Study of TST002 Injection in Postmenopausal Women With Osteoporosis or Low Bone Mass

Primary Purpose: Efficacy and safety evaluation of TST002 in postmenopausal osteoporosis and low bone mass.

Design: 5-arm, randomized, double-blind (denosumab arm open-label), placebo- and active-comparator (denosumab)-controlled, parallel-group study with stratified block randomization by screening BMD T-score (Stratum 1: T-score ≥ -2.00; Stratum 2: T-score < -2.00 at all sites). Enrollment capped at <20% Stratum 1 participants per arm.

All participants receive daily calcium (600-1200 mg elemental) and vitamin D (725-1450 IU) supplementation from screening through study end, with an optional vitamin D loading dose for those with baseline 25(OH)D 20-40 ng/mL.

Unblinding: Primary analysis after all participants complete Week 24 is performed by an unblinded CRO team; investigators, participants, and the CRO study team (except for the open-label denosumab arm) remain blinded until final study unblinding

• Denosumab (Drug): Active comparator
• Placebo (Drug): Vehicle Placebo

Primary outcomes

• Percent change from baseline in lumbar spine Bone Mineral Density (BMD) [Baseline to Week 24]: Lumbar spine (L1-L4) bone mineral density, central imaging read (DXA)

Secondary outcomes

• Percent change from baseline in lumbar spine Bone Mineral Density (BMD) [Weeks 12 and 52]: Central imaging read (DXA)
• Percent change from baseline in total hip Bone Mineral Density (BMD) [Weeks 12, 24, and 52]: Central imaging read (DXA)
• Percent change from baseline in femoral neck Bone Mineral Density (BMD) [Weeks 12, 24 and 52]: Central imaging DXA
• TST002 plasma concentration [Up to 52 weeks]: Plasma concentrations at each dosing timepoint
• Percent change from baseline in bone turnover markers [Up to 52 weeks]: P1NP, β-CTX, OC, BSAP, TRACP-5b, and total sclerostin
• Anti-drug antibody (ADA) positivity rate [Up to 52 weeks]: Immunogenicity - proportion positive and time to first positive
• Incidence of adverse events [Up to 52 weeks]: AEs, vital signs, physical exam, and clinically significant lab abnormalities (CTCAE v6.0 graded)
• TST002 Concentration-time [Up to 52 weeks]: Area under curve (AUC)
• TST002 Peak Plasma Concentration [Up to 52 weeks]: Cmax
• TST002 Trough Concentrations [Up to 52 weeks]: Ctrough
• TST002 Half-life [Up to 52 weeks]: T1/2
• TST002 Systemic Clearance [Up to 52 weeks]: CL
• TST002 Volume of Distribution [Out to 52 weeks]: Vd
• TST002 Effects on total Sclerostin [Up to 52 weeks]: Pharmacodynamic effects
• TST002 Effects on total P1NP [Up to 52 weeks]: Pharmacodynamic effects of Serum N-terminal propeptide of procollagen type 1
• TST002 Effects on total B-CTX [Out to 52 weeks]: Pharmacodynamic effects of Beta-C-terminal telopeptide
• TST002 Effects on total OC [Out to 52 weeks]: Pharmacodynamic effects of osteocalcin
• TST002 Effects on total BSAP [Up to 52 weeks]: Pharmacodynamic effects of Bone-specific alkaline phosphatase
• TST002 Effects on total TRACP-5b [Up to 52 weeks]: Pharmacodynamic effects of Tartrate-Resistant Acid Phosphatase 5b

Sex: Female, ages: 45 Years to 80 Years

Inclusion Criteria:

1. Voluntary signed informed consent; able to walk freely; willing/able to complete all study procedures.
2. BMI 18.0-30.0 kg/m² (inclusive); body weight ≥45 kg.
3. Postmenopausal women aged 45-80 years (inclusive) at screening, postmenopausal ≥2 years (≥12 consecutive months without spontaneous vaginal bleeding/spotting).
4. BMD T-score <-2.00 at lumbar spine (L1-L4 total), total hip, or femoral neck at screening; OR history of fragility fracture with T-score <-1.00 at one of these sites (central imaging read).
5. At least 2 contiguous evaluable vertebrae (L1-L4) and at least one evaluable hip for DXA assessment.
6. No disease, per investigator history/exam/workup, likely to significantly affect the study or increase health risk (documented exceptions permitted with justification).

Exclusion Criteria:

1. BMD T-score ≤-3.50 at lumbar spine, total hip, or femoral neck at screening.
2. Prior hip fracture.
3. ≥2 vertebral fractures on screening lateral spine X-ray (investigator-assessed).
4. Known skeletal, endocrine, or rheumatic disease that could confound results (e.g., Paget's disease, osteomalacia, osteopetrosis, osteogenesis imperfecta, sclerosteosis, rheumatoid arthritis, ankylosing spondylitis, Cushing's disease, hyperprolactinemia, uncontrolled thyroid disease, hyper-/hypoparathyroidism, or CN VIII compression hearing loss).
5. Prior osteoporosis therapy (incl. trial participation) within protocol-specified washout windows (IV bisphosphonates, oral bisphosphonates, denosumab/cathepsin K inhibitors, tibolone/cinacalcet/calcitonin, teriparatide/PTH analogs, systemic estrogen/SERMs, strontium ranelate/fluoride, hormonal castration therapy, systemic glucocorticoids ≥5 mg/day prednisone-equivalent for >14 days) - see protocol for exact windows per agent.
6. History of TMJ disorder, TMJ osteonecrosis, or atypical fracture.
7. Hypercalcemia or hypocalcemia (albumin-corrected) at screening.
8. Serum 25(OH)D <20 ng/mL at screening.
9. History of MI, or serious cardiac disease (CAD, NYHA class II-IV heart failure) within 6 months before screening.
10. History of stroke (cerebral infarction, ischemic or hemorrhagic).
11. ALT/AST >3× ULN; ALP >2.5× ULN; total bilirubin or creatinine >1.5× ULN at screening.
12. Multiple myeloma, primary/metastatic bone malignancy, or history of skeletal radiotherapy.
13. Malignancy within 5 years before screening (except cured skin squamous/basal cell carcinoma or documented cured in situ cervical cancer, no recurrence ≥3 months before dosing).
14. Known hypersensitivity to study drug.
15. History of solid organ or bone marrow transplant.
16. Positive HIV, syphilis, HCV antibody, or HBsAg at screening; or HBcAb-positive with detectable HBV DNA.
17. Active tuberculosis within 6 months before screening.
18. Participation in another clinical trial within 30 days or 5 half-lives of the investigational product (whichever longer) before screening.
19. Any other condition the investigator judges unsuitable for participation, a safety risk, or interfering with study assessments/completion.