Exposure–Response Modeling of Monthly Migraine Days for Efficacy of Atogepant in Patients With Episodic or Chronic Migraine

This work aimed to develop an appropriate model to evaluate the exposure-response relationship (ERR) for monthly migraine days (MMD) in atogepant's key migraine prevention clinical trials to support dose selection. The ERR between atogepant concentration and MMD over time was analyzed utilizing data from one phase 2b/3 and three phase 3 studies in patients with episodic or chronic migraine (EM/CM). Several distribution models were evaluated for placebo data, whereas two modified normal distributions were introduced enabling bounded MMD modeling. Exposure metrics and shapes for ERR were tested for the most suitable distribution. Stepwise covariate search, visual predictive checks, and plots of model-predicted MMD over the range of exposure metrics were utilized in model development, evaluation, and selection. The final MMD exposure-response model was able to model patients with EM/CM simultaneously and was based on a modified normal distribution with E_max ERR on C_min. The model adequately described the observed data over time. Due to the E_max relationship, MMD at Week 9-12 plateaued around their model-based atogepant C_min-EC₉₀ of 3.71 nM, which is similar to most C_min exposures seen at the 10 mg once-daily regimen. All approved atogepant dosages for EM/CM achieve effective concentrations to inhibit the calcitonin gene-peptide receptor by 90%. Patients who have been failed by conventional oral migraine preventive treatments or patients with a higher baseline MMD may require a longer treatment period to reach atogepant's maximal effect. No significant difference in efficacy was evident in patients exposed to prior oral migraine preventives compared to treatment-naïve patients.