JNJ-4178 (adafosbuvir, odalasvir, and simeprevir) in Japanese patients with chronic hepatitis C virus genotype 1 or 2 infection with or without compensated cirrhosis: the Phase IIa OMEGA-3 study

Abstract

Background The efficacy, safety, and pharmacokinetics of the combination of three direct-acting antiviral (DAA) agents (adafosbuvir [also known as AL-335], odalasvir, and simeprevir) were investigated in DAA treatment-naïve Japanese patients with genotype (GT)1 or GT2 chronic hepatitis C virus (HCV) infection, with or without compensated cirrhosis. Methods In this Phase IIa, open-label, multicenter study-OMEGA-3 (NCT02993250)-patients received JNJ-4178 (adafosbuvir 800 mg once daily [QD], odalasvir 25 mg QD, and simeprevir 75 mg QD) for 8 (non-cirrhotic patients; Cohort 1) or 12 (cirrhotic patients; Cohort 2) weeks. Patients were followed-up to 24 weeks following the end of treatment (EOT). The primary endpoint was safety, including adverse events (AEs). Results Overall, 33 patients were enrolled into Cohort 1 (N = 22) or 2 (N = 11) and received combined treatment with JNJ-4178. During the treatment and follow-up phases, a higher percentage of patients in Cohort 2 (81.8%)

Advances in Nucleoside and Nucleotide Analogues in Tackling Human Immunodeficiency Virus and Hepatitis Virus Infections

“…The active phosphate form of adafosbuvir (ALS‐022235) hinders HCV‐RdRp and terminates RNA synthesis. The patients showed mild detrimental effects such as headache and upper respiratory tract infection but, interestingly, no relapse of the infection was observed [87–88] . AL‐335 and its metabolites do not interact with host cell polymerases and therefore does not create mitochondrial toxicity.…”

“…Another drug, adafosbuvir (AL‐335), a uracil nucleoside analogue, is under development (clinical trial NCT02339207) to enhance antiviral efficacy and lessening of treatment duration of chronic HCV infections. In DAAs for chronic HCV infection, a Phase II clinical trial of AL‐335, simeprevir (an approved protease inhibitor) and odalasvir (an investigational NNI) are considered [87] . The active phosphate form of adafosbuvir (ALS‐022235) hinders HCV‐RdRp and terminates RNA synthesis.…”

“…In DAAs for chronic HCV infection, a Phase II clinical trial of AL-335, simeprevir (an approved protease inhibitor) and odalasvir (an investigational NNI) are considered. [87] The active phosphate form of adafosbuvir (ALS-022235) hinders HCV-RdRp and terminates RNA synthesis. The patients showed mild detrimental effects such as headache and upper respiratory tract infection but, interestingly, no relapse of the infection was observed.…”

“…The patients showed mild detrimental effects such as headache and upper respiratory tract infection but, interestingly, no relapse of the infection was observed. [87][88] AL-335 and its metabolites do not interact with host cell polymerases and therefore does not create mitochondrial toxicity. In combination therapy, AL-335 shows lower drugdrug interactions and high drug resistance barrier.…”

Treatment progress and expansion in Japan: From interferon to direct-acting antiviral

“…This triple therapy was approved in 2016 but was discontinued in 2018. As another triple DAA combination therapy, adafosbuvir (nucleotide polymerase inhibitor of NS5B) plus odalasvir (NS5A inhibitor) plus SMV (NS3/4A protease inhibitor), was being tested in clinical trials (61). SVR rates of this regimen for 8 weeks in patients with chronic hepatitis and for 12 weeks in those with cirrhosis were both 100%; however, this regimen was never used clinically.…”