A Phase ii dose finding study of lonafarnib and ritonavir with or without interferon alpha for chronic delta hepatitis.

BACKGROUND & AIMS Proof-of-concept studies demonstrated lonafarnib (LNF), a first-in-class, oral prenylation inhibitor, efficacy in HDV-infected patients. The LOnafarnib With Ritonavir for HDV-2 (LOWR-2) study's aim was to identify optimal combination regimens of lonafarnib + ritonavir (RTV) ± pegylated interferon alfa (PEG-IFNα) with efficacy and tolerability for longer term dosing. Here we report the safety and efficacy at end of treatment (EOT) for up to 24 weeks. APPROACH & 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 lonafarnib (lonafarnib ≥ 75 mg po bid + ritonavir) (N=19, 12 wks); all-oral low dose lonafarnib (lonafarnib 25 or 50 mg po bid + ritonavir) (N=24, 24 wks) and combination low dose lonafarnib with PEG-IFNα (lonafarnib 25 or 50 mg po bid + ritonavir + PEG-IFNα) (N=12, 24 wks). The primary endpoint, ≥ 2 log10 decline or < LLOQ of HDV-RNA from baseline at EOT, was reached in 46% (6/13) and 89% (8/9) of patients receiving the all-oral regimen of lonafarnib 50 mg bid + ritonavir, and combination regimens of lonafarnib (25 or 50 mg bid) + ritonavir + PEG-IFNα, respectively. In addition, multiple patients experienced well-tolerated transient post-treatment ALT increases resulting in HDV RNA negativity and ALT normalization. The proportions of grade 2 and 3 GI adverse events in the high vs low dose groups were 49% (37/76) and only 22% (18/81), respectively. CONCLUSIONS Lonafarnib, boosted with low dose ritonavir, is a promising all-oral therapy, and maximal efficacy achieved with PEG-IFNα addition. The identified optimal regimens support the first Phase 3 (D-LIVR) study of lonafarnib for the treatment of HDV.