ALG-000184 (pevifoscorvir sodium) monotherapy in participants with chronic HBV infection: a phase 1, multicentre,...

ALG-000184 (pevifoscorvir sodium) is a prodrug of the class-E (empty) capsid assembly modulator (CAM), ALG-001075. CAM-Es prevent hepatitis B virus (HBV) replication by inhibiting capsid assembly and pregenomic RNA encapsidation and preventing covalently closed circular DNA (cccDNA) establishment. This part of the study aimed to assess the safety, tolerability, pharmacokinetics and short-term antiviral activity of ALG-000184 in participants with HBeAg-negative and HBeAg-positive chronic HBV infection to determine the subsequent development pathway for this novel therapeutic.

ALG-000184-201 was a phase 1, multicentre, randomised, dose escalation trial designed to evaluate the safety and pharmacokinetics of ALG-000184 in healthy participants (parts 1-2, reported separately) and antiviral activity in treatment-naive or currently not treated participants with chronic HBV infection (part 3, presented here). Eligible participants were 18-65 years old with BMI 18·0-35·0 kg/m², and HBeAg-negative or HBeAg-positive chronic HBV infection with serum HBV DNA concentration more than 2000 IU/mL and serum ALT concentrations less than 5 times the upper limit of normal. Eligible patients were randomly assigned (4:1) to receive 28 days of oral ALG-000184 (10 mg, 50 mg, 100 mg, or 300 mg) or matching placebo once per day. Randomisation was managed via an interactive web response system and other than knowing the dose being evaluated in each cohort, all investigational site personnel and study participants were unaware of treatment assignments. The primary objective of this study was to evaluate the safety and tolerability of ALG-000184 in all randomly assigned participants (intention to treat population) using safety data including all treatment emergence adverse events, physical exam and vital signs findings, 12-lead electrocardiogram, and clinical laboratory findings. This study was registered at ClinicalTrials.gov, NCT04536337, and is complete.

Between March 16, 2021, and Oct 13, 2022, 135 participants were screened for inclusion from seven clinical investigational sites in Hong Kong, China, Moldova, New Zealand, and the UK. 76 participants did not meet one or more of the inclusion criteria or met one or more exclusion criteria and 59 participants were enrolled and randomly assigned to receive ALG-000184 10 mg (n=14), 50 mg (n=8), 100 mg (n=16), or 300 mg (n=10) or placebo (n=11). Participants had a median age of 37·0 years (IQR 31·0-45·5). 30 (51%) of 59 patients were male and 29 (49%) were female. 40 (68%) of patients were Asian. 28 (58%) of 48 participants assigned to receive ALG-000184 and seven (64%) of 11 in the placebo group experienced at least one treatment-emergent adverse event (TEAE). The most common TEAEs were increased alanine aminotransferase (ALT; 15 [31%] of 48 participants assigned to ALG-000184 and two [18%] of 11 participants assigned to placebo), increased aspartate aminotransferase (AST) concentrations (12 participants [25%] vs one [9%]), hyperuricemia (five [10%] vs two [18%]), headache (four [8%] vs one [9%]), elevated amylase (three [6%] vs none) and upper respiratory tract infection (three [6%] vs none). There were two serious adverse events unrelated to ALG-000184 (mild spinal pain and spontaneous pneumothorax). There were no deaths in the study. Doses of 10 mg to 300 mg ALG-000184 for 28 days resulted in multi-log reduction of HBV DNA (about 3-4 log₁₀ IU/mL) and HBV RNA (about 0·5-3·0 log₁₀ copies per mL). 19 (83%) of 23 HBeAg-negative participants achieved HBV DNA levels less than the lower limit of quantification (10 IU/mL) and 23 (100%) achieved HBV RNA levels less than the lower limit of quantification (10 copies per mL). Due to higher baseline levels, no HBeAg-positive participant achieved HBV DNA or HBV RNA less than the lower limit of quantification by 28 days. A decrease in HBsAg of 0·5 log₁₀ IU/mL was observed in one HBeAg-positive participant who received 100 mg ALG-000184 and four of eight HBeAg-positive participants who received 300 mg ALG-000184 for 28 days had decreases of 0·2-0·8 log₁₀ IU/mL. ALG-000184 had a dose-dependent linear pharmacokinetic profile.

ALG-000184 was safe and well tolerated, demonstrated predictable pharmacokinetic properties, and reduced HBV DNA and HBV RNA at all doses regardless of HBeAg status. These results support the evaluation of 300 mg ALG-000184 over longer periods in larger studies to determine its potential role in chronic suppressive therapy, with or without a nucleos(t)ide analogue, or as part of a finite curative regimen.

Aligos Therapeutics.