EMA Validates Filings for Denosumab Biosimilar Candidate HLX14 for Osteoporosis

The European Medicines Agency has validated the marketing authorization applications (MAAs) for HLX14, an investigational denosumab biosimilar for the reference agents Xgeva and Prolia.¹

Denosumab has received global approval under a variety of trade names and across multiple indications, inducing the management of osteoporosis in postmenopausal women with an increased risk of fracture.

The MAA submissions were based on data from a phase 3 study (NCT05352516) comparing the efficacy, safety, tolerability, and immunogenicity of HLX14 with European Union–sourced reference denosumab in this patient population. In April 2024, Shanghai Henlius Biotech, Inc. and Organon announced that the trial met both its primary efficacy and pharmacodynamic end points.²

Denosumab is a human monoclonal IgG2 antibody that has a high affinity and specificity for RANKL. After binding to the RANK receptor on the surface of osteoclast precursors and osteoclasts, it prevents the interaction of RANKL/RANK. Accordingly, osteoclasts are unable to form, function, or survive, leading to decreased bone resorption in cortical and trabecular bone.³

The randomized, double-blind, international, multicenter, parallel-controlled trial enrolled ambulatory postmenopausal women with osteoporosis between 60 and 90 years of age.⁴ Postmenopausal status was defined as more than 2 years of menopause. Patients were also required to have a bone mineral density (BMD) T-score between –2.5 and –4.0 at the lumbar spine or total hip as assessed by the central imaging vendor at the time of screening; and at least 2 vertebrae in the L1 to L4 region of the lumbar spine and at least 1 hip that were evaluable by dual-energy x-ray absorptiometry.

Patients were excluded from the study for factors including the presence of diseases that may affect bone metabolism; thyroid disorders; serious primary diseases in the cardiovascular, cerebrovascular, or hematopoietic system; rheumatoid arthritis or ankylosing spondylitis; malabsorption syndrome or various gastrointestinal disorders associated with malabsorption; severe renal impairment due to renal disease with a glomerular filtration rate less than 30 mL/min; hepatic diseases; or serious primary diseases in the cardiovascular, cerebrovascular, or hematopoietic system, as judged by the investigator.

Once enrolled, eligible patients were stratified according to body mass index and geographic region, and randomly assigned 1:1 to receive either 60 mg of HLX14 or reference denosumab through subcutaneous injection every 6 months for a total of 3 doses.

The primary end points of this study were the percentage change in BMD at the lumbar spine from baseline to week 52 assessed by central imaging, and area under the effect–time curve for percentage change of serum type I collagen C-telopeptide (s-CTX) from baseline to week 26.

Secondary efficacy end points included the percent change from baseline in BMD at the lumbar spine to week 26, week 52, and week 78; fracture rate from baseline to week 52 and week 78; percent change in BMD at lumbar spine from baseline to week 26 and week 78; percent change in BMD at total hip from baseline to week 26, week 52, and week 78; and percent change in BMD at the femoral neck from baseline to week 26, week 52, and week 78. Secondary pharmacodynamic end points are the relative percent change in s-CTX and relative percent change in serum procollagen type I N propeptide. Both were assessed from baseline to within 7 days prior to the second dose, within 7 days prior to the third dose, and at the end-of-study visit.

References

1. European Medicines Agency (EMA) validates Henlius and Organon filings for Prolia and Xgeva (denosumab) biosimilar candidate HLX14. News Release. Organon. May 23, 2024. Accessed May 24, 2024. https://www.organon.com/news/european-medicines-agency-ema-validates-henlius-and-organon-filings-for-prolia-and-xgeva-denosumab-biosimilar-candidate-hlx14/
2. Phase 3 comparative clinical study of Prolia and Xgeva (denosumab) biosimilar candidate HLX14 met primary endpoints. News Release. Organon. April 8, 2024. Accessed May 24, 2024. https://www.organon.com/news/phase-3-comparative-clinical-study-of-prolia-and-xgeva-denosumab-biosimilar-candidate-hlx14-met-primary-endpoints/
3. Sandoz receives European Commission approval for Wyost and Jubbonti, the first and only biosimilars of denosumab in Europe. News release. Sandoz. May 22, 2024. Accessed May 24, 2024. https://www.globenewswire.com/news-release/2024/05/22/2886160/0/en/Sandoz-receives-European-Commission-approval-for-Wyost-and-Jubbonti-the-first-and-only-biosimilars-of-denosumab-in-Europe.html
4. A study to evaluate the efficacy and safety of HLX14 vs. denosumab Prolia in postmenopausal women with osteoporosis at high risk of fracture. ClinicalTrials.gov. Updated August 8, 2023. Accessed May 20, 2024. https://clinicaltrials.gov/study/NCT05352516