Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study

Abstract

Objectives: To assess the efficacy and safety of olokizumab (OKZ), a monoclonal antibody against the interleukin-6 (IL-6) cytokine, versus placebo (PBO) in patients with prior inadequate response to tumour necrosis factor inhibitors (TNFi-IRs).

Methods: In this 24-week multicentre, placebo-controlled, double-blind study, the patients were randomised in a 2:2:1 ratio to receive subcutaneously administered OKZ 64 mg once every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or PBO plus methotrexate. At week 16, the patients on PBO were randomised to receive either OKZ regime. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. Disease Activity Score 28-joint count C-reactive protein (DAS28 (CRP))<3.2 at week 12 was the major secondary efficacy endpoint. Safety and immunogenicity were assessed.

Results: In 368 patients randomised, ACR20 response rates were 60.9% in OKZ q2w, 59.6% in OKZ q4w and 40.6% in PBO (p<0.01 for both comparisons). Achievement of DAS28 (CRP) <3.2 was significantly different, favouring the OKZ arms. Improvements in efficacy and patient-reported outcomes were maintained throughout 24 weeks and were noted after week 16 in patients who switched from PBO.Dose-related treatment-emergent serious adverse events were 7% in OKZ q2w, 3.2% in OKZ q4w and none in the PBO group.

Conclusions: Direct inhibition of IL-6 with OKZ resulted in significant improvements in the signs and symptoms of rheumatoid arthritis compared with PBO in TNF-IR patients with a similar safety profile as observed for monoclonal antibodies to the IL-6 receptor.

Trial registration number: NCT02760433.

Keywords: antirheumatic agents; arthritis, rheumatoid; autoimmune diseases.

Conflict of interest statement

Competing interests: The analysis was funded by JSC R-Pharm. EF: Research grants from BMS, Eli Lilly, Novartis, Roche; consulting fees from Abbvie, BMS, Eli Lilly, Gilead Sciences, Galapagos, Novartis, Roche, Sanofi, Sobi; speakers’ bureau for Abbvie, BMS, Eli Lilly, Gilead Sciences, Galapagos, Medac, Novartis, Roche, Sanofi, Sobi. SF: Consulting fees from ICON and PPD contract research organisations, shareholder of Pfizer, INC stocks, consulting fees from R-Pharm. EK: Employee of R-Pharm, with no R-Pharm stock; ML: Research grants from Amgen, Biogen, UCB, Sun Pharmaceuticals, Abbvie, Pfizer, Novartis, Lilly, GSK, R-Pharm. EN: Speakers’ bureau for AbbVie, Eli Lilly, Janssen, Novartis, Pfizer. SG and MS: Employees of R-Pharm, with no R-Pharm stock. JS: Research grants from Abbvie, Astra-Zeneca, Lilly; consulting fees from Abbvie, Galapagos/Gilead, Novartis-Sandoz, BMS, Samsung, Sanofi, Chugai, R-Pharma, Lilly; speakers’ bureau for Samsung, Lilly, R-Pharm, Chugai, MSD, Janssen, Novartis-Sandoz; Editor, ARD. RF: Consulting fees from AbbVie, BMS, Gilead, Galvani, GSK, Janssen, Eli Lilly, Novartis, Pfizer, R-Pharm, UCB; speakers bureaus for AbbVie; Pfizer; R-Pharm. Disclosure forms provided by the authors are available in the full text of this article.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Gatekeeping strategy. pSup, q2w and pSup, q4w represent p values from a one-sided test of superiority vs placebo for OKZ dose regimens 64 mg q2w and q4w, respectively. ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS28 (CRP), Disease Activity Score 28 based on CRP; HAQ-DI, Health Assessment Questionnaire Disability Index; OKZ, olokizumab; q2w, every 2 weeks; q4w, every 4 weeks; Wk, week.

Figure 2

Patient disposition. *One patient was randomised to OKZ 64 mg q4w but actually received OKZ 64 mg q2w. Patients who discontinued treatment early and entered safety follow-up period were considered completers for the whole study if they performed all three follow-up visits. Therefore, the number of those who completed study can be higher than the number of treatment completers. AE, adverse event; IC, informed consent; ITT, intention-to-treat; MTX, methotrexate; N, number patient in the arm; N (%), number (%) patients; %, the percentage of subjects is calculated relative to the total number of subjects in the population; OKZ, olokizumab; OLE, open-label extension; PBO, placebo; q2w, every 2 weeks; q4w, every 4 weeks.

Figure 3

Efficacy results during the double‐blind treatment period (ITT population). ACR, American College of Rheumatology; CDAI, Clinical Disease Activity Index; DAS28 (CRP), Disease Activity Score 28 based on C-reactive protein; HAQ-DI, Health Assessment Questionnaire Disability Index; ITT, intention-to-treat; OKZ, olokizumab; PBO, placebo; q2w, every 2 weeks; q4w, every 4 weeks.

Figure 4

Mean changes in laboratory values during the double‐blind treatment period (Safety population). HDL, high-density lipoproteins; LDL, low-density lipoproteins; OKZ, olokizumab; PBO, placebo; q2w, every 2 weeks; q4w, every 4 weeks. Elements of these data were presented at the annual meeting of the American College of Rheumatology 2021 and the British Society of Rheumatology Conference 2021.