046: Exposure-Response Analysis to Inform QT Prolongation Potential for Cedirogant

Statement of Purpose, Innovation or Hypothesis: Investigational drugs with systemic availability should be assessed for the potential to delay cardiac ventricular repolarization, typically in a thorough QT study. Exposure-response analysis of QT data collected from early-phase studies provides an alternative approach. Cedirogant is an orally available inverse agonist of retinoic acid-related orphan receptor gamma, thymus (RORγt) developed for treatment of chronic plaque psoriasis. In this study, we aimed to characterize its QT prolongation potential through an exposure-response analysis using QT data collected from a Phase 1 study.

Description of Methods & Materials: In a double-blinded, balanced crossover study, healthy participants (N=24) were randomized to one of six sequences to receive a single dose of 375 mg cedirogant, 750 mg cedirogant, or placebo under fasting conditions over three different periods. Blood samples and triplicate electrocardiograms (ECGs) were collected to obtain cedirogant plasma concentrations and QT data, respectively. QT intervals were corrected using Fridericia’s correction methods (QTcF) and further analyzed in a linear mixed-effects model. ECG sensitivity was assessed by evaluating the effect of food on QTcF in Period 2. A linear mixed-effects analysis was performed using ECG data collected in participants receiving placebo on Day 1 and their corresponding ECG data collected on Day 6 before and after breakfast.

Data & Results: Cedirogant reached maximum plasma concentration (C_max) with a median time of 4 hours. The observed cedirogant C_max were 10.2 and 17.5 µg/mL following administration of 375 mg and 750 mg doses, respectively. QTcF was shortened by 5.4 and 7.1 msec at 3 and 4 hours, respectively, after food relative to fasting conditions, which are statistically significant and within the range of food effect previously reported.
The linear mixed-effects analysis indicated a significant (p-value = 0.004) relationship between cedirogant plasma concentrations and changes in QTcF from baseline (ΔQTcF). However, the model-predicted upper bound of the one-sided 95% confidence interval of placebo-corrected ΔQTcF (ΔΔQTcF) at the highest clinically relevant mean exposure was 8.7 msec, which was lower than the threshold level (i.e., 10 msec) of regulatory concern (Figure 1).

Interpretation, Conclusion or Significance: The analysis demonstrated a positive association between cedirogant plasma concentrations and QT. However, the predicted extent of QT prolongation by cedirogant under the high clinical exposure scenario suggests that an expanded ECG safety evaluation may not be warranted in later phases of drug development.

Disclosures: This study was funded by AbbVie. AbbVie contributed to the study design, research, and interpretation of data, reviewing, and approving the publication. All authors are employees of AbbVie and may hold stock or options.

Citations/References:

Additional Information/Authors: No additional information.