PTH-Independent CaSR Inhibition with the Oral Calcilytic Encaleret Improves Calcium Homeostasis in Post-Surgical Hypoparathyroidism: A Phase 2 Open-Label Proof-of-Concept Trial

PTH-Independent CaSR Inhibition with the Oral Calcilytic Encaleret Improves Calcium Homeostasis in Post-Surgical Hypoparathyroidism: A Phase 2 Open-Label Proof-of-Concept Trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article PTH-Independent CaSR Inhibition with the Oral Calcilytic Encaleret Improves Calcium Homeostasis in Post-Surgical Hypoparathyroidism: A Phase 2 Open-Label Proof-of-Concept Trial Iris Hartley, Rachel Gafni, Xiaobai Li, Ashna Grover, Elizabeth Ferguson, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9499053/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract The calcium-sensing receptor (CaSR) maintains calcium homeostasis by regulating parathyroid hormone (PTH) secretion and directly modulating renal calcium reabsorption. In the kidney, PTH and renal CaSR signaling exert opposing effects on tubular calcium reabsorption and urinary calcium excretion, complicating efforts to define their independent contributions to overall calcium regulation. To examine the PTH-independent effects of CaSR inhibition on renal calcium handling, we administered a calcilytic (CaSR antagonist) to individuals with post-surgical hypoparathyroidism (PSH). In this open-label, phase 2, proof-of-concept study (NCT0573515), ten adults (26-69y) with chronic PSH were orally administered the calcilytic encaleret for up to 5 days. Calcitriol was discontinued one day prior, and calcium and calcitriol were individually titrated based on blood calcium. Mean fractional excretion of calcium (FECa) decreased by 39±29% (p=0.002) by end of treatment. Albumin-corrected serum calcium increased from 8.5±0.3 mg/dL (mean±SD, normal 8.4-10.2) at time 0 to 9.2±0.6 (p=0.002) at 48 hours while urinary calcium decreased from 405±200 mg/day (m:<250; f:<350) to 180±100 (p=0.0005). Although mean intact PTH increased modestly 30 minutes after the first encaleret dose (7.3±3.1 pg/mL to 12.3±7.9 pg/mL; normal 15-65; p=0.008), levels rapidly returned to baseline without further excursions for the remainder of the study. No serious adverse events (AEs) were reported. Transient mild hypercalcemia and headache in 1 participant were the only treatment-related AEs. In PSH, encaleret reduced urinary Ca and increased serum Ca, demonstrating the PTH-independent role of CaSR signaling in renal calcium handling and supporting further study of encaleret as an oral treatment for patients with PSH. Biological sciences/Physiology/Calcium and vitamin D Health sciences/Endocrinology/Endocrine system and metabolic diseases/Metabolic bone disease Health sciences/Diseases/Endocrine system and metabolic diseases/Metabolic bone disease Full Text Additional Declarations There is a conflict of interest I.H., R.G., E.F., C.M., K.P., K.A., M.C., and K.R. received research funding through a Cooperative Research and Development Agreement (CRADA) between Calcilytix Therapeutics, Inc. and the National Institute of Dental and Craniofacial Research (NIDCR), NIH. A.S., A.M., M.S.R., and S.A. are employees of Calcilytix Therapeutics, Inc/BridgeBio Pharma Inc. M.C. and E.N. are paid consultants for Calcilytix Therapeutics, Inc. I.H., R.G., M.S.R., K.R., and M.C. are inventors on a pending patent application filed by Calcilytix Therapeutics, Inc. and the U.S. Government related to the treatment of hypoparathyroidism using calcilytic compounds, including encaleret. Supplementary Files PSHsupplement.pdf Supplemental Material NIHManuscriptCoverSheet.pdf NIH Publishing Agreement Cite Share Download PDF Status: Under Review Version 1 posted Reviewer # 1 agreed at journal 29 Apr, 2026 Reviewers invited by journal 27 Apr, 2026 Submission checks completed at journal 24 Apr, 2026 Editor assigned by journal 22 Apr, 2026 First submitted to journal 22 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9499053","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":628790979,"identity":"8fd3fcab-f664-4ecd-8643-8424fcbbe21b","order_by":0,"name":"Iris 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In the kidney, PTH and renal CaSR signaling exert opposing effects on tubular calcium reabsorption and urinary calcium excretion, complicating efforts to define their independent contributions to overall calcium regulation. To examine the PTH-independent effects of CaSR inhibition on renal calcium handling, we administered a calcilytic (CaSR antagonist) to individuals with post-surgical hypoparathyroidism (PSH).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this open-label, phase 2, proof-of-concept study (NCT0573515), ten adults (26-69y) with chronic PSH were orally administered the calcilytic encaleret for up to 5 days. Calcitriol was discontinued one day prior, and calcium and calcitriol were individually titrated based on blood calcium. Mean fractional excretion of calcium (FECa) decreased by 39±29% (p=0.002) by end of treatment. 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