ECE2022 Rapid Communications Rapid Communications 8: Calcium and Bone (7 abstracts)
Temporal effects of encaleret (CLTX-305) on mineral physiology in autosomal dominant hypocalcemia type 1 (ADH1): results from a phase 2B, open-label, dose-ranging study [NCT04581629]
Rachel Gafni 1 , Iris Hartley 1 , Kelly Roszko 1 , Karen Pozo 1 , Edward Nemeth 2 , Ramei Sani-Grosso 3 , Arun Mathew 3 , Ananth Sridhar 3 , Mary Scott Roberts 3 , Jonathan Fox 3 & Michael Collins 1
1National Institutes of Health, Skeletal Diseases and Mineral Homeostasis Section, Bethesda, United States; 2MetisMedica, Toronto, Canada; 3Calcilytix Therapeutics, Inc, San Francisco, United States
Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function variants in the calcium-sensing receptor (CaSR, gene: CASR) and is characterized by hypocalcemia, hyperphosphatemia, low parathyroid hormone (PTH), and hypercalciuria. Calcilytics (negative allosteric modulators of the CaSR) decrease the sensitivity of activated receptors to extracellular calcium and normalize blood and urine abnormalities in ADH1 rodent models. Encaleret is an oral calcilytic under investigation as a treatment for ADH1. Data on the encouraging effects of encaleret on PTH and blood and urine calcium (Ca) were previously reported. Here we expand on those data and describe the temporal and relative changes in PTH, nephrogenous cAMP (NcAMP), tubular reabsorption of phosphate (TRP), blood phosphate (Pi) and Ca, fractional excretion of Ca (FECa), 1,25-dihydroxyvitamin D (1,25(OH)2 D), and intact FGF23 (fibroblast growth factor 23) after encaleret administration. Six adults (22-60 years) with ADH1 due to 4 CASR variants were studied in Period 1 of a Phase 2b, open-label, dose-ranging study. Subjects received sequential, increasing daily doses of encaleret for 3d (30 mg, 90 mg, 180 mg) followed by 180mg bid on day 4 and 120 mg or 180 mg bid on day 5, while undergoing frequent blood and urine sampling. The temporal changes in the mean±SD values over 24 hr on day 4 are compared to baseline (blood volume limitations only allowed for collection of the mineral panel parameters through day 4). PTH was low at baseline (3.4±4.5 pg/ml, normal 10-65), rose rapidly, peaked at 2 hr (65.0±49.2), and remained normal through the 24 hrs measured. NcAMP rose by 4hr and was significantly increased through the 24 hrs measured. TRP and Pi decreased rapidly and remained significantly decreased through 24 hrs. FECa was 0.03±0.02 at baseline, was significantly decreased by 4hr, which was maintained through 24 hrs. Blood albumin-corrected Ca was below normal prior to 0hr dosing (7.6±0.6 mg/dl, normal 8.4-10.2), was normal by 4hr and remained significantly increased from 8-24 hrs. 1,25(OH)2 D was below normal at 0hr, increased and remained in the normal range from 4-24 hrs. Intact FGF23 was above normal at time 0hr and surprisingly remained unchanged over the 13hrs monitored, despite the reported changes in Pi, PTH and 1,25(OH)2 D. Bone turnover markers CTX and P1NP were unchanged compared with day 1. Encaleret was well-tolerated, with no serious adverse events reported. The observed temporal changes of key mineral homeostasis factors and normalization of blood Ca and FECa in encaleret-treated subjects with ADH1 shed light on mineral physiology and potential utility of encaleret in ADH1.
Article tools
My recent searches
My recently viewed abstracts
Authors
Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more