across the globe

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