Biosimilars of rituximab

Biosimilars/General | Posted 27/02/2015 post-comment1 Post your comment

Last update: 8 January 2021

Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of immune system B cells. Rituximab destroys B cells and is therefore used to treat diseases that are characterized by excessive number of B cells, overactive B cells or dysfunctional B cells. This includes many lymphomas, leukaemias, transplant rejection and autoimmune disorders.

Rituximab V13D29

The originator product, Roche’s MabThera/Rituxan (rituximab), was approved by the US Food and Drug Administration (FDA) in November 1997 and by the European Medicines Agency (EMA) in June 1998 [1]. MabThera/Rituxan had sales of CHF 7.3 billion (Euros 6.4 billion) in 2016, before the advent of biosimilars, see Table 1.

The patents on MabThera/Rituxan expired in the US in September 2016 and in Europe in February 2013 [1]. Some of the rituximab biosimilars and non-originator biologicals* approved or in development are presented in Table 1.

Table 1: Biosimilars and non-originator biologicals* of rituximab approved or in development
Company name, Country Product name Stage of development
Amgen, USA ABP 798 Biosimilar in active development, according to Amgen’s Form 10-K for 2013. One of four biosimilars for oncology indications that Amgen is developing in collaboration with Actavis [2]. Phase III study in NHL expected to be completed in December 2018. Positive phase I/III trial results reported in January 2019. Accepted for review by FDA in December 2019 [3].
Apotex (Apobiologix), Canada - In pipeline
AryoGen Pharmed, Iran* Zytux Approved by Iran’s FDO in May 2015 [4]
Biocad, Russia* AcellBia/Usmal (BCD-020) Non-originator biological (AcellBia) approved in Russia in April 2014. Similar biotherapeutic product (Usmal) approved in Bolivia and Honduras in June 2017. ‘Similar biologic’ (Acellbia) recommended for approval in India in July 2017. Approved in Bosnia and Herzegovina in March 2020 [5].
BioXpress Therapeutics, Switzerland - In pipeline
Boehringer Ingelheim, Germany BI 695500 Phase I and III trials expected to be completed in June and August 2015, respectively, but halted in October 2015
Cadila Pharmaceuticals, India Ritucad Launched in India in July 2020 [6]
Celltrion/Hospira (Pfizer), South Korea/USA Truxima/Blitzima/ Ritemvia/Rituzena (previously Tuxella) (CT‑P10) Phase I trial completed. Phase III trials for RA and lymphoma expected to be completed in January 2017 and February 2017/March 2018, respectively. Collaborating with Teva in Canada and the US. Approved by South Korea's MFDS in November 2016 [7]. Truxima approved by EC in February 2017. Blitzima, Ritemvia and Rituzena (previously Tuxella) approved by EC in July 2017 [8]. Approved by Australia’s TGA in April 2018 [9]. WHO announced prequalitfication in May 2020 [10].
Celltrion/Teva Pharmaceutical Industries, South Korea/Israel CT‑P10 Approved by FDA in November 2018 [11]. Positive phase III results in lymphoma reported in December 2018. Launched in Brazil in May 2020 [12].
Dr Reddy’s Laboratories, India* Reditux Reditux marketed in Bolivia, Chile, India and Peru [12, 13]
Hetero Group, India* Maball ‘Similar biologic’ approved in India in August 2015 [13]
iBio, USA - Rituximab produced in non-transgenic green plants. Alliance made with GE Healthcare in 2012. Deal made with CC-Pharming for copy biological in China in October 2019.
Innovent Biologics/Eli Lilly, China*/USA Halpriza (IBI301) Approved by China's NMPA in October 2020 [14] 
Intas Biopharmaceuticals, India* MabTas ‘Similar biologic’ approved in India in February 2013 [13]
JHL Biotech, Taiwan* JHL1101  Phase I PK/PD trial started in February 2016. First patient dosed in a European trail of JHL1101 in March 2017. Made deal with Sanofi giving Sanofi rights to commercialize JHL1101 in China.
mAbxience/Laboratorio Elea, Spain/Argentina* Novex (RTXM83) Medicamento biológico similar approved in Argentina in October 2013 Phase III trial in Non-Hodgkins Lymphoma expected to be completed in July 2017
Mabion/Mylan, Poland/India* Mabion CD20 Phase III trial in lymphoma expected to be completed in June 2016. Agreement signed with Mylan to commercialize Mabion CD20 in EU and non-EU Balkan states in November 2016. Submitted to EMA for approval in June 2018, withdrawn application in April 2020 [15].
Oncobiologics/Viropro, USA - Biosimilar in development; one of six monoclonal antibody biosimilars for which the companies are collaborating.
Pfizer, USA Ruxience (PF-05280586) Phase I/II trial in RA completed, extension study and phase III trial in lymphoma expected to be completed in August 2015 and November 2016, respectively. Positive phase III results in LTB-FL reported in December 2018. Approved by FDA in 2018 [11], by EC in April 2020 [8], and by Health Canada in May 2020 [16].
Probiomed, Mexico* Kikuzubam Kikuzubam marketed in Mexico [12], withdrawn in March 2014.
Reliance Life Sciences, India* RituxiRel ‘Similar biologic’ approved in India in February 2015 [13]
Samsung BioLogics, South Korea SAIT101 Phase III trial in RA halted in 2012
Sandoz, Switzerland Rixathon/Riximyo (GP2013) Approved by EC in 19 June 2017 [8]. Approved in Australia in November 2017 [9]. Accepted for review by FDA in September 2017 [31] Rejected by FDA in May 2018. Decided not to pursue rituximab in the US in November 2018. Approved by Health Canada in April 2020 [16].
Shanghai Henlius Biotech (Fosun Pharma), China* HLX01 Phase III trial in BCL completed in May 2018. Positive results reported in November 2018. Assigned into CNDA’s priority evaluation list in early 2018.
Sinocelltech, China* - Phase III
Stada Arzneimittel, Germany - Made a deal with Gedeon Richter in 2011 for rituximab
Teva Pharmaceutical Industries/ Celltrion, Israel/South Korea   Truxima (TL011) Approved by FDA in November 2018 [11]. Launched in the US and in Brazil in May 2020.
Torrent Pharmaceuticals/Reliance Life Sciences, India* - Exclusive licensing agreement announced in December 2014 for adalimumab, cetuximab and rituximab ‘similar biologics’.
TRPharma, Turkey* Redditux Strategic collaboration agreement made with Dr Reddy’s for three biosimilars in Turkey. Redditux approved in Turkey in January 2018.
Zenotech Laboratories, India* Rituximab ‘Similar biologic’ approved in India in February 2013 [13]
BCL: B-cell lymphoma; CNDA: China National Drug Administration; EC: European Commission; EMA: European Medicines Agency; FDA: US Food and Drug Administration; FDO: Food and Drug Organization (Iran’s National Regulatory Authority); LTB-FL: low tumour burden follicular lymphoma; MFDS: Ministry of Food and Drug Safety; National Medical Products Administration (NMPA); NHL: Non-Hodgkin’s Lymphoma; ODAC: Oncologic Drugs Advisory Committee; PK: pharmacokinetics; PD: pharmacodynamics; RA: rheumatoid arthritis; TGA: Therapeutic Goods Administration (Australia).
*See editor’s comment 

The fact that the patents on the originator product, Roche’s MabThera/Rituxan (rituximab), already expired in Europe in February 2013, is perhaps spurring development and explains the many companies that are working on biosimilars of rituximab.

Celltrion/Hospira (Pfizer) received EC approval for their rituximab biosimilar Truxima (CT-P10) in February 2017 [13] and for Blitzima, Ritemvia and Rituzena (previously Tuxella) in July 2017 [8]. Sandoz, the generics division of Novartis, received EC approval for its rituximab biosimilar Rixathon/Riximyo (GP2013) on 19 June 2017 [8], and has decided not to pursue rituximab in the US in November 2018, and has received Health Canada’s approval in April 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 Turkey, ‘similar biologics’ approved in India, ‘biocomparables’ approved in Mexico, ‘similar biotherapeutic products’ approved in Latin America, ‘biogenerics’ approved in Iran, copy biologicals approved in China and ‘medicamento biológico similares’ approved in Argentina 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. GaBI Online - Generics and Biosimilars Initiative. Amgen expands biosimilars programme [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 27]. Available from: www.gabionline.net/Biosimilars/News/Amgen-expands-biosimilars-programme 
3. GaBI Online - Generics and Biosimilars Initiative. Amgen on both sides of the biosimilar arena [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 8]. Available from: www.gabionline.net/Biosimilars/General/Amgen-on-both-sides-of-the-biosimilar-arena 
4. GaBI Online - Generics and Biosimilars Initiative. Iran approves its first rituximab biogeneric [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Nov 10]. Available from: www.gabionline.net/Biosimilars/News/Iran-approves-its-first-rituximab-biogeneric 
5. GaBI Online - Generics and Biosimilars Initiative. Non-originator biologicals approved in Bosnia and Herzegovina [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 8]. Available from: www.gabionline.net/Biosimilars/News/Non-originator-biologicals-approved-in-Bosnia-and-Herzogovina 
6. GaBI Online - Generics and Biosimilars Initiative. Cadila Pharmaceuticals launches two similar biologics in India [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 8]. Available from: www.gabionline.net/Biosimilars/News/Cadila-Pharmaceuticals-launches-two-similar-biologics-in-India 
7. GaBI Online - Generics and Biosimilars Initiative. Biosimilar rituximab approved in South Korea [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Apr 14]. Available from: www.gabionline.net/Biosimilars/News/Biosimilar-rituximab-approved-in-South-Korea 
8. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 8]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe 
9. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Australia [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 8]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Australia 
10. GaBI Online - Generics and Biosimilars Initiative. WHO prequalifies first rituximab biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 8]. Available from: www.gabionline.net/Biosimilars/General/WHO-prequalifies-first-rituximab-biosimilar 
11. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in the US [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 8]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-the-US 
12. GaBI Online - Generics and Biosimilars Initiative. Similar biotherapeutic products approved and marketed in Latin America [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 27]. Available from: www.gabionline.net/Biosimilars/General/Similar-biotherapeutic-products-approved-and-marketed-in-Latin-America 
13. GaBI Online - Generics and Biosimilars Initiative. ‘Similar biologics’ approved and marketed in India [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Feb 27]. Available from: www.gabionline.net/Biosimilars/General/Similar-biologics-approved-and-marketed-in-India 
14. GaBI Online - Generics and Biosimilars Initiative. Innovent and Eli Lilly receive approval for rituximab copy biological in China [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 8]. Available from: www.gabionline.net/Biosimilars/News/Innovent-and-Eli-Lilly-receive-approval-for-rituximab-copy-biological-in-China
15. GaBI Online - Generics and Biosimilars Initiative. Mabion withdraws application for rituximab biosimilar in EU [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 8]. Available from: www.gabionline.net/Biosimilars/News/Mabion-withdraws-application-for-rituximab-biosimilar-in-EU  
16. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Canada [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2021 Jan 8]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Canada 

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Source: Amgen, Anmat, ClinicalTrials.gov

comment icon Comments (1)
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Posted 28/02/2015 by Ak
Updated info

There is also a Rituximab from Elea Laboratory (from Argentina) called Novex.

Elea is part of chemo group from Spain.

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