Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism

The calcium sensing receptor (CaSR)plays an important role inmaintaining calcium homeostasis. The use of calcimimetic cinacalcethas been established to activate CaSR and normalize hypercalcemia.However, cinacalcet has limitations due to its high cLogP and pK (a). A systematic optimization of cinacalcet toreduce its cLogP and pK (a) yielded compound 23a (LNP1892). Compound 23a showed excellentpotency and a favorable pharmacokinetics profile, and lacked the liabilitiesof cinacalcet, making it a highly differentiated precision calcimimetic.In adenine-diet-induced chronic kidney disease (CKD) models, 23a demonstrated robust and dose-dependent efficacy, as measuredby plasma parathyroid hormone (PTH) levels. It also showed an excellentsafety profile in animal studies. Phase 1 clinical trials with 23a in healthy volunteers confirmed its excellent safety,tolerability, and effectiveness in lowering PTH levels in a dose-dependentmanner, without causing symptomatic hypocalcaemia. Encouraged by thesepromising results, LNP1892 was taken to a Phase 2 study in CKD patients.