Biosimilars of trastuzumab

Biosimilares/General | Posted 19/09/2014 0 Post your comment

Last update: 15 January 2021

Trastuzumab is a monoclonal antibody that binds to and inactivates the human epidermal growth factor receptor 2 (HER2)/neu receptor. In some cancers, notably certain types of breast cancers, HER2 is over-expressed, and causes cancer cells to reproduce uncontrollably. Trastuzumab is therefore used to treat HER2 positive (HER2+) breast cancers.

The originator product, Roche’s Herceptin (trastuzumab), was approved by the US Food and Drug Administration (FDA) in September 1998 and by the European Medicines Agency (EMA) in August 2000 [1]. Herceptin had 2018 worldwide sales of CHF 7.0 billion (US$7.5 billion).

The patents on Herceptin will expire in the US in June 2019 and expired in Europe in July 2014 [1]. Some of the trastuzumab biosimilars approved or in development are presented below, see Table 1.

*Table 1: Biosimilars and non-originator biologicals of trastuzumab approved or in development**
Company name, Country	Product name	Stage of development
Actavis (Allergan)/Amgen/Synthon, USA/The Netherlands	Kanjinti (ABP 980)	Approved by EMA in March 2018 [2]. Submitted to FDA for approval in July 2017. Rejected by FDA in June 2018. Approved by Health Canada in October 2020 [3].
Alteogen/Cristalia, South Korea/Brazil*	ALT-L2	Phase I. Gained patent for SC version (ALT-LS2) in March 2019 [4].
Anke Biotechnology, China*	-	Phase III
Apotex (Apobiologix), Canada	-	In pipeline
AryoGen Pharmed, Iran*	AryoTrust	Approved by Iran’s FDO
Biocad, Russia*	HERtiCAD (BCD-022)	Non-originator biological approved in Russia in January 2016. Approved in Bosnia and Herzegovina in March 2020 [5].
Biocon/Mylan, India*/USA	CanMab/Hertraz	‘Similar biologic’ approved in India in October 2013 [6].
Biocon/Mylan, India*/USA	Hercules/Ogivri (US) (MYL-1401O) Zedora	Approved by FDA [7] and Brazil’s ANVISA [8] in December 2017. Approved by EMA in October 2018 [2].
BioXpress Therapeutics, Switzerland	-	In pipeline
Celltrion /Teva Pharmaceuticals Industries, South Korea/ Israel	Herzuma (CT-P6)	Marketed in South Korea following approval in January 2014 [9]. Collaborating with Teva in US and Canada. Approved by EC in February 2018 [2]. Submitted to Japan’s MHLW for approval in April 2017. Approved by Australia's TGA in August 2018 [9], by FDA in December 2018 [7] and by Japan's MHLW for 3-cycle method [10] and by Health Canada [3] in September 2019. Positive results from Phase Ib/II trial when used with pembrolizumab (Keytruda) and chemotherapy.
Daiichi Sankyo/Amgen [21], Japan/USA	[trastuzumab biosimilar 2]	Approved by Japan's MHLW in September 2018 [10]. Launched in Japan in November 2018.
Dr Reddy's Laboratories, India*	Hervycta	‘Similar biologic’ launched in India in July 2018 [6].
EirGenix, Taiwan	EG12014	Positive data from phase I bioequivalence trial reported in May 2017
Genor Biopharma, China*	-	Phase III
Hanwha Chemical, South Korea	HD201	Phase I trial in Europe as of 2013
Oncobiologics/Viropro, USA	ONS-1050	Biosimilar in development; one of six monoclonal antibody biosimilars for which the companies are collaborating. Phase I trial expected to start in 2018.
Pfizer/Hospira, USA	Trazimera (PF‑05280014)	Approved by FDA in March 2019 [7]. Approved by EC in July 2018 [2]. Approved by Japan's MHLW in September 2018 [10]. Approved by Australia's TGA in August 2019 [9].
PlantForm, Canada	-	Launch, in partnership with a pharmaceutical company, in world markets expected in 2016
Prestige Biopharma, Singapore	HD201	Phase I trial in EU completed in 2014 and Phase III trial ongoing
Samsung Bioepis (Biogen/Samsung)/Daewoong Pharmaceutical/Merck (MSD), South Korea/USA	Ontruzant (EU/US)/ Samfenet (Korea) (SB3)	Approved in Europe in November 2017 [2]. Approved by Korea’s MFDS on 9 November 2017 [11] and launched in March 2018. Approved by FDA in January 2019 [7]. Ontruzant launched in US in April 2020 [12] and in Brazil in September 2020 [13].
Shanghai CP Guojian Pharmaceutical, China*	Saiputing	Approved by CFDA in June 2014, but then withdrawn.
Shanghai Henlius Biotech (Fosun Pharma), China*	Zercepac (HLX02)	Phase III trial in breast cancer started in March 2017. Expected to be completed in August 2021. Positive results reported in November 2018. Approved by EC in July 2020 [2].
Stada Arzneimittel/Gedeon Richter, Germany/Hungary	-	Collaborating on biosimilars of trastuzumab and infliximab. Richter signed technology transfer and in-licensing agreement with DM Bio in October 2016
Tanvex BioPharma, Taiwan*	TX05	Phase III trial and extension in Hungary ongoing as of February and August 2018, respectively.
EEA: European Economic Area, this area includes the 28 European Union member states, plus Iceland, Liechtenstein and Norway; EU: European Union, EMA: European Medicines Agency; FDA: US Food and Drug Administration; CFDA: China Food and Drug Administration; FDO: Food and Drug Organization (Iran’s National Regulatory Authority); HER2+: human epidermal growth factor receptor 2 positive; MHLW: Japan’s Ministry of Health, Labour and Welfare; MFDS: Ministry of Food and Drug Safety; MSD: Merck Sharp & Dohme; ODAC: Oncologic Drugs Advisory Committee; TGA: Therapeutic Goods Administration. *See editor’s comment

Actavis/Amgen had submitted application for approval for its trastuzumab biosimilar, Kanjinti, to FDA but was rejected in June 2018, requesting ‘additional technical information’; Kanjinti has received approval by Health Canada in October 2020 [3].

Biocad’s trastuzuma non-originator biologiacl Herticad was approved in Bosnia and Herzegovina in March 2020 [5].

Biocon/Mylan had a tough route to approval in Europe. They originally submitted their marketing application to the EMA for approval of their trastuzumab biosimilar back in August 2016. But they withdrew their application from EMA as part of ‘procedural requirements’ after implementation of corrective and preventive actions and re-inspection of Biocon’s ‘Drug Product facility’ in Bangalore were required before a good manufacturing practice (GMP) compliance certificate would be issued for the site. The pair then re-submitted their application to EMA in December 2017 and finally received a positive CHMP recommendation for their trastuzumab biosimilar, Ogivri, in October 2018. Biocon/Mylan received approval for their trastuzumab biosimilar, Ogivri (trastuzumab-dkst) from FDA [7] and Brazil’s ANVISA [8] in December 2017, also by EMA in October 2018 [2].

Celltrion received approval for its trastuzumab biosimilar, Herzuma, from the Korean Ministry of Food and Drug Safety (MFDS) in January 2014 [11]. The company also received EMA approval in December 2017 [2] and FDA approval in December 2018 [12] for Herzuma (CT‑P6). Celltrion has further received approval by Japan's MHLW for 3-cycle method [10] and by Health Canada in September 2019 [3]. A phase Ib/II study has shown that Herzuma is effective in patients with human epidermal growth factor receptor 2 positive (HER2+) gastric cancer when used in combination with the antibody treatment pembrolizumab (Keytruda) and chemotherapy.

Pfizer received approval by EC for its trastuzumab biosimilar Trazimera in July 2018 [2], by Japan’s MHLW in September 2018 [10], by FDA in March 2019 [7] and by Australia’s TGA in August 2019 [9].

Samsung Bioepis, a joint venture between South Korean electronics giant Samsung and biotechnology company Biogen, received marketing approval for its trastuzumab biosimilar, Ontruzant (EU/US) from the EMA in November 2017 [2] and from the FDA in January 2019 [7], and its Samfenet (SB3) was approved by MFDS Korea in November 2017. Ontruzant was launched in US in April 2020 [12] and in Brazil in September 2020 [13].

Shanghai Henlius’ trastuzumab biosimilar, Zercepac, was approved by EC in July 2020 [15].

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 ‘non-originator biologicals’ approved in Russia and Taiwan, ‘similar biologics’ approved in India, ‘biogenerics’ approved in Iran and ‘copy biologicals’ approved in China 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

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Source: EMA, US FDA

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