Inclusion Criteria:

• Participant must be at least 16 years of age, at the time of signing the informed consent or assent.
• Participants must have a documented pathogenic activating variant, or variant of uncertain significance, of the CASR gene associated with biochemical findings of hypoparathyroidism either present at Screening or a documented history of both:
  • cCa < 8.6 mg/dL (2.2 mmol/L) in participants 16 to < 18 years, or < 8.5 mg/dL (2.1 mmol/L) in participants ≥ 18 years iPTH < 40 pg/mL (4.2 pmol/L);
  • Note: A genetic analysis report for CASR will be acceptable. In the absence of any documentation for the CASR variant, participants must be willing to undergo CASR variant analysis. Participants who have undergone an allogeneic bone marrow transplant must provide either CASR variant analysis report performed prior to the bone marrow transplant or provide a buccal swab for variant analysis. Participants who have received a blood transfusion must wait 2 weeks following the blood transfusion before undergoing CASR variant analysis.
• Participants must have a documented history of symptoms or signs of ADH1. Symptoms of ADH1 include agitation, anxiety, back pain, brain fog, bronchospasm, blepharospasm, cardiac failure, cognitive impairment, difficulty focusing/concentration, esophageal spasm, facial spasm, headaches, hypoesthesia (including facial and oral), irritability, laryngospasm, muscle cramping, muscle fatigue, muscle spasms, muscle tightness, muscle twitching, musculoskeletal pain, musculoskeletal stiffness, myalgia, nephrolithiasis, nervousness, paresthesia (including oral), polydipsia, polyuria, seizure, tetany, throat tightness, or tremor. Signs of ADH1 include basal ganglia or other cerebral calcification, Chvostek sign, hypercalciuria, nephrocalcinosis, papilledema, premature cataracts, prolonged QT interval on ECG, pseudotumor cerebri, or Trousseau sign.
• Participants 16 to < 18 years old must have closed growth plates on hand radiograph.
• Participants treated with thiazide diuretics must discontinue thiazides for at least 14 days prior to Screening through Period 3 Week 24. When the thiazide is being used as an antihypertensive, alternative therapy will be prescribed by the Investigator as needed.
• Participants treated with phosphate binders must discontinue the phosphate binders at least one day prior to the Screening Visit.
• Participants treated with magnesium or potassium supplements must be willing to discontinue such treatment prior to the first dose of encaleret.
• Participants treated with potassium-sparing diuretics must be willing to discontinue such treatment prior to the first dose of encaleret.
• Participants must meet SoC Optimization criteria.
• Male participants must use highly effective contraceptive method (eg, condoms with spermicidal gel or foam) during vaginal intercourse and should not father a child nor donate sperm while taking encaleret and for 3 months after the last dose of encaleret. Condoms are not required if the participant is vasectomized or if the participant’s partner is not a female of childbearing potential.
• Postmenopausal females and females not of childbearing potential may participate in this study without use of contraception:
  • Females are considered postmenopausal if they have had 12 months of natural (spontaneous) amenorrhea without an alternative medical cause and must be confirmed with plasma FSH;
  • Females are considered not of childbearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy) or hysterectomy. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment, shall she be considered not of childbearing potential.

• Females of childbearing potential, defined as all females physiologically capable of becoming pregnant, must use two highly effective methods of contraception starting at Screening and for 3 months following the last dose of encaleret. Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Capable of giving signed informed consent or assent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria: 

• cCa and 24-hr UCa both within the respective reference ranges (cCa = 8.6-10.5 mg/dL in participants 16 to < 18 years or 8.5-10.5 mg/dL in participants ≥ 18 years and UCa < 250 mg/day for women and < 300 mg/day for men) at Screening Visit.
  • Note: Exclusion Criteria only applies to participants on SoC who have not participated in CLTX-305-201.
• History of hypocalcemic seizure within the past 3 months preceding Screening.
• History of thyroid or parathyroid surgery.
• Pregnant or nursing (lactating) women, where pregnancy is confirmed by a positive β-hCG laboratory test.
• History of treatment with PTH 1-84 or 1-34 within the 2 months preceding Screening and requiring SoC doses exceeding > 1.2 × their pre-PTH treatment total daily doses or bone turnover markers, CTx and P1NP, > upper limit of normal for sex, age (men only) and menopausal status (women only).
• Received any investigational medicinal product other than encaleret within 30 days or 5 half-lives, whichever is longer, prior to the first day on study, or are in follow-up for another interventional clinical study during Screening. If the half-life of an investigational medicinal product is unknown, then 30 days prior to Screening.
• Blood 25-OH Vitamin D level < 25 ng/mL.
• If participant has a blood 25-OH Vitamin D level < 25 ng/mL at the Screening Visit, they will be prescribed cholecalciferol or ergocalciferol supplementation per the Investigator. Once the 25-OH Vitamin D level is > 25 ng/mL, the participant will be eligible to enroll in the study (if still within Screening period) or re-screen for the study.
• Estimated glomerular filtration rate < 30 mL/minute/1.73 m^2 using CKD-EPIcr_R (for participants < 18 years old the Bedside Schwartz equation should be used). 
• 12-lead resting ECG with clinically important abnormalities except for asymptomatic QTc prolongation clinically ascribed to hypocalcemia.
• Participants with positive HBsAg, Hepatitis A IgM, or HIV viral serology test at the Screening Visit. Participants who are in complete remission from Hepatitis C as evidence by sensitive assay ≥ 12 weeks after completion of HCV therapy may participate in the study.
• Male or female participants planning to conceive a child prior to the LTE.
• Hypersensitivity to any active substance or excipient of encaleret. 
• Presence or history of any disease or condition (eg, drug or alcohol dependency) that, in the view of the Investigator, would affect the participant’s safety or places the participant at high risk of poor treatment compliance or of not completing the study.

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

Eligibility last updated 11/30/22. Questions regarding updates should be directed to the study team contact.