Rituximab Biosimilar Shows Bioequivalency to Reference Biologics

Biosimilar GP2013 demonstrated bioequivalency to its reference biologic, rituximab, in patients with active rheumatoid arthritis (RA), in a randomized double-blind study published in the Annals of Rheumatic Diseases.¹

Josef S. Smolen, MD, from the Medical University of Vienna, Austria, and colleagues, sought to determine whether the biosimilar GP2013 would retain equivalent pharmacokinetic and pharmacodynamic properties when compared with its biologic reference agent RTX (ClinicalTrials.gov identifier: NCT01274182).

In the international multicenter study of 312 patients with RA, patients were randomly assigned to receive intravenous GP2013 (1000 mg; n=133) or its reference product in the United States, RTX-US (n=92) or in the European Union, RTX-EU (n=87), depending on their location. All patients received methotrexate (7.5 to 25 mg/week; MTX) and folic acid during the study. Patients were included if they were intolerant or refractory to disease-modifying antirheumatic drugs (DMARDs) and to one or more tumor necrosis factor inhibitor (TNFi).

The primary end point was the predetermined bioequivalence range from 80% to 125% for all 3 study drugs.² The study’s principal efficacy objective was to demonstrate noninferiority of GP2013 to RTX, using the change in disease activity score (DAS28) after 24 weeks of treatment. Secondary efficacy end points included the American College of Rheumatology (ACR) response rates, the Clinical Disease Activity Index, the Simplified Disease Activity Index, and the Health Assessment Questionnaire Disability Index.

The bioequivalency of the 3 biologics was measured using the geometric mean ratio, which was 1.093 for RTX-US vs RTX-EU (90% CI, 0.989-1.208); 1.012 for GP2013 vs RTX-US (90% CI, 0.925-1.108); and 1.106 for GP2013 vs RTX-EU (90% CI, 1.010-1.210).

The primary efficacy outcome was also met. The change from baseline to week 24 in the Disease Activity Score in 28 joints (DAS28) was –2.07 and –2.11 for GP2013 and RTX, respectively.

The findings are similar to earlier trials in which RTX was compared with placebo and later with another biosimilar, CT-P10.^3,4

Adverse events, including serious adverse events, were comparable in the 2 reference biologics and its biosimilar, GP2013. However, 3 patients in the study died; 1 died of breast cancer during the screening process, 1 accidentally overdosed on methotrexate in the GP2013 group, and 1 died of pericarditis in the RTX group.

Summary and Clinical Applicability

The biosimilar GP2013, when combined with methotrexate in patients with active RA, indicated bioequivalency to RTX, its approved reference agent in the United States and Europe. If approved by the United States Food and Drug Administration (FDA), the biosimilar could provide another treatment option in patients with RA.

Limitations and Disclosures

The current study may have produced more robust efficacy data than previous trials due to differences in patient population (RA severity and number of prior TNFi used). 

Liyi Cen, Tamas Shisha, and Peijuan Zhu are employees of Sandoz/Hexal. Andra Balanescu, Juan Gomez-Reino, Alan Kivitz, Morton Scheinberg, Josef S. Smolen, and Hans-Peter Tony received investigator fees from Sandoz, a Novartis Division. The study was funded by Hexal, a Sandoz Company for all countries except the USA, and by Sandoz for USA. Sandoz is a Novartis Division.

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References

1. Smolen JS, Cohen SB, Tony HP, et al. A randomised, double-blind trial to demonstrate bioequivalence of GP2013 and reference rituximab combined with methotrexate in patients with active rheumatoid arthritis [published online June 21, 2017]. Ann Rheum Dis.  doi:10.1136/annrheumdis-2017-211281
2. Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, US Food and Drug Administration. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product: guidance for industry. December 2016.  www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm397017.pdf Accessed August 4, 2017.
3. Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54(9):2793-2806. doi:10.1002/art.22025
4. Yoo DH, Suh C-H, Shim SC, et al. A multicentre randomised controlled trial to compare the pharmacokinetics, efficacy and safety of CT-P10 and innovator rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76:566-570. doi:10.1136/annrheumdis-2016-209540