Background/Purpose: Obexelimab is a novel bifunctional antibody that inhibits B cells, CD19-expressing plasma cells, and plasmablast activity and has the potential to provide clinical benefit across multiple autoimmune disorders. The purpose of this analysis was to 1) develop a population exposure-response model to relate QTc interval to obexelimab plasma concentration in healthy volunteers, and patients with RA or IgG4-RD following intravenous (IV) or subcutaneous (SC) administration of obexelimab and 2) predict the mean drug-induced changes in QTc from baseline at clinically relevant and observed supra-therapeutic concentrations.  

Methods: A population exposure-response model was developed to describe the relationship between QTc and obexelimab concentration using data from 4 studies: 1) a randomized, double-blinded, placebo controlled, single ascending dose Phase 1 study in healthy volunteers (0.03 to 10 mg/kg, IV), 2) a multiple dose Phase 1 open-label bioavailability study in healthy volunteers given IV or SC (125 to 375 mg SC or 250 mg IV every other week or 125 mg SC weekly) for a total of 3 doses, 3) a randomized, double-blinded, placebo controlled, ascending multiple dose Phase 2a study in patients with RA (0.3 to 10 mg/kg, IV) every other week for up to 6 administrations, 4) an open-label Phase 2 study in patients with IgG4-RD (5 mg/kg or 90/180 mg, IV) every other week for up to 12 administrations.

Pharmacokinetics (PK) samples and electrocardiogram (ECG) data were collected at corresponding times. ECGs were recorded digitally using a computerized 12-lead ECG recorder when subjects rested quietly in a supine position for at least 5 minutes. The analysis used 1356 time-matched Concentration-QTc records from 164 subjects (97 males and 67 females).

Various nonlinear mixed effect model forms relating plasma concentration to QTc prolongation were analyzed using NONMEM software (version 7.3, ICON Development Solutions, Ellicott City, MD). The predictive adequacy of the final model was assessed, and it was used to predict QTc change from baseline at clinically relevant and observed supra-therapeutic concentrations.

Results: A linear model form was selected as the final model based on objective function and goodness of fit assessments. Sex covariate and inter-individual variability were added on intercept parameter. The estimated slope parameter was negative and close to zero [-0.0000210 (-0.000034; -0.00000798)]; supporting the conclusion that obexelimab does not produce clinically relevant effects on the QTc interval. The predictive checks indicated that the final model was adequate to make predictions of mean change in QTc from baseline. The predicted change QTc interval at clinically relevant and supra-therapeutic concentrations were negative; indicating that obexelimab does not cause QTc prolongation. This finding aligns with the lack of obexelimab related cardiac safety findings in these populations.

Conclusion: A linear model form was adequate to predict obexelimab concentration-induced changes in QTc. Obexelimab did not produce any clinically relevant effect on electrocardiographic QTc interval in healthy volunteers, RA or IgG4-RD patients.   

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-population-modeling-and-simulation-of-the-effect-of-obexelimab-exposure-on-the-qtc-interval-in-healthy-volunteers-and-patients-with-rheumatoid-arthritis-or-igg4-related-disease/