Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects

Abstract

Background: The nucleotide analog AL-335 is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor being evaluated as treatment for chronic HCV infection.

Methods: This three-part randomized, double-blind study evaluated the safety and pharmacokinetics of single and multiple ascending oral doses of AL-335. Healthy volunteers (HVs) received single doses of AL-335 (100-1,200 mg) or placebo in a fasted or fed (400 mg) state. Non-cirrhotic subjects (HCV genotype [GT]1-4) and GT1-infected subjects with Child Pugh A cirrhosis received multiple doses of AL-335 (400, 800, 1,200 mg) or placebo once daily (QD) for 7 days.

Results: Forty-eight HVs and 64 subjects with HCV GT1-4 were randomized and received treatment. AL-335 was well tolerated in HVs and HCV-infected subjects with/without cirrhosis. AL-335 was rapidly absorbed and converted to the metabolites ALS-022399 and ALS-022227. ALS-022227 exposure increased less than dose-proportionally and was unaffected by food, while AL-335 and ALS-022399 exposure increased with food by 85% and 50%, respectively, in HVs. Rapid and dose-dependent reductions in HCV-RNA were observed in GT1-infected subjects. In non-cirrhotic, GT1-4-infected subjects receiving AL-335 800 mg QD, potent antiviral activity was observed, regardless of genotype (mean maximum reductions in HCV-RNA of 4.0-4.8 log10 IU/mL). The same dose in GT1-infected cirrhotic subjects resulted in a 3.5 log10 IU/mL mean maximum reduction in HCV-RNA.

Conclusions: AL-335 was well tolerated when administered as single and multiple doses, with an acceptable pharmacokinetic profile. The drug also demonstrated potent antiviral activity in HCV GT1-4-infected subjects, including GT1-infected subjects with cirrhosis.

Trial registration: ClinicalTrials.gov NCT02339207.

Conflict of interest statement

The authors have read the journal's policy and the authors of this manuscript have the following competing interests: MWM and LB were employees of Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies, at the time of the study. EB has been the Principal Investigator in clinical trials on HCV sponsored by Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies, Atea Pharmaceuticals, and Janssen. TT has a project-based contractual relationship with ARENSIA. AS-C has been the Principal Investigator in clinical trials on HCV sponsored by AbbVie, Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies, Boehringer Ingelheim, Janssen, and Merck Sharp & Dohme. LV is an employee of Janssen and a shareholder of Johnson & Johnson. BA and AP are employees of Biotrial. CW, TNK, JV, and NK are employees of Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies, and are shareholders of Johnson & Johnson. SC, QZ, LMB, and JF were employees of Alios BioPharma Inc., part of the Janssen Pharmaceutical Companies, at the time of the study, and are shareholders of Johnson & Johnson. There are no patents, products in development or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1

(A) Study design and (B) subject disposition.aAll randomized subjects in the GT4–6 cohort were infected with GT4; b8/48 subjects (from AL-335 400 mg tablet cohort) were enrolled in Part I and then re-dosed in fed state. ECG = electrocardiogram, fasted = in fasted state, fed = in fed state, GT = genotype, I/E = inclusion/exclusion, MAD = multiple ascending doses, QD = once daily, SAD = single ascending doses.

Fig 2

(A) Mean plasma concentration of ALS-022227 after SAD in Part I/II (top) and after MAD in Part III on Days 1 and 7 (bottom) in healthy volunteers; (B) Mean plasma concentration of AL-335, ALS-022399, and ALS-022227 after multiple doses of AL-335 administered as 800 mg QD in HCV GT1-infected subjects without cirrhosis (Part III, cohort 2). fed = in fed state, GT = genotype, HCV = hepatitis C virus, MAD = multiple ascending doses, QD = once daily, SAD = single ascending doses.

Fig 3. Mean (±SEM) HCV-RNA change from baseline (log10 IU/mL) over time following multiple oral administrations of AL-335 (tablet form) under fed conditions (Part III, Days 1–7; pharmacodynamic set).

Values below the LLOQ (aBaseline is defined as the average of Day -2 and Day 1 pre-dose values; bAll randomized subjects in the GT4–6 cohort were infected with GT4. GT = genotype, HCV = hepatitis C virus, LLOQ = lower limit of quantification, MAD = multiple ascending doses, QD = once daily, RNA = ribonucleic acid, SEM = standard error of the mean.

Fig 4. Mean maximal change from baseline in HCV-RNA per cohort between Day 1 and Day 10 in Part III.

aAll randomized subjects in the HCV GT4–6 cohort were infected with GT4. Baseline is defined as the average of Day -2 and Day 1 pre-dose values. comp = compensated, GT = genotype, HCV = hepatitis C virus, RNA = ribonucleic acid, SD = standard deviation.