University of North Carolina at Chapel Hill / Bristol Myers Squibb Lawrence Township, New Jersey, United States
Background: Abatacept (ORENCIA®), a selective T cell stimulation modulator, has several indications including rheumatoid arthritis and acute Graft versus Host Disease (GVHD). Given abatacept’s immune modulator properties, a multicenter clinical trial (ACVIT-1 IM) was conducted for its potential to treat patients with moderate to severe COVID-19. This analysis aimed to examine the population pharmacokinetic (PPK) model utilizing available abatacept clinical trial data including with ACTIV-1 IM data, and to analyze abatacept ER for efficacy in COVID-19 patients using the abatacept exposures determined by the updated PPK model. Methods: PPK analysis included 3,920 PK samples of 905 subjects pooled from eight clinical trials. A previously published PPK model was updated to test new covariates with a single forward addition step followed by backward elimination, and then used to simulate abatacept exposure in COVID-19 patients. The ER analysis included data from 915 COVID-19 patients (402 on abatacept; 513 on standard of care (SoC)). ER efficacy analysis evaluated time to recovery over Day 28 and death over Days 28 and 60. Cox proportional hazard models were used for time-to-event analysis, and ER relationship between efficacy outcomes and abatacept exposures was assessed by logistic regression. Results: The final PPK model included the effects of baseline body weight (WTB), eGFR, sex, GVHD Cohort, and COVID-19 disease state on CL; WTB, sex, and COVID-19 disease state on VC; and WTB on VP. The median time to recovery was 9 days in both abatacept- and SoC-treated patients, while higher abatacept exposure (Cmin;d28) identified patients with higher likelihood of recovery from moderate to severe COVID-19, adjusting for baseline corticosteroid use, weight, age and treatment. Logistic regression revealed significant ER between Cmin;d28 and recovery probability, controlling for baseline corticosteroid use, age and treatment. Also, patients in the lowest Cmin;d28 quartile recovered slower than those in SoC, which may be explained by other unknown risk factors associated with these subjects. There was no significant relationship between any exposure variable and death through Day 28 or 60. Conclusion: ER analysis suggests that higher abatacept exposure may enhance recovery rates in moderate to severe COVID-19 patients with no significant impact on mortality.
