A randomized, double-blind, placebo-controlled phase 2b trial using the novel predictive genetic biomarker DGM4 for liafensine in treatment-resistant depression

Prior clinical trials evaluating liafensine for treatment-resistant depression (TRD) in unselected patients did not demonstrate benefit vs controls. A novel pharmacogenomic biomarker, DGM4, was discovered as a predictor of liafensine’s efficacy and assessed in this new prospective clinical trial. In this biomarker-guided, randomized, double-blind, placebo-controlled Phase 2b trial, 189 DGM4-positive TRD patients were randomized 1:1:1 to once daily oral liafensine 1 mg, 2 mg, or placebo. The Montgomery Åsberg Depression Rating Scale (MADRS) total score change at Day 42 was 15.4±0.90 for liafensine vs 11.0±1.31 for placebo (p=0.0056). Statistically significant improvements were also seen in all secondary endpoints. Adverse events were tolerable with low rates of meaningful events. Liafensine was efficacious and well tolerated in DGM4-positive TRD patients with statistically significant and clinically meaningful improvements, validating DGM4 as a predictive biomarker for liafensine. This represents one of the first pharmacogenomic biomarkers validated in a randomized clinical trial in psychiatry.