PaTHway CHINA TRIAL: A Trial to Investigating the Safety, Tolerability and Efficacy of TransCon PTH in Adults With Hypoparathyroidism

Inclusion Criteria:

1. Males and females, ≥18 years of age
2. Subjects with postsurgical chronic HP, or auto-immune, genetic, or idiopathic HP forat least 26 weeks. Diagnosis of HP is established based on historic hypocalcemia inthe setting of inappropriately low (below the ULN of local laboratory) serum PTHlevels.
3. Requirement for doses of SoC (e.g., calcitriol, alfacalcidol, calcium supplements) ator above a minimum threshold: • requirement for a dose of calcitriol ≥0.5 μg/day, or alfacalcidol ≥1.0 μg/day and (elemental) calcium ≥800 mg/day (e.g., calcium citrate, calcium carbonate etc.) for atleast 12 weeks prior to Screening. In addition, the dose of calcitriol, oralfacalcidol, and calcium should be stable for at least 5 weeks prior to Screening
4. Optimization of supplements prior to randomization to achieve the target serum levelsof:

• 25(OH) vitamin D levels of 10-100 ng/mL (25-250 nmol/L) and
• Magnesium level in the normal range, or just below the normal range i.e.: ≥1.3mg/dL (0.53 mmol/L) and
• Albumin-adjusted sCa level in the normal range, or just below the normal range,i.e.: 7.8-10.6 mg/dL (or 1.95-2.64 mmol/L)

5. The subject demonstrates a 24-hour uCa excretion of ≥125 mg/24h (on a sample collectedwithin 52 weeks prior to Screening or during the Screening Period)
6. BMI 17- 40 kg/m2 at Screening
7. If ≤25 years of age, radiological evidence of epiphyseal closure based on X-ray ofnon-dominant wrist and hand
8. Thyroid-stimulating hormone (TSH) within normal laboratory limits within the 6 weeksprior to Visit 1; if on suppressive therapy for a history of thyroid cancer, TSH levelmust be ≥0.2 mIU/L
9. If treated with thyroid hormone replacement therapy, the dose must have been stablefor at least 5 weeks prior to Screening
10. eGFR ≥30 mL/min/1.73 m2 during Screening
11. Able to perform daily SC self-injections of study drug (or have a designee to performinjections) via a pre-filled injection pen
12. Able and willing to provide written and signed ICF in accordance with GCP

Exclusion Criteria:

1. Impaired responsiveness to PTH (pseudohypoparathyroidism) which is characterized asPTH-resistance, with elevated PTH levels in the setting of hypocalcemia
2. Any disease that might affect calcium metabolism or calcium-phosphate homeostasis orPTH levels other than HP, such as active hyperthyroidism; Paget disease of bone;severe hypomagnesemia; type 1 diabetes mellitus or poorly controlled type 2 diabetesmellitus (HbA1C >9%, documented HbA1C result drawn within 12 weeks prior to Screeningis acceptable); severe and chronic liver, or renal disease; Cushing syndrome; multiplemyeloma; active pancreatitis; malnutrition; rickets; recent prolonged immobility;active malignancy (other than low-risk well differentiated thyroid cancer ornon-melanoma skin cancer); active hyperparathyroidism; parathyroid carcinoma within 5years prior to Screening; acromegaly;or multiple endocrine neoplasia
3. High risk thyroid cancer within 2 years, requiring suppression of TSH <0.2 mIU/L
4. Long term use of loop diuretics, phosphate binders (other than calcium supplements),digoxin, lithium, methotrexate, biotin >30 µg/day, or systemic corticosteroids (otherthan as replacement therapy)
5. Use of thiazide diuretic within 4 weeks prior to the 24-hour urine collectionscheduled to occur within 1 week prior to Visit 1
6. Use of PTH-like drugs (whether commercially available or through participation in aninvestigational trial), including PTH (1-84), PTH (1-34), or other N-terminalfragments or analogs of PTH or PTH-related protein, within 4 weeks prior to Screening
7. Use of other drugs known to influence calcium and bone metabolism, such as calcitonin,fluoride tablets (>0.5 mg/day), strontium, or cinacalcet hydrochloride, within 12weeks prior to Screening
8. Use of osteoporosis therapies known to influence calcium and bone metabolism, i.e.,bisphosphonate (oral or intravenous [IV]), denosumab, raloxifene, or romosozumabtherapies within 2 years prior to Screening
9. Non-hypocalcemic seizure disorder with a history of a seizure within 26 weeks prior toScreening
10. Increased risk for osteosarcoma, such as those with Paget's disease of bone orunexplained elevations of alkaline phosphatase, hereditary disorders predisposing toosteosarcoma, or with a prior history of substantial external beam or implantradiation therapy involving the skeleton
11. Pregnant or lactating women
12. Male who has a female partner who intends to become pregnant or is of childbearingpotential and is unwilling to use adequate contraceptive methods during the trial
13. Diagnosed drug or alcohol dependence within 3 years prior to Screening
14. Disease processes that adversely affect gastrointestinal absorption, including but notlimited to short bowel syndrome, significant small bowel resection, gastric bypass,tropical sprue, active celiac disease, active ulcerative colitis, active Crohn'sdisease, gastroparesis and AIRE gene mutations with malabsorption
15. Severe cardiac disease within 26 weeks prior to Screening including but not limited tocongestive heart failure, myocardial infarction, severe or uncontrolled arrhythmias,bradycardia (resting heart rate <48 beats/minute, unless chronic and asymptomatic),symptomatic hypotension or systolic BP <80 mm Hg or diastolic <40 mm Hg or poorlycontrolled hypertension (systolic BP >165 mm Hg or diastolic >95 mm Hg). In theabsence of a prior history of hypertension, an isolated BP >165/95 mm Hg in thesetting of white coat hypertension/anxiety may not be exclusionary and a measurementcan be repeated prior to randomization
16. Cerebrovascular accident within 5 years prior to Screening
17. Within 26 weeks prior to Screening: acute colic due to nephrolithiasis, or acute gout.Subjects with asymptomatic renal stones are permitted
18. Participation in any other interventional trial in which receipt of investigationaldrug or device occurred within 8 weeks (or within 5.5 times the half-life of theinvestigational drug) (whichever comes first) prior to Screening
19. Any disease or condition that, in the opinion of the investigator, may requiretreatment or make the subject unlikely to fully complete the trial, or any conditionthat presents undue risk from the investigational product or procedures, includingtreated malignancies that are likely to recur within the approximate 3.5-year durationof the trial
20. Known allergy or sensitivity to PTH or any of the excipients [metacresol, mannitol,succinic acid, NaOH/(HCl)]
21. Likely to be non-compliant with respect to trial conduct
22. Any other reason that in the opinion of the investigator would prevent the subjectfrom completing participation or following the trial schedule