Efficacy and safety of the cystic fibrosis transmembrane conductance regulator inhibitor GLPG2737 for autosomal dominant polycystic kidney disease: phase 2a MANGROVE study

BACKGROUND: There is a need for improved disease-targeting therapies for autosomal dominant polycystic kidney disease (ADPKD). This study evaluated the efficacy and safety of GLPG2737, a cystic fibrosis transmembrane conductance regulator inhibitor, in ADPKD. METHODS: MANGROVE (NCT04578548) was an exploratory, phase 2a, proof-of-concept, randomized, multicentre study. Eligible patients were aged 18-50 years with rapidly progressing, typical ADPKD. Patients were randomly assigned (2:1) to double-blind treatment with once-daily, oral GLPG2737 150 mg or placebo for 52 weeks. This was followed by a 52-week open-label extension (OLE) period, in which all patients received GLPG2737. Both periods had a 4-week follow-up period without treatment. Primary endpoints were the mean percentage change from baseline in height-adjusted total kidney volume (htTKV), and frequency and severity of treatment-emergent adverse events (TEAEs). A key secondary endpoint was the mean change from baseline in estimated glomerular filtration rate (eGFR). RESULTS: Overall, 89 patients were screened between 10 November 2020 and 2 March 2023; 66 patients received treatment (GLPG2737, n = 44; placebo, n = 22), and 61 patients completed the double-blind period (GLPG2737, 41/44; placebo, 20/22). Changes in htTKV from baseline to week 52 did not differ between GLPG2737 and placebo (GLPG2737: 8.2% [95% confidence interval (CI) 6.0%, 10.4%]; placebo: 9.2% [95% CI 6.1%, 12.4%]; between-treatment difference: -0.91% [95% CI: -4.34%, 2.64%], P = 0.61). There were no life-threatening TEAEs or deaths. Similar proportions of patients had treatment-related TEAEs in the GLPG2737 (13/44, 30%) and placebo (6/22, 27%) groups. Mean between-treatment difference for change in eGFR from baseline to week 52 (GLPG2737 vs placebo) was not significant - 2.31 mL/min/1.73 m2 (95% CI - 5.64, 1.02; P = 0.17). CONCLUSIONS: Overall, GLPG2737 was generally well tolerated. However, GLPG2737 150 mg once daily was not efficacious in reducing htTKV or slowing eGFR decline over 52 weeks compared with placebo. Thus, the study was terminated early after the double-blind period; results from the OLE period are reported in brief.