Evaluation of Efficacy, Safety, Pharmacokinetics, and Immunogenicity of LY06006 Versus Denosumab in Postmenopausal Osteoporosis: A Randomized, Double-Blind Study
- Trial ID
- 2024-513591-18-00
- Protocol
- LY06006/MRCT-301
Trial statistics
Objectives
The primary objective of this study is to demonstrate **equivalent efficacy** between LY06006 and EU-Prolia in terms of bone mineral density (BMD) in female participants with **postmenopausal osteoporosis**. This is clinically relevant as BMD is a critical indicator of bone strength and fracture risk in osteoporosis management. Additionally, for EU filing, the study aims to demonstrate similar pharmacodynamic (PD) profiles between LY06006 and EU-Prolia, focusing on the bone resorption marker sCTX, which is important for understanding the treatment's impact on bone turnover.
Secondary objectives include:
- Providing additional comparative efficacy data of LY06006 with EU-Prolia in female participants with postmenopausal osteoporosis.
- Providing additional comparative PD data on LY06006 with EU-Prolia in the same population.
- Evaluating the safety of LY06006 compared to EU-Prolia.
- Assessing the pharmacokinetic (PK) profile of LY06006 compared to EU-Prolia.
- Evaluating the immunogenicity of LY06006 compared to EU-Prolia.
These secondary objectives are crucial for a comprehensive understanding of the therapeutic profile of LY06006, including its safety, PK, and immunogenicity, which are essential for ensuring the treatment's overall efficacy and safety in clinical practice.
Participants
The clinical trial involves a total of **70 participants**, specifically targeting female individuals diagnosed with **postmenopausal osteoporosis**. The study population comprises ambulatory postmenopausal women aged between 55 and 90 years, with a specific upper age limit of 75 years for participants in the Czech Republic. Participants are required to have a body weight ranging from 50 kg to 90 kg. The trial exclusively includes female subjects, with no male participants involved. The selection criteria ensure that participants have a bone mineral density (BMD) consistent with a T-score between -2.5 and -4.0 at the lumbar spine, as measured by DXA. Additionally, participants must have at least two lumbar vertebrae in the L1-L4 region and one hip evaluable for BMD measurement. The trial does not involve any vulnerable populations, and participants are expected to be able to read, understand, and provide informed consent. Lifestyle factors such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, parallel-group, active-controlled** study to evaluate the efficacy, safety, pharmacokinetics, and immunogenicity of LY06006 compared with EU-Prolia in postmenopausal women with **osteoporosis**. The trial aims to demonstrate equivalent efficacy between the two treatments in terms of bone mineral density (BMD) and similar pharmacodynamics (PD) in terms of the bone resorption marker sCTX. The study is expected to last approximately 18 months, with an estimated recruitment start date of April 27, 2023, and an estimated end date of June 6, 2025.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, postmenopausal status, and BMD measurements. Follow-up visits will occur at regular intervals to monitor BMD changes, bone turnover markers, adverse events, and other safety parameters. These visits will include assessments such as physical and dental examinations, clinical laboratory tests, and 12-lead ECGs. The end-of-study visit will conclude the participant's involvement, with final evaluations of BMD and other endpoints.
Participant involvement is expected to last for the full duration of the trial, approximately 18 months, unless early termination is warranted. Conditions that may lead to early termination include non-compliance with the study protocol, withdrawal of consent, or the occurrence of adverse events that necessitate discontinuation. The trial will adhere to rigorous scientific and ethical standards to ensure the validity and reliability of the results.
Treatment
The clinical trial involves the administration of two **experimental medications** to evaluate their efficacy, safety, pharmacokinetics, and immunogenicity in postmenopausal women with osteoporosis. The first medication, **Prolia**, is a 60 mg solution for injection in a pre-filled syringe. It contains the active substance **denosumab**, a protein of non-human origin. Prolia is administered via **subcutaneous use**. The dosage regimen involves a maximum daily dose of 60 mg, with a total maximum dose of 180 mg over the treatment period. The treatment period is set for a maximum of 18 months. The product is manufactured by Amgen Europe B.V. and has undergone repacking and labeling modifications for the trial.
The second medication, **LY06006**, is also an injection containing the active substance **denosumab**. This product is provided by Shandong Boan Biotechnology Co., Ltd. and is administered through **subcutaneous use**. Similar to Prolia, LY06006 has a maximum daily dose of 60 mg and a total maximum dose of 180 mg over the treatment period, which is also set for a maximum of 18 months. LY06006 serves as the test product in this comparative study.
Both medications are evaluated in a randomized, double-blind, parallel-group, active-controlled study. The trial aims to demonstrate equivalent efficacy between LY06006 and EU-Prolia in terms of bone mineral density (BMD) in female participants with postmenopausal osteoporosis. Additionally, for EU filing, the study seeks to demonstrate similar pharmacodynamics (PD) between the two medications concerning the bone resorption marker sCTX. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the equivalence of LY06006 and EU-Prolia in terms of bone mineral density (BMD) in female participants with postmenopausal **osteoporosis**. The primary objective is to demonstrate equivalent efficacy between the two treatments. Secondary endpoints include the percentage change from baseline (%CfB) in lumbar spine BMD at Month 6, total hip BMD at Months 6 and 12, and femoral neck BMD at Months 6 and 12. Additionally, the trial will assess %CfB in the bone resorption marker sCTX at various timepoints, including Months 0.5, 1, 2, 3, 6, 9, and 12, as well as %CfB in sP1NP at Months 1, 6, and 12.
Measurements will be collected using dual-energy X-ray absorptiometry (DXA) for BMD assessments. The trial will also monitor serum drug concentrations and the incidence of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) at baseline and at specified intervals throughout the study. Safety assessments will include adverse events (AEs), serious adverse events (SAEs), vital signs, physical and dental examinations, clinical laboratory tests, 12-lead ECGs, and injection site reaction assessments. These parameters will be measured at baseline and at various timepoints up to Month 18, ensuring a comprehensive evaluation of the treatment's efficacy and safety profile.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Participant is ≥ 55 to ≤ 90 years of age inclusive, (upper age limit of 75 years inclusive, for participants in Czech Republic only), at the time of signing the informed consent.
- Participant is an ambulatory postmenopausal woman (defined as lack of menstrual period for at least 12 months prior to Screening Visit, for which there is no other obvious pathological or physiological cause). - Serum FSH test can be done at the Screening Visit in case of uncertainty (for participants to be enrolled in the study in Bulgaria, FSH test is mandatory. FSH levels should be above the cut-off for postmenopausal women, as provided by the central laboratory). - Female participants who underwent bilateral oophorectomy (with or without hysterectomy) at least 6 weeks prior to the Screening Period are eligible to participate.
- Participant is diagnosed with osteoporosis, with absolute BMD consistent with a T-score of ≤ -2.5 and ≥ -4.0 at the lumbar spine (L1-L4 region) as measured by DXA at the Screening Visit.
- Participant has at least two lumbar vertebrae in L1-L4 region and one hip evaluable by DXA for BMD measurement at the Screening Visit.
- Participant has body weight ≥ 50 kg and ≤ 90 kg at Screening.
- Participant is able to read and understand, and willing to provide signed informed consent as described in Appendix 1, Section 10.1.3 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
Exclusion Criteria
- Participant has a history of any severe or more than two moderate vertebral fractures as determined by central reading of lateral spine X-ray at Screening Visit.
- Participant has any malignancy (except fully resected cutaneous basal cell or squamous cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years.
- Participant has known history of liver cirrhosis.
- Participant has known history of hepatitis B, hepatitis C, or HIV infection, or an active infection including, but not limited to SARS-CoV-2, tests positive for hepatitis B (positive HBsAg, positive anti-HBc with negative anti-HBs), hepatitis C (hepatitis C antibody), or HIV antibody during the Screening Period.
- Participant has oral or dental conditions: a. Prior history or current evidence of osteomyelitis or osteonecrosis of the jaw. b. Active dental or jaw condition which requires oral surgery. c. Invasive dental procedure planned during the study or within the past 6 months (e.g., tooth extraction, dental implants, oral surgery). d. Non-healed dental or oral surgery. e. Active periodontal disease. f. Poor oral hygiene.
- Participant has a history of major surgery within 8 weeks prior to the Screening Period or planned, anticipated major surgery during the study.
- Participant has a history and/or presence of significant cardiac disease or ECG abnormalities indicating significant risk for participating in the study as judged by the Investigator.
- Participant shows contraindications to denosumab therapy (e.g., hypocalcemia), or calcium or vitamin D supplementation before starting study intervention administration.
- Participant requires ongoing use of any osteoporosis treatment (other than calcium and vitamin D supplements).
- Participant has a history and/or presence of hip fracture.
- Participant has a history and/or presence of atypical femur fracture.
- Participant presents with any active healing fracture, per assessment of the Investigator.
- Participant has a history of bilateral hip replacement (unilateral is allowed if the other hip is evaluable by DXA).
- Participant has history and/or presence of osteonecrosis of the external auditory canal.
- Evidence of any of the following conditions which may affect BMD or interfere with the interpretation of the findings: a. Participant has a history of bone disease e.g., osteomalacia, osteopetrosis, Paget's disease, or osteogenesis imperfecta. b. Participant has a history of metabolic or other endocrinologic diseases such as Cushing's disease, hyperprolactinemia, hypopituitarism, acromegaly, malabsorption syndrome (or any gastrointestinal disorders associated with malabsorption, e.g., Crohn's disease and chronic pancreatitis). c. Participant has a history of chronic inflammatory diseases, obvious sclerosis, osteophytosis, severe scoliosis, or other degenerative changes due to other co-morbidities. d. Participant has a history or current hyperparathyroidism or hypoparathyroidism. Note: Mild non-clinically significant secondary hyperparathyroidism may be acceptable upon discussion with the Medical Monitor. e. Participant has current uncontrolled hyperthyroidism or hypothyroidism. Note: Participants with hypothyroidism who are on stable thyroid hormone replacement therapy may be allowed per the following criteria: • If TSH level is within normal range, the participant is eligible. • If TSH level is elevated (> upper limit of normal and ≤ 10.0 µIU/mL) and serum free T4 is within normal range, the participant is eligible. • If a marginally low TSH level results from therapy , the participant may be enrolled after discussion with the Medical Monitor. Note: 2) If TSH is marginally out of normal range, serum free T4 is within normal range, and there are no plausible medical conditions resulting in the abnormal TSH level, the participant may be enrolled with the approval from the Medical Monitor. f. Participant has other disease conditions where there is bone/joint involvement (e.g., rheumatoid arthritis, ankylosing spondylitis, gout, multiple myeloma, achondroplasia, bone metastases, renal osteodystrophy, osteomyelitis).
- Participant has hypocalcemia (defined as albumin adjusted serum calcium level < 2.0 mmol/L [8.0 mg/dL]) or hypercalcemia (defined as albumin adjusted serum calcium levels >2.62 mmol/L [10.50 mg/dL]).
- Participant has vitamin D deficiency (defined as 25-hydroxy vitamin D level < 20 ng/mL [< 50 nmol/L]). Note: Oral replenishment of vitamin D is permitted at the discretion of the Investigator and in accordance with local standard of care during the Screening Period. Participants can be enrolled if a repeat test (post supplementation) prior to enrollment shows corrected 25-hydroxy vitamin D level ≥ 20 ng/mL (≥ 50 nmol/L).
- Use of any of the below medications that can affect BMD: a. Denosumab used at any time prior to Screening Visit. b. Oral bisphosphonates at any dose for osteoporosis treatment: • Used for > 3 years cumulatively at Screening Visit. • At any dose used within 1 year prior to Screening Visit (if ≤ 3 years of use cumulatively). c. Intravenous bisphosphonate at any dose within 5 years prior to Screening Visit. d. PTH or PTH analogues at any dose within 2 years prior to Screening Visit. e. Systemic HRT (oral or transdermal estrogen), SERMs, tibolone, aromatase inhibitors, or androgens at any dose within 1 year prior to Screening Visit. Note: Exceptionally, non-systemic vaginal estrogen treatment is permitted. f. Calcitonin, or its derivatives, and calcimimetics (such as cinacalcet or etelcalcetide) at any dose within 12 months prior to Screening Visit. g. Calcitriol, paricalcitol, alfacalcidol, or eldecalcitol within 3 months of the Screening Visit. h. Fluoride or strontium at any dose at any time prior to Screening Visit. i. Romosozumab or cathepsin K inhibitors received at any time prior to Screening Visit. j. Systemic glucocorticoids (≥ 5 mg prednisone or equivalent per day for more than 10 days or cumulative ≥ 50 mg) within 3 months prior to Screening Visit. k. If the participant is currently on proton pump inhibitors (PPIs) and will continue to use PPIs while on the study, the total of the chronic use of PPIs exceeds 24 months or had past use of PPIs for more than 24 month AND within 3 months prior to Screening Visit. If the participant is currently on proton pump inhibitors (PPIs) and will continue to use PPIs while on the study, the total of the chronic use of PPIs exceeds 24 months or had past use of PPIs for more than 24 month AND within 3 months prior to Screening Visit.
- Participant is receiving or has received another investigational product within 1 month or 5 half-lives of the other investigational product, whichever is longer, before study intervention administration in this study.
- Participant has DXA measurements where: a. Height, weight, or girth measurements may preclude accurate DXA measurements in the Investigator’s opinion. b. BMD absolute value is consistent with a T-score < -4.0 at the total hip or femoral neck.
- Participant has severe renal impairment (defined as participant in dialysis or with an eGFR < 30 mL/min per MDRD formula).
- Participant has inadequate hepatic function (ALT and/or AST ≥ 2 × ULN).
- Participant presents with clinically significant leukopenia, neutropenia, or anemia as judged by the Investigator.
- Participant has a known intolerance to calcium or vitamin D supplements.
- Participant has a history of prescription drug abuse or any illicit drug use within 6 months prior to Screening Visit.
- Participant has a history of alcohol abuse (defined as consuming more than 3 drinks on any day or more than 7 drinks per week) according to medical history within 6 months prior to Screening Visit.
- Participant is a smoker or has used nicotine and nicotine-containing products within 12 months of Screening Visit.
- Participant has a known sensitivity to mammalian cell-derived drug products and/or a history of hypersensitivity to any of the ingredients of study interventions.
- Participant is immunosuppressed for any reason.
- Participant has any other conditions including clinically significant medical conditions/disorders/diseases, psychiatric status, or laboratory abnormalities that in the opinion of the Investigator might interfere with the participant’s ability to participate in the study, would pose a risk to the participant’s safety, or interfere with the study evaluation, procedure, or completion.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Bulgaria | Not Recruiting | 27 Apr 2023 | 6 |
 Czechia | Not Recruiting | 27 Apr 2023 | 24 |
 Poland | Not Recruiting | 27 Apr 2023 | 430 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Prolia 60 mg solution for injection in pre-filled syringe | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS USE | 60 | 18 | PRD3618669 |
LY06006 | Test | INJECTION | SUBCUTANEOUS USE | 60 | 18 | PRD11581650 |