A Cohort Study on the Safety and Efficacy of XH-02 in Treating Hypoparathyroidism

An Expanded Cohort Study on the Safety and Efficacy of mRNA Nucleic Acid Drug XH-02 in Treating Adult Hypoparathyroidism

XH-02 is an mRNA nucleic acid drug that expresses PTH in the body following intravenous or subcutaneous injection, providing PTH replacement therapy for patients with hypoparathyroidism. Previous clinical studies have demonstrated the safety of subcutaneously administered XH-02 in several patients with hypoparathyroidism and have yielded clear efficacy results. This study aims to further validate the safety and efficacy of subcutaneously injected XH-02 in the treatment of hypoparathyroidism in a expanded cohort.

Inclusion Criteria:

1. Age ≥18 years, both males and females eligible;
2. History of postoperative chronic HP or autoimmune, genetic, or idiopathic HP for at least 26 weeks. The diagnosis of HP is established based on the presence of inappropriately low serum PTH levels concurrent with hypocalcemia in the past.
3. Poorly controlled or intolerant to conventional treatment (calcium and vitamin D) for hypoparathyroidism;
4. BMI 17-40 kg/m² (inclusive) at screening;
5. If age ≤25 years, radiographic evidence of epiphyseal closure based on X-ray results of the wrist and palm of the non-dominant hand.

Exclusion Criteria:

1. Impaired PTH response (pseudohypoparathyroidism), characterized by PTH resistance and elevated PTH levels in the presence of hypocalcemia;
2. Allergic constitution, or allergy to the investigational drug or polyethylene glycol (PEG)-based drugs;
3. Any disease other than HP that may affect calcium metabolism, calcium-phosphorus homeostasis, or PTH levels, such as active hyperthyroidism; Paget's disease of bone; severe hypomagnesemia; type 1 diabetes mellitus or poorly controlled type 2 diabetes mellitus (HbA1C >9%; HbA1C test results from blood samples collected within 12 weeks prior to screening are acceptable); severe and chronic liver or kidney disease; Cushing's syndrome; multiple myeloma; active pancreatitis; malnutrition; rickets; recent prolonged immobilization; active malignancy (except for low-risk well-differentiated thyroid cancer or non-melanoma skin cancer); active hyperparathyroidism; parathyroid carcinoma occurring within 5 years prior to screening; acromegaly; or multiple endocrine neoplasia;
4. Pregnant or breastfeeding women;
5. Male partners with female partners planning to become pregnant, or partners of childbearing potential who are unwilling to use adequate contraceptive methods during the study period;
6. Patients with high-risk thyroid cancer requiring TSH suppression to <0.2 mIU/L within 2 years, or those with a history of tumors;
7. Use of loop diuretics, phosphate binders (except calcium supplements), digoxin, lithium, methotrexate, biotin >30 mcg/day, or systemic corticosteroids (except as replacement therapy);
8. Use of PTH-like drugs (whether commercially available or obtained through participation in clinical trials), 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;
9. Participation in any other interventional trial receiving investigational drugs or devices within 8 weeks prior to screening, or still within 5.5 half-lives of the investigational drug from the trial in which they participated;
10. Presence of uncontrolled hypertension at baseline, or a history of the following cardiovascular or cerebrovascular diseases, including: (1) unstable angina; (2) cardiac arrhythmias requiring medication or severe arrhythmias; (3) myocardial infarction; (4) heart failure class III or higher (NYHA classification), second-degree or higher atrioventricular block; (5) cerebral infarction (excluding lacunar infarction), cerebral hemorrhage, or other such diseases;
11. Increased risk of osteosarcoma, such as having Paget's disease of bone or unexplained elevated alkaline phosphatase, having genetic disorders predisposing to osteosarcoma, or having a prior history of extensive external beam or implant radiation therapy involving bone;
12. Disease processes that adversely affect gastrointestinal absorption, including but not limited to short bowel syndrome, significant small bowel resection, gastric bypass surgery, tropical sprue, active celiac disease, active ulcerative colitis, active Crohn's disease, gastroparesis, and autoimmune regulator gene mutations associated with malabsorption;
13. Any medical or other condition that, in the investigator's judgment, may affect the conduct of the study, interfere with the study results, or increase the risk to the subject/study.