Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19

Abstract

Background: Bemnifosbuvir (AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of persons with COVID-19. Direct assessment of drug disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug levels at the primary site of SARS-CoV-2 infection are achieved.

Objectives: This Phase 1 study in healthy subjects aimed to assess the bronchopulmonary pharmacokinetics, safety and tolerability of repeated doses of bemnifosbuvir.

Methods: A total of 24 subjects were assigned to receive bemnifosbuvir twice daily at doses of 275, 550 or 825 mg for up to 3.5 days.

Results: AT-511, the free base of bemnifosbuvir, was largely eliminated from the plasma within 6 h post dose in all dosing groups. Antiviral drug levels of bemnifosbuvir were consistently achieved in the lungs with bemnifosbuvir 550 mg twice daily. The mean level of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, measured in the epithelial lining fluid of the lungs was 0.62 µM at 4-5 h post dose. This exceeded the target in vitro 90% effective concentration (EC90) of 0.5 µM for antiviral drug exposure against SARS-CoV-2 replication in human airway epithelial cells. Bemnifosbuvir was well tolerated across all doses tested, and most treatment-emergent adverse events reported were mild in severity and resolved.

Conclusions: The favourable pharmacokinetics and safety profile of bemnifosbuvir demonstrates its potential as an oral antiviral treatment for COVID-19, with 550 mg bemnifosbuvir twice daily currently under further clinical evaluation in persons with COVID-19.

Figure 1.

Activation pathway of bemnifosbuvir (AT-527). Circles indicate bemnifosbuvir structural features critical to its potent antiviral activity/lack of toxicity. ADALP1, adenosine deaminase-like protein 1; CatA, cathepsin A; CES1, carboxylesterase 1; GUK1, guanylate kinase 1; HINT1, histidine triad nucleotide binding protein 1; MP, monophosphate; NDPK, nucleoside-diphosphate kinase; 5′-NTase, 5′-nucleotidase.

Figure 2.

Mean (±SD) plasma concentration–time profiles of AT-511 (a) and AT-273 (b) on the last dosing day up to 12 h post dose of 275, 550 and 825 mg bemnifosbuvir (BEM) dosage regimens (inserts: semi-log plots with no SD for clarity). ‘0 h’ is pre-dose (morning), ‘4 h’ is 4 h or pre-BAL (4–5 h, as applicable), and ‘10 h’ is pre-BAL (11–12 h). Values below the limit of quantification are imputed to 0. Panel (a): at each dose level, n = 8 except at 10 h (n = 4).

Figure 3.

Correlation between plasma and ELF AT-273 levels. ELF AT-273 levels with 275 mg twice daily at the 4 h timepoint were BLQ and therefore excluded.

Figure 4.

Relationship between AM AT-9010 and plasma and ELF AT-273 levels. AM AT-9010 and corresponding plasma and ELF AT-273 levels were available 4–5 h after the last dose from four subjects who received bemnifosbuvir 825 mg twice daily for 3.5 days. AM AT-9010 versus plasma AT-273: open circles with solid linear regression line. AM AT-9010 versus ELF AT-273: open squares with dashed linear regression line.