Arthritis is an inflammatory condition that affects people worldwide leading to disabilities and decreasing the quality of life. Rheumatoid Arthritis (RA) is the most prevalent inflammatory arthritis that has triggered a revolution of treatment options over the last few decades. Though there is currently no cure for the condition, treatment regimens focus on alleviating symptoms, such as join paint & inflammation, as early as possible. These include disease-modifying antirheumatic drugs (DMARDs), such as methotrexate (MTX), or nonsteroidal anti-inflammatory drugs (NSAIDs). Patients with RA often experience renal insufficiency as a co-morbidity due to treatment with DMARDs or NSAIDs. MTX used with tumor necrosis factor (TNF) inhibitors, such as adalimumab, have shown superior efficacy than with MTX treatment alone. However, limited studies have investigated treatment strategies for RA patients with renal insufficiency, particularly those patients who are undergoing hemodialysis.
Anti-tumor necrosis factor-α (TNF-α) agents have demonstrated notable safety and efficacy in patients with RA & renal insufficiency [1, 2]. Adalimumab is an example of a TNF-α agent that was found to have no effect on renal function in patients with RA who were experiencing renal insufficiency and undergoing hemodialysis [3]. Not only was it the pharmaceutical market’s leading biologic, but it also triggered the development of biosimilars that are widely used. However, it is important to reduce the time-to-market for such biosimilars, after they have received approval, so that patients have quicker access to cost-effective alternatives without compromising on safety and efficacy.
Adalimumab, a monoclonal antibody, was the 3rd TNF-inhibitor that was approved by the US FDA in 2002 after etanercept and infliximab, and by EMA in 2003. In addition to treating RA, it has been indicated for treating other conditions such as Crohn’s disease, psoriatic arthritis, psoriasis, and ankylosing spondylitis among others, and was the highest selling drug that generated a revenue of $19.8 billion in 2020 and crossed the $20 billion mark in 2021 [4]. In the United states, the average one month treatment with Adalimumab by Abbvie (Humira) costs USD 6000. Adalimumab Biosimilars provide cheaper alternatives without compromising on the safety and efficacy.
Biosimilars of adalimumab
The following biosimilars have been approved by the FDA and/or EMA based on pre-clinical and clinical studies that demonstrated similarity between the reference product, adalimumab, and the biosimilars in terms of safety, efficacy, pharmacokinetics, and immunogenicity:
| Biosimilar | US FDA approval | EMA approval |
| ABP 501 | 2016 | 2017 |
| BI 695501 | 2017 | 2017 |
| SB5 | 2019 | 2017 |
| MSB11022 | – | 2019 |
| FKB327 | 2020 | 2018 |
| PF-06410293 | 2019 | 2020 |
| GP2017 | 2018 | 2018 |
A comprehensive review conducted by Lu and colleagues consolidated the pre-clinical and clinical trial results for the biosimilars and concluded that the endpoints in these trials were similar for the reference product, adalimumab, and its biosimilars [5]. However, the FDA has not issued the ‘interchangeability’ status for these biosimilars that would allow switching at pharmacy level without the need to consult a physician. Indeed, minor differences exist in terms of the safety, efficacy, and immunogenicity for the biosimilars, and more head-to-head comparisons are required to be able to deem these biosimilars ‘interchangeable’ by the US FDA. However, with the new statement issued by EMA and HMA in September 2022, biosimilars are already considered interchangeable without the need to consult practicing physicians.
Indeed, from a consumer or patient perspective, the price difference between the reference product and biosimilar is a crucial factor. An investigation by Manova and colleagues found that the price difference between adalimumab and its biosimilars was between 36% and 39% at manufacturing level which depicted a “successful measure” for price decrease for 17 European countries. Their literature review suggested that the difference in retail price between the reference and the biosimilar products were between 15% to 30% [6]. Additionally, when prices for TNF inhibitor biosimilars were compared between Europe and Canada, there was a significant difference where the price discount was larger in Canada: 36% vs 22% (Canada vs Northern Europe) and 36% vs 18% (Canada vs Southern Europe) [7]. However, every region or country establishes different policies for biosimilars which influences affects the number and variety of biosimilars on the market [8].
Patent disputes- a cost to medical care
While adalimumab biosimilars have been approved by both the FDA and EMA, these have not reached the US market due to lawsuits between biosimilar and reference product manufacturers that relate to biologic drug patent disputes. For example, ABP 501 was approved by the FDA in September 2016 but is expected to reach the market in January 2023 [9]. However, in the European Union, biosimilars reached the market in 2018 and have significantly contributed towards cost savings. The National Health Service (NHS) of England highlighted that roughly $134 million, or £110 million, were saved as a result of biosimilar used between late 2018 and 2019 [10]. A study by Lee and colleagues found that $2.19 billion could have been saved had adalimumab biosimilars been marketed after receiving FDA approval in 2016. However, there was an increase on annual net spending on the reference product, adalimumab, by around 40% as a result of the increase in net price of the product [11]. Therefore, there is a need to ensure that biosimilars reach the market upon receiving approval for not only patients but also to alleviate the cost burden on medical and healthcare systems.
DDReg has been working with its customers for biosimilar filings in EU and some of the complex markets from Rest of the World (ROW). It has successfully registered many biosimilars in markets like Malaysia, Algeria, Colombia, Saudi Arab and is currently in process to register few biosimilar in EU.
References and Further Reading:
- Hueber AJ, Tunc A, Schett G, Manger B. Anti-tumour necrosis factor α therapy in patients with impaired renal function. Annals of the rheumatic diseases. 2007 Jul 1;66(7):981-2.
- Cho SK, Sung YK, Park S, Bae SC. Etanercept treatment in rheumatoid arthritis patients with chronic kidney failure on predialysis. Rheumatology international. 2010 Sep;30(11):1519-22.
- Sumida K, Ubara Y, Suwabe T, Hayami N, Hiramatsu R, Hasegawa E, Yamanouchi M, Hoshino J, Sawa N, Takaichi K. Adalimumab treatment in patients with rheumatoid arthritis with renal insufficiency. Arthritis Care & Research. 2013 Mar;65(3):471-5.
- 50 of 2021’s best-selling pharmaceuticals | Drug Discovery (drugdiscoverytrends.com)
- Lu X, Hu R, Peng L, Liu M, Sun Z. Efficacy and safety of adalimumab biosimilars: current critical clinical data in rheumatoid arthritis. Frontiers in Immunology. 2021 Apr 6;12:638444.
- Manova M, Savova A, Vasileva M, Terezova S, Kamusheva M, Grekova D, Petkova V, Petrova G. Comparative price analysis of biological products for treatment of rheumatoid arthritis. Frontiers in pharmacology. 2018 Sep 20;9:1070.
- Gauthier, G., Syed, I. A., Hancock-Howard, R., and Gauthier, A. (2017). Biosimilar discounts are not similar: a comparison of the prices and discounts of anti-TNF biosimilars between Canada and Europe. Value Health 20:A567. doi: 10.1016/j. jval.2017.08.958
- Rémuzat, C., Dorey, J., Cristeau, O., Ionescu, D., Radière G., and Toumi M. (2017). Key drivers for market penetration of biosimilars in Europe. J. Mark. Access Health Policy 5:1272308. doi: 10.1080/20016689.2016.1272308
- FDA approves Amjevita, a biosimilar to Humira | FDA
- NHS England » NHS cuts medicines costs by three quarters of a billion pounds
- Lee CC, Najafzadeh M, Kesselheim AS, Sarpatwari A. Cost to medicare of delayed adalimumab biosimilar availability. Clinical Pharmacology & Therapeutics. 2021 Oct;110(4):1050-6.