A Study Comparing the Pharmacokinetic Similarity of MB09 and EU/US-Sourced Xgeva

A Randomised, Double-blind, Three-arm, Single-dose, Parallel Study to Compare the Pharmacokinetics, Pharmacodynamics, Safety, and Immunogenicity Profile of MB09 (Denosumab Biosimilar) and EU/US-sourced Xgeva® in Healthy Male Volunteers

Randomized, double blind, parallel group, single dose, 3 arm study to investigate and compare the PK, PD, safety and immunogenicity profile of MB09 with EU/US-Xgeva® in healthy male subjects.

During the course of the study, the similarity in pharmacokinetics will be assessed by sampling the levels of drug in the blood, and by comparing these levels among the different administration arms. Pharmacodynamics, safety, tolerability, and immunologic response to the administered drugs will also be evaluated throughout.

The primary PK parameter endpoints are AUC0-last and Cmax for denosumab. The secondary PK endpoints will include all other PK parameters for denosumab, including AUC0-∞, Tmax, CL and t1/2.

For the primary PK Analysis, an analysis of variance (ANOVA) model with treatment and stratification factors as fixed effects will be performed on the natural log transformed values of Cmax, AUC0 last, and AUC0-∞.

Estimates of geometric mean ratios together with the corresponding 90% confidence intervals (CI) will be derived for the comparisons of the PK parameters as follows:

• MB09 versus EU-Xgeva®
• MB09 versus US-Xgeva®
• EU-Xgeva® versus US-Xgeva®

Bioequivalence will be concluded if the 90% CIs for the test to reference ratios of the geometric least square means for AUC0-last and Cmax are entirely contained within the [80%, 125%] interval.

For the PD Analysis, an analysis of covariance (ANCOVA) model with treatment and stratification factors as fixed effects and logged pre-dose sCTX concentrations fitted as a covariate will be performed on the natural log-transformed values of AUEC0 253 and AUIC0 253.

Adverse events will be coded using MedDRA Version 24. All AE data will be presented in a data listing. Treatment-emergent AEs will be summarised by treatment and overall, as well as by severity and relationship to study drug. Serious AEs and AEs leading to discontinuation of study drug will also be presented in the data listings and summarised by treatment and overall.

The incidence of ADA to denosumab and the neutralizing potential and titre of positive ADAs will be reported. All immunogenicity data will be presented in the data listings.

Inclusion Criteria:

1. The subject is a male of any race, between 28 and 55 years of age, inclusive, at screening.
2. The subject has a BMI between 18.5 and 29.9 kg/m2, inclusive, (total body weight between 60 and 95 kg, inclusive) at screening and check-in.
3. The subject is considered by the investigator to be in good general health as determined by medical history, clinical laboratory test results (congenital nonhaemolytic hyperbilirubinemia [eg, Gilbert's syndrome] is acceptable), vital sign measurements (systolic BP ≥90 mm Hg and ≤140 mm Hg, diastolic BP ≥50 mm Hg and ≤90 mm Hg), 12 lead ECG results, and physical examination findings at screening and check in.
4. The subject must use an adequate method of contraception (eg, condom) or be willing to practice sexual abstinence during the study starting from the day of dosing and for 140 days after dosing. The subject must agree to not donating sperm during the study and for at least 140 days after dosing. Participating subject's female partner of childbearing potential should use an additional form of contraception such as an intra uterine device, barrier method with spermicide, oral contraceptive, injectable progesterone, or sub-dermal implant starting from the male partner's day of dosing until at least 140 days after dosing. The female partner of the participating subject should be familiar with the use of the respective contraceptive methods. Intra-uterine devices and hormonal methods for contraception should be used for at least 1 menstruation cycle prior to the administration of study drug.
5. The subject must be able to comprehend and willing to sign an ICF and to abide by the study restrictions. Subjects must have signed an ICF before any study-related procedure or evaluation is performed.

Exclusion Criteria:

1. The subject has had previous exposure to denosumab.
2. The subject has a significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, haematological, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the investigator.
3. The subject has a history of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the investigator.
4. The subject has any current or recent history of infections, including localised infections (within 2 months prior to screening for any serious infection that requires hospitalisation or IV anti-infective or within 14 days prior to screening for any active infection which requires oral treatment).
5. The subject has a dental or jaw disease requiring oral surgery or dental surgery within 6 months prior to study product administration or plans to have dental surgery within 6 months after dosing.
6. The subject has a history of osteomyelitis or osteonecrosis of the jaw requiring suturing within 30 days before dosing, or within 30 days after the last study visit.
7. The subject has a medically significant dental disease or dental neglect, with signs and/or symptoms of local or systemic infection that would likely require a dental procedure during the course of the study. Standard dentistry treatments (eg, dental filling or prophylaxis/cleaning) are allowed.
8. The subject has clinically relevant history of alcoholism, addiction or drug/chemical abuse prior to check in, and/or positive urinary test for alcohol or drugs of abuse at screening or check in.
9. The subject has positive hepatitis panel (HBV and HCV) or positive HIV test. Subjects whose results are compatible with prior immunisation and not infection may be included at the discretion of the investigator.
10. The subject has participated in a clinical study involving administration of an investigational drug (new chemical entity), with dosing in the past 90 days prior to Day 1, or within 5 half-lives of the investigational drug used in the study, whichever is longer.
11. The subject has used or intends to use slow-release medications/products considered to still be active within 30 days prior to check in, unless deemed acceptable by the investigator.
12. The subject has used or intends to use any nonprescription medications/products (except paracetamol [up to 2 g/day] and ibuprofen [800 mg/day]), including vitamins, minerals, supplements (eg, Biotin), and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to check in, unless deemed acceptable by the investigator. Vitamin C, vitamin D, and calcium in daily recommended doses (≤1000 mg elemental calcium and 1000 IU vitamin D based on screening levels of vitamin D) are allowed.
13. The subject has received the COVID-19 vaccine within 14 days before Day 1 or plans to receive a COVID-19 vaccine within 12 weeks after study drug dosing or has positive test for COVID 19 during screening or presence of COVID 19 symptoms within 4 weeks prior to Day -1.
14. The subject has received a live or attenuated vaccine within 3 months prior to screening or has the intention to receive a vaccine during the study. The subject intends to travel to a region where a vaccination will be required due to endemic disease during the study.
15. The subject has used tobacco- or nicotine-containing products within 1 year prior to check-in or anytime during the study, or has a positive cotinine test upon screening or check-in.
16. The subject has donated blood within 60 days prior to dosing, plasma from 14 days prior to screening, or platelets from 42 days prior to dosing.
17. The subject has poor peripheral venous access.
18. Subjects who, in the opinion of the investigator, should not participate in this study.