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Cedirogant is an inverse agonist of retinoic acid‐related orphan receptor gamma, thymus (RORγt) developed for treatment of psoriasis. This study aimed to characterize pharmacokinetics, pharmacodynamics, safety, and tolerability of cedirogant following a single oral dose in Japanese participants and multiple oral doses in Japanese and Chinese participants. The single doses evaluated in healthy Japanese participants were 75, 225, and 395 mg. The multiple doses evaluated in both healthy Japanese and Chinese participants was 375 mg once daily for 14 days. Cedirogant plasma exposure increased dose proportionally with administration of single doses. Maximum cedirogant plasma concentration was reached within a median time of 4‐5 hours after dosing. The harmonic mean elimination half‐life ranged from 19 to 25 hours. Cedirogant pharmacokinetics were similar between Japanese and Chinese participants. Compared with healthy Western participants in a cross‐study analysis, steady‐state cedirogant plasma exposure was 38%‐73% higher in Japanese or Chinese participants. Ex vivo interleukin‐17 inhibition increased in a dose‐dependent manner and was maximized by 375 mg once‐daily doses. The cedirogant regimens tested were generally well tolerated, and no new safety issues were identified. The results supported enrollment of Japanese and Chinese subjects in subsequent clinical trials for cedirogant. [ABSTRACT FROM AUTHOR]

This article discusses the impact of the COVID-19 pandemic on the design and conduct of clinical trials. A working group was formed to collect data on the experiences of IQ member companies regarding the pandemic's effects on clinical trials, including missed doses and missing pharmacokinetic/pharmacodynamic data. The survey results showed that the majority of clinical trials were conducted as planned, but some were paused or delayed. The pandemic also led to changes in trial design, such as reduced number of visits and wider sample collection windows. Mitigation strategies, such as remote visits and use of local laboratories, were implemented to minimize the impact of COVID-19 on trials. The article also includes case studies that highlight innovative approaches used during the pandemic, such as virtual matched healthy controls and decentralized trials. Overall, the findings provide valuable insights into the impact of the pandemic on clinical trials and offer potential strategies for future drug development. [Extracted from the article]

Cedirogant (ABBV‐157) is an orally bioavailable inverse agonist of retinoic acid‐related orphan receptor gamma thymus. Data from 2 Phase 1 studies were used to characterize cedirogant pharmacokinetics and evaluate target engagement. Cedirogant plasma concentrations and ex vivo interleukin 17A (IL‐17A) concentrations from healthy participants and participants with moderate to severe psoriasis (PsO) were analyzed in a population pharmacokinetic and pharmacodynamic modeling framework to characterize cedirogant pharmacokinetics following single and multiple doses and assess ex vivo IL‐17A inhibition in relation to cedirogant exposure. Cedirogant population pharmacokinetics were best described by a 2‐compartment pharmacokinetic model with delayed absorption and an enzyme turnover compartment to describe cytochrome P450 3A autoinduction. The pharmacokinetics of cedirogant were comparable between healthy participants and participants with PsO. Cedirogant steady‐state average and maximum plasma concentrations were predicted to be 7.56 and 11.8 mg/L, respectively, for participants with PsO for the 375 mg once‐daily regimen on Day 14. The apparent clearance and apparent volume of distribution for cedirogant were estimated to be 24.5 L/day and 28.2 L, respectively. A direct maximum inhibition model adequately characterized the exposure‐response relationship of cedirogant and ex vivo IL‐17A inhibition, indicating no temporal delay between exposure and response with a saturable inhibition of IL‐17A. Model‐estimated half‐maximal inhibitory concentration and maximum inhibition values for cedirogant inhibition of ex vivo IL‐17A were 0.56 mg/L and 0.76, respectively. The established relationship between cedirogant exposure and biomarker effect supported dose selection for the Phase 2 dose‐ranging study in patients with PsO. [ABSTRACT FROM AUTHOR]

Upadacitinib is an orally administered, selective, Janus kinase inhibitor that is approved for several auto‐immune conditions, such as axial spondyloarthritis, an inflammatory rheumatic disease that includes ankylosing spondylitis (AS) and non‐radiographic axial spondyloarthritis (nr‐axSpA). The approvals of upadacitinib for the treatment of AS and nr‐axSpA were based on the safety and efficacy data for upadacitinib 15 mg once‐daily compared to placebo from the SELECT‐AXIS 1 and SELECT‐AXIS 2 studies. Population pharmacokinetic analyses based on data from 244 patients with axSpA showed that the pharmacokinetics of upadacitinib were comparable in subjects with AS and nr‐axSpA. Exposure‐response relationships were characterized for key efficacy and safety end points using data from 482 patients with axSpA. The exposure‐response analyses for efficacy based on Assessment of SpondyloArthritis International Society (ASAS)20 and ASAS40 responses at week 14, showed a clear differentiation from placebo with no evidence of increased responses with increasing upadacitinib plasma exposures. There were no clear exposure‐response trends observed for safety end points that included serious infections, herpes zoster, pneumonia, lymphopenia (grade ≥3), neutropenia (grade ≥3), or a greater than 2 g/dL decrease in hemoglobin from baseline through week 14. The exposure‐response analyses for efficacy and safety presented here supported the favorable benefit–risk profile with the use of upadacitinib 15 mg once‐daily for the treatment of axSpA. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Upadacitinib is a selective Janus kinase (JAK) inhibitor which is approved by the US Food and Drug Administration, the European Medicines Agency, as well as other agencies around the world for the treatment of several chronic inflammatory diseases, including rheumatic, dermatologic, and gastrointestinal diseases. Through inhibition of JAK, upadacitinib inhibits phosphorylation of downstream effector proteins, which consequently inhibits cytokine signaling for key pathways involved in inflammatory diseases. Upadacitinib more potently inhibits JAK1 than other JAK isoforms. The pharmacokinetics, pharmacodynamics, efficacy, and safety of upadacitinib were characterized in many clinical trials, which demonstrated the superiority of upadacitinib treatment over placebo or an active comparator in rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, non‐radiographic axial spondyloarthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis. The safety profile of upadacitinib supported a favorable benefit–risk profile across all the approved indications. In this article, we review the mechanism of action of upadacitinib and describe how the JAK–STAT (Janus kinase–signal transducers and activators of transcription) pathway is involved in the pathogenesis of several chronic and progressive immune‐mediated inflammatory diseases. In addition, this review also provides an overview of key clinical trials that were conducted as well as relevant data which supported the clinical development of upadacitinib and informed the recommended dose(s) in each of the approved indications. [ABSTRACT FROM AUTHOR]

Upadacitinib is an oral Janus kinase inhibitor approved for the treatment of rheumatoid arthritis (RA) and recently approved by the European Medicines Agency for the treatment of psoriatic arthritis (PsA). The efficacy and safety profile of upadacitinib in PsA have been established in the SELECT‐PsA program in two global phase III studies, which evaluated upadacitinib 15 and 30 mg q.d. The analyses described here characterized upadacitinib pharmacokinetics and exposure‐response relationships for efficacy and safety endpoints using data from the SELECT‐PsA studies. Upadacitinib pharmacokinetics in patients with PsA were characterized through a Bayesian population analysis approach and were comparable to pharmacokinetics in patients with RA. Exposure‐response relationships for key efficacy and safety endpoints were characterized using data from 1916 patients with PsA. The percentage of patients achieving efficacy endpoints at week 12 (American College of Rheumatology [ACR]50 and ACR70), 16 and 24 (sIGA0/1) increased with increasing upadacitinib average plasma concentration over a dosing interval, whereas no clear exposure‐response trend was observed for ACR20 at week 12 or ACR20/50/70 at week 24 within the range of plasma exposures evaluated in the phase III PsA studies. No clear trends for exposure‐response relationships were identified for experiencing pneumonia, herpes zoster infection, hemoglobin less than 8 g/dl, lymphopenia (grade ≥ 3), or neutropenia (grade ≥ 3) after 24 weeks of treatment. Shallow relationships with plasma exposures were observed for serious infections and hemoglobin decrease greater than 2 g/dl from baseline at week 24. Based on exposure‐response analyses, the upadacitinib 15 mg q.d. regimen is predicted to achieve robust efficacy in patients with PsA and to be associated with limited incidences of reductions in hemoglobin or occurrence of serious infections. [ABSTRACT FROM AUTHOR]

Upadacitinib is a selective Janus kinase 1 inhibitor that was recently approved for treatment of rheumatoid arthritis and is currently being evaluated for treatment of several other autoimmune diseases, including atopic dermatitis (AD). The relationships between upadacitinib plasma exposure and efficacy (assessed as Eczema Area Severity Index [EASI]‐75, EASI‐90, and Investigator Global Assessment [IGA] 0/1) in subjects with moderate to severe atopic dermatitis were characterized using the data from 167 subjects who were enrolled in a phase 2b dose‐ranging study. Subjects were randomized to receive once daily doses of monotherapy treatment with upadacitinib extended‐release 7.5, 15, or 30 mg or placebo for 16 weeks. Logistic regression models were developed and utilized to simulate efficacy for upadacitinib with an approximate phase 3 sample size. Based on exposure‐response models, 15 mg once daily is predicted to achieve EASI‐75, EASI‐90, and IGA 0/1 responses in 48%, 26%, and 29% of subjects, respectively, compared with placebo responses of 9%, 2%, and 2%, respectively, whereas 30 mg once daily is predicted to provide an additional approximately 20% greater efficacy for these end points relative to 15 mg once daily. These analyses supported the selection of upadacitinib doses that are being evaluated in ongoing global phase 3 studies in atopic dermatitis. [ABSTRACT FROM AUTHOR]