Biosimilars approved in the US

Biosimilares/General | Posted 14/08/2015 post-comment3 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).

FDA V17F30

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 Formycon/Klinge Pharma
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 4
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 14
*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

comment icon 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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