Mohamed-Eslam F. Mohamed, Yuli Qian, Ronilda D'Cunha, Teresa Sligh, Laura K. Ferris, Ann Eldred, Gweneth F. Levy, Shuai Hao, Shashikanth Gannu, David G. Rizzo, Wei Liu, Sasha Jazayeri, Howard Sofen, Roberto Carcereri De Prati
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.
{"title":"Pharmacokinetics, safety, and efficacy of cedirogant from phase I studies in healthy participants and patients with chronic plaque psoriasis","authors":"Mohamed-Eslam F. Mohamed, Yuli Qian, Ronilda D'Cunha, Teresa Sligh, Laura K. Ferris, Ann Eldred, Gweneth F. Levy, Shuai Hao, Shashikanth Gannu, David G. Rizzo, Wei Liu, Sasha Jazayeri, Howard Sofen, Roberto Carcereri De Prati","doi":"10.1111/cts.13682","DOIUrl":"https://doi.org/10.1111/cts.13682","url":null,"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.","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138816711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wonsuk Shin, Min Young Park, Jongwoo Kim, Jihyeon Kim, Jun Hee Nam, Jongwon Choi, A-Young Yang, Hyounggyoon Yoo, Yil-Seob Lee, Anhye Kim
Bersiporocin, a potent and selective prolyl-tRNA synthetase inhibitor, is expected to show a synergistic effect with pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis. To validate the combination therapy of bersiporocin with pirfenidone or nintedanib, a randomized, open-label, two-part, one-sequence, three-period, three-treatment study was designed to evaluate the effect of drug-drug interactions (DDIs) regarding their pharmacokinetics, safety, and tolerability in healthy participants. In addition, the pharmacokinetic profiles of the newly formulated enteric-coated bersiporocin tablet were evaluated after single and multiple administrations. The potential effects of cytochrome P450 2D6 (CYP2D6) genotyping on bersiporocin pharmacokinetics and DDI were also explored. In Part 1, participants were sequentially administered a single dose of pirfenidone 600 mg, a single dose of bersiporocin 150 mg followed by multiple doses and bersiporocin in combination with pirfenidone. In Part 2, participants were sequentially administered a single dose nintedanib 150 mg, multiple doses of bersiporocin 150 mg, and bersiporocin in combination with nintedanib. A 46 participants completed the study. There was no significant pharmacokinetic DDI between bersiporocin, and pirfenidone or nintedanib. All adverse events (AEs) were mild to moderate and did not include serious AEs suggesting bersiporocin alone or in combination therapy were well-tolerated. The newly formulated bersiporocin 150 mg tablet showed a moderate accumulation index. There was no significant difference in the pharmacokinetic profiles after administration of bersiporocin alone or in combination therapy between CYP2D6 phenotypes. In conclusion, there is no significant DDI regarding the pharmacokinetics, safety, and tolerability of bersiporocin administration with pirfenidone or nintedanib.
{"title":"No drug-drug interactions between selective prolyl-trna synthetase inhibitor, bersiporocin, and pirfenidone or nintedanib in healthy participants","authors":"Wonsuk Shin, Min Young Park, Jongwoo Kim, Jihyeon Kim, Jun Hee Nam, Jongwon Choi, A-Young Yang, Hyounggyoon Yoo, Yil-Seob Lee, Anhye Kim","doi":"10.1111/cts.13701","DOIUrl":"https://doi.org/10.1111/cts.13701","url":null,"abstract":"Bersiporocin, a potent and selective prolyl-tRNA synthetase inhibitor, is expected to show a synergistic effect with pirfenidone or nintedanib in patients with idiopathic pulmonary fibrosis. To validate the combination therapy of bersiporocin with pirfenidone or nintedanib, a randomized, open-label, two-part, one-sequence, three-period, three-treatment study was designed to evaluate the effect of drug-drug interactions (DDIs) regarding their pharmacokinetics, safety, and tolerability in healthy participants. In addition, the pharmacokinetic profiles of the newly formulated enteric-coated bersiporocin tablet were evaluated after single and multiple administrations. The potential effects of cytochrome P450 2D6 (CYP2D6) genotyping on bersiporocin pharmacokinetics and DDI were also explored. In Part 1, participants were sequentially administered a single dose of pirfenidone 600 mg, a single dose of bersiporocin 150 mg followed by multiple doses and bersiporocin in combination with pirfenidone. In Part 2, participants were sequentially administered a single dose nintedanib 150 mg, multiple doses of bersiporocin 150 mg, and bersiporocin in combination with nintedanib. A 46 participants completed the study. There was no significant pharmacokinetic DDI between bersiporocin, and pirfenidone or nintedanib. All adverse events (AEs) were mild to moderate and did not include serious AEs suggesting bersiporocin alone or in combination therapy were well-tolerated. The newly formulated bersiporocin 150 mg tablet showed a moderate accumulation index. There was no significant difference in the pharmacokinetic profiles after administration of bersiporocin alone or in combination therapy between CYP2D6 phenotypes. In conclusion, there is no significant DDI regarding the pharmacokinetics, safety, and tolerability of bersiporocin administration with pirfenidone or nintedanib.","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":"53 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138816464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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