Study of the PTH-independent Effects of Encaleret on Mineral Homeostasis in Subjects With Postsurgical Hypoparathyroidism (PSH)

• INCLUSION CRITERIA:

Participants must meet the following criteria for inclusion during screening:

1. Be able to understand and sign a written informed consent form, which must beobtained prior to initiation of study procedures.

2. Age >= 18 years

3. Postmenopausal women are allowed to participate in this study: a. Women are considered postmenopausal and not of childbearing potential if theyhave had 12 months of natural (spontaneous) amenorrhea with an appropriate clinicalprofile (e.g., age appropriate, history of vasomotor symptoms) or have had surgicalbilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6weeks prior to start of the study. In the case of oophorectomy alone, only when thereproductive status of the woman has been confirmed by follow up hormone levelassessment, shall she be considered not of childbearing potential.

4. Body mass index (BMI) >= 18.5 to < 39 kg/m^2

5. Have a diagnosis of PSH, either permanent PSH (Cohort 1, surgery >= 12 months ago)or recent PSH (Cohort 2, surgery < 12 months ago).

6. Participants must have achieved an albumin-corrected blood calcium level of 7.8-10.2mg/dL on conventional therapy without significant symptoms of hypocalcemia orhypercalcemia.

7. Participants being treated with thiazide diuretics may be enrolled if they arewilling and able to discontinue thiazides for at least 5 half-lives prior toinitiation of encaleret and remain off during the study treatment period. (5half-lives of hydrochlorothiazide = 75 hours; chlorothiazide = 10 hours;chlorthalidone = 12.5 days). If the thiazide is being used as an antihypertensive,as opposed to use as a urine calcium-lowering drug, alternative therapy will beoffered.

8. Participants being treated with strong CYP3A4 inhibitors (including clarithromycin,telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir,indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) may be enrolledif they are willing and able to discontinue these medications for at least 5half-lives prior to initiation of encaleret and remain off during the studytreatment period.

9. Participants being treated with magnesium or potassium citrate supplements shoulddiscontinue such treatment starting on Day -2.

10. Participants being treated with medications that have impacts on mineral metabolismwhich investigators believe may impact study endpoints may be enrolled if they arewilling and safely able to discontinue the medication for at least 5 half-livesprior to initiation of encaleret and remain off during the study treatment period

EXCLUSION CRITERIA:

Participants who meet any of the following criteria during Screening will not be eligible to participate in the study:

1. History of treatment with any PTH analog (i.e., PTH 1-84, PTH 1-34, TransCon PTH,etc.) within the previous 3 months

2. History of prior treatment with encaleret

3. History of hypocalcemic seizure within the past 3 months

4. Blood 25-OH Vitamin D level <25 or >60 ng/mL

5. If subject has a blood 25-OH Vitamin D level < 25 ng/mL at the screening visit,they will be prescribed cholecalciferol or ergocalciferol supplementation. Oncethe 25-OH Vitamin D level is >= 25 ng/mL, the subject will be eligible tocontinue to the treatment phase of the study.

6. If a subject has a blood 25-OH Vitamin D level >60 ng/mL at the screeningvisit, their vitamin D supplementation will be adjusted. Once the 25-OH VitaminD level is <=60 ng/mL, the subject will be eligible to continue to thetreatment phase of the study.

7. Participants with hemoglobin (Hgb) lower than the lower limit of normal. a. If subject has a low Hgb at the screening visit due to iron, B12, or folatedeficiency, they will be prescribed supplementation. Once the Hgb level within thenormal range, the subject will be eligible to continue to the treatment phase of thestudy.

8. Abnormal laboratory values which in the opinion of the investigator, would make thesubject not suitable for participation in the study

9. Estimated glomerular filtration rate (eGFR) < 50 mL/minute/1.73 m2 using CKD-EPI.

10. Insufficient hepatic function defined as one of the following:

• Total Bilirubin > 1.5 x ULN OR

• Aspartate transaminase (AST) > 2x ULN OR

• Alanine transaminase (ALT) > 2x ULN

9. 12-lead resting electrocardiogram (ECG) with clinically significant abnormalities.Participants with screening QTcF (using the Frederica equation) > 450 milliseconds (ms) will not be eligible for the treatment phase of the study.

• If a participant has a prolonged QTcF during screening due to a reversiblecause of long QT (for example hypocalcemia or QT-prolonging medications), thesubject may be eligible for the treatment phase of the study if the reversiblecause can be addressed, and repeat ECG shows QTcF <=450 milliseconds.

10. Clinically significant cardiac disease including any of the following:

• Congestive heart failure requiring treatment (NY Heart Association grade >= 2)

• History of clinically significant cardiac arrythmias including ventriculararrhythmias, atrial fibrillation, or conduction abnormalities

• History of unstable angina pectoris or acute myocardial infarction

11. Participants with positive hepatitis B surface antigen (HBsAg) or Hepatitis Aimmunoglobulin M (IgM) at the Screening Visit. Participants who are in completeremission from Hepatitis C as evidence by sensitive assay >=12 weeks aftercompletion of HCV therapy are allowed to participate in the study. Participants withhuman immunodeficiency virus (HIV) infection on a stable dose of anti-retroviraltherapy who have an undetectable viral load are allowed to participate in the study.

12. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of afemale after conception and until the termination of gestation, confirmed by apositive serum hCG laboratory test

13. Clinically significant abnormalities in thyroid function tests. This does notinclude participants with non-clinically significant or treated thyroid diseases (e.g. subclinical hypothyroidism, hypothyroidism on treatment, etc). Participants onTSH-suppression therapy for thyroid cancer are allowed to participate in this studyregardless of TSH level.

14. Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using highly effective methods of contraceptionduring dosing and for 3 months following the discontinuation of study treatment.Highly effective contraception methods include:

• Total abstinence (when this is in line with the preferred and usual lifestyleof the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods ofcontraception.

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy) or tubal ligation at least six weeks before taking studytreatment. In case of oophorectomy alone, only when the reproductive status ofthe woman has been confirmed by follow up hormone level assessment.

• Male sterilization (at least 6 months prior to screening). For femaleparticipants on the study the vasectomized male partner should be the solepartner for that subject.

• Combination of the following (a+c or b+c):

1. Use of oral, injected or implanted hormonal methods of contraception orother forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermalhormone contraception

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

3. Barrier method of contraception: Condom or Occlusive cap (diaphragm orcervical/vault caps) with spermicidal foam/gel/film/cream/vaginalsuppository

4. Sexually active male participants who are unwilling to use a condom during vaginalintercourse while taking the encaleret (study drug) and for 3 months after the lastdose of the study drug. Participants should not father a child during activeparticipation in the study starting with the first encaleret dose. Condoms are notrequired if the subject is vasectomized or if the subject s partner is not a womanof child-bearing potential.

5. Hypersensitivity to any active substance or excipient of encaleret

6. History of drug or alcohol dependency within 12 months preceding the Screening Visit

7. Current participation in other investigational drug studies

8. Unwillingness to refrain from blood donation within 12 weeks prior to admissionvisit through one year after the last dose of the study drug. If subject donatedblood within 12 weeks of the screening visit, they will need to wait until 12 weekshave passed since blood donation for the admission visit.

9. Participants who have a history of diseases of mineral metabolism other thanhypoparathyroidism or hyperparathyroidism which investigators believe may impactstudy endpoints (for example, X-linked hypophosphatemia, rickets, etc).

10. Participants with history of the following:

• Any cancer except for thyroid cancer, basal cell skin cancer or squamous cellcancer in the last 5 years. Subjects with history of thyroid, basal cell orsquamous cell cancers should have received definitive treatment for theirmalignancies prior to enrollment.

• Skeletal malignancies

• Bone metastases

• Irradiation (radiotherapy) to the skeleton

• Any other disease that increases the likelihood for osteosarcoma (ex. Paget sdisease).

• Unexplained elevations of alkaline phosphatase