Pharmacokinetics and pharmacodynamics of the proposed biosimilar denosumab GP2411 and reference denosumab in healthy males

ABSTRACT

Background

This Phase I study compared the pharmacokinetic (PK) and pharmacodynamic (PD) similarity of GP2411 proposed denosumab biosimilar to reference denosumab (a monoclonal antibody for specific pro-resorptive conditions).

Research design and methods

Healthy males (28–65 years, 50–90 kg) were randomized to a single sub-therapeutic subcutaneous injection of 35 mg GP2411, EU-Xgeva® or US-Xgeva®, and followed for 39 weeks. The primary endpoints were AUC_inf, AUC_last, and C_max.

Results

Four hundred ninety-two participants completed treatment. The 90% confidence intervals (CIs) (AUC_inf, AUC_last, and C_max) and 95% CI of the geometric mean ratios of AUEC of % change from baseline in serum CTX were fully contained within the prespecified equivalence margins (0.80, 1.25), demonstrating similarity. The occurrence of treatment-emergent adverse events (TEAEs) with GP2411, EU-Xgeva® and US-Xgeva® was similar (72.9%, 76.0%, and 71.0% of participants, respectively). Most were Grade 1 or 2, <30% were treatment-related, and there was only one TEAE-related study discontinuation. Rates of positive anti-drug antibodies (ADAs) were similar (57.8%, 64.9%, and 69.1% of participants respectively), but immunogenicity was only borderline detectable and of very low magnitude. Ninety-nine percent of positive ADAs were transient.

Conclusion

GP2411 demonstrated similarity with EU-Xgeva® and US-Xgeva® in PK, PD, safety, and immunogenicity in this population.

Clinical trial registration

EudraCT 2019-001651-39

Plain Language Summary

Denosumab is a biological treatment that inhibits bone degradation. It is very effective in conditions characterized by elevated bone degradation, such as osteoporosis in women who have gone through the menopause, and in the treatment of specific bone cancers. However, the cost of the original patented denosumab (‘reference denosumab’) treatment may result in fewer eligible patients receiving denosumab treatment. A biosimilar is highly similar to the original treatment but at a lower price, enabling more patients to benefit.

GP2411 is being developed as a proposed biosimilar to denosumab. This Phase I clinical trial was the first clinical trial to compare GP2411 to the EU and US versions of the reference denosumab (EU-Xgeva® and US-Xgeva®). All three products were given at a dose of 35 mg to 502 healthy males. The dose was lower than the dose that would be used in clinical practice to provide a more sensitive evaluation of similarity. Healthy males were chosen because they have fewer hormonal fluctuations than females, and are considered the most appropriate population for detecting differences in pharmacological effects of denosumab.

The results demonstrate that GP2411 proposed denosumab biosimilar is highly similar to the reference products in absorption, distribution, and elimination, and other outcomes, including bone turnover. The incidence of adverse events was also comparable, most adverse events were very mild, and GP2411 was not associated with a higher rate of immune reactions.

These results support its continued development and GP2411 may, in future, enable more patients to benefit from denosumab treatment.

KEYWORDS:

• Biosimilar
• denosumab
• GP2411
• immunogenicity
• pharmacodynamics
• pharmacokinetics
• phase I
• safety

Declaration of interest

B Vogg, J Poetzl, R El Galta, A Schwebig and S Sekhar are employees of Hexal AG (a Sandoz company). R Fuhr is employee of Parexel International GmbH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have received an honorarium from Expert Opinion on Biological Therapy for their review work. The reviewers have no other relevant financial relationships to disclose.

Ethics statement

All participants provided written informed consent before entering the study. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and with the ICH E6 guideline for good clinical practice. It was also reviewed and approved by the ethics committee of the Land Berlin, Berlin, Germany.

Author contributions

B Vogg contributed to writing, review and editing, conceptualization, software, data curation, methodology, formal analysis and validation. J Poetzl contributed to review and editing, conceptualization, data curation, methodology and validation. R El Galta contributed to review and editing, conceptualization, data curation, methodology, formal analysis and validation. R Fuhr contributed to writing, review and editing and investigation. A Schwebig contributed to writing, review and editing and conceptualization. S Sekhar contributed to review and editing, conceptualization, data curation and methodology. All authors contributed to the article and approved the submitted version.

Acknowledgments

We thank the people who participated in this study. Medical writing assistance was provided by Syneos Health Medical Communications, and funded by Hexal AG, Holzkirchen, Germany. Data from this study was previously presented in summary form at the 2023 ASCO Annual Meeting I, held from 2 to 6 June in Chicago. The corresponding abstract was published in Journal of Clinical Oncology: Vogg B, Poetzl J, El Galta R, Fuhr R, Schwebig A, and Sekhar S. Pharmacokinetics and pharmacodynamics of proposed denosumab biosimilar and reference denosumab in healthy male subjects. DOI: 10.1200/JCO.2023.41.16_suppl.e14500 Journal of Clinical Oncology 41, no. 16_suppl (June 01, 2023) e14500-e14500. Published online May 31, 2023.

Data availability statement

Data from this study are available from the corresponding author on request.

Additional information

Funding

This study was funded by Hexal AG, Holzkirchen, Germany.