Evaluation of AGA2118 Efficacy and Safety in Postmenopausal Osteoporosis: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to determine the effect of treatment with **AGA2118** versus placebo at Month 12 on the percent change from Baseline in bone mineral density (BMD) at the lumbar spine in postmenopausal women with low BMD. This is clinically relevant as it addresses the management of **postmenopausal osteoporosis**, a condition characterized by decreased bone mass and increased fracture risk, by potentially improving BMD and reducing fracture risk.

Secondary objectives include: - Evaluating the effect of treatment with AGA2118 versus placebo at different timepoints on percent change from Baseline in BMD at the lumbar spine, total hip, femoral neck, and one-third distal radius. - Assessing the effect of treatment with AGA2118 versus placebo at different time points on percent change from Baseline in [CCI]. - Evaluating the incidence of new clinical fractures (vertebral and nonvertebral) from Baseline to Month 12.

The clinical trial involves a total of **90 participants** who are exclusively **postmenopausal women**. The study population is comprised of healthy, ambulatory women aged between **55 and 80 years**. Participants were selected based on specific criteria, including a **Bone Mineral Density (BMD) T-score** of less than or equal to -2.5 but greater than -3.5 at the lumbar spine, total hip, or femoral neck. The trial does not include male subjects or any vulnerable populations. Lifestyle factors such as diet and physical activity were not specified as part of the selection criteria. The primary focus of the study is to assess the effect of treatment with AGA2118 compared to a placebo on the percent change from baseline in BMD at the lumbar spine over a 12-month period in women with low BMD.

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study designed to evaluate the safety, tolerability, and efficacy of AGA2118 in postmenopausal women with low bone mineral density (BMD). The primary objective is to determine the effect of AGA2118 treatment versus placebo on the percent change from baseline in BMD at the lumbar spine at Month 12. The trial is expected to commence recruitment on January 10, 2025, and conclude by August 31, 2027. Participants will be randomly assigned to receive either AGA2118, a **monoclonal antibody** administered as a subcutaneous injection, or a placebo. The maximum treatment period is 24 months, with a maximum daily dose of 840 mg and a total dose of 20,160 mg.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age (55-80 years) and BMD T-score. Following randomization, participants will attend follow-up visits at Months 1, 3, 6, 9, and 12 to monitor BMD changes at various sites, including the lumbar spine, total hip, femoral neck, and one-third distal radius. The incidence of new clinical fractures will also be evaluated. The end-of-study visit will occur at Month 12, marking the completion of the participant's involvement in the trial. The expected duration of participant involvement is approximately 12 months, with conditions for early termination including adverse events or withdrawal of consent.

The clinical trial involves the administration of **AGA2118**, a monoclonal antibody, as the experimental medication. AGA2118 is provided in the form of a **solution for injection**. The active substance, AGA2118, is a protein of other origin, and the pharmaceutical form is specifically designed for subcutaneous injection. The maximum daily dose of AGA2118 is 840 mg, with a total maximum dose of 20,160 mg over the treatment period. The treatment is administered over a maximum period of 24 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

The study also includes a **placebo** to match AGA2118, which serves as the comparator treatment. The placebo is designed to mimic the appearance and administration route of the experimental medication, ensuring the study remains double-blind. The placebo is administered via subcutaneous injection, similar to AGA2118, to maintain consistency in the treatment protocol. The use of a placebo allows for the evaluation of the safety, tolerability, and efficacy of AGA2118 in comparison to a non-active treatment, providing a control for assessing the true effects of the experimental medication.

The efficacy of AGA2118 in postmenopausal women with low bone mineral density (BMD) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percent change from baseline to Month 12 in lumbar spine BMD. Secondary endpoints include the percent change from baseline to Months 3 and 6 in lumbar spine, total hip, femoral neck, and one-third distal radius BMD, as well as the percent change from baseline to Month 12 in total hip, femoral neck, and one-third distal radius BMD. Additionally, the percent change from baseline to Months 1, 3, 6, 9, and 12 in [CCI] and the incidence of new clinical fractures (vertebral and nonvertebral) between baseline and Month 12 will be evaluated.

Measurements will be conducted at specified timepoints, including baseline, Months 1, 3, 6, 9, and 12, using appropriate tools and instruments for BMD assessment. The study is designed as a Phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-finding trial. The main objective is to determine the effect of treatment with AGA2118 versus placebo on the percent change from baseline in BMD at the lumbar spine over a 12-month period. The trial will involve healthy, ambulatory, postmenopausal women aged 55 to 80 with a BMD T-score of ≤-2.5 to >-3.5 at the lumbar spine, total hip, or femoral neck.