PTH-independent Effects of Encaleret

Study Description:

This will be a single-site, proof-of-principle, open-label study to explore the PTH-independent effects of encaleret on calcium homeostasis in participants with low or undetectable PTH levels as a result of neck surgery (PSH).

Objectives:

Primary Objective:

-Evaluate the PTH-independent effects of encaleret on renal calcium handling in participants with PSH.

Secondary Objectives:

-Evaluate the ability of encaleret to normalize blood calcium while maintaining a normal urinary calcium in participants with PSH.

Primary Endpoint:

-- Percent change in Fractional Excretion of Calcium (FECa) from baseline (Day -1) to the final day of treatment (Day 6 or the last measurement while on encaleret). FECa calculated using fasting blood levels and spot urine collection.

Secondary Endpoints:

-- Proportion of participants who achieve a concomitant normal or elevated fasting blood calcium (albumin-corrected calcium>8.5 mg/dL) and a normal 24-hour urinary calcium level (<250 mg/24 hours for women, <300 mg/24 hours for men) on encaleret at any point between day 1 and day 5.

• INCLUSION CRITERIA:

Participants must meet the following criteria for inclusion during screening:

• Be able to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
• Age >= 18 years
• Postmenopausal women are allowed to participate in this study:

a. Women are considered postmenopausal and not of childbearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least 6 weeks prior to start of the study. 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.

• Body mass index (BMI) >= 18.5 to < 39 kg/m^2
• Have a diagnosis of PSH, either permanent PSH (Cohort 1, surgery >= 12 months ago) or recent PSH (Cohort 2, surgery < 12 months ago).
• Participants must have achieved an albumin-corrected blood calcium level of 7.8-10.2 mg/dL on conventional therapy without significant symptoms of hypocalcemia or hypercalcemia.
• Participants being treated with thiazide diuretics may be enrolled if they are willing and able to discontinue thiazides for at least 5 half-lives prior to initiation of encaleret and remain off during the study treatment period. (5 half-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 be offered.
• Participants being treated with strong CYP3A4 inhibitors (including clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) may be enrolled if they are willing and able to discontinue these medications for at least 5 half-lives prior to initiation of encaleret and remain off during the study treatment period.
• Participants being treated with magnesium or potassium citrate supplements should discontinue such treatment starting on Day 2.
• Participants being treated with medications that have impacts on mineral metabolism which investigators believe may impact study endpoints may be enrolled if they are willing and safely able to discontinue the medication for at least 5 half-lives prior 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:

• History of treatment with any PTH analog (i.e., PTH 1-84, PTH 1-34, TransCon PTH, etc.) within the previous three (3) months
• History of prior treatment with encaleret
• History of hypocalcemic seizure within the past 3 months
• Blood 25-OH Vitamin D level <25 or >60 ng/mL

• 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. Once the 25-OH Vitamin D level is >= 25 ng/mL, the subject will be eligible to continue to the treatment phase of the study.
• If a subject has a blood 25-OH Vitamin D level >60 ng/mL at the screening visit, their vitamin D supplementation will be adjusted. Once the 25-OH Vitamin D level is <=60 ng/mL, the subject will be eligible to continue to the treatment phase of the study.
• 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 folate deficiency, they will be prescribed supplementation. Once the Hgb level within the normal range, the subject will be eligible to continue to the treatment phase of the study.

• Abnormal laboratory values which in the opinion of the investigator, would make the subject not suitable for participation in the study
• Estimated glomerular filtration rate (eGFR) < 50 mL/minute/1.73 m^2 using CKD-EPI.
• 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
• 12-lead resting electrocardiogram (ECG) with clinically significant abnormalities. Participants with screening QTcF (using the Fridericia 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 reversible cause of long QT (for example hypocalcemia or QT-prolonging medications), the subject may be eligible for the treatment phase of the study if the reversible cause can be addressed, and repeat ECG shows QTcF <=450 milliseconds.
• 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 ventricular arrhythmias, atrial fibrillation, or conduction abnormalities
• History of unstable angina pectoris or acute myocardial infarction
• Participants with positive hepatitis B surface antigen (HBsAg) or Hepatitis A immunoglobulin M (IgM) at the screening visit. Participants who are in complete remission from Hepatitis C (HCV) as evidence by sensitive assay >=12 weeks after completion of HCV therapy are allowed to participate in the study. Participants with human immunodeficiency virus (HIV) infection on a stable dose of anti-retroviral therapy who have an undetectable viral load are allowed to participate in the study.
• Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive serum human chorionic gonadotropin (hCG) laboratory test
• Clinically significant abnormalities in thyroid function tests. This does not include participants with non-clinically significant or treated thyroid diseases (e.g. subclinical hypothyroidism, hypothyroidism on treatment, etc.). Participants on thyroid-stimulating hormone (TSH)-suppression therapy for thyroid cancer are allowed to participate in this study regardless of TSH level.
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for three (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 lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female participants on the study the vasectomized male partner should be the sole partner for that subject.
• Combination of the following (a+c or b+c):

• Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception
• Placement of an intrauterine device (IUD) or intrauterine system (IUS)
• Barrier method of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
• Sexually active male participants who are unwilling to use a condom during vaginal intercourse while taking the encaleret (study drug) and for 3 months after the last dose of the study drug. Participants should not father a child during active participation in the study starting with the first encaleret dose. Condoms are not required if the subject is vasectomized or if the subject's partner is not a woman of child-bearing potential.
• Hypersensitivity to any active substance or excipient of encaleret
• History of drug or alcohol dependency within 12 months preceding the screening visit
• Current participation in other investigational drug studies
• Unwillingness to refrain from blood donation within 12 weeks prior to admission visit through one year after the last dose of the study drug. If subject donated blood within 12 weeks of the screening visit, they will need to wait until 12 weeks have passed since blood donation for the admission visit.
• Participants who have a history of diseases of mineral metabolism other than hypoparathyroidism or hyperparathyroidism which investigators believe may impact study endpoints (for example, X-linked hypophosphatemia, rickets, etc.).
• Participants with history of the following:

• Any cancer except for thyroid cancer, basal cell skin cancer or squamous cell cancer in the last 5 years. Subjects with history of thyroid, basal cell or squamous cell cancers should have received definitive treatment for their malignancies prior to enrollment.
• Skeletal malignancies
• Bone metastases
• Irradiation (radiotherapy) to the skeleton
• Any other disease that increases the likelihood for osteosarcoma (ex. Paget's disease).
• Unexplained elevations of alkaline phosphatase