Optimizing lonafarnib treatment for the management of chronic delta hepatitis: The lowr HDV – 1 study

ABSTRACT

Background and rationale: In a proof-of-concept (POC) study, the oral prenylation inhibitor lonafarnib (LNF) decreased HDV RNA during 4 weeks of treatment. Here we explored optimal LNF regimens. Methods: 15 patients (5 groups; 3 per group) completed dosing as follows: 1) LNF 200 mg BID (12 weeks); 2) LNF 300 mg BID (12 weeks); 3) LNF 100 mg TID (5 weeks); 4) LNF 100 mg BID + pegylated interferon alfa (PEG-IFNα) 180 mcg QW (8 weeks); and 5) LNF 100 mg BID + ritonavir (RTV) 100 mg QD (8 weeks). Tolerability and efficacy were assessed. Results: Higher LNF monotherapy doses had greater decreases in HDV viral load than achieved in the original POC study. However, this was associated with increased gastrointestinal adverse events. Addition of RTV 100 mg QD to a LNF 100 mg BID regimen yielded better antiviral responses than LNF 300 mg BID monotherapy, and with less side effects. A similar improvement was observed with LNF 100 mg BID + PEG-IFNα 180 mcg QW. 2/6 patients who received 12 weeks of LNF experienced transient post-treatment ALT increases resulting in HDV RNA negativity and ALT normalization. Conclusions: The CYP3A4 inhibitor RTV allows a lower LNF dose to be used while achieving higher levels of post-absorption LNF, yielding better antiviral responses and tolerability. In addition, combining LNF with PEG-IFNα achieved more substantial and rapid HDV RNA reduction, compared to historical responses with PEG-IFNα alone. 12 weeks of LNF can result in post-treatment HDV RNA negativity in some patients, which we speculate results from restoring favorable immune responses. These results support further development of LNF with RTV boosting and exploration of the combination of LNF with PEG-IFN. This article is protected by copyright. All rights reserved.

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