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

被引:48
作者
Yurdaydin, Cihan [1 ,2 ,3 ]
Keskin, Onur [1 ]
Yurdcu, Esra [2 ]
Caliskan, Aysun [1 ]
Onem, Soner [1 ]
Karakaya, Fatih [1 ]
Kalkan, Cagdas [1 ]
Karatayli, Ersin [2 ,4 ]
Karatayli, Senem [2 ,4 ]
Choong, Ingrid [5 ]
Apelian, David [5 ]
Koh, Christopher [6 ]
Heller, Theo [6 ]
Idilman, Ramazan [1 ]
Bozdayi, A. Mithat [2 ]
Glenn, Jeffrey S. [7 ,8 ]
机构
[1] Univ Ankara, Dept Gastroenterol, Med Sch, Ankara, Turkey
[2] Univ Ankara, Hepatol Inst, Ankara, Turkey
[3] Koc Univ, Dept Gastroenterol & Hepatol, Med Sch, Istanbul, Turkey
[4] Saarland Univ, Med Ctr, Dept Med 2, Homburg, Germany
[5] Eiger BioPharmaceut Inc, Palo Alto, CA USA
[6] NIDDK, Translat Hepatol Sect, Liver Dis Branch, NIH, Bethesda, MD 20892 USA
[7] Stanford Sch Med, Dept Med, Div Gastroenterol & Hepatol & Microbiol & Immunol, Stanford, CA 94305 USA
[8] Palo Alto Vet Adm, Palo Alto, CA USA
关键词
INHIBITION; REGRESSION; END;
D O I
10.1002/hep.32259
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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-IFN alpha) 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-IFN alpha (LNF 25 or 50 mg po bid + RTV + PEG-IFN alpha) (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-IFN alpha, 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-IFN alpha addition. The identified optimal regimens support a phase 3 study of LNF for the treatment of HDV.
引用
收藏
页码:1551 / 1565
页数:15
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