Efficacy and Safety of Subcutaneous Injection of XH-02 in the Treatment of Adult Hypoparathyroidism

Efficacy and Safety of Subcutaneous Injection of mRNA Nucleic Acid Drug XH-02 in the Treatment of 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. Animal studies have shown pharmacodynamic effects of XH-02, with a favorable safety profile. A clinical study of intravenously administered XH-02 has been completed in patients with hypoparathyroidism, yielding clear pharmacodynamic results and demonstrating good safety. This study aims to evaluate the safety and efficacy of subcutaneously injected XH-02 in patients with hypoparathyroidism.

Inclusion Criteria:

1. Aged 18-65 years (inclusive of 18 and 65), male or female.
2. A history of postoperative chronic hypoparathyroidism (HP) or autoimmune, genetic, or idiopathic HP for at least 26 weeks. HP is confirmed based on a previous occurrence of hypocalcemia accompanied by an inappropriately low serum parathyroid hormone (PTH) level (below the upper limit of the local laboratory's normal range). Note: If the subject does not have a documented diagnosis of chronic HP but has experienced hypocalcemia accompanied by an inappropriately low serum PTH level for at least 26 weeks prior to screening, and the investigator determines that the diagnosis of chronic HP is met, this criterion is considered fulfilled.
3. Inadequate control of hypoparathyroidism with conventional treatment (calcium and vitamin D) or intolerance to such treatment.
4. At screening, Body Mass Index (BMI) of 17-40 kg/m² (inclusive).
5. If aged ≤25 years, radiographic evidence of epiphyseal closure based on X-ray examination of the wrist and hand of the non-dominant hand.

Exclusion Criteria:

1. Impaired response to PTH (pseudohypoparathyroidism), characterized by resistance to PTH and elevated PTH levels during hypocalcemia.
2. Known allergies, or a history of allergy to the investigational drug or polyethylene glycol (PEG).
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; history of parathyroid cancer within 5 years prior to screening; acromegaly; or multiple endocrine neoplasia.
4. History of vaccination within 4 weeks prior to enrollment, or planned vaccination during the study period.
5. Women who are pregnant or breastfeeding.
6. Patients with high-risk thyroid cancer requiring TSH suppression to <0.2 mIU/L within the past 2 years, or those with a history of malignancy.
7. Subjects requiring long-term use of diuretics, phosphate binders (except calcium supplements), digoxin, lithium, methotrexate, biotin >30 μg/day, or systemic corticosteroids (except as replacement therapy). Patients requiring long-term use of hormones or immunosuppressants (e.g., for rheumatic or autoimmune diseases) will not be enrolled in this study. Note: Subjects who can discontinue these medications during the study may be enrolled, but they must be discontinued for at least 5.5 half-lives prior to Visit 1 blood sample collection. Biotin must be discontinued for at least 1 day prior to screening blood sample collection. These medications are prohibited throughout the study.
8. Use of PTH-like drugs (either commercially available or obtained through participation in a clinical 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.
9. Participation in any other interventional trial and receipt of investigational drug or device within 8 weeks prior to screening, or still within 5.5 half-lives of the drug from a previously participated trial.
10. Presence of uncontrolled hypertension at baseline, or a history of the following cardiovascular or cerebrovascular diseases, including: (1) Unstable angina; (2) Arrhythmia requiring medication or severe arrhythmia; (3) Myocardial infarction; (4) Class III or higher heart failure (per NYHA classification), second-degree or higher atrioventricular block; (5) Cerebral infarction (except lacunar infarction), cerebral hemorrhage, or other such conditions.
11. Increased risk of osteosarcoma, for example, having Paget's disease of bone or unexplained elevated alkaline phosphatase, genetic disorders predisposing to osteosarcoma, or previous exposure to high-dose external beam radiation or implant radiotherapy to the skeleton.
12. Abnormal laboratory test results meeting any of the following criteria: Blood routine: Neutrophil count (NEUT#) <1.5×10⁹/L; Platelet count (PLT) <90×10⁹/L; Hemoglobin (Hb) <90g/L; Eosinophil count (EOS#) >0.5×10⁹/L. Liver and kidney function: Total bilirubin or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) exceeding the normal range; eGFR <60 ml/min/1.73m².
13. Any other medical or other condition that, in the investigator's judgment, might affect the conduct of the study or interfere with the study results, or might increase the risk to the subject.