Biosimilars approved in the US

Biosimilars/General | Posted 14/08/2015 3 Post your comment

Last update: 23 July 2024

In the US, a legal framework for approving biosimilars was established in 2009, via the Biologics Price Competition and Innovation Act of 2009 (BPCI Act).

The BPCI Act is part of the healthcare reform legislation, which was signed into law on 23 March 2010 by President Barack Obama. The BPCI Act establishes an abbreviated approval pathway for biological products that are demonstrated to be ‘highly similar’ (biosimilar) to, or ‘interchangeable’ with, a US Food and Drug Administration (FDA)-licensed biological product.

Zarxio (filgrastim-sndz) was the first product approved in the US as a biosimilar in 2015 [1].

To date, FDA has approved 56 biosimilars within the product classes of: 1) insulin; 2) granulocyte colony-stimulating factor; 3) monoclonal antibodies and 4) tumour necrosis factor-alpha (TNF-α), 5) vascular endothelial growth factor (VEGF) inhibitor, as shown in see Table 1.

Of these, 13 are approved as interchangeable biosimilars, as shown in Table 2. Table 3 presents the follow-on biologicals approved by the FDA.

In the FDA approval of biosimilars, infliximab-dyyb was approved under two brand names: Inflectra (Pfizer) in 2016 and Zymfentra (Celltrion) in 2023. On 5 March 2024, denosumab-bddz from Sandoz was approved under two brand names: Jubbonti and Wyost.

Table 1: FDA approved biosimilars*
Product name	Active substance	Therapeutic area	Authorization date	Manufacturer/ Company name
Abrilada (adalimumab-afzb)	adalimumab	Ankylosing spondylitis Crohn’s disease Juvenile arthritis Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	15 Nov 2019 5 Oct 2023§	Pfizer
Ahzantive (aflibercept-mrbb)	aflibercept	Age-related neovascular (wet) macular degeneration (nAMD) Diabetic macular oedema Diabetic retinopathy Macular oedema	28 Jun 2024
Alymsys (bevacizumab-maly)	bevacizumab	NSCLC Cervical cancer Colorectal cancer Glioblastoma Ovarian, fallopian tube or primary peritoneal cancer Renal cell carcinoma	13 Apr 2022	Amneal Pharmaceuticals
Amjevita (adalimumab-atto)	adalimumab	Ankylosing spondylitis Crohn’s disease Juvenile arthritis Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	23 Sep 2016	Amgen
Avsola (infliximab-axxq)	infliximab	Ankylosing spondylitis Crohn’s disease Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	6 Dec 2019	Amgen
Avzivi (bevacizumab-tnjn)	bevacizumab	Cervical cancer Epithelial ovarian, fallopian tube, or primary peritoneal cancer Metastatic colorectal cancer Metastatic renal cell carcinoma Non-squamous non-small cell lung cancer Recurrent glioblastoma in adults	6 Dec 2023	Bio-Thera Solutions, marketed by Sandoz
Bekemv (eculizumab-aeeb)	eculizumab	Atypical haemolytic uraemic syndrome (aHUS) Paroxysmal nocturnal haemoglobinuria (PNH)	28 May 2024§	Amgen
Byooviz (ranibizumab-runa)	ranibizumab	Macular oedema Macular oedema following RVO mCNV Wet AMD	17 Sep 2021 Jun 2022§	Samsung Bioepis
Cimerli (ranibizumab-eqrn)	ranibizumab	Diabetic macular oedema Diabetic retinopathy Macular oedema following RVO mCNV Wet AMD	2 Aug 2022^§	Coherus Biosciences/22 Jan 2024 acquired by Sandoz
Cyltezo (adalimumab-adbm)	adalimumab	Ankylosing spondylitis Crohn’s disease Juvenile arthritis Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	25 Aug 2017 15 Oct 2021^§	Boehringer Ingelheim
Erelzi (etanercept-szzs)	etanercept	Axial spondyloarthritis Polyarticular juvenile idiopathic arthritis Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis	30 Aug 2016	Sandoz
Eticovo (etanercept-ykro)	etanercept	Axial spondyloarthritis Polyarticular juvenile idiopathic arthritis Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis	25 Apr 2019	Samsung Bioepis
Fulphila (pegfilgrastim-jmdb)	pegfilgrastim	Febrile neutropenia	4 Jun 2018	Biocon/Mylan
Fylnetra (pegfilgrastim-pbbk)	pegfilgrastim	Febrile neutropenia	26 May 2022	Kashiv Biosciences (Amneal Pharmaceuticals)
Hadlima (adalimumab-bwwd)	adalimumab	Ankylosing spondylitis Crohn’s disease Juvenile arthritis Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	23 Jul 2019	Samsung Bioepis
Hercessi (trastuzumab-strf)	trastuzumab	HER2 breast cancer HER2 metastatic gastric or gastroesophageal junction adenocarcinoma	29 Apr 2024	Henlius, marketed by Accord
Herzuma (trastuzumab-pkrb)	trastuzumab	Breast cancer	14 Dec 2018	Celltrion/Teva Pharmaceutical Industries
Hulio (adalimumab-fkjp)	adalimumab	Ankylosing spondylitis Crohn’s disease Juvenile arthritis Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	6 Jul 2020	Mylan/Biocon
Hyrimoz (adalimumab-adaz)	adalimumab	Ankylosing spondylitis Crohn’s disease Juvenile arthritis Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	30 Oct 2018	Sandoz
Idacio (adalimumab-aacf)	adalimumab	Ankylosing spondylitis Crohn’s disease Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	13 Dec 2022	Fresenius Kabi
Inflectra (infliximab-dyyb) see also Zymfentra	infliximab	Ankylosing spondylitis Crohn’s disease Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	5 Apr 2016	Pfizer (Hospira)
Ixifi (infliximab-qbtx)	infliximab	Ankylosing spondylitis Crohn’s disease Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	13 Dec 2017	Pfizer
Jubbonti (denosumab-bddz) see also Wyost	denosumab	Postmenopausal osteoporosis Osteoporosis in men Breast cancer treatment–induced bone loss Prostate cancer treatment–induced bone loss Glucocorticoid-induced osteoporosis	5 Mar 2024§	Sandoz
Kanjinti (trastuzumab-anns)	trastuzumab	HER2 breast cancer HER2 metastatic gastric or gastroesophageal junction adenocarcinoma	13 Jun 2019	Amgen
Lusduna^# (tentative approval)	insulin glargine	Diabetes	22 Jul 2018	Merck Sharpe & Dohme
Mvasi (bevacizumab-awwb)	bevacizumab	NSCLC Colorectal neoplasms Renal cell carcinoma Ovarian neoplasms Breast neoplasms	14 Sep 2017	Amgen/Allergan
Nivestym (filgrastim-aafi)	filgrastim	Autologous peripheral blood progenitor cell collection and therapy Bone marrow transplantation Cancer Myeloid leukaemia Neutropenia	20 Jul 2018	Pfizer (Hospira)
Nypozi (filgrastim-txid)	filgrastim	Febrile neutropenia	28 Jun 2024	Tanvex
Nyvepria (pegfilgrastim-apgf)	pegfilgrastim	Febrile neutropenia	10 Jun 2020	Pfizer (Hospira)
Ogivri (trastuzumab-dkst)	trastuzumab	HER2 breast cancer HER2 metastatic gastric or gastroesophageal junction adenocarcinoma	1 Dec 2017	Biocon/Mylan
Ontruzant (trastuzumab-dttb)	trastuzumab	HER2 breast cancer HER2 metastatic gastric or gastroesophageal junction adenocarcinoma	18 Jan 2019	Samsung Bioepis/Merck
Opuviz (aflibercept-yszy)	aflibercept	Diabetic macular edema Diabetic retinopathy Macular edema following retinal vein occlusion Neovascular (wet) age-related macular degenerationRetinal vein occlusion	20 May 2024§	Samsung Bioepis/Biogen
Pyzchiva (ustekinumab-ttwe)	ustekinumab	Crohn's disease plaque psoriasis psoriatic arthritis ulcerative colitis	28 Jun 2024#	Samsung Bioepis
Releuko (filgrastim-ayow)	filgrastim	Febrile neutropenia	25 Feb 2022	Kashiv Biosciences (Amneal Pharmaceuticals)
PF708^#(tentative approval)	teriparatide	Osteoporosis	7 Oct 2019	Pfenex
Renflexis (infliximab-abda)	infliximab	Ankylosing spondylitis Crohn’s disease Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	21 Apr 2017	Samsung Bioepis/Merckk
Retacrit (epoetin alfa-epbx)	epoetin alfa	Anaemia (chronic kidney disease, Zidovudine, chemotherapy) Reduction of allogeneic red blood cell transfusions	15 May 2018	Pfizer (Hospira)
Releuko (filgrastim-ayow)	filgrastim	Febrile neutropenia	25 Feb 2022	Kashiv Biosciences (Amneal Pharmaceuticals)
Rezvoglar (insulin glargine-aglr)	insulin glargine	Diabetes	17 Dec 2021§	Eli Lilly
Riabni (rituximab-arrx)	rituximab	Chronic lymphocytic leukemia Rheumatoid arthritis Granulomatosis with polyangiitis Non-Hodgkin lymphoma	17 Dec 2020	Amgen
Ruxience (rituximab-pvvr)	rituximab	Chronic lymphocytic leukemia Granulomatosis with polyangiitis Non-Hodgkin lymphoma	23 Jul 2019	Pfizer
Selarsdi (ustekinumab-aekn)	ustekinumab	plaque psoriasis (PsO) psoriatic arthritis (PsA)	16 Apr 2024
Semglee (insulin glargine-yfgn)	insulin glargine	Diabetes	11 Jun 2020 28 Jul 2021^§	Biocon/Viatris (formerly Mylan)
Simlandi (adalimumab-ryvk)	adalimumab	Ankylosing Spondylitis Crohn’s Disease Hidradenitis Suppurativa Juvenile Idiopathic Arthritis Plaque Psoriasis Psoriatic Arthritis Rheumatoid Arthritis Ulcerative Colitis Uveitis	23 Feb 2024§	Alvotech, marketed by Teva
Stimufend (pegfilgrastim-fpgk)	pegfilgratim	Supportive care medicine for patients with non-myeloid cancer	1 Sep 2022	Fresenius Kabi
Tofidence (tocilizumab-bavi)	tocilizumab	Polyarticular Juvenile Idiopathic Arthritis Rheumatoid Arthritis Systemic Juvenile Idiopathic Arthritis	29 Sep 2023	Bio-Thera Solutions, marketed by Biogen
Trazimera (trastuzumab-qyyp)	trastuzumab	HER2 breast cancer HER2 metastatic gastric or gastroesophageal junction adenocarcinoma	11 Mar 2019	Pfizer
Truxima (rituximab-abbs)	rituximab	Non-Hodgkin lymphoma	28 Nov 2018	Celltrion/Teva Pharmaceutical Industries
Tyenne (tocilizumab-aazg)	tocilizumab	Giant cell arteritis Polyarticular juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis	7 Mar 2024	Fresenius Kabi
Tyruko (natalizumab-sztn)	natalizumab	Multiple sclerosis Relapsing-remitting multiple sclerosis	25 Aug 2023	Sandoz
Udenyca (pegfilgrastim-cbqv)	pegfilgrastim	Febrile neutropenia	2 Nov 2018	Coherus Biosciences
Vegzelma (bevacizumab-adcd)	bevacizumab	Glioblastoma Metastatic breast cancer Metastatic colorectal cancer Non-small cell lung cancer	27 Sep 2022	Celltrion
Wezlana (ustekinumab-auub)	ustekinumab	Ankylosing spondylitis Crohn’s disease Juvenile arthritis Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	31 Oct 2023§	Amgen
Wyost (denosumab-bddz) see also Jubbonti	denosumab	Prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumours Giant cell tumour of bone Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy	5 Mar 2024§	Sandoz
Yesafili (aflibercept-jbvf)	aflibercept	Diabetic macular edema Diabetic retinopathy Macular edema following retinal vein occlusion Neovascular (wet) age-related macular degeneration Retinal vein occlusion	20 May 2024§	Biocon
Yuflyma (adalimumab-aaty)	adalimumab	Ankylosing spondylitis Crohn disease Hidradenitis suppurativa Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis	May 2023	Celltrion
Yusimry (adalimumab-aqvh)	adalimumab	Ankylosing spondylitis Crohn’s disease Juvenile arthritis Psoriatic arthritis Psoriasis Rheumatoid arthritis Ulcerative colitis	17 Dec 2021	Coherus Biosciences/27 June 2024 acquied by Hong Kong King-Friend Industrial
Zarxio (filgrastim-sndz)	filgrastim	Autologous peripheral blood progenitor cell collection and therapy Bone marrow transplantation Cancer Myeloid leukaemia Neutropenia	6 Mar 2015	Sandoz
Ziextenzo (pegfilgrastim-bmez)	pegfilgrastim	Febrile neutropenia	4 Nov 2019	Sandoz
Zymfentra (infliximab-dyyb) see also Inflectra	infliximab	maintenance treatment of adult patients with moderately to severely active ulcerative colitis and Crohn’s disease	23 Oct 2023	Celltrion
Zirabev (bevacizumab-bvzr)	bevacizumab	Breast neoplasms Colorectal neoplasms NSCLC Ovarian neoplasms Renal cell carcinoma	27 Jun 2019	Pfizer
*Data updated 23 July 2024 ^§Date approved as an interchangeable biosimilar. Semglee was approved as the first interchangeable biosimilar in the US on 28 July 2021 [5]. #Provisional determination on interchangeability AMD: age-related macular degeneration; FDA: US Food and Drug Administration; mCNV: myopic choroidal neovascularization; NSCLC: non-small-cell lung carcinoma; ODAC: Oncologic Drugs Advisory Committee; RVO: retinal vein occlusion.

Table 2 details the total number of biosimilars and interchangeable biosimilars approved by the FDA since 2017. The 13 interchangeable biosimilars approved are: Abrilada (adalimumab-afzb); Byooviz (ranibizumab-runa); Cimerli (ranibizumab-eqrn); Cyltezo (adalimumab-adbm); Jubbonti (denosumab-bddz); Opuviz (aflibercept-yszy); Rezvoglar (insulin glargine-aglr); Semglee (insulin glargine-yfgn); Simlandi (adalimumab-ryvk); Wezlana (ustekinumab-auub); Wyost (denosumab-bddz), Yesafili (aflibercept-jbvf). The FDA granted provisional determination for interchangeability designation for Pyzchiva [2].

Table 2: Overview of biosimilars and Interchangeable biosimilars approved by FDA*
		Approved biosimilars
Brand name	Active substance	Total no. approved	Interchangeable designation
Humira	adalimumab	10	3
Eylea	aflibercept	2	2
Avastin	bevacizumab	5
Prolia & Xgeva	denosumab	2	2
Soliris	eculizumab	1	1
Epogen/Procrit	epoetin alfa	1
Enbrel	etanercept	2
Neupogen	filgrastim	3
Remicade	infliximab	5
Lantus	insulin glargine	2	2
Tysabri	natalizumab	1
Neulasta	pegfilgrastim	6
Lucentis	ranibizumab	2	2
Rituxan	rituximab	3
Actemra	tocilizumab	2
Herceptin	trastuzumab	6
Stelara	ustekinumab	3	1
	TOTAL	56	13
*Data updated 23 July 2024

FDA has approved six follow-on biologicals in the product classes of enoxaparin sodium (Enoxaparin sodium and M-Enoxaparin); insulin (Admelog, Basaglar and Lusduna) and teriparatide (PF708), see Table 3. The approval for one insulin glargine (Lusduna) and teriparatide follow-on biological (PF708) are tentative pending patent litigation.

Table 3: FDA approved follow-on biologicals*
Product name	Active substance	Therapeutic area	Authorization date	Manufacturer/ Company name
Admelog^#	insulin lispro	Diabetes	11 Dec 2017	Sanofi
Basaglar^#	insulin glargine	Diabetes	16 Dec 2015	Eli Lilly/ Boehringer Ingelheim
Enoxaparin sodium§	Enoxaparin sodium	Prophylaxis of Deep Vein Thrombosis	14 Mar 2019	Amphastar Pharms
M-Enoxaparin§	Enoxaparin sodium	Prophylaxis of Deep Vein Thrombosis	23 Jul 2010	Momenta/Sandoz, India/Germany
Lusduna# (tentative approval)	insulin glargine	Diabetes	20 Jul 2017	Merck Sharpe & Dohme
PF708^#(tentative approval)	teriparatide	Osteoporosis	7 Oct 2019	Pfenex
*Data updated 11 March 2024 ^#Admelog, Basaglar, Lusduna and PF708 were approved via the FDA’s abbreviated 505(b)(2) pathway as follow-on products not as biosimilars. No insulin lispro or glargine products were licensed under the Public Health Service Act at the time of filing, so there was no ‘reference product’ for a proposed biosimilar product. ^§Product not approved under the 351k legislation in the US

As of the end of July 2024, the FDA has approved a total of 58 biosimilars, including six follow-on biologicals that did not undergo the BLA 351K process for use in the US.

Two somatropins – Omnitrope (Sandoz) and Valtropin (LG Life Sciences, Biopartners) – have been approved by FDA in 2007 as a follow-on protein product. Omnitrope is being marketed in the US since 2007 for GHD in children and adults.

The landmark decision by FDA to approve its first biosimilar came in the wake of a unanimous vote two months earlier by FDA advisors who recommended approval of Zarxio [3]. Sandoz, the generics division of Novartis, already markets its biosimilar filgrastim product under the brand name Zarzio in more than 40 countries outside the US [4].

Most of the products approved so far have been approved as biosimilars, not as interchangeable products. According to the BPCI Act, only a biological that has been approved as interchangeable may be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product.

FDA has designated placeholder non-proprietary names that include a 4-digit random suffix, for all of the biosimilars that it has approved to date. The agency issued final guidance on the naming of biologicals in January 2017 [5].

FDA made a landmark decision on 28 July 2021 to approve the insulin glargine biosimilar Semglee (insulin glargine-yfgn) as the first interchangeable biosimilar product approved in the US for the treatment of diabetes [6].

Related articles
Biosimilars approved in Europe

US guidelines for biosimilars

References
1. GaBI Online - Generics and Biosimilars Initiative. FDA approves its first biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Aug 14]. Available from: www.gabionline.net/Biosimilars/News/FDA-approves-its-first-biosimilar
2. GaBI Online - Generics and Biosimilars Initiative. FDA approves its first biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2024 Jul 23]. Available from: www.gabionline.net/biosimilars/news/fda-approves-third-ustekinumab-biosimilar-pyzchiva
3. GaBI Online - Generics and Biosimilars Initiative. FDA advisers recommend approval of filgrastim biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Aug 14]. Available from: www.gabionline.net/Biosimilars/News/FDA-advisers-recommend-approval-of-filgrastim-biosimilar
4. GaBI Online - Generics and Biosimilars Initiative. FDA accepts biosimilar filgrastim application [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2015 Aug 14]. Available from: www.gabionline.net/Biosimilars/News/FDA-accepts-biosimilar-filgrastim-application
5. GaBI Online - Generics and Biosimilars Initiative. FDA issues final guidance on naming biologicals [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2018 Feb 9]. Available from: www.gabionline.net/Guidelines/FDA-issues-final-guidance-on-naming-biologicals
6. GaBI Online - Generics and Biosimilars Initiative. FDA approves first interchangeable insulin glargine biosimilar [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2022 Jul 1]. Available from: www.gabionline.net/Guidelines/FDA-issues-final-guidance-on-naming-biologicals

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Source: US FDA

Comments (3)

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Posted 04/10/2016 by Louis B, GaBI Online Editorial Office

Response to ‘Biosimilars’ posted 18/03/2016

Dear Kauntay Parekh, thank you for your valid and interesting comment on this article. Thank you for sharing your thoughts on this subject. We would be delighted if you would consider submitting a short Commentary paper on this topic to GaBI Journal.
Please feel free to reach us at editorial@gabi-journal.net for further information.

Thank you again and we hope to hear from you soon.
Best regards, Louis.

Posted 18/03/2016 by Kauntay Parekh

Biosimilars

Hi, Hemanth Kumar,

1. How many phase I, II, III trials are needed to be conducted for a Biosimilar in US and EU?
Ans: In US and EU, biosimilar applicant has to discuss with drug regulatory authority to decide the clinical trial (CT) pathway for the particular product (For US FDA and for EU EMA). These regulatory authority devise the CT pathway based on the products similarity with reference biologic (Based on analytical data).
Overall, the more similar the biosimilar product to reference product based on analytical data, the lesser CT will be required.

2. What is the trial duration for these trials (In general)?
Ans: Trial duration varies from product to product but generally these trials get completed within 2-4 years.

3. How the development timelines and trial size differ for biosimilars from their reference biologic drugs?
Ans: Unlike reference product sponsor, biosimilar applicant has to prove similarity, efficacy, safety and toxicity data comparable to reference biologic. Hence, the CT size required for biosimilar is smaller than the reference biologic.

Posted 31/08/2015 by Hemanth Kumar G

Biosimilars

Dear Sir/Madam,
Thank you very much for your articles and news about Biosimilars and generics world at gabionline.
I observed from one of your articles that it takes less than 2 years for completion of Biosimilar pivotal trials, I have a few queries regarding that.
1. How many phase I, II, III trials are needed to be conducted for a Biosimilar in US and EU?
2. What is the trial duration for these trials (In general) ?
3. How the development timelines and trial size differ for Biosimilars from their reference biologic drugs?

I would be grateful if you can answer these queries

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