Liver and Bile
Hepatology. 2022;75(6):1551–65
A phase 2 dose-finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis
Background and aims: Proof-of-concept studies demonstrated lonafarnib (LNF), a first-in-class oral prenylation inhibitor, efficacy in patients infected with hepatitis delta virus (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 the authors report the safety and efficacy at end of treatment for up to 24 weeks.
Approach and results: 55 patients with chronic HDV were consecutively enrolled in an open-label, single-center, phase 2 dose-finding study. There were 3 main treatment groups: high-dose LNF (LNF ≥ 75 mg by mouth [p.o.] twice daily [bid] + RTV) (n = 19, 12 weeks); all-oral low-dose LNF (LNF 25 or 50 mg p.o. bid + RTV) (n = 24, 24 weeks), and combination low-dose LNF with PEG-IFNα (LNF 25 or 50 mg p.o. bid + RTV + PEG-IFNα) (n = 12, 24 weeks). The primary end point, ≥ 2 log10 decline or < lower limit of quantification of HDV-RNA from baseline at end of treatment, was reached in 46% (6/13) and 89% (8/9) 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 post-treatment alanine aminotransferase (ALT) increases, resulting in HDV-RNA negativity and ALT normalization. The proportions of grade 2 and 3 gastrointestinal adverse events in the high-dose versus low-dose groups were 49% (37/76) and only 22% (18/81), respectively.
Conclusions: Lonafarnib (LNF), boosted with low-dose ritonavir, is a promising all-oral therapy, and maximal efficacy is achieved with pegylated interferon alpha addition. The identified optimal regimens support a phase 3 study of LNF for the treatment of hepatitis delta virus.