The Effect of Linzagolix on Bone Mineral Density (BMD): Safety Results From a Dose-Ranging Trial [21J]

INTRODUCTION: Linzagolix is a new, non-peptide, GnRH receptor antagonist being developed to treat endometriosis-associated pain (EAP). The EDELWEISS trial is a Phase 2b, double-blind, randomized, placebo-controlled, multicenter, dose-ranging trial in and Europe evaluating oral once daily doses of 50, 75, 100 and 200 mg taken for 24 weeks. Subjects randomized to placebo were crossed-over to 100 mg after 12 weeks. METHODS: IRB approval was obtained. Participants were women with surgically confirmed endometriosis and moderate to severe EAP. Women with a history of osteoporosis or other metabolic bone disease were excluded. BMD of the femoral neck, total hip and lumbar spine was assessed by DXA at baseline and after 12 and 24 weeks of treatment. Reading of DXA scans and monitoring of scan quality, including cross-calibration between sites, was centralized. RESULTS: 327 patients were randomized and treated. Mean percent (95% CI P value) BMD changes for lumbar spine from baseline to week 24 in the 50, 75, 100 and 200 mg dose groups were 0.137% (-0.83, -1.11 P=.777), -0.798% (-1.57, -0.03 P=.042), -1.365% (-2.14, -0.59, P<.001), -2.602% (-3.56, -1.65, P<.001), respectively. BMD of femoral neck and total hip showed a similar pattern but with generally smaller changes from baseline. CONCLUSION: Mean BMD losses at 24 weeks were <1% at doses of 50 and 75 mg and increased with increasing dose up to 2.6% for 200 mg. Long term use of 75 mg daily is not expected to require concomitant estrogen/progestin add-back therapy, while higher doses may require it.