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Abstract: FR-OR08

Encaleret Normalized Mineral Homeostasis in Autosomal Dominant Hypocalcemia Type 1 (ADH1) in a Phase 2 Study

Session Information

Category: Bone and Mineral Metabolism

  • 402 Bone and Mineral Metabolism: Clinical

Authors

  • Roszko, Kelly, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, United States
  • Gafni, Rachel, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, United States
  • Hartley, Iris R., National Institute of Dental and Craniofacial Research, Bethesda, Maryland, United States
  • Nemeth, Edward F., MetisMedica, Toronto, Ontario, Canada
  • Pozo, Karen A., National Institute of Dental and Craniofacial Research, Bethesda, Maryland, United States
  • Lombardi, Ed, Calcilytix Therapeutics, San Francisco, California, United States
  • Roberts, Mary Scott, Calcilytix Therapeutics, San Francisco, California, United States
  • Adler, Scott H., Calcilytix Therapeutics, San Francisco, California, United States
  • Collins, Michael, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, United States
Background

Gain-of-function variants in the calcium-sensing receptor (CaSR) cause ADH1, a disorder of low PTH, hypocalcemia, hypercalciuria, & hyperphosphatemia. Therapy with calcium and active vitamin D worsens hypercalciuria and can lead to renal morbidity. Calcilytics (negative allosteric modulators of the CaSR) decrease the CaSR’s sensitivity to extracellular calcium and correct biochemical abnormalities in rodent models. Encaleret is an oral calcilytic under investigation as a potential treatment for ADH1.

Methods

Thirteen adults with ADH1 participated in a Phase 2b open-label dose-ranging study. Mean (range) therapy at screening was: calcium 2120mg/day (750-4800); calcitriol 0.7µg/day (0.2-2.0). These and thiazides were stopped before encaleret initiation. Periods 1 and 2 evaluated safety/tolerability and dose-finding. Period 3 (P3) was a 24-week (W24) outpatient period to optimize dosing and assess safety and efficacy. Encaleret doses were individually titrated to normalize corrected blood calcium (cCa).

Results

P3W24 mean±SD encaleret sulfate dose was 86±70mg BID (5-190 BID). Encaleret was well-tolerated with no serious adverse events reported; there were no treatment or study discontinuations. Encaleret resulted in dose-dependent increases in iPTH and normalization of mineral homeostasis (table):

Conclusion

This study represents a molecularly-targeted, precision medicine approach to ADH1 treatment. The consistent and sustained normalization of cCa and 24-hr UCa are clinically meaningful and support Phase 3 evaluation of the efficacy and safety of encaleret as a potential treatment for ADH1.

ParameterBaselineP3W24
iPTH (nl 10-65 pg/mL)6.3±7.831.3±20.8**
cCa (nl 8.4-10.2 mg/dL)7.1±0.49.0±0.6**
24-hr UCa (nl<250-300 mg/d)395±216189±72*
Fractional Excretion of Ca0.025±0.0140.016±0.003*
Phos (nl 2.3-4.7 mg/dL)4.5±1.13.5±0.6**
Tubular reabsorption of Phos (nl 85-95%)91±586±5**
Mg (nl 1.6-2.6 mg/dL)1.7±0.22.0±0.2**
Fractional Excretion of Mg10.7±6.87.2±4.0**
24-hr Urine citrate (nl<250-1190 mg/d)487±255421±254
1,25 OH2-vitamin D (nl 20-70 pg/mL)19.5±4.430.2±14.0*
eGFR mL/min/1.73 m284±2583±23

Data presented are 24-hour mean±SD values from P3W24 compared to baseline. *=p<0.05**= p<0.01

Funding

  • Other NIH Support