Background/Purpose: Olokizumab (OKZ) is a humanized monoclonal antibody targeting IL-6 [1]. Here we present the results of a global phase III, head-to-head, randomized placebo (PBO) controlled clinical trial (RCT) in patients with active Rheumatoid Arthritis (RA) despite methotrexate (МТX) with a comparator arm of adalimumab (ADA).

Methods: This double-blind RCT (ClinicalTrials.gov Identifier NCT02760407, CREDO2) was conducted in the United States, European Union, Latin America, United Kingdom and Russia. Patients were randomized 2:2:2:1 to receive subcutaneous (SC) injections of OKZ 64 mg every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w), ADA 40mg q2w or PBO for 24 weeks, on background of МТX.

After week (Wk) 24, eligible patients could continue into an open-label study or enter a Safety Follow-Up Period of 20 weeks.

The primary endpoint was the percent of patients achieving an American College of Rheumatology 20 response (ACR20) at Wk 12.

Secondary endpoints at Wk 12 included the percentage of subjects achieving Disease Activity Score 28-joint count – C-reactive protein (DAS28-CRP) < 3.2 and improvement of physical ability from baseline to Wk 12 measured by the Health Assessment Questionnaire-Disability Index (HAQ-DI); at Wk 24, ACR50 response rate and percentage of subjects achieving Clinical Disease Activity Index (CDAI) ≤2.8. Safety outcomes included adverse events (AEs), serious adverse events (SAEs) and laboratory abnormalities.

Results: A total of 1648 subjects were randomized. Baseline characteristics were comparable across treatment arms (Table 1).

Most patients completed 24 weeks of treatment: 421 (90.7%) in q2w arm, 437 (91.2%) in q4w arm, 413 (89.4%) in ADA arm and 208 (85.6%) in PBO arm and most enrolled into the open-label extension study: 410 (88.4%), 127 (89.4%), 422 (88.1%), 397 (85.9%) and 199 (81.9%) patients, respectively.

Both regimens of OKZ were statistically superior to PBO in all primary and secondary endpoints. Furthermore, non-inferiority to ADA was demonstrated for the pre-defined endpoints of ACR20 and DAS28-CRP < 3.2 for both OKZ treatment groups (Table 2).

The efficacy outcomes were maintained throughout the 24-week period of the study.

Overall incidence of treatment-emergent adverse events (TEAEs) was 70.0% in OKZ q2w arm; 70.9% in OKZ q4w arm, 65.4% in ADA arm and 63.4% in PBO, TEAEs leading to study treatment discontinuation were reported in 4.5%, 6.3%, 5.6% and 3.7% patients, respectively. The number of deaths were comparable among arms: 3 (0.6%; 2 infections, 1 cerebrovascular accident) in the OKZ q2w arm, 2 (0.4%; 1 infection, 1 myocardial ischemia) in OKZ q4w arm, 1 (0.2%; infection) in ADA arm and 1 (0.4%; sudden death) in PBO.

The most common treatment-emergent serious adverse events (TESAEs) were infections (Table 3).

Conclusion: Treatment with OKZ 64 mg q2w and OKZ 64 mg q4w plus МТX was associated with significant improvements in the signs, symptoms and physical function of RA compared to PBO plus МТX and non-inferior to ADA plus МТX over a 24-week period.

OKZ was generally well tolerated and no new safety signals have been observed.

References:

Shaw S, Bourne T, et al. MAbs 2014;6(3):774-782.

Table 1. Demographic and Other Baseline Characteristics (intent-to-treat population). 1 – 100% patients were on MT; 2 – upper limit of normal 6 mg/L; TJC, tender joint count; SJC, swollen joint count

Table 2. Key efficacy results (intent-to-treat population) NRI. NRI, non-responder imputation; LSM, least squares mean; 1, non-Inferiority for each OKZ arm vs ADA is achieved if the lower limit of the 97.5% CI is greater than the protocol defined non-inferiority margin of _12%; 2, non-inferiority for each OKZ arms vs ADA is achieved if the lower limit of the 97.5% CI is greater than the protocol defined non-inferiority margin of -7.5%; **p-value difference from PBO < 0.001; ***p-value difference from PBO < 0.0001; SE, Standard Error

Table 3. Number and percentage of TESAE (Safety Population)

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