A New Nucleotide Analog Is Well Tolerated, Efficacious Against HCV Genotype 1-4

Hepatitis C virus in liver, human body
Hepatitis C virus in liver, human body
A new nucleotide analog is a pangenotypic HCV nonstructural protein 5B inhibitor that is well tolerated when administered in single and multiple doses.

A new nucleotide analog, AL-335, is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor that is well tolerated when administered in single and multiple doses and has demonstrated potent antiviral activity in HCV genotype 1- to 4-infected patients, according to the results of a randomized double-blind study (clinicaltrials.gov number: NCT02339207) published in PLoS ONE.1

Although direct-acting antiviral agents have several advantages over traditional therapies for treating HCV, they lack pangenotypic coverage of HCV genotypes, have a persistent risk for drug-drug interactions, and require treatment of at least 12 weeks duration.2,3 Alternatively, AL-335 is an investigational HCV NS5B inhibitor that has demonstrated pangenotypic coverage, a high barrier to resistance, and a limited risk for drug-drug interactions in vitro.4,5 

Researchers at 4 sites in France, Georgia, Moldova, and Romania assessed the initial safety and pharmacokinetics of single ascending doses of AL-335 up to 1200 mg for up to 7 days in 48 healthy volunteers and 64 patients with HCV genotype 1 to 4 with or without Child Pugh A cirrhosis (genotype 1 only).1 They found that AL-335 was well tolerated, rapidly absorbed, and converted to the metabolites ALS-022399 and ALS-022227. Rapid and dose-dependent reductions in HCV-RNA were observed in genotype 1-infected patients. Potent antiviral activity (mean maximum reductions in HCV-RNA, 4.0-4.8 log10 IU/mL) was observed in non-cirrhotic, genotype 1- to 4-infected patients receiving AL-335 800 mg daily. The same dose in genotype-1-infected patients with Child Pugh A cirrhosis resulted in similar, although slightly lower magnitude, reductions in HCV-RNA (≤3.5 log10 IU/mL). 

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“In conclusion, AL-335 doses up to 1200 mg for durations of up to 7 days appear to be generally safe and well tolerated, with a favorable pharmacokinetic profile regardless of HCV genotype or cirrhosis” reported the investigators.1


  1. McClure MW, Berliba E, Tsertsvadze T, et al. Safety, tolerability, and pharmacokinetics of AL-335 in healthy volunteers and hepatitis C virus-infected subjects. PLoS ONE. 2018;13(10): e0204974.
  2. Falade-Nwulia O, Suarez-Cuervo C, Nelson DR, Fried MW, Segal JB, Sulkowski MS. Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review. Ann Intern Med. 2017;166(9):637-648.
  3. Bidell MR, McLaughlin M, Faragon J, Morse C, Patel N. Desirable characteristics of hepatitis C treatment regimens: a review of what we have and what we need. Infect Dis Ther. 2016;5(3):299-312.
  4. Tan H, Shaw K, Jekel A, et al. Preclinical characterization of AL-335, a potent uridine based nucleoside polymerase inhibitor for the treatment of chronic hepatitis C. J Hepatol. 2015;S577-S578.
  5. Vijgen L, Fevery B, Jekle A, et al. In vitro virology profile of the 3 direct-acting antiviral combination of AL-335, odalasvir and simeprevir. J Hepatol. 2017;S533-S534.