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.

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 (<15 IU/mL) and with HCV-RNA detected have been replaced by the LLOQ value (= 15 IU/mL). Not detected values have been replaced by 10 IU/mL. ^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.