Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of <scp>AL</scp>‐335, odalasvir, and simeprevir in healthy subjects

Kakuda, Thomas N.; McClure, Matthew W.; Westland, Christopher; Vuong, Jennifer; Homery, Marie-Claude; Poizat, Gwendoline; Viguerie, Laure; Denot, Caroline; Patat, Alain; Zhang, Qingling; Hui, James; Apelian, David; Smith, David B.; Chanda, Sushmita; Fry, John

doi:10.1002/prp2.395

Cited by 8 publications

(10 citation statements)

References 21 publications

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“…A phase I study (AL‐335‐602; NCT02512562) previously evaluated the pharmacokinetics of these three drugs in healthy volunteers. This study observed much higher exposures for AL‐335, and mild increases in simeprevir and odalasvir when co‐administered …”

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confidence: 61%

“…The initial patient population (treatment‐naïve, GT1‐infected subjects without cirrhosis) and treatment regimen (AL‐335 400 mg once‐daily [QD] + odalasvir 50 mg QD + simeprevir 100 mg QD for 8 weeks) to be evaluated in cohort 1 were predefined based on the results from study AL‐335‐602 in healthy volunteers, available pharmacodynamic data from the AL‐335 monotherapy study AL‐335‐601 (NCT02339207), the phase IIa odalasvir/sofosbuvir study (ACH102‐017), and simeprevir phase II/III studies (NCT00882908; NCT01567735) . Populations and regimens to be evaluated in subsequent cohorts were determined based on emerging data.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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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.

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confidence: 61%

Section: Methodsmentioning

confidence: 99%

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

et al. 2018

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“…The lower exposure to odalasvir and simeprevir can be attributed to the lower doses of odalasvir and simeprevir used in OMEGA‐1. The lower exposure to AL‐335, but similar exposure of the metabolites, can be explained by the lower magnitude of interaction among odalasvir, simeprevir, and AL‐335 due to the lower doses used …”

Section: Discussionmentioning

confidence: 99%

“…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 .…”

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confidence: 99%

“…Triple DAA regimens for fewer than 8 weeks have resulted in SVR12 (SVR 12 weeks after the end of treatment [EOT]) rates of typically less than 90% in treatment-naïve HCV GT1-infected patients. (11,12) 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, (13) 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.…”

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

Zeuzem

Bourgeois

Greenbloom³

et al. 2019

Hepatology

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The combination of three direct‐acting antiviral agents (AL‐335, odalasvir, and simeprevir: JNJ‐4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic hepatitis C virus (HCV) genotype (GT)‐1‐infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA‐1. This multicenter, randomized, open‐label study (NCT02765490) enrolled treatment‐naïve and interferon (±ribavirin) treatment‐experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL‐335 800 mg, odalasvir 25 mg, and simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8‐week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a‐infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment‐related serious AEs. All randomized patients completed treatment. Conclusion: In HCV‐infected patients, 6 and 8 weeks of treatment with JNJ‐4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated.

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Nucleoside Antiviral Agents for HCV

et al. 2020

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Pharmacokinetics, safety, and tolerability of the 2‐ and 3‐direct‐acting antiviral combination of AL‐335, odalasvir, and simeprevir in healthy subjects

Cited by 8 publications

References 21 publications

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

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

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

Nucleoside Antiviral Agents for HCV

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