Biosimilars of denosumab

Last update: 11 December 2020

Denosumab is a humanized monoclonal antibody that is an inhibitor of the receptor activator of nuclear factor kappa-B ligand (RANKL), which works by preventing the development of osteoclasts which are cells that break down bone. It is used for the treatment of osteoporosis, treatment-induced bone loss, metastases to bone and giant cell tumour of bone.

The originator product, Amgen’s Prolia/Xgeva (denosumab), was approved by the US Food and Drug Administration (FDA) on 1 June 2010. Prolia was approved by the European Medicines Agency (EMA) for the treatment of bone resorption and postmenopausal osteoporosis on 26 May 2010 and Xgeva was approved for the treatment of bone fractures and neoplasm metastasis on 13 July 2011 [1]. Prolia/Xgeva had combined worldwide net sales of US$3.6 billion in 2017, and is a target for biosimilars developers.

The patents on Prolia/Xgeva will expire in the US on 19 February 2025 and will expire in Europe on 25 June 2022, except for France, Italy, Spain and the UK, where they will expire in 2025 [1]. Some of the denosumab biosimilars and non-originator biologicals* approved or in development are presented in Table 1.

*Table 1: Biosimilars and non-originator biologicals of denosumab approved or in development**
Company name, Country	Product name	Stage of development
AryoGen Pharmed, Iran*	-	Phase III trial in osteoporosis expected to be completed in December 2019
BioXpress Therapeutics, Switzerland	-	In pipeline [2]
Henlius, China*	HLX14	China’s NMPA accepted clinical trial application in March 2020 [3] and IND in May 2020 [4]
Intas Pharmaceuticals, India*	-	Phase III trial in osteoporosis expected to be completed in August 2017
JHL Biotech, Taiwan	JHL1266	Phase I trial started in Australia in May 2020 [5]
Neuclone, Australia	-	Preclinical [6]
Oncobiologics, USA	ONS-4010	Preclinical [7]
Samsung Bioepis, South Korea	SB16	Phase I trial initiated in November 2020 [8]
IND: Investigational New Drug; NMPA: National Medical Products Administration (formerly CFDA: China Food and Drug Administration). *See editor’s comment.

China-based Shanghai Henlius Biotech announced that the clinical trial application and investigational new drug application of denosumab copy biological HLX4 on 9 March and 27 May 2020, respectively, had been accepted by the NMPA [3, 4].

Taiwan-based JHL Biotech announced on 18 May 2020 that the first group of subjects has been randomized and dosed in the week of 11 May 2020 in the company’s Australian phase I clinical trial of its candidate denosumab biosimilar (JHL1266) in healthy subjects [5].

Samsung Bioepis announced on 10 November 2020 that it was initiating a phase I clinical trial for SB16, a proposed biosimilar referencing Amgen’s Prolia (denosumab). The trial will be a randomized, double-blind, three-arm, parallel group, single-dose study to compare the pharmacokinetics (PK), pharmacodynamics, safety, tolerability and immunogenicity between SB16 and the reference (from either the EU or US) in healthy male volunteers.

Editor’s comment
European Medicines Agency regulatory requirements ensure the same high standards of quality, safety and efficacy for biosimilars as for originator biologicals, and also include a rigorous comparability exercise with the reference product but they are not universally accepted by regulatory bodies outside of the European Union (EU). It should be noted that ‘copy biologicals’ approved in China, ‘similar biologics’ approved in India and ‘biogenerics’ approved in Iran might not have been authorized if they had been subjected to the strict regulatory processes required for approval of biosimilars in the EU.

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References
1. Derbyshire M. Patent expiry dates for biologicals: 2018 update. Generics and Biosimilars Initiative Journal (GaBI Journal). 2019;8(1):24-31. doi:10.5639/gabij.2019.0801.003
2. BioXpress Therapeutics. Biosimilar pipeline [Page on Internet]. [cited 2018 Feb 23]. Available from: www.bioxpress.com/#!pipeline/c6gz
3. GaBI Online - Generics and Biosimilars Initiative. Denosumab copy biological clinical trial application accepted in China [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Dec 11]. Available from: www.gabionline.net/Biosimilars/News/Denosumab-copy-biological-clinical-trial-application-accepted-in-China
4. GaBI Online - Generics and Biosimilars Initiative. China accepts IND application for denosumab copy biological HLX14 [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Dec 11]. Available from: www.gabionline.net/Biosimilars/News/China-accepts-IND-application-for-denosumab-copy-biological-HLX14
5. GaBI Online - Generics and Biosimilars Initiative. First subjects dosed in Australian phase I study of denosumab biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Dec 11]. Available from: www.gabionline.net/Biosimilars/Research/First-subjects-dosed-in-Australian-phase-I-study-of-denosumab-biosimilar
6. GaBI Online - Generics and Biosimilars Initiative. Denosumab biosimilar being developed in Australia [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Feb 23]. Available from: www.gabionline.net/Biosimilars/News/Denosumab-biosimilar-being-developed-in-Australia
7. Oncobiologics. Product pipeline. [Page on Internet]. [cited 2018 Feb 23]. Available from: www.oncobiologics.com/as_biosimilars-pipeline
8. GaBI Online - Generics and Biosimilars Initiative. Biosimilar advances for Samsung Bioepis [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Dec 11]. Available from: www.gabionline.net/Biosimilars/General/Biosimilar-advances-for-Samsung-Bioepis

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Source: Amgen, EMA, US FDA