Biosimilars are defined by the US Food and Drug Administration (FDA) as a biological product that is ‘highly similar to’ an approved biological product (the ‘reference’ or ‘originator’ or ‘bio-originator’ product) and that has ‘no clinically meaningful differences’ in safety or effectiveness compared to the reference product.
The number of biosimilars in development has grown since the Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was passed by the US Congress with the intent of reducing costs and thereby increasing patients’ access to biologicals. The European Medicines Agency (EMA) proposed initial guidelines for development of biosimilars in 2005 [1] and biosimilars for rheumatic disease have been available in Europe and South Korea since 2013 with CT‑P13, an infliximab biosimilar, being the first biosimilar approved for the treatment of rheumatic disease [2].
CT‑P13 is known in the marketplace as Remsima (Pfizer) or Inflectra (Celltrion). Adoption of the infliximab biosimilar in Europe has varied from country to country. In countries such as Denmark and Norway, where the governmental health authorities have mandated utilization of biosimilar infliximab, cost savings of 30−60% have been realized. However, in the rest of Europe and in South Korea uptake has varied from a low of 25% with cost savings of 15% to 30% [3].
Adalimumab is the most commonly prescribed biological. It is approved for rheumatoid arthritis as well as psoriasis, psoriatic arthritis, juvenile inflammatory arthritis, Crohn’s disease, ulcerative colitis and hidradenitis suppurativa. Multiple adalimumab biosimilars have been and are in development. The first adalimumab biosimilar approved was ABP 501 as Amjevita in the US and Amgevita in Europe in 2016 [4].
ABP 501 was approved by the regulatory agencies based on the totality of the evidence. Extensive structural and functional analyses were conducted comparing ABP 501 to originator adalimumab demonstrating that the biosimilar was highly similar in structure not withstanding minor differences that had no impact on function of the molecule. Multiple assays were performed evaluating functional attributes such as antibody-dependent cell-mediated cytotoxicity (ADCC), Complement Dependent Cytotoxicity (CDC) and FcGamma binding were performed demonstrating equivalency between the biosimilar and the originator molecule based on pre-specified criteria established by the regulatory agencies. Pharmacokinetic studies in healthy volunteers demonstrated bioequivalence of the biosimilar to the originator in parameters such as area under the curve (AUC) and maximum (or peak) serum concentration (Cmax).
ABP 501 was compared to adalimumab in a phase III clinical trial in rheumatoid arthritis (RA) patients in combination with methotrexate [5].In this randomized, double-blind, active comparator-controlled, 26-week study, 526 patients with moderate to severe active RA despite methotrexate were randomized (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks. The primary endpoint was risk ratio (RR) of ACR20 (20% or greater improvement in American College of Rheumatology assessment criteria) between groups at Week 24. The primary hypothesis that the two treatments were equivalent would be confirmed if the 90% confidence interval (CI) for RR of ACR20 at Week 24 fell between (0.738, 1.355), thereby demonstrating that ABP 501 is similar to adalimumab based on pre-study discussions with the regulatory authorities.
The ACR20 response at Week 24 was 74.6% (ABP 501) and 72.4% (adalimumab). Week 24 RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis. Changes from baseline in Disease Activity Score for 28 joints, including C-reactive protein (DAS28‑CRP), ACR50, and ACR70 were similar. There were no clinically meaningful differences in adverse events and laboratory abnormalities. A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding anti-drug antibodies.
This study demonstrating equivalent efficacy along with an additional study of ABP 501 in psoriasis patients as monotherapy demonstrating equivalent response in improvement in Psoriasis Area and Severity Index 75% (PASI75) scores supported regulatory approval, which has been granted by FDA and EMA [6].
Two subsequent adalimumab biosimilars, Cyltezo and Imraldi, were approved in 2017 by regulatory authorities and several others are in development [3]. Amgen also had its adalimumab biosimilar approved in Europe under the trade name Solymbic (ABP 501) [3]. Hopefully with several choices available significant cost savings and improved access for patients to these highly effective therapies will be realized.
Conflict of interest
Several of the authors of the research paper [5] reported conflicts of interest, including having received grants and personal fees from Amgen and other pharmaceutical companies. For full details of the authors’ conflict of interest, see the research paper [5].
Abstracted by Professor Stanley Cohen, Clinical Professor of Internal Medicine, University of Texas Southwestern Medical School, Medical Director, Metroplex Clinical Research Center Director, Rheumatology Division, Presbyterian Hospital, Dallas, Texas, USA.
Editor’s comment
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Reducing healthcare costs and building trust in biosimilar medicines
Safety assessment of biosimilars in Europe: a regulatory perspective
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References
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2. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Oct 13]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe
3. GaBI Online - Generics and Biosimilars Initiative. Economic considerations for rheumatoid arthritis biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Oct 13]. Available from: www.gabionline.net/Biosimilars/Research/Economic-considerations-for-rheumatoid-arthritis-biosimilars
4. GaBI Online - Generics and Biosimilars Initiative. Biosimilars of adalimumab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2017 Oct 13]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-of-adalimumab
5. Cohen S, Genovese M, Choy E, et al. Efficacy and safety of the biosimilar ABP 501 compared with adalimumab in patients with moderate to severe rheumatoid arthritis: a randomized, double-blind, phase III equivalence study. Ann Rheum Dis. 2017;0:1-9.
6. Papp K, Bachelez H, Costanzo A, et al. Clinical similarity of the biosimilar ABP 501 compared with adalimumab after single transition: long-term results from a randomised, double-blind, 52-week, phase 3 study in moderate-to-severe plaque psoriasis patients. Br J Dermatol. 2017 Jul 28. doi:10.1111/bjd.15857. [Epub ahead of print].
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