FDA Accepts Biologic License Application for Biosimilar Denosumab

The FDA accepted a biologic license application for HLX14 (Organon), an investigational biosimilar of denosumab (Prolia/Xgeva; Amgen). Denosumab is a bone anti-resorptive medication that is used to treat osteoporosis and other bone-related disorders, which include individuals with bone metastases from solid tumors, postmenopausal women at high fracture risk, and men at an increased risk of fracture due to osteoporosis or glucocorticoid-induced bone loss.^1,2

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Denosumab is a total human immunoglobin G2 monoclonal antibody that binds to the receptor activator of NF kappa B ligand (RANKL). It binds to RANKL and blocks it from bonding to the receptors, which inhibits the osteoclast maturation and bone resorption, according to the National Library of Medicine.²

The data for the submission is based on head-to-head studies for the proposed biosimilar, including comparative quality analytical studies and 2 clinical studies. The comparative quality analytical study included a 2-part phase 1 study in healthy Chinese adult male patients. Part 1 was open-label and randomized, and part 2 was a double-blinded randomized study. Part 1 also included 2 arms, with a primary end point of pharmacokinetic parameters comparing the biosimilar and Prolia sourced from the European Union. Part 2 included 4 arms, with the primary objective to compare the pharmacokinetic similarity of the biosimilar, US-, EU-, and China-sourced Prolia.¹

The second study was a randomized, double-blind phase 3 clinical trial that compared the efficacy, safety, tolerability, and immunogenicity of the proposed biosimilar with the reference product sourced from the EU in postmenopausal women with osteoporosis at high risk of fracture.¹

There were 478 women included in the study who received treatment 1:1 of either the biosimilar or the reference product. There was a 28-day screening period, 546 day treatment period, and an end-of-study visit on day 547. During the treatment period, individuals received a total of 3 doses of the subcutaneous injection of either drug every 6 months.³

The primary end points were efficacy and pharmacodynamic at 52 weeks. The secondary end points included secondary efficacy and secondary pharmacodynamic at 78 weeks.³

The results showed that both primary end points were met, which included the percentage change in bone mineral density at the lumbar spine and the effect-time curve for percentage change of serum type I collagen C-telopeptide.⁴

In March 2024, the FDA approved 2 denosumab biosimilars from Sandoz, which became the first FDA-approved biosimilars for the reference product to treat all indications. Further, they are also approved as interchangeable for the reference medications, Prolia and Xgeva, for both of their indications.⁵

REFERENCES

1. US FDA Accepts Biologics License Application (BLA) for HLX14, Biosimilar Candidate of PROLIA/XGEVA (denosumab). News release. Organon. October 30, 2024. Accessed October 30, 2024. https://www.businesswire.com/news/home/20241029648679/en/US-FDA-Accepts-Biologics-License-Application-BLA-for-HLX14-Biosimilar-Candidate-of-PROLIAXGEVA-denosumab

2. Hildebrand GK, Patel P, Kasi A. Denosumab. [Updated 2024 Feb 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535388/

3. 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 identification: NCT05352516. Updated September 20, 2024. Accessed October 30, 2024. https://clinicaltrials.gov/study/NCT05352516

4. Phase 3 Comparative Clinical Study of Prolia and Xgeva (denosumab) Biosimilar Candidate HLX14 Met Primary Endpoints. News release. Organon. Aprul 8, 2024. Accessed October 30, 2024. https://www.organon.com/news/phase-3-comparative-clinical-study-of-prolia-and-xgeva-denosumab-biosimilar-candidate-hlx14-met-primary-endpoints/

5. Gallagher A. FDA Approves Two Denosumab Biosimilars for All Indications of Reference Products. Pharmacy Times. March 5, 2024. Accessed October 30, 2024. https://www.pharmacytimes.com/view/fda-approves-2-denosumab-biosimilars-for-all-indications-of-reference-products