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

Abstract

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

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.…”

“…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 drug‐drug interactions and high drug resistance barrier [88] …”

“…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.…”

RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic

“…16- TP exhibits potent inhibition of NS5B polymerase with IC 50 values as low as 27 nM. In an HCV subgenomic replicon assay, the phosphoramidate prodrug of 16 demonstrated very potent activity with EC 50 values as low as 20 nM [ 91 ]. The administration of 16 in combination with simeprevir and odalasvir has been evaluated in human phase II clinical trials and has shown promising efficacy and safety results.…”

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

“…Adafosbuvir (also known as AL-335) is a pro-drug of a uridine-based nucleotide analog polymerase (NS5B) inhibitor with potent antiviral activity against HCV GTs 1-6 [13][14][15].…”