Phase 2B dose selection of BG00011 for the treatment of idiopathic pulmonary fibrosis (IPF)

Introduction: avb6 is upregulated on alveolar epithelial cells in IPF patients and drives the activation of TGF-b. BG00011 is an anti-αvβ6 monoclonal antibody. The BG00011 phase 2A, conducted in patients with IPF, demonstrated TGF-b suppression as evidenced by reduction in pSMAD2 signaling and TGF-b dependent gene expression in bronchoalveolar lavage (BAL) cells. Preclinical models have shown maximal fibrosis inhibition correlating with 70% pSMAD reduction. Objectives: To select an optimal phase 2B dose based on the exposure response (E/R) analysis and to assess potential covariates that could impact exposure in the phase 2A study. Methods: PK and BAL biomarker data were evaluated in forty one subjects from five ascending dose cohorts. An E/R analysis was performed using area under the curve at steady state and percent change from baseline in pSMAD2 from BAL cells. Body weight and sex were evaluated to determine their influence on PK variability. Results: BG00011 showed dose proportional increase in exposure from 0.015 to 1.0 mg/kg, and greater than proportionally at doses >1.0 mg/kg. The E/R curve showed a steep dose-response between the 0.3 and 1.0 mg/kg doses. The dose of 0.7 mg/kg was projected to allow for exploration of the efficacious portion of the E/R curve. Body weight and sex did not influence exposure, thus allowing for the selection of a flat dose of 56mg (based on an average weight of ~80 kg for patients from this and previous IPF trials). Conclusion: The E/R analysis from the 2A study, along with knowledge from preclinical models, allowed for the selection of a flat dose that is optimal for exploration of key portion of the E/R curve in the phase 2B trial.