A Trial Investigating the Safety, Tolerability and Efficacy of TransCon PTH Administered Daily in Adults With Hypoparathyroidism

PaTHway TRIAL: A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Trial, With an Open-Label Extension, Investigating the Safety, Tolerability and Efficacy of TransCon PTH Administered Subcutaneously Daily in Adults With Hypoparathyroidism

During the first 26 weeks of the trial, participants were randomly assigned to one of two groups: one group received TransCon PTH and one group received placebo. All participants started with study drug at a dose of 18 mcg/day and were individually and progressively titrated to an optimal dose in dose increments of 3 mcg/day. TransCon PTH or placebo were administered as a subcutaneous injection using a pre-filled injection pen. Neither trial participants nor their doctors knew who had been assigned to each group. After the 26 weeks, participants continued in the trial as part of a long-term extension study. During the extension, all participants received TransCon PTH, with the dose adjusted to their individual needs. This was a global trial that was conducted in the United States, Canada, Germany, Denmark, Norway, Italy, and Hungary.

Inclusion Criteria:

1. Males and females, ≥18 years of age

2. Subjects with postsurgical chronic HP, or auto-immune, genetic, or idiopathic HP for at least 26 weeks. Diagnosis of HP is established based on historic hypocalcemia in the setting of inappropriately low serum PTH levels

3. Requirement for doses of SoC (e.g., calcitriol, alfacalcidol, calcium supplements) at or above a minimum threshold:

   • For countries other than Japan: 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 at least 12 weeks prior to Screening. In addition, the dose of calcitriol, or alfacalcidol, or calcium should be stable for at least 5 weeks prior to Screening
   • For Japan: requirement for a dose of calcitriol ≥1.0 μg/day, or alfacalcidol ≥2.0 μg/day for at least 12 weeks prior to Screening. In addition, the dose of calcitriol or alfacalcidol should be stable for at least 5 weeks prior to Screening. In Japan only (due to local practice and dietary patterns), there is no requirement to exceed a minimum dose of calcium supplements

4. Optimization of supplements prior to randomization to achieve the target serum levels of:

   • 25(OH) vitamin D levels of 20-80 ng/mL (49-200 nmol/L) and
   • Magnesium level in the normal range, or just below the normal range and
   • Albumin-adjusted or ionized sCa level in the normal range, or just below the normal range

5. The subject demonstrates a 24-hour uCa excretion of ≥125 mg/24h (on a sample collected within 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 of nondominant wrist and hand

8. Thyroid-stimulating hormone (TSH) within normal laboratory limits within the 6 weeks prior to Visit 1; if on suppressive therapy for a history of thyroid cancer, TSH level must be ≥0.2 mIU/mL

9. If treated with thyroid hormone replacement therapy, the dose must have been stable for at least 5 weeks prior to Screening

10. eGFR ≥30 mL/min/1.73 m2 during Screening

11. Able to perform daily subcutaneous self-injections of study drug (or have a designee to perform injections) via a pre-filled injection pen

12. Able and willing to provide written and signed informed consent in accordance with GCP

Exclusion Criteria:

1. Impaired responsiveness to PTH (pseudohypoparathyroidism) which is characterized as PTH-resistance, with elevated PTH levels in the setting of hypocalcemia
2. Any disease that might affect calcium metabolism or calcium-phosphate homeostasis or PTH levels other than HP, such as active hyperthyroidism; Paget disease of bone; severe hypomagnesemia; type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus (HbA1C >9%, documented HbA1C result drawn within 12 weeks prior to Screening is acceptable); severe and chronic liver, or renal disease; Cushing syndrome; multiple myeloma; active pancreatitis; malnutrition; rickets; recent prolonged immobility; active malignancy (other than low-risk well differentiated thyroid cancer or basal cell skin cancer); active hyperparathyroidism; parathyroid carcinoma within 5 years prior to Screening; acromegaly; or multiple endocrine neoplasia types 1 and 2
3. High risk thyroid cancer within 2 years, requiring suppression of TSH <0.2 mIU/mL
4. Use of loop diuretics, phosphate binders (other than calcium supplements), digoxin, lithium, methotrexate, biotin >30 μg/day, or systemic corticosteroids (other than as replacement therapy)
5. Use of thiazide diuretic within 4 weeks prior to the 24-hour urine collection scheduled to occur within 1 week prior to Visit 1
6. Use of PTH-like drugs (whether commercially available or through participation in an investigational trial), including PTH(1-84), PTH(1-34), or other N-terminal fragments 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 12 weeks 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 romosozumab therapies within 2 years prior to Screening
9. Non-hypocalcemic seizure disorder with a history of a seizure within 26 weeks prior to Screening
10. Increased risk for osteosarcoma, such as those with Paget's disease of bone or unexplained elevations of alkaline phosphatase, hereditary disorders predisposing to osteosarcoma, or with a prior history of substantial external beam or implant radiation therapy involving the skeleton
11. Pregnant or lactating women
12. Male who has a female partner who intends to become pregnant or is of childbearing potential 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 not limited to short bowel syndrome, significant small bowel resection, gastric bypass, tropical sprue, active celiac disease, active ulcerative colitis, active Crohn's disease, gastroparesis and AIRE gene mutations with malabsorption
15. Chronic or severe cardiac disease within 26 weeks prior to Screening including but not limited to congestive 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 poorly controlled hypertension (systolic BP >165 mm Hg or diastolic >95 mm Hg). In the absence of a prior history of hypertension, an isolated BP >165/95 in the setting of white coat hypertension/anxiety may not be exclusionary and a measurement can 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 investigational drug or device occurred within 8 weeks (or within 5.5 times the half-life of the investigational drug (whichever comes first) prior to Screening
19. Any disease or condition that, in the opinion of the investigator, may require treatment or make the subject unlikely to fully complete the trial, or any condition that presents undue risk from the investigational product or procedures, including treated malignancies that are likely to recur within the approximate 3.5-year duration of 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 subject from completing participation or following the trial schedule