Imraldi was approved in Europe in August 2017 [2] and Hadlima (adalimumab-bwwd) was approved in the US in July 2019 [3].

Biosimilar approval does not require the manufacturer to re-establish efficacy but is instead based on the demonstration that there are no clinically meaningful differences from the reference product [4, 5].

Samsung Bioepis/Merck demonstrated that SB5 and the reference product (Humira) were highly similar in terms of analytical structure, function and pharmacokinetics (PK). The phase I PK study (NCT02144714) was carried out in 189 healthy subjects after a single 40 mg subcutaneous injection and demonstrated PK similarity, as well as similar safety and tolerability [6]. A phase III study was then carried out in RA (NCT02167139).

The phase III RA study (NCT02167139) was a randomized, double-blind, parallel-arm, active comparator-controlled, 52-week equivalence study in 544 patients with moderate to severe active RA despite methotrexate therapy. During the study, patients were randomized to SB5, EU-sourced Humira or US-sourced Humira (40 mg subcutaneous) every 2 weeks. At Week 24, patients on Humira were re-randomized to SB5 or Humira until Week 52.

ACR20* and ACR50 response at Week 52 showed a trend of superior response in both SB5 and SB5/Humira-switch groups compared to the Humira group, using the per-protocol set (upper limit of CI: 15.9%, exceeding ±15%) but not using the full analysis set. The percentage of subjects who achieved major clinical response (ACR70 for 6 consecutive months) at Week 52 was 15.7% in the SB5 group, 15.3% in the switch group and 9.7% in the Humira group. Since the study was not designed to show similarity at Week 52, these findings were not considered as superior response. Other response measures (ACR50/70, DAS28**) were similar. Samsung Bioepis also reported that at Week 24, the ACR20 improvement from baseline was within the pre-specified equivalence margin for SB5 compared to Humira, leading the company to conclude that the biosimilar is ‘clinically equivalent’ to Humira [7].

The incidence of anti-drug antibodies (ADAs) was similar between SB5 and Humira groups (33.1 vs 32.0% up to Week 24, respectively). Overall, treatment emergent adverse events (AEs) occurred in 35.8% of the SB5 and 40.7% of the Humira group; 10.1 and 11.7%, respectively, were considered related to the study drug. The number of injection site reactions was higher in Humira recipients (32 reactions in 4 patients) compared to SB5 recipients (9 reactions in 8 patients) at Week 52, although the proportions of patients were comparable (3.1 vs 3.0%, respectively). The rate of discontinuation due to AEs was lower in the SB5 than in the Humira group (0.7 vs 3.3% at Week 24; 1.5 vs 2.4% at Week 52).

*The ACR20 is the American College of Rheumatology criteria for clinical improvement in patients with rheumatoid arthritis, indicating a 20% improvement across a series of diagnostic parameters.

**Disease Activity Score-28 for rheumatoid arthritis with C-Reactive Protein.

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References
1. Zhao S, Chadwick L, Mysler E, Moots RJ. Review of Biosimilar Trials and Data on Adalimumab in Rheumatoid Arthritis. Curr Rheumatol Rep. 2018;20(10):57.
2. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 4]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe
3. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in the US [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 4]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-the-US
4. GaBI Online - Generics and Biosimilars Initiative. EU guidelines for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 4]. Available from: www.gabionline.net/Guidelines/EU-guidelines-for-biosimilars
5. GaBI Online - Generics and Biosimilars Initiative. US guidelines for biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 4]. Available from: www.gabionline.net/Guidelines/US-guidelines-for-biosimilars
6. GaBI Online - Generics and Biosimilars Initiative. Phase I results for candidate adalimumab, etanercept and infliximab biosimilars [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 4]. Available from: www.gabionline.net/Biosimilars/Research/Phase-I-results-for-candidate-adalimumab-etanercept-and-infliximab-biosimilars
7. GaBI Online - Generics and Biosimilars Initiative. Phase III results of adalimumab biosimilar demonstrate equivalence [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 May 4]. Available from: www.gabionline.net/Biosimilars/Research/Phase-III-results-of-adalimumab-biosimilar-demonstrate-equivalence

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