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Endocrine Abstracts (2023) 90 RC8.4 | DOI: 10.1530/endoabs.90.RC8.4

ECE2023 Rapid Communications Rapid Communications 8: Calcium and Bone (6 abstracts)

Encaleret (CLTX-305) normalized mineral homeostasis parameters in patients with autosomal dominant hypocalcemia type 1: Results over 12 months in a phase 2 study (NCT04581629)

Michael Collins 1 , Iris Hartley 1 , Kelly Roszko 1 , Edward Nemeth 2 , Karen Pozo 1 , Winsome Boykin 1 , Arun Mathew 3 , Mary Scott Roberts 3 & Scott Adler 3

1National Institutes of Health, Skeletal Diseases and Mineral Homeostasis Section, Bethesda, United States; 2MetisMedica; 3Calcilytix Therapeutics, Inc, San Francisco, United States

Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function calcium-sensing receptor gene (CASR) variants, is characterized by low parathyroid hormone (PTH) levels, hypocalcemia, hypercalciuria, hyperphosphatemia and hypomagnesemia. Conventional therapy (calcium and active vitamin D) worsens hypercalciuria, which may result in renal complications. Calcilytics, such as encaleret, are negative allosteric modulators of the calcium-sensing receptor (CaSR). They decrease the hypersensitivity of ADH1 variants to extracellular calcium and normalize biochemical abnormalities in rodent models of ADH1. This Phase 2b open-label study examined the effect of the oral investigational calcilytic encaleret on mineral homeostasis in participants with ADH1. It was comprised of 3 periods followed by a long-term extension (LTE). Conventional therapy was discontinued prior to encaleret initiation. Periods 1&2 examined dose-finding and safety/tolerability. Dosing was optimized and safety and efficacy were assessed over 24 outpatient weeks in Period 3 (P3); all participants continued in the LTE. Thirteen adults with ADH1 were enrolled. Encaleret was individually titrated to normalize albumin-corrected calcium (cCa) and minimize hypercalciuria. Encaleret was well-tolerated with no serious adverse events reported. There were no treatment discontinuations or withdrawals prior to the LTE; one participant withdrew during the LTE for family planning. The mean±SD encaleret sulfate dose at week 24 of P3 (P3W24, n=13) was 86±70 mg BID and remained stable through month 6 of the LTE (LTEM6, n=12;75±66 mg BID). Twenty-four hour mean±SD values from P3W24 and LTEM6 compared to baseline are shown. This study represents a molecularly-targeted, precision medicine approach to the treatment of ADH1. The consistent and sustained results over 12 outpatient months establish a clinically meaningful efficacy, tolerability, and safety profile for encaleret as a potential treatment for adults with ADH1.

Parathyroid hormone (nl 10-65 pg/ml) 6.1±8.0 23.2±23.0* 42.3±13.6**
Albumin-corrected calcium (nl 8.4-10.2 mg/dl) 7.1±0.4 8.9±0.5** 9.2±0.5**
24-hr Urine calcium (nl<250-300 mg/d) 426±254 202±83** 180±101**
Phosphorus (nl 2.3-4.7 mg/dl) 4.5±1.1 3.7±0.5** 3.2±0.6**
Magnesium (nl 1.6-2.6 mg/dl) 1.7±0.2 2.0±0.2** 2.0±0.2**
Collagen cross-linked C-telopeptide† (pg/ml) 266±161744±565** 1074±756**
Procollagen type 1 N-propeptide‡ (mg/l) 27±12 104±87** 93±57**
24-hr Urine citrate†† (nl<450-550 mg/d) 487±254439±224313±141*
*=P<0.05;**=P<0.01; †CTX: men 93 – 630 (31 – 50 years), 35 – 836 (51 – 70 years); women: 25 – 573 (pre-menopausal), 104 – 1008 (post-menopausal) ; ‡P1NP: men: 22 – 87: women: 19 – 83 (pre-menopausal), 16 – 96 (post-menopausal); ††Urine citrate: Period 2, Day 1 collection was baseline

Volume 90

25th European Congress of Endocrinology

Istanbul, Turkey
13 May 2023 - 16 May 2023

European Society of Endocrinology 

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