Encaleret (CLTX-305) Normalized Mineral Homeostasis Parameters in Patients with Autosomal Dominant Hypocalcemia Type 1 over 12 months in a Phase 2 Study (NCT04581629)

Gafni Rachel I; Hartley Iris R; Roszko Kelly L; Nemeth Edward F; Pozo Karen A; Boykin Winsome P; Mathew Arun S; Roberts Mary Scott; Adler Scott H; Collins Michael T

Autosomal dominant hypocalcemia type 1 (ADH1), caused by gain-of-function variants in the calcium-sensing receptor (CaSR) gene, is characterized by low parathyroid hormone (PTH), hypocalcemia, hypercalciuria, hyperphosphatemia, and hypomagnesemia. Patients usually present in childhood, at a median age of 4y, often with severe symptoms of hypocalcemia. Conventional therapy (calcium and active vitamin D) worsens hypercalciuria and can lead to renal morbidity. Calcilytics that act as negative allosteric modulators of the CaSR decrease the sensitivity of hyperactive receptors to extracellular calcium and normalize biochemical abnormalities in ADH1 rodent models. In this 3-period, Phase 2b open-label study, conventional therapy was stopped and participants were treated with encaleret, an oral investigational calcilytic. Periods 1&2 included dose-finding and safety/tolerability evaluation. Period 3 (P3) optimized dosing and assessed safety and efficacy over 24 outpatient weeks. Participants subsequently entered a long-term extension (LTE). Thirteen adults (22-60y) with ADH1 received encaleret, individually titrated to normalize albumin-corrected calcium (cCa) and minimize hypercalciuria and hypophosphatemia. 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 P3, Week 24 (P3W24 [n=13 ]) was 78±67mg BID and remained stable at LTE Month 6 (LTEM6 [n=12 ]) (75±66mg BID). Twenty-four hour mean±SD PTH, calcium, phosphate, magnesium, and urinary Ca normalized with encaleret treatment (Table). Bone turnover markers increased, remaining within the normal range for most participants.


Parameter (normal range)	Baseline^††	P3W24^††	LTEM6^‡‡
iPTH (10-65 pg/mL)	6.3±7.8	35.3±10.2**	42.3±13.6**
cCa (8.4-10.2 mg/dL)	7.1±0.4	9.2±0.5**	9.2±0.5**
Urinary calcium (<250-300 mg/d)	395±216	202±83*	163±89*
Phosphate (2.3-4.7 mg/dL)	4.5±1.1	3.4±0.4**	3.2±0.6**
Magnesium (1.6-2.6 mg/dL)	1.7±0.2	2.0±0.2**	2.0±0.2**
CTX^† (pg/mL)	253±111^§	784±686**	1074±756**
P1NP^‡ (mg/L)	34±10^§	102±87**	93±57**
P<0.05; P<0.01;^§n=7 ; ^††n=13 ; ^‡‡n=12 . ^†CTX (collagen cross-linked C-telopeptide): Men: 93–630 (31–50y), 35–836 (51–70y); Women: 25–573 (pre-menopausal), 104–1008 (post-menopausal). ^‡P1NP (procollagen type 1 N-propeptide): Men: 22–87; Women: 19–83 (pre-menopausal), 16–96 (post-menopausal)

This study represents a molecularly-targeted, precision medicine approach to ADH1 therapy. The consistent and sustained results over 12 outpatient months establish a clinically meaningful profile that supports further evaluation of encaleret as a potential treatment for adults and children with ADH1.

IMPE Abstracts

FC7.1