A Phase 3 Study to Compare Biosimilar Denosumab With Prolia®

The study will be divided into three periods: Screening period: up to 35 days; Double-blind treatment period of 12 months; and Open-label, switch-over period of six months.

Five hundred four (504) patients (252 patients in each treatment arm) will be enrolled in this study. All eligible patients will be randomized in the double blind treatment period in a 1:1 ratio to receive either ENZ215 or Prolia® (60 mg) subcutaneously (SC) on Day 1 and Month 6. These participants will complete study at 12 months. A PK sub-study will be conducted in a subset of 120 participants with 60 participants in each arm.

A subset of 120 participants randomised to Prolia arm and who completed 12 months of the double-blind treatment period without any significant safety concerns per the Investigator's discretion will be offered to enroll in the open-label, switch-over extension period. After re-consenting for the open-label, switch-over study, the participants will be re-randomised in a 1:1 ratio to receive either ENZ215 or Prolia® (60 mg) SC at Month 12. These participants will complete the study at Month 18.

Inclusion criteria

• Willing to provide voluntary written informed consent and able to comply with the protocol requirements
• Postmenopausal women aged ≥ 55 and ≤ 85 years globally, except for Spain. In Spain specifically refer to the below criteria:

• Postmenopausal women aged ≥ 75 and ≤ 85 years with LS T-score ≤ -2.5 or
• Postmenopausal women aged ≥ 65 and < 75 years with LS T-score is ≤ -2.5 and a prior fragility fracture (except for hip fracture), including non-exclusionary vertebral fractures
• In both cases (i.e. criteria a and b), it must also be that these are women who present a contraindication for the use of bisphosphonates or who do not tolerate the oral route.
• Body weight ≥ 50 kg and ≤ 90 kg
• Diagnosed with osteoporosis, with absolute BMD consistent with T-scores of ≤ 2.5 and ≥ - 4.0 at the lumbar spine (L1-L4 region) as measured by dual-energy X ray absorptiometry (DXA) at screening
• At least 5 years of postmenopausal status confirmed by follicle-stimulating hormone (FSH) levels at screening
• At least one hip joint and two vertebrae in L1-L4 region evaluable by DXA
• No other clinically significant medical history, vital signs, physical examination, laboratory profiles as deemed by the Investigator or designee that would pose a risk to participant safety or interfere with the study evaluation, procedures or completion

Exclusion criteria

• Known hypersensitivity to denosumab or any of the excipients of the study drug
• Known intolerance to, or malabsorption of calcium or vitamin D supplements
• Previous exposure to Prolia® or any other denosumab biosimilar
• Previous use of oral bisphosphonates:

• Used for 3 or more years cumulatively
• If used for < 3 years, use within the past 12 months prior to screening
• Use of intravenous bisphosphonates within the past 5 years prior to screening. If used more than 5 years prior, patients will be excluded if cumulative use was > 3 years.
• Use of parathyroid hormone or its derivatives, hormone replacement therapy, romosozumab, selective estrogen-receptor modulators, or tibolone or calcitonin within 12 months prior to enrollment Note: occasional use of intravaginal estrogen treatment is not exclusionary
• Any prior use of fluoride or strontium
• Systemic glucocorticoids (≥ 5 mg prednisone equivalent per day or cumulative dose ≥ 50 mg) for more than 10 days within 3 months prior to enrollment (topical and inhaled corticosteroids are allowed)
• Other bone active drugs (i.e. drugs affecting bone metabolism) including heparin, anti epileptics (except for benzodiazepines and pregabalin), antidepressants such as SSRIs, SNRIs, antipsychotics, systemic ketoconazole, adrenocorticotrophic hormone (ACTH), lithium, protease inhibitors, gonadotropin releasing hormone (GnRH) agonists, or anabolic steroids within the past 3 months prior to screening or requiring treatment with these agents during the study.

Note: Please refer to Section 6.11 for a comprehensive list of prohibited medications

• Known sensitivity to drug products derived from mammalian cell lines such as hormones, enzymes, cytokines, bone morphogenic proteins, clotting factors, antibodies, and fusion protein therapeutics. Patients with any known hypersensitivity to complex proteins such as monoclonal antibodies will be excluded.
• History of one severe or more than two moderate vertebral fractures per Genant classification as determined by the central reading center
• History of hip fracture or bilateral hip replacement
• Total hip or femoral neck T-score <-4.0
• History and/or presence of atypical femoral fracture
• Presence of any active healing fracture according to the Investigator's assessment
• History of any transplant or chronic immunosuppression (including patients on immunosuppressive therapy)
• Severe liver dysfunction (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] > 3 times upper limit of normal)
• Positive testing for hepatitis B (hepatitis B virus surface antigen [HbsAg]) or hepatitis C (hepatitis C virus antibody [HCV Ab]) virology
• Known history of human immunodeficiency virus (HIV) infection or positive serology for HIV at screening
• Significantly impaired renal function (determined by glomerular filtration rate of < 45 mL/min/1.73 m2 by the Modification of Diet in Renal Disease (MDRD) formula, as calculated by the central laboratory) or receiving dialysis
• Oral or dental conditions:

• Osteomyelitis or history and/or presence of osteonecrosis of the jaw (ONJ)
• Presence of risk factors for ONJ (e.g., periodontal disease, poorly fitting dentures, poor oral hygiene, invasive dental procedures such as tooth extractions within 6 months prior to screening)
• Active dental or jaw condition which requires oral surgery
• Planned invasive dental procedure
• Major surgery within 8 weeks prior to screening or anticipated major surgery during the study
• Clinically significant leukopenia, neutropenia, or anemia as determined by the Investigator or any other clinically significant medical condition or laboratory abnormality that, in the opinion of the Investigator, would pose a risk to patient safety or interfere with adherence to study procedures, study completion, or the interpretation of study results Note: In case of an abnormal laboratory result which in the opinion of the investigator may be an error, is borderline, or indeterminate for inclusion in the study, the investigator may consider repeating the test once in order to rule out laboratory error.
• Patient with an active infection or history of infection as follows:

• Any active infection for which systemic anti-infectives were used within 4 weeks prior to randomization
• A serious infection defined as requiring hospitalization or intravenous anti infectives within 8 weeks prior to randomization
• Recurrent or chronic infections or other active infection that, in the opinion of the Investigator, might compromise the safety of the patient
• Evidence of any of the following conditions per laboratory test results, medical history, electrocardiogram (ECG), DXA, or X-ray review:

• Uncontrolled hyperthyroidism or hypothyroidism Note: Clinical significance of abnormal TSH values in patients on stable replacement therapy due to hypothyroidism or on anti-thyroid medication should be assessed and discussed with the Medical Monitor.
• History or current hyperparathyroidism or hypoparathyroidism (intact parathyroid hormone levels not within normal range) Note: Mild secondary hyperparathyroidism in the context of vitamin D deficiency may be acceptable upon discussion with the Medical Monitor.
• Vitamin D deficiency defined as 25 (OH) vitamin D level < 20 ng/mL (< 50 nmol/L) Note: Patients can be enrolled if a repeat test (post supplementation) prior to enrollment shows corrected 25 (OH) vitamin D level ≥ 20 ng/mL (≥ 50 nmol/L).
• Current hypocalcemia (albumin-adjusted serum calcium < 8.0 mg/dL [< 2.0 mmol/L]) or hypercalcemia (albumin-adjusted serum calcium > 10.6 mg/dL [> 2.62 mmol/L])
• History of parathyroid surgery
• Any bone or metabolic disease which may affect BMD or interfere with the interpretation of the findings, e.g., osteomalacia, osteogenesis imperfecta, osteopetrosis, achondroplasia, Paget's disease, rheumatoid arthritis, ankylosing spondylitis, Cushing's disease, hyperprolactinemia, or malabsorption syndrome
• Any malignancy, including solid tumors, and hematologic malignancies (except basal cell carcinoma and squamous cell carcinomas of the skin, cervical, or breast ductal carcinoma in situ, that have been completely excised and are considered cured) within the last 5 years
• Known or suspected history of alcoholism (including heavy drinking defined as consuming more than 3 drinks on one day or more than 7 drinks per week) or substance abuse within the past 12 months prior to the first dosing that the Investigator believes would interfere with understanding or completing the study
• Current heavy smoking, defined as smoking 20 or more cigarettes per day.
• Participated in any other clinical study in last 30 days prior to screening
• History and/or presence of significant cardiac disease as per Investigator's discretion, including but not restricted to:

i. History of cardiac arrhythmia or long QT syndrome or ECG abnormalities at screening indicating significant risk for safety (e.g., that required hospitalization, emergency cardioversion, or defibrillation) ii. History and/or presence of myocardial infarction within 6 months before screening iii. History and/or presence of New York Heart Association (NYHA) class III or IV heart failure

• Suspected signs and symptoms of COVID-19/confirmed COVID-19 or with recent history of travel/contact (less than 2 weeks from screening) with any COVID-19 positive patient/isolation/quarantine