Safety, Pharmacokinetics and Efficacy of MBX 2109 in Patients With Hypoparathyroidism

Inclusion Criteria:

1. Is an adult ≥18 years of age at the time of the Screening visit. a. If ≤25 years of age, radiological evidence of epiphyseal closure based on X-rayof non-dominant wrist and hand

2. Has a diagnosis of one of the following types of hypoparathyroidism for at least 26weeks prior to the Screening visit:

3. Postsurgical chronic hypoparathyroidism

4. Idiopathic hypoparathyroidism

5. Autoimmune hypoparathyroidism (e.g., isolated autoimmune hypoparathyroidism;stable, well-managed patients with autoimmune polyglandular syndrome type 1/autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy withoutcurrent or past malabsorption at the discretion of the principal investigator [PI])

6. On a dose for at least 4 weeks prior to the Screening visit of the following:

7. Calcitriol ≥0.5 µg per day or alfacalcidol ≥1 ug per day (active vitamin D)

8. Elemental calcium (citrate or carbonate) supplement ≥800 mg per day a) If the patient had a history of hypercalcemia on the above active vitamin Dand/or calcium doses, the patient may be eligible to participate in the study onlower doses of calcitriol, alfacalcidol and/or elemental calcium with approval ofthe medical monitor

9. At the Screening visit or at completion of the Optimization Period, the followingserum analytes must be within the following ranges:

• AdjCa: 8.2 to 10.6 mg/dL (2.05 to 2.65 mmol/L), inclusive, targeting the lowerhalf of the reference range

• 25 (OH)D: 30 to 64 ng/mL (75 to 160 nmol/L), inclusive

• Magnesium: within the normal range of 1.8 to 2.6 mg/dL (0.65 to 1.05 mmol/L; 1.3 mEq/L to 2.1 mEq/L), inclusive; if the patient had a history of not beingsuccessful in maintaining serum magnesium within the normal reference range, alevel slightly below the normal range (≥1.3 mg/dL [≥0.53 mmol/L]) may beacceptable with approval by the medical monitor 1.3 mEq/L to 2.1 mEq/L),inclusive

5. Has an estimated glomerular filtration rate >60 mL/min/1.73 m2, as estimated usingthe Chronic Kidney Disease Epidemiology Collaboration equation, at the Screeningvisit.

6. Has thyroid-stimulating hormone (TSH) within normal laboratory limits prior torandomization. If patient is on thyroid medication, the dose should be stable for atleast 4 weeks. If TSH is not within normal limits at screening, the dose of thyroidmedication may be adjusted and TSH repeated in 4 weeks. If receiving suppressivetherapy for a history of (differentiated) thyroid cancer, TSH level must be ≥0.2mIU/L.

7. Can comprehend and is willing to sign an informed consent form (ICF) and to abide bythe study restrictions, study visits, and procedures.

Exclusion Criteria:

1. Has a known history of pseudohypoparathyroidism (impaired responsiveness to PTH,which is characterized as PTH-resistance, with elevated PTH levels in the setting ofhypocalcemia).

2. Has any disease (other than hypoparathyroidism) that might affect calcium metabolismor calcium-phosphate homeostasis or PTH levels (e.g., disorders of the calciumsensing receptor [e.g., autosomal dominant hypocalcemia type 1] are exclusionary).

3. Use any of the following therapies:

4. Loop diuretics, thiazide diuretics, phosphate binders (other than calciumcarbonate or citrate), digoxin, lithium, methotrexate, raloxifenehydrocholoride, or acute systemic corticosteroids within 4 weeks prior to theScreening Visit;

• Chronic systemic corticosteroid use is allowed if the dose has been stablefor 4 weeks prior to Screening visit

2. PTH or PTH-related protein drugs such as PTH(1-84) and PTH(1-34) within 4 weeksof the Screening visit;

3. Oral or intravenous bisphosphonates, denosumab, or romosozumab-aqqg within 18months of the Screening visit; or

4. Other drugs known to influence calcium and bone metabolism such as calcitonin,fluoride tablets (>0.5 mg per day), strontium or cinacalcet hydrochloridewithin 3 months of the Screening visit.

5. Had a non-hypocalcemic seizure within 6 months of the Screening visit. Note: ahistory of seizures that occur in the setting of hypocalcemia is not exclusionary

6. Is at an increased risk for osteosarcoma (e.g., Paget's disease, prior history ofsubstantial external beam or implant radiation therapy involving the skeleton,unexplained elevations of alkaline phosphatase)

7. Is affected by active or uncontrolled disease processes that may adversely affectgastrointestinal absorption at the discretion of the PI.

8. Has a history of an active or untreated malignancy or are in remission from aclinically significant malignancy (other than differentiated thyroid cancer, basalor squamous cell skin cancer, in situ carcinomas of the cervix, or in situ prostatecancer) for less than 2 years from the Screening visit.

9. Has any clinically significant cardiovascular disease within 6 months prior to theScreening visit such as symptomatic heart failure, an acute coronary syndrome,uncontrolled arrhythmia, or cerebrovascular accident.

10. Has a clinically significant abnormal 12-lead ECG in the opinion of the investigatorat the Screening visit suggestive of underlying cardiac disease.

11. Has a seated systolic blood pressure <100 mmHg or >165 mmHg and/or diastolic bloodpressure >100 mmHg at the Screening visit. If outside this range, measurement can berepeated on another day for eligibility purposes within the Screening Period. If onmedications for hypertension, the doses should be stable for 4 weeks prior to theScreening visit.

12. Has a history of symptomatic nephrolithiasis within 3 months of the Screening visit.

13. Has an episode of acute gout within 2 months of the Screening visit.

14. Has any major surgery performed within the 6 months prior to the Screening visit orplans to have surgical procedures that might interfere with the patient's ability tocomplete the study.

15. Is pregnant, lactating or a woman of childbearing potential (WOCBP) who plans toconceive during the study.

16. WOCBP must use at least 2 highly effective methods of contraception throughoutthe study and for 6 weeks following administration of the last dose of studydrug.

17. A heterosexually active male patient and his female partner(s) of childbearingpotential must agree to use 2 effective birth control methods for the durationof the study and for 90 days after the last dose of study drug. A male patientmust agree to refrain from sperm donation from the date of screening until 90days after his last dose of study drug.

18. Has any disease or condition that, in the opinion of the investigator, may make thepatient unlikely to fully complete the study, or any condition that presents unduerisk from the investigational product or procedures.

19. Has a known allergy or sensitivity to PTH or any of the excipients used in MBX 2109.

20. Has a diagnosis of drug or alcohol dependence within 12 months prior to theScreening visit.

21. Has participated in any other interventional trial in which the patient received aninvestigational drug within 2 months or within 5 half-lives of the investigationaldrug (whichever is the longest) prior to the Screening visit.

22. Has any other reason that, in the opinion of the investigator, would prevent thepatient from completing participation or following the study schedule.