A phase 2 dose-finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis.

Autor: Yurdaydin C; Department of GastroenterologyUniversity of Ankara Medical SchoolAnkaraTurkey.; Hepatology InstituteUniversity of AnkaraAnkaraTurkey.; Department of Gastroenterology and HepatologyKoç University Medical SchoolIstanbulTurkey., Keskin O; Department of GastroenterologyUniversity of Ankara Medical SchoolAnkaraTurkey., Yurdcu E; Hepatology InstituteUniversity of AnkaraAnkaraTurkey., Çalişkan A; Department of GastroenterologyUniversity of Ankara Medical SchoolAnkaraTurkey., Önem S; Department of GastroenterologyUniversity of Ankara Medical SchoolAnkaraTurkey., Karakaya F; Department of GastroenterologyUniversity of Ankara Medical SchoolAnkaraTurkey., Kalkan Ç; Department of GastroenterologyUniversity of Ankara Medical SchoolAnkaraTurkey., Karatayli E; Hepatology InstituteUniversity of AnkaraAnkaraTurkey.; Department of Medicine IISaarland University Medical CenterSaarland UniversityHomburgGermany., Karatayli S; Hepatology InstituteUniversity of AnkaraAnkaraTurkey.; Department of Medicine IISaarland University Medical CenterSaarland UniversityHomburgGermany., Choong I; Eiger BioPharmaceuticals, Inc.Palo AltoCaliforniaUSA., Apelian D; Eiger BioPharmaceuticals, Inc.Palo AltoCaliforniaUSA., Koh C; Translational Hepatology SectionLiver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMarylandUSA., Heller T; Translational Hepatology SectionLiver Diseases BranchNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institutes of HealthBethesdaMarylandUSA., Idilman R; Department of GastroenterologyUniversity of Ankara Medical SchoolAnkaraTurkey., Bozdayi AM; Hepatology InstituteUniversity of AnkaraAnkaraTurkey., Glenn JS; Departments of Medicine (Division of Gastroenterology and Hepatology) and Microbiology & ImmunologyStanford School of MedicineStanfordCaliforniaUSA.; Palo Alto Veterans AdministrationPalo AltoCaliforniaUSA.
Jazyk: angličtina
Zdroj: Hepatology (Baltimore, Md.) [Hepatology] 2022 Jun; Vol. 75 (6), pp. 1551-1565. Date of Electronic Publication: 2021 Dec 23.
DOI: 10.1002/hep.32259
Abstrakt: Background and Aims: Proof-of-concept studies demonstrated lonafarnib (LNF), a first-in-class oral prenylation inhibitor, efficacy in patients infected with HDV. The lonafarnib with ritonavir for HDV-2 (LOWR-2) study's aim was to identify optimal combination regimens of LNF + ritonavir (RTV) ± pegylated interferon alpha (PEG-IFNα) with efficacy and tolerability for longer-term dosing. Here we report the safety and efficacy at end of treatment for up to 24 weeks.
Approach and Results: Fifty-five patients with chronic HDV were consecutively enrolled in an open-label, single-center, phase 2 dose-finding study. There were three main treatment groups: high-dose LNF (LNF ≥ 75 mg by mouth [po] twice daily [bid] + RTV) (n = 19, 12 weeks); all-oral low-dose LNF (LNF 25 or 50 mg po bid + RTV) (n = 24, 24 weeks), and combination low-dose LNF with PEG-IFNα (LNF 25 or 50 mg po bid + RTV + PEG-IFNα) (n = 12, 24 weeks). The primary endpoint, ≥2 log 10 decline or < lower limit of quantification of HDV-RNA from baseline at end of treatment, was reached in 46% (6 of 13) and 89% (8 of 9) of patients receiving the all-oral regimen of LNF 50 mg bid + RTV, and combination regimens of LNF (25 or 50 mg bid) + RTV + PEG-IFNα, respectively. In addition, multiple patients experienced well-tolerated transient posttreatment alanine aminotransferase increases, resulting in HDV-RNA negativity and alanine aminotransferase normalization. The proportions of grade 2 and 3 gastrointestinal adverse events in the high-dose versus low-dose groups were 49% (37 of 76) and only 22% (18 of 81), respectively.
Conclusions: LNF, boosted with low-dose RTV, is a promising all-oral therapy, and maximal efficacy is achieved with PEG-IFNα addition. The identified optimal regimens support a phase 3 study of LNF for the treatment of HDV.
(© 2021 American Association for the Study of Liver Diseases.)
Databáze: MEDLINE
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