Pharmacokinetic, Safety and Immunogenicity Phase I Study of HLX14 Versus Prolia® in Healthy Male Subjects

A Randomised, Parallel, Single-Dose, Subcutaneous Injection, Phase I Clinical Study Of HLX14 Versus Prolia® (Denosumab) In Chinese Healthy Adult Male Subjects For Comparison In Pharmacokinetic Characteristics, Safety, And Immunogenicity

Part I of the study： This is a randomised, single-dose, subcutaneous injection, parallel study designed to compare the PK of HLX14 and EU-sourced Prolia® in healthy Chinese adult male subjects, and to assess the safety, tolerability, and immunogenicity of these 2 drugs.

Part II of the study： This is a randomised, double-blind, four-arm, single-dose, subcutaneous injection, parallel-controlled study to evaluate the PK, PD, safety, tolerability, and immunogenicity between-group following a single subcutaneous injection of HLX14 or US, EU, CN-sourced Prolia®.

Study Overview

• Status: Completed
• Conditions: Healthy Male Volunteers
• Intervention / Treatment: Drug: HLX14; Drug: EU-Prolia®; Drug: US-Prolia®; Drug: CN-Prolia®

• Study Type: Interventional
• Enrollment (Actual): 252
• Phase: Phase 1

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Huashan Hospital,Fudan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Males aged> 28 and ≤ 65 years;
2. Body weight ≥ 50 kg, body mass index (BMI) = body weight (kg)/body height2 (m2), BMI ≥ 19 and ≤ 26 kg/m2;
3. With no disease history, or with abnormal prior medical history which has no effect on the trial as judged by the physician;
4. Normal or abnormal without clinical significance in physical examination, vital signs, ECG, chest imaging, clinical laboratory test, etc.;
5. Before the trial, sign the informed consent form (ICF) and have a full understanding of trial content, process, and possible adverse events (AEs); be able to complete the study as per protocol requirements.

Exclusion Criteria:

1. With a history of allergy to study drugs, calcium, and/or vitamin D, or with a history of allergy to drugs or others not suitable for participating in this study as judged by the investigators;
2. With the following clinically significant diseases (including but not limited to digestive system, kidney diseases, liver diseases, nervous diseases, blood system, endocrine system, tumor, respiratory system, immune diseases, mental diseases, cardiovascular and cerebrovascular diseases, or any condition that may affect bone metabolism);
3. With a history of upper respiratory tract infection and other acute infections within 2 weeks prior to screening;

4. Occurred or suffering from osteomyelitis or ONJ (Osteonecrosis of the jaw) previously.

   The dental or jaw disease that is active, requiring oral surgery; or dental or oral surgery wounds have not healed; or planned for invasive dental surgery during the study.

5. Occurrence of fracture or bone-related surgery within 6 months prior to screening;
6. With rash, scar, tattoo, etc. at administration site that may affect drug absorption;
7. Blood donation or massive blood loss (> 450 mL) within 3 months prior to screening;
8. Use of any prescription drugs, over-the-counter (OTC) drugs, vitamin products, or traditional Chinese medicines within 28 days prior to screening;
9. Participation in any drug clinical trials and use of any investigational/comparator drugs within 3 months prior to screening;

10. Administration of the following drugs affecting bone metabolism:

    1. Administration history of denosumab or its biosimilar products, romosozumab or its biosimilar products, cathepsin K inhibitors, diphosphonates, fluorides, or stronitum;
    2. Administration of the following within 12 months before screening: parathyroid hormone or its derivatives, hormone replacement therapy (HRT), selective estrogen receptor modulators (SERM), tibolone, anabolic steroids, testosterone, androgen, and gonadotropin-releasing hormone agonists (GnRH-a);
    3. Administration of any prescription drug or OTC drug within 6 months or 10 half-lives of drug elimination (whichever is the longer) before screening that may have impact on the objectives of the study at the discretion of the investigator, including but not limited to heparin, warfarin, anticonvulsants (excluding benzodiazepine), systemic ketoconazole, adrenocorticotropic hormone (ACTH), cinacalcet, aluminum, lithium, protease inhibitors (PI), methotrexate (MTX), calcitonin, calcitriol, diuretics, and glucocorticoids for oral administration or injection (daily administration of ≥ 5 mg prednisone or equivalent drugs for more than 10 days);
11. Use of any biological products (excluding vaccine) or monoclonal antibodies within 6 months prior to screening;
12. Vaccination within 1 month prior to screening;
13. With a history of alcohol abuse (14 units of alcohol per week: 1 unit = 285 mL of beer, 25 mL of spirit, or 100 mL of wine), or positive for alcohol breath test;
14. With a history of substance abuse or drug abuse, or positive for drug screen;
15. Positive for tobacco screen;
16. With significant changes in physical activity within 6 months prior to screening, or not agree to abstain from strenuous physical exercise during the trial;
17. Positive for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antibody, or treponema pallidum antibody (TPPA);
18. Abnormal serum calcium level (beyond the laboratory reference range) during the screening;
19. Ear temperature > 37.5 °C during the screening period; and/or sitting systolic blood pressure (SBP) > 140 mmHg or < 90 mmHg, and/or diastolic blood pressure (DBP) > 90 mmHg or < 50 mmHg; and/or pulse rate > 100 beats/min or < 50 beats/min during the screening.
20. Clinically significant abnormal ECG or QTcF > 450 ms during screening, or with a prior history of clinically significant abnormal ECG;
21. Unwilling to take adequate contraceptive measures during the study.
22. Subjects who, in the opinion of the investigators, are not eligible to participate in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part I: HLX14 group; Part I: HLX14 are given subcutaneous injection at a single dose of 60 mg.	Drug: HLX14; healthy volunteers receive HLX14 (60mg) once
Active Comparator: Part I: EU-Prolia® group; Part I: EU-Prolia® are given subcutaneous injection at a single dose of 60 mg.	Drug: EU-Prolia®; healthy volunteers receive EU-Prolia® (60mg) once
Experimental: Part II: HLX14 group; Part II: HLX14 are given subcutaneous injection at a single dose of 60 mg.	Drug: HLX14; healthy volunteers receive HLX14 (60mg) once
Active Comparator: Part II: EU-Prolia® group; Part II: EU-Prolia® are given subcutaneous injection at a single dose of 60 mg.	Drug: EU-Prolia®; healthy volunteers receive EU-Prolia® (60mg) once
Active Comparator: Part II: US-Prolia® group; Part II: US-Prolia® are given subcutaneous injection at a single dose of 60 mg.	Drug: US-Prolia®; healthy volunteers receive US-Prolia® (60mg) once
Active Comparator: Part II: CN-Prolia® group; Part II: CN-Prolia® are given subcutaneous injection at a single dose of 60 mg.	Drug: CN-Prolia®; healthy volunteers receive CN-Prolia® (60mg) once

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
AUC(0-t)	Area under the serum concentration-time curve from time 0 to the last concentration-quantifiable time t of denosumab	from 0 to day 274
Cmax	Maximum serum concentration following administration of denosumab	from 0 to day 274
AUC0-inf	Area under the serum concentration-time curve from time 0 to infinity	from 0 to day 274

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tmax	Time to reach maximum serum concentration following administration	from 0 to day 274
CL/F	Total clearance	from 0 to day 274
λz	Apparent terminal elimination rate constant	from 0 to day 274
t1/2	Elimination half life	from 0 to day 274
Vd/F	Apparent volume of distribution	from 0 to day 274
%AUCex	Area extrapolated from time to infinity as a percentage of total AUC0-inf	from 0 to day 274
MRT	Mean residence time	from 0 to day 274
AUC0-28d and AUC0-112d	Area under the drug concentration-time curve from day 0 to day 28 (4 weeks) and from day 0 to day 112 (16 weeks)	from 0 to day 112
AUEC0-t	Area under the effect-time curve from time zero to last time of quantifiable concentration of serum CTX1	from 0 to day 274
Imin	Minimum observed concentration of serum CTX1	from 0 to day 274
Imax	Maximum percent inhibition of serum CTX1	from 0 to day 274
Tmin	Time to reach Imin of serum CTX1	from 0 to day 274

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
AEs and SAEs	Adverse events and serious adverse events	from 0 to day 274
Physical examination		from 0 to day 274
Vital signs		from 0 to day 274
Injection site reactions		from 0 to day 274
Laboratory tests (haematology, serum chemistry, and urinalysis)		from 0 to day 274
12-lead ECG		from 0 to day 274
ADA and NAb	Positive rate of anti-drug antibody, including neutralising antibody	from 0 to day 274

Collaborators and Investigators

• Sponsor: Shanghai Henlius Biotech
• Investigators: Principal Investigator: Jing Zhang, Doctor, Huashan Hospital

Publications and helpful links

General Publications

• Li N, Chu N, Zhu L, Wu X, Wei Q, Wang J, Hu X, Yu H, Wang Q, Yuan W, Huang K, Zhang J. Pharmacokinetics, pharmacodynamics, safety, and immunogenicity of HLX14 versus reference denosumab in healthy males: A randomized phase I study. Clin Transl Sci. 2024 Dec;17(12):e70089. doi: 10.1111/cts.70089.
• American Society for Clinical Pharmacology and Therapeutics. Clin Pharmacol Ther. 2022 Mar;111 Suppl 1:S5-S80. doi: 10.1002/cpt.2521. No abstract available. Erratum In: Clin Pharmacol Ther. 2022 Apr 17:1344. doi: 10.1002/cpt.2599.

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2020
• Primary Completion (Actual): September 12, 2023
• Study Completion (Actual): September 12, 2023

Study Registration Dates

• First Submitted: August 27, 2020
• First Submitted That Met QC Criteria: August 27, 2020
• First Posted (Actual): September 1, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 16, 2025
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: HLX14-001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No