SAT237 AZP-3601, A Novel PTH 1 Receptor Agonist, Induces Rapid Reduction And Normalization Of Urinary Calcium In Chronic Hypoparathyroid Patients

Abstract

Abstract Disclosure: L. Figueres: None. I. Takacs: None. E. Mezosi: None. A. Soto: None. P. Kamenicky: None. S. Lemoine: None. F. Borson-Chazot: None. I. Capel: None. M.A. Galvez moreno: None. M. Ovize: Employee; Self; employee. T. OuldRouis: Employee; Self; employee. S. allas: Employee; Self; employee. M. Sumeray: Employee; Self; employee. M. Mannstadt: Consulting Fee; Self; consultant. Background: Conventional therapy with oral calcium (Ca) and active vitamin D (vitD) supplementation for chronic hypoparathyroidism (cHP) can induce or aggravate hypercalciuria and may lead to detrimental long-term renal complications. AZP-3601 is a novel 36-amino-acid peptide designed to activate the R0 conformation of the PTH 1 receptor which produces a prolonged calcemic response despite a short half-life. This phase 2 study examined the effects of AZP-3601 on urinary Ca (uCa) excretion in two consecutive cohorts (C1 and C2) of cHP patients. Methods: Following an optimization period, during which Ca and active vitD doses were adjusted to achieve baseline albumin-adjusted serum calcium within the target range of 7.8 to 9.0 mg/dL, patients received a daily sc. injection of AZP-3601 at initial doses of 20 µg/day (C1) or 10 µg/day (d) (C2), while simultaneously reducing their Ca and active vitD . Subsequent up-titration to a maximum daily dose of 60 µg (C1) or 80 µg(C2) was allowed. Twenty-four-hour urinary Ca excretion (24h-uCa), fractional excretion of Ca (FECa), 24h-urinary phosphate (24h-uP), serum phosphate (sP) were assessed at baseline and at D84. Pooled data from 24 patients who completed the study are presented here. Results: Twenty-four patients (18 women) aged (SD) 56(11) years were taking 0.61(0.26) µg/d active vitD and 1733(1442) mg oral Ca at baseline. At D84 , active vitD and oral Ca were each discontinued in 88% of patients, while mean albumin-adjusted serum calcium remained within the target range. Mean 24h-uCa decreased from 325(172) mg/24h to 207(107) mg/24h and 130(91) mg/24h at D14 and D84, respectively. In 13 patients with hypercalciuria at baseline, we observed a 67% reduction of 24h-uCa at D84 and a normalization of 24h-uCa in 92% of them. From baseline to D84, mean FECa decreased in the entire population and in patients with hypercalciuria. Between baseline to D84, 24h-uP excretion increased from 721(331) mg/24h to 794(238) mg/24h while mean sP decreased from 4.3(0.8) mg/dL to 3.7(0.6) mg/dL. Conclusion: These data demonstrate that AZP-3601 treatment maintained sCa within the target range after withdrawal of conventional therapy likely acting via a potent effect on the tubular reabsorption of calcium. The observed significant improvement in both uCa and sP is expected to translate to a clinically meaningful benefit for cHP patients in the long-term. Presentation: Saturday, June 17, 2023