Department of GastroenterologyUniversity of Ankara Medical SchoolAnkaraTurkey.
Hepatology InstituteUniversity of AnkaraAnkaraTurkey.
Hepatology. 2022 Jun;75(6):1551-1565. doi: 10.1002/hep.32259. Epub 2021 Dec 23.
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.
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 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.
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.
概念验证研究表明，洛那法尼（LNF）是一种首创的口服前蛋白异戊二烯基转移酶抑制剂，对感染 HDV 的患者有效。洛那法尼联合利托那韦治疗 HDV-2（LOWR-2）研究的目的是确定 LNF+利托那韦（RTV）±聚乙二醇干扰素 α（PEG-IFNα）的最佳联合治疗方案，以实现更长时间的治疗，同时具有疗效和耐受性。在此，我们报告了治疗结束时最长 24 周的安全性和疗效。
55 例慢性 HDV 患者连续入组一项开放性、单中心、2 期剂量探索研究。主要有三组治疗：高剂量 LNF（LNF 口服，每日两次，每次≥75mg；+RTV）（n=19，12 周）；全口服低剂量 LNF（LNF 25 或 50mg，口服，每日两次+RTV）（n=24，24 周），以及 LNF 联合 PEG-IFNα 的低剂量联合治疗（LNF 25 或 50mg，口服，每日两次+RTV+PEG-IFNα）（n=12，24 周）。主要终点为治疗结束时 HDV-RNA 较基线下降≥2 log 或<定量下限，接受全口服 LNF 50mg 每日两次+RTV 治疗的患者中分别有 46%（13 例中的 6 例）和 89%（9 例中的 8 例）达到该终点，而接受 LNF（25 或 50mg 每日两次）+RTV+PEG-IFNα 联合治疗的患者中分别有 89%（9 例中的 8 例）和 100%（12 例中的 12 例）达到该终点。此外，多名患者出现可耐受的治疗后短暂性丙氨酸氨基转移酶升高，导致 HDV-RNA 阴性和丙氨酸氨基转移酶正常化。高剂量组和低剂量组的 2 级和 3 级胃肠道不良事件比例分别为 49%（76 例中的 37 例）和仅 22%（81 例中的 18 例）。
LNF 联合低剂量 RTV 是一种很有前途的全口服治疗方法，与 PEG-IFNα 联合使用可达到最大疗效。确定的最佳治疗方案支持 LNF 治疗 HDV 的 3 期研究。
