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

Study Overview
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Brief Summary
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The primary purpose of this study is to evaluate the safety, tolerability and effectiveness of encaleret in participants with Autosomal Dominant Hypocalcemia Type 1 (ADH1).

Official Title
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A Phase 2b, Open-label Dose-ranging Study Evaluating the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics, and Efficacy of CLTX-305 (Encaleret) in Autosomal Dominant Hypocalcemia (ADH) Type 1

Conditions
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Autosomal Dominant Hypocalcemia (ADH)

Intervention / Treatment
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* Drug: Encaleret


Participation Criteria
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Eligibility Criteria
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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 kg/m2 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 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 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 ng/mL Participants with hemoglobin (Hgb) < 13 g/dL for men and < 12 g/dL for women Estimated glomerular filtration rate (eGFR) < 25 mL/minute/1.73 m2 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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1: Ascending + Steady-State Dose<br>Period 1: Participants will receive an ascending dose of encaleret once daily for the first 3 days. Participants will then receive an individualized dose of encaleret twice daily for 2 days. Period 2: Participants will receive encaleret twice daily for 5 days at a single dose level based on responses from Period 1. Period 3: After completion of Period 2, participants will be eligible to receive encaleret for an additional 24 weeks. Long-Term Extension (LTE): At the end of the study, participants will also have an option to receive encaleret for up to an additional 2 years. | Drug: Encaleret<br>* Tablets administered orally<br>* Other names: CLTX-305;|
| Experimental: Cohort 2: Steady-State Dose<br>Participants will directly be enrolled into Period 2, and receive encaleret twice daily at a dose based on data and responses from Cohort 1 Period 1. Period 2: Participants will receive encaleret twice daily for 5 days. Period 3: After completion of Period 2, participants will be eligible to receive encaleret for an additional 24 weeks. LTE: At the end of the study, participants will also have an option to receive encaleret for up to an additional 2 years. | Drug: Encaleret<br>* Tablets administered orally<br>* Other names: CLTX-305;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events (AEs) |  | Up to 3 years | 
| Change From Baseline in Albumin-Corrected Blood Calcium Concentrations (cCa) |  | Up to 25 weeks | 
| Rate of Urinary Calcium Excretion |  | Predose, Up to 24 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Intact Parathyroid Hormone (iPTH) Concentration in Blood |  | Predose, Up to 24 hours postdose | 
| Area Under the Concentration-Time Curve Etrapolated to infinity (AUC0-inf) |  | Predose, Up to 24 hours postdose | 
| Maximum Plasma Concentration (Cmax) |  | Predose, Up to 24 hours postdose | 
| Time to Maximum Plasma Concentration (Tmax) |  | Predose, Up to 24 hours postdose | 
| Change From Baseline in Blood Calcium Concentration (cCa) |  | Up to 3 years | 
| Urinary Calcium Clearance as Assessed by Fractional Excretion |  | Up to 3 years | 
| Urinary Calcium Clearance as Assessed by 24-Hour Total Excretion |  | Up to 3 years | 
| Renal Function as Assessed by Estimated Glomerular Filtration Rate (eGFR) |  | Up to 3 years | 
| Serum levels of 1,25-(OH)2 Vitamin D |  | Up to 3 years | 
| Magnesium, Phosphate, Creatinine Levels as Assessed by Blood Sample Examinations |  | Up to 3 years | 
| PH, Magnesium, Phosphate, Sodium, Potassium, Creatinine, cyclic adenosine monophosphate (cAMP), Citrate Levels as Assessed by Urine Sample Examinations |  | Up to 3 years | 
| Bone Resorption Markers as Assessed by Collagen Cross-Linked C-Telopeptide (CTx) |  | Up to 3 years | 
| Bone Formation Markers as Assessed by Blood Procollagen Type 1 N-Propeptide (P1NP) |  | Up to 3 years |