Safety, Tolerability, and Efficacy of Encaleret in Participants With Autosomal Dominant Hypocalcemia (ADH) Type 1

• Encaleret (Drug), also known as CLTX-305: Tablets administered orally

Primary outcomes

• Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs) [Day 1 up to 16 months]: Adverse events (AEs) were defined as any untoward medical occurrence associated with the use of an intervention in humans, whether or not considered intervention-related. Treatment-emergence was defined as any AE(s) regardless of relationship to investigational medicinal product (IMP), that had an onset or worsened in severity on or after the first dose of IMP.
• Period 3: Change From Baseline in Albumin-Corrected Blood Calcium Concentrations (cCa) [Baseline, Week 24]
• Period 3: Rate of Urinary Calcium Excretion [Week 24]

Secondary outcomes

• Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood [15 minutes pre-dose on Day 5 of Periods 1 and 2 (Periods were 5 days)]: Blood samples were taken for analysis of iPTH concentrations. iPTH concentrations were analyzed via an electrochemiluminescence immunoassay.
• Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret [Periods 1 and 2: Day 5 (Periods were 5 days)]
• Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret [Periods 1 and 2: Day 5, Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]
• Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret [Periods 1 and 2: Day 5; Period 3: Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]
• Periods 2 and 3: Change From Baseline in Blood Calcium Concentration (cCa) [Period 2: Baseline, Day 5 (Period was 5 days), Period 3: Baseline, Week 24 (Period was 24 weeks)]: Data values presented are for the change from baseline for the average values at the specified timepoints/visits.
• Period 3: Urinary Calcium Clearance as Assessed by Fractional Excretion [Period 3: Week 24, 15 minutes pre-dose (Period was 24 weeks)]: Fractional Excretion of Calcium was derived as (Urine Calcium at the interval considered * Serum Creatinine at the end of the interval considered)/(Serum Calcium at the end of the interval considered * Urine Creatinine at the interval considered) and is presented as percentage.
• Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion [Periods 1 and 2: Day 5; Period 3, Week 24 (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]
• Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) [Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose) (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]: eGFR was calculated using Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) formula (mL/min/1.73m\^2) = 141 x min (SCr/K, 1)\^α x max(SCR /K,1)-1.209 x 0.993Age x 1.018 \[if female\] x 1.159 \[if Black\], where SCr is the serum creatinine (mg/dL), K = 0.7 for female and 0.9 for males, α is -0.329 for female and -0.411 for males.
• Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D [Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]
• Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations [Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3: Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]
• Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations [Periods 1 and 2: Day 5 (0-24h post-dose), Period 3: Week 24 (0-24h post-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]
• Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations [Periods 1 and 2: Day 5 (0-24 hours post-dose), Period 3: Week 24: (0-24 hours post-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]
• Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations [Periods 1 and 2: Day 5 (0-24h post-dose), Period 3: Week 24 (0-24h post-dose); (Period was 5 days for periods 1 and 2; 24 weeks for period 3)]
• Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations [Periods 1 and 2: Day 5 (0-4h post-dose), Period 3: Week 24 (0-4h post dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]
• Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx) [Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3 Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]: Blood samples were taken for analysis of bone resorption markers (CTx).
• Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP) [Periods 1 and 2: Day 5 (15 minutes pre-dose), Period 3 Week 24 (15 minutes pre-dose); (Period was 5 days for Periods 1 and 2; 24 weeks for Period 3)]: Blood samples were taken for analysis of bone formation markers (P1NP).

Sex: All, ages: 16 Years to any

Key Inclusion Criteria:

* Be able to understand and sign a written informed consent or assent form, which must be obtained prior to initiation of study procedures.
* Postmenopausal women are allowed to participate in this study
* Body mass index (BMI) ≥ 18.5 to < 39 kilograms (kg)/square meter (m\^2)
* Have an activating mutation of the Calcium-sensing receptor (CASR) gene
* Participants being treated with thiazide diuretics may be enrolled if they are willing and able to discontinue thiazides
* Participants being treated with strong Cytochrome P3A4 (CYP3A4) inhibitors should ideally, if clinically appropriate, discontinue these medications during the screening period
* Participants being treated with magnesium or potassium citrate supplements should discontinue such treatment starting on Day -1 during Period 1 and Period 2 and may be asked to discontinue treatment during Period 3

Key Exclusion Criteria:

* History of treatment with parathyroid hormone (PTH) 1-84 or 1-34 within the previous 3 months
* History of hypocalcemic seizure within the past 3 months
* Blood 25-OH Vitamin D level < 25 nanograms (ng)/milliliter (mL)
* Participants with hemoglobin (Hgb) < 13 grams (g)/deciliter (dL) for men and < 12 g/dL for women
* Estimated glomerular filtration rate (eGFR) < 25 mL/minute/1.73 m\^2 using Chronic Kidney Disease Epidemiology Collaboration (for participants <18 years old the Schwartz equation will be calculated)
* 12-lead resting electrocardiogram (ECG) with clinically significant abnormalities
* Participants with positive hepatitis B surface antigen (HBsAg), hepatitis A immunoglobulin M (IgM), or human immunodeficiency virus (HIV) viral serology test results at the Screening Visit
* Pregnant or nursing (lactating) women
* History of drug or alcohol dependency within 12 months preceding the Screening Visit
* History of thyroid or parathyroid surgery
* Current participation in other investigational drug studies
* Unwillingness to refrain from blood donation within 12 weeks prior to Screening Visit from the start of the study enrollment through one year after the last dose of the study drug

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Participant flow

Outcome results

• Periods 1, 2 and 3: Number of Participants With Treatment-emergent Adverse Events (TEAEs) (Primary), Count of participants, Participants: Period 1: Encaleret 5; Periods 2 and 3: Encaleret 13
• Period 3: Change From Baseline in Albumin-Corrected Blood Calcium Concentrations (cCa) (Primary), Mean, milligrams (mg)/deciliter (dL): Period 3: Encaleret 1.9 +/- 0.48
• Period 3: Rate of Urinary Calcium Excretion (Primary), Mean, mg/24hour (hr): Period 3: Encaleret 202 +/- 83
• Periods 1 and 2: Intact Parathyroid Hormone (iPTH) Concentrations in the Blood (Secondary), Mean, Picograms (pg)/milliliter (mL): Period 1: Encaleret 43.8 +/- 34.06; Period 2: Encaleret
• Periods 1 and 2: Area Under the Concentration-Time Curve Extrapolated to Infinity (AUC0-inf) of Encaleret (Secondary), Mean, hour (hr)*nanogram (ng)/milliliter (mL): Period 1: Encaleret 11283.7 +/- 3556.12; Period 2: Encaleret
• Periods 1, 2 and 3: Maximum Plasma Concentration (Cmax) of Encaleret (Secondary), Mean, nanograms (ng)/milliliter (mL): Period 1: Encaleret 2593.3 +/- 655.89; Period 2: Encaleret ; Period 3: Encaleret
• Periods 1, 2 and 3: Time to Maximum Plasma Concentration (Tmax) of Encaleret (Secondary), Median, hour: Period 1: Encaleret 1.1 (1.0 to 3.0); Period 2: Encaleret ; Period 3: Encaleret
• Periods 2 and 3: Change From Baseline in Blood Calcium Concentration (cCa) (Secondary), Mean, milligram (mg)/ deciliter (dL): Period 2: Encaleret 1.5 +/- 0.60; Period 3: Encaleret
• Period 3: Urinary Calcium Clearance as Assessed by Fractional Excretion (Secondary), Mean, percentage: Period 3: Encaleret 0.016 +/- 0.004
• Periods 1, 2 and 3: Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion (Secondary), Mean, mg/24hr: Period 1: Encaleret 84 +/- 146; Period 2: Encaleret ; Period 3: Encaleret
• Periods 1, 2 and 3: Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) (Secondary), Mean, mL/min/1.73m^2: Period 1: Encaleret 91.1 +/- 18.73; Period 2: Encaleret ; Period 3: Encaleret
• Periods 1, 2 and 3: Serum Levels of 1,25-(OH)2 Vitamin D (Secondary), Mean, picograms per milliliter (pg/mL): Period 1: Encaleret 25.8 +/- 12.24; Period 2: Encaleret ; Period 3: Encaleret
• Periods 1, 2 and 3: Magnesium, Phosphorus, and Creatinine Levels as Assessed by Blood Sample Examinations (Secondary), Mean, mg/dL: Period 1: Encaleret 2.2 +/- 0.36; Period 2: Encaleret ; Period 3: Encaleret
• Periods 1, 2 and 3: Creatinine, Phosphorus, Magnesium, and Citrate Total Excretion Levels as Assessed by Urine Sample Examinations (Secondary), Mean, mg/24hr: Period 1: Encaleret 1454 +/- 248; Period 2: Encaleret ; Period 3: Encaleret
• Periods 1, 2 and 3: pH as Assessed by Urine Sample Examinations (Secondary), Mean, pH: Period 1: Encaleret 6.2 +/- 2.02; Period 2: Encaleret ; Period 3: Encaleret
• Periods 1, 2 and 3: Potassium and Sodium Total Excretion Levels as Assessed by Urine Sample Examinations (Secondary), Mean, Milliequivalents (meq)/24hr: Period 1: Encaleret 79.00 +/- 48.662; Period 2: Encaleret ; Period 3: Encaleret
• Periods 1, 2 and 3: Cyclic Adenosine Monophosphate (cAMP) Total Excretion Levels as Assessed by Urine Sample Examinations (Secondary), Mean, nanomoles per deciliter (nmol/dL): Period 1: Encaleret 2.98 +/- 0.795; Period 2: Encaleret ; Period 3: Encaleret
• Periods 1, 2 and 3: Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx) (Secondary), Mean, Picograms per milliliter (pg/mL): Period 1: Encaleret 386 +/- 165; Period 2: Encaleret ; Period 3: Encaleret
• Periods 1, 2 and 3: Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP) (Secondary), Mean, Micrograms per liter (mcg/L): Period 1: Encaleret 27.33 +/- 5.007; Period 2: Encaleret ; Period 3: Encaleret

Adverse events

Time frame: Up to 16 months

Other adverse events by term

• Study Protocol (PDF, 2023-05-18)
• Statistical Analysis Plan (PDF, 2023-06-26)

• Calcilytix Medical Director, Study director, Calcilytix Therapeutics, Inc., a BridgeBio company