Short‐Duration AL‐335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis

Abstract

This open‐label, phase IIa study assessed the safety, pharmacokinetics, and efficacy of direct‐acting antiviral agent (DAA) regimens in patients with chronic hepatitis C virus (HCV) infection. Multiple 6‐12‐week oral regimens of 400‐800 mg once daily (QD) AL‐335 + 50 mg QD/every other day odalasvir ± 75‐150 mg QD simeprevir were evaluated in treatment‐naïve, HCV genotype (GT)1/3‐infected patients without cirrhosis. Safety/pharmacokinetic parameters, HCV‐RNA, and sequencing data were assessed. Treatment regimens for later study cohorts were adjusted based on emerging data. In total, 112 patients were enrolled. Three serious treatment‐emergent adverse events occurred, one of which (a Mobitz type 1 second‐degree atrioventricular block [Wenckebach]) was possibly related to high odalasvir exposure and resulted in premature discontinuation of study drugs. No other clinically significant safety findings were identified. GT1‐infected patients receiving 3‐DAA for 6‐8 weeks achieved 100% sustained virologic response 12 weeks and 24 weeks after the end of treatment (sustained virologic response [SVR12/24]). GT1‐infected patients receiving 2‐DAA or GT3‐infected patients receiving 3‐DAA had SVR12/24 less than 90%, whether treated for 8 weeks or 12 weeks. Virologic failure was associated with the emergence of generally persistent NS5A and/or transient NS5B resistance‐associated substitutions in most patients. Pharmacokinetic characteristics of the three drugs were also elucidated. Conclusions: In treatment‐naïve subjects without cirrhosis, AL‐335 + odalasvir + simeprevir for 6‐8 weeks was generally safe and highly efficacious against HCV GT1. However, inadequate efficacy was observed for the 2‐DAA regimen in GT1‐infected subjects and the 3‐DAA regimen in GT3‐infected subjects.

JNJ‐4178 (AL‐335, Odalasvir, and Simeprevir) for 6 or 8 Weeks in Hepatitis C Virus‐Infected Patients Without Cirrhosis: OMEGA‐1

“…None of the reported SAEs or grade 3/4 AEs were considered related to the study drugs, and no AEs led to permanent treatment discontinuation. These findings are in line with earlier studies with the same regimen . Based on a cardiac SAE, a Wenckebach‐type atrioventricular block (not associated with clinical/echocardiographic abnormalities) reported in the AL‐335‐604 study for a patient receiving AL‐335 400 mg + odalasvir 50 mg qd + simeprevir 100 mg qd for 8 weeks, a reduced dose of odalasvir (25 mg qd) was used in OMEGA‐1 and an extensive observation of cardiac safety was included.…”

“…In general, the exposure in this study was similar to the exposure in the patients without cirrhosis (cohorts 2, 3, and 5 from AL‐335‐604), who received similar average daily doses of the 3‐DAA combination: AL‐335 800 mg qd, odalasvir 50 mg every other day, and simeprevir 75 mg qd …”

“…OMEGA‐1 was a phase IIb study that aimed to further explore the efficacy and safety of 6 and 8 weeks of treatment with JNJ‐4178 (3‐DAA combination of AL‐355, odalasvir, and simeprevir) in patients with HCV GT1, 2, 4, 5, and 6 infection without cirrhosis. Of note, HCV GT3‐infected patients were excluded from OMEGA‐1 based on inadequate efficacy with the JNJ‐4178 regimen for 8 or 12 weeks in the phase IIa study AL‐335‐604 …”

“…The 3‐DAA combination of AL‐335, odalasvir, and simeprevir has been evaluated in a phase I study (AL‐335‐602; NCT02512562) in healthy subjects, and a phase IIa study (AL‐335‐604; NCT02569710) in HCV‐infected patients with/without compensated cirrhosis. In the AL‐335‐604 study, an SVR rate 24 weeks after EOT (SVR24) of 100% was achieved with 6 or 8 weeks of treatment in GT1‐infected patients without cirrhosis . In both studies the regimen was well tolerated, and these studies guided the dose selection for each component of the combination to be further evaluated as AL‐335 800 mg once daily (qd), odalasvir 25 mg qd, and simeprevir 75 mg qd (known as JNJ‐4178).…”

“…AL‐335 is an investigational, uridine‐based, nucleotide analog, HCV NS5B polymerase inhibitor with potent pangenotypic antiviral activity against HCV GT1‐6 …”