The Effects of Encaleret (CLTX-305) on Mineral Physiology in Autosomal Dominant Hypocalcemia Type 1 (ADH1) Demonstrate Proof-of-Concept: Early Results From an Ongoing Phase 2b, Open-Label, Dose-Ranging Study

Abstract

Autosomal dominant hypocalcemia type 1 (ADH1) is a rare form of hypoparathyroidism caused by gain-of-function pathogenic variants in the gene (CASR) encoding the calcium-sensing receptor (CaSR). It is characterized by variable degrees of hypocalcemia, hyperphosphatemia, and hypomagnesemia, inappropriately low levels of parathyroid hormone (PTH) and hypercalciuria. Conventional therapy includes oral calcium and activated Vitamin D, targeting blood calcium at or slightly below the low-normal level to minimize hypocalcemic symptoms. This supplementation typically causes or exacerbates hypercalciuria, which may lead to nephrolithiasis, nephrocalcinosis, and renal insufficiency. It has been demonstrated in in vitro and in vivo models of ADH1, as well as in a Phase 2b clinical study (Roberts et al, JBMR 2019) that calcilytics (negative allosteric modulators of the CaSR), have the ability to shift the concentration-response relationship between extracellular calcium and the mutant CaSR towards normal. Six adults with ADH1 due to four distinct activating variants of the CASR were studied in an ongoing, three period, Phase 2b, open-label, dose-ranging study [NCT04581629] of the calcilytic encaleret (CLTX-305). Calcium, magnesium, and calcitriol supplements were discontinued at the start of Period 1, and subjects received sequential, increasing daily doses of encaleret for 3d (30 mg, 90 mg, 180 mg) followed by 120 or 180 mg twice daily on day 4 and 5, while undergoing frequent blood and urine sampling. The mean baseline PTH was 3.4 ± 4.5 pg/mL (mean ± SD; nl 10–65); on encaleret, there was a rapid, dose-dependent increase in PTH to a mean level of 64.8 ± 49.6 pg/mL over 24 hours by day 5. Albumin-corrected blood calcium (cCa) increased from a baseline of 7.6 ± 0.6 mg/dL (nl 8.4–10.2) to a 24-hour mean on day 5 of 9.0 ± 0.5 mg/dL. Phosphorus decreased from a baseline of 4.5 ± 0.7 mg/dL (nl 2.3–4.7) to a 24-hour day 5 mean of 2.9 ± 0.5 mg/dL. Magnesium increased from a baseline of 1.6 ± 0.4 mg/dL (nl 1.6–2.6) to a 24-hour day 5 mean of 2.0 ± 0.5 mg/dL. Blood calcium, phosphorus and magnesium were mostly maintained within the normal range in ADH1 subjects by days 4 and 5. Twenty-four hour urine calcium was elevated at the screening visit while subjects were on conventional therapy (436 ± 255 mg/day, nl < 250–300) and decreased with increasing doses of encaleret to 63 ± 127 mg/day on day 5. Urinary calcium excretion became normal in 3 subjects and undetectable in 3 subjects while on encaleret. Encaleret was well-tolerated, with no serious adverse events reported. The consistent mineral responses following encaleret administration in all six ADH1 subjects with four distinct CASR genotypes represents preliminary proof-of-concept that encaleret may be an efficacious treatment for ADH1. The longer-term evaluation of encaleret in ADH1 subjects is ongoing.

Genetics of monogenic disorders of calcium and bone metabolism

“…102,103 Preclinical and clinical studies have also indicated the potential utility of calcilytic drugs, which are CaSR negative allosteric modulators, as targeted therapies for ADH1. 100,[104][105][106] Patients with ADH1 may also exhibit ectopic calcification, and some develop a Bartter syndrome, characterized by renal salt wasting leading to volume depletion, hyper-reninaemic hyperaldosteronism, and hypokalaemic alkalosis. 61 Only a few kindreds with ADH2 have been reported and these patients have similar biochemical features to ADH1, although appear to have a milder urinary phenotype with less hypercalciuria.…”

“…Small clinical studies have reported that recombinant PTH is effective for treating symptomatic ADH1 patients without increasing urine calcium excretion 102,103 . Preclinical and clinical studies have also indicated the potential utility of calcilytic drugs, which are CaSR negative allosteric modulators, as targeted therapies for ADH1 100,104–106 . Patients with ADH1 may also exhibit ectopic calcification, and some develop a Bartter syndrome, characterized by renal salt wasting leading to volume depletion, hyper‐reninaemic hyperaldosteronism, and hypokalaemic alkalosis 61 .…”

Evaluation and Management of Hypoparathyroidism Summary Statement and Guidelines from the Second International Workshop

“…(143) The calcilytic encaleret was recently shown to normalize serum calcium, phosphorus, and magnesium as well as urine calcium in an early Phase 2 study. (144) Knowledge Gaps and Future Research Directions…”

Management of Hypoparathyroidism

“…Urinary calcium excretion, which was elevated at baseline, became normal in three patients and undetectable in three while on encaleret. ( 95 )…”

“…Urinary calcium excretion, which was elevated at baseline, became normal in three patients and undetectable in three while on encaleret. (95) Patient Perspective Members of The HypoPARAthyroidism Association, Inc. believe that a single treatment strategy may not be ideal for all patients. Each patient with HypoPT has different symptoms and complications.…”