Article Text

Olokizumab plus methotrexate: safety and efficacy over 106 weeks of treatment
  1. Eugen Feist1,2,
  2. Roy M Fleischmann3,4,
  3. Saeed Fatenejad5,
  4. Daria Bukhanova6,
  5. Sergey Grishin6,
  6. Sofia Kuzkina6,
  7. Michael Luggen7,
  8. Evgeniy Nasonov8,
  9. Mikhail Samsonov6,
  10. Josef S Smolen9
  1. 1Rheumatology and Clinical Immunology, HELIOS Fachklinik Vogelsang/Gommern, Vogelsang, Germany
  2. 2Experimental Rheumatology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
  3. 3Medicine, University of Texas Southwestern, Dallas, Texas, USA
  4. 4Metroplex Clinical Research Center, Dallas, Texas, USA
  5. 5SFC Medica, LLC, Charlotte, North Carolina, USA
  6. 6Medical, R-Pharm JSC, Moscow, Russian Federation
  7. 7University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
  8. 8Institute of Rheumatology, V.A. Nasonova Research, Moscow, Russian Federation
  9. 9Division of Rheumatology, Department of Medicine 3, Medical University of Vienna, Wien, Austria
  1. Correspondence to Professor Eugen Feist, Rheumatology and Clinical Immunology, HELIOS Fachklinik Vogelsang/Gommern, Vogelsang, Sachsen-Anhalt, Germany; Eugen.Feist{at}helios-gesundheit.de

Abstract

Objective To report long-term safety and tolerability of olokizumab (OKZ) in combination with methotrexate (MTX) in subjects with active rheumatoid arthritis (RA), using pooled data from three randomised clinical trials (RCT) followed by open-label extension (OLE) study.

Methods Cumulative data from three phase 3 core trials and their OLE were analysed. Safety variables assessed included treatment-emergent adverse events (AEs), serious AEs (SAEs), AEs of special interest and laboratory results. Efficacy assessments included ACR20/50/70 responses, Disease Activity Score 28 (C-reactive protein) <3.2, CDAI remission and low disease activity (LDA), SDAI remission and LDA, HAQ-DI decrease of 0.22 unit and Boolean 2.0 remission.

Results A total of 2304 patients received OKZ in combination with MTX either once every 2 weeks or once every 4 weeks. Event rates per 100 patient-years in OKZ every 2 weeks and OKZ every 4 weeks, respectively, were 9.57 and 9.13 for SAEs; 2.95 and 2.34 for serious infections; 0.09 and 0.05 for gastrointestinal perforations; 0.58 and 0.83 for major adverse cardiovascular events; and 0.45 and 0.50 for malignancies. No increase in the rate of any AE was observed over 106 weeks of treatment. The evaluation of laboratory variables demonstrated the expected changes, like neutropenia, elevation of liver enzymes and blood lipids. Clinical response rates remained stable during the OLE.

Conclusion The long-term safety and tolerability of OKZ in combination with MTX remained stable. The efficacy of OKZ was maintained through week 106. These findings support OKZ as a treatment option for patients with active RA.

  • Antirheumatic Agents
  • Arthritis, Rheumatoid
  • Cytokines

Data availability statement

Data are available on reasonable request. On request by email to SG, sa.grishin@rpharm.com, R-Pharm will provide access to individual deidentified participant data from R-Pharm-sponsored global interventional clinical studies. R-Pharm will also consider requests for the protocol, data dictionary and statistical analysis plan. Data may be requested from R-Pharm trials 24 months after study completion.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Olokizumab, an inhibitor of the IL-6 ligand, has been shown to be effective in three phase III randomised clinical trial in methotrexate (MTX)-IR (inadequate responders) and TNF (tumour necrosis factor)-IR rheumatoid arthritis (RA) patients.

WHAT THIS STUDY ADDS

  • This analysis provides the comprehensive long-term safety report of olokizumab in RA. Olokizumab in combination with MTX was generally safe and well tolerated in the treatment of patients with RA in dosages of 64 mg every 2 weeks or every 4 weeks subcutaneous over a period of 106 weeks.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • Olokizumab is a new treatment option for both biological naïve as well as non-responding to TNF inhibitors patients with RA. The long-term safety profile was attributed to the mechanism of action of IL-6 inhibition. This should be considered in the future management of patients.

Introduction

Interleukin-6 (IL-6) is a pleiotropic cytokine with proinflammatory functions. IL-6 binds to its receptor and glycoprotein 130 (gp130) on the surface of most cells. This trimer formation ultimately leads to inflammatory signal transduction through the cell membrane. Biological agents that target the IL-6 receptor (R) and IL-6 signalling pathway demonstrated efficacy in patients with rheumatoid arthritis (RA).1 Olokizumab (OKZ), a humanised monoclonal antibody, targets the IL-6 ligand directly, inhibiting IL-6-mediated trimer formation required for signal transduction rather than indirectly via IL-6R inhibition as do the inhibitors of IL-6 currently approved for RA treatment.2

OKZ in combination with methotrexate (MTX) was studied in the phase 3 CREDO clinical programme encompassing three phase 3, randomised, double-blind, placebo (PBO)-controlled and active-controlled, multicentre 24-week studies. OKZ improved the signs and symptoms of RA, physical function and health status in patients with moderately to severely active RA refractory to MTX (CREDO1—NCT02760368 and CREDO2—NCT02760407) or to anti-TNF agents (CREDO3—NCT02760433). In addition, OKZ in combination with MTX in doses of 64 mg every 2 weeks or every 4 weeks demonstrated superiority to PBO and non-inferiority to adalimumab (ADA).2 3

Patients who participated in the core double-blind randomised clinical trials (RCTs) could continue to receive OKZ therapy in an open-label extension (OLE) CREDO4 study (NCT03120949 from 4 July 2017 to 1 September 2021). This report includes long-term OKZ safety and efficacy data pooled across all the phase 3 studies and thus provides important information for future clinical practice since patients treated with an effective drug usually continue therapy for many years.

Methods

Patient population

The core RCTs enrolled adults with active RA, not responding adequately to MTX, a conventional synthetic disease-modifying antirheumatic drug (csDMARD) or a TNF inhibitor. Patients who completed the 24 week treatment period, were offered continuation of OKZ therapy in the OLE. Inclusion and exclusion criteria for the core studies have been previously reported.2 3

Study design

In the core RCTs, depending on the study, patients not responding to MTX or TNF inhibitors were randomised to receive subcutaneous injections of OKZ every 2 weeks, OKZ every 4 weeks, PBO (CREDO1, 2, 3) or ADA every 2 weeks (CREDO 2). At week 16 of CREDO3 study, all patients in the PBO group were re-randomised to receive OKZ 64 mg every 2 weeks or every 4 weeks.

Patients who completed the core RCTs and consented to participate in the OLE, either continued the same OKZ regimen or were randomised from ADA or PBO to one of the two OKZ regimens at week 24. The OLE included 82 week of treatment followed by a 20 week safety follow-up period (online supplemental figure S1).

Supplemental material

Safety assessments

Safety assessments included adverse events (AEs) and serious AEs (SAEs) coded using the Medical Dictionary for Regulatory Activities V.25.1 and evaluation of laboratory abnormal values. AEs of special interest included infections and serious infections (SI), malignancies, elevation of lipids, systemic injection and hypersensitivity reactions, gastrointestinal (GI) perforations, cardiovascular (CV) events, cytopenias, potential hepatotoxicity, injection site reactions, demyelination in the peripheral or central nervous system, autoimmune disorders and venous thromboembolism (VTE). Potential hepatotoxicity was defined as increase of alanine aminotransferase (ALT) or aspartate aminotransferase (AST)>3× ULNs and was reported as SAE in the following cases: ALT or AST>3× to ≤5×ULN and symptoms, determined by the Investigator, were the result of hepatic injury; ALT or AST>5×ULN for ≥2 weeks, regardless of total bilirubin or accompanying symptoms; ALT>8×ULN at any time and; ALT or AST>3×ULN and total bilirubin >2×ULN (for more details see online supplemental materials, p. 4).

Abnormal laboratory values of interest included deviations in creatinine, ALT, AST, bilirubin, platelets, neutrophil count, haemoglobin, total cholesterol, high-density and low-density lipoprotein cholesterol (HDC and LDC), lipoprotein(a); mycobacterium tuberculosis test positive and prolonged activated partial thromboplastin time (APTT).

An independent drug safety monitoring board and CV adjudication committee was established and was responsible for evaluating major adverse cardiac events (MACEs).

Clinical response

Efficacy assessments included American College of Rheumatology (ACR)20/50/70 responses, Disease Activity Score 28 (DAS28) (C-reactive protein, CRP)<3.2, CDAI remission and low disease activity (LDA), SDAI remission and LDA, HAQ-DI meaningful change (decrease of >0.22 units) and Boolean 2.0 remission.4 For details, see online supplemental table S1. These assessments were done in accordance with the European Alliance of Associations for Rheumatology (EULAR) recommendations for reporting extension trials.5

Statistical analysis

Safety and efficacy data were analysed using descriptive statistics and no statistical comparison between the treatment groups was conducted.

The safety population included all subjects who received at least one dose of OKZ. Patients were analysed based on received treatment: (1) OKZ every 2 weeks (received OKZ every 2 weeks during RCT or OLE or both) and (2) OKZ every 4 weeks (received OKZ every 4 weeks during RCT or OLE or both). The baseline value for safety variables was the latest value prior to the first dose of OKZ.

AEs were summarised as number of events and exposure-adjusted event rates (ERs) that were defined as number of events per 100 patients-years (PYs) of observation time. Total duration of observation was defined as the time from the first dose to the time of the last safety observation. Total duration of observation was used as the denominator for exposure-adjusted AE rates. The extent of exposure was calculated as last dose date minus first dose date plus 14/28 days for every 2 weeks/every 4 weeks dose regimen, regardless of unplanned intermittent discontinuations.

Efficacy assessments were analysed in the intent-to-treat (ITT) population that included all randomised patients in the RCTs and according to the group to which the patients were originally assigned. The following analysis groups were evaluated: (1) OKZ every 2 weeks (received OKZ every 2 weeks during the RCTs and OLE); (2) OKZ every 4 weeks (received OKZ every 4 weeks during RCTs and OLE); (3) ADA (received ADA during the RCTs and OKZ during OLE); (4) PBO (received PBO during the RCTs and OKZ during the OLE). Depending on the OKZ interval, the ADA and PBO patients were ultimately grouped within the respective OKZ dose regimen (figure 1). The baseline value for efficacy variables was the initial baseline from the RCT studies. Missing intermediate data were imputed from the surrounding visits. Patients who discontinued study or did not enter the OLE were considered as non-responders. In addition, efficacy analysis was conducted as a completer analysis, which was based on patients who had data available at the analysis time point (as observed). There was no confirmatory analysis for the efficacy variables.

Figure 1

Patient disposition. *32 patients were re-randomised to OKZ every 2 weeks and 26 patients to OKZ every 4 weeks in CREDO3 study at week 16. ADA, adalimumab; OKZ, olokizumab; OLE, open-label extension; PBO, placebo.

Results

Patient disposition

A total of 2444 patients were randomised to the core RCTs (online supplemental table S2). Among these patients, 2104 (86.1%) were enrolled to the OLE and 1709 (69.9%) completed the OLE (figure 1). Overall, 396 (16.2% of those randomised initially) patients discontinued treatment during the OLE: 180 (7.4%) due to AEs, 159 (6.5%) due to patient decision, 12 (0.5%) were lost to follow-up, 9 (0.4%) due to lack of efficacy, 10 (0.4%) due to protocol violation and 26 (1.1%) for other reasons.

A total of 2304 patients received OKZ every 2 weeks or every 4 weeks in combination with MTX. The overall exposure to OKZ was 3625 PYs with a mean treatment duration of 1.6 years (maximum 2.4). Exposure was 1839.5 PY with OKZ every 2 weeks and 1785.8 PY with OKZ every 4 weeks regimen.

Demographics and clinical characteristics were well balanced between the OKZ groups (table 1, online supplemental table S3).

Table 1

Demographics and other baseline characteristics

Safety

Adverse events

Overall AEs occurred in 1873 patients in OKZ groups (82.1% in OKZ every 2 weeks; 80.5% in OKZ every 4 weeks) and ER per 100 PY was 221.28 in OKZ every 2 weeks and 214.92 in OKZ every 4 weeks (table 2). A total of 257 (11.2 (12.0%) patients discontinued OKZ treatment due to AEs (figure 1). The rate of AEs leading to treatment discontinuation was 5.86/100 PY and 6.47/100 PY in OKZ every 2 weeks and OKZ every 4 weeks groups, respectively. Most common AEs leading to discontinuation were ALT increased, cellulitis and pneumonia (table 2).

Table 2

Summary of adverse events

Most frequently reported AEs were in system organ class ‘Infections and infestations’: ER was 45.44/100 PY in OKZ every 2 weeks and 44.89/100 PY in OKZ every 4 weeks. Opportunistic infections occurred with ER 1.12/100 PY in OKZ every 2 weeks group and 1.19/100 PY in OKZ every 4 weeks (table 2). The ER of infections was consistent during the OLE with no difference between groups (figure 2). The rate of infections was similar in the core trials and OLE (online supplemental table S4). Of 51 cases of opportunistic infections, 48 were caused by varicella zoster virus (none were disseminated or multidermatomal), and 3 cases of pulmonary tuberculosis developed in patients treated with OKZ with a negative QuantiFERON test at baseline who lived in areas where tuberculosis is endemic.

Figure 2

Exposure-adjusted rate of AEs by 12-week interval: infection, malignancies, MACE. AEs, adverse events; MACE, major adverse cardiac event; OKZ, olokizumab; PY, patients-years.

Systemic injection reactions occurred with a similar rate of 10.02/100 PY in OKZ every 2 weeks and 10.56/100 PY in OKZ every 4 weeks. One case of anaphylactic reaction occurred with OKZ every 4 weeks (during the core RCT). The rate of injection site reactions was comparable in both OKZ regimens (ER 9.53/100 PY in every 2 weeks and 9.00/100 PY in every 4 weeks).

The exposure-adjusted ER of autoimmune disorders was 2.91/100 PY and 3.26/100 PY, in OKZ every 2 weeks and OKZ every 4 weeks, respectively (table 2) which were mostly RA flares, rheumatoid nodules and psoriasis.

Malignancies were reported in 10 (0.9%) patients with OKZ every 2 weeks and 11 (1.0%) with OKZ every 4 weeks with an ER 0.45 and 0.50/100 PY, respectively (table 2). No unusual types of malignancies or clustering were observed.

GI perforation occurred in two patients treated with OKZ every 2 weeks and in one patient with OKZ every 4 weeks (table 2). Two of these three patients received concomitant therapy with glucocorticoids and one had a history of diverticulitis.

Demyelination in peripheral or central nervous system was rare; one case of encephalomyelitis was reported in the OKZ 64 mg every 2 weeks group.

Serious adverse events

SAEs were reported in 317 (13.8%) patients with a rate of 9.57/100 PY with OKZ every 2 weeks and 9.13/100 PY with OKZ every 4 weeks during the RCT+OLE period. The most commonly reported SAEs were infections and infestations, investigations (mainly due to increased ALT) and musculoskeletal and connective tissue disorders (mainly due to hospitalisations for joint replacement surgery for progressive damage characterised as osteoarthritis by treating physicians). SI occurred similarly with OKZ every 2 weeks (2.95/100 PY) and every 4 weeks (2.34/100 PY). The most frequently reported SIs were pneumonia (ER 0.36/100 PY with OKZ every 2 weeks; 0.41/100 PY with OKZ every 4 weeks), cellulitis (ER 0.22/100 PY with OKZ every 2 weeks and 0.46/100 PY with OKZ every 4 weeks) and erysipelas (ER 0.22/100 PY with OKZ every 2 weeks and 0.28/100 PY with OKZ every 4 weeks) (table 2). In patients who switched from ADA to OKZ every 4 weeks, there was a slight increase in infections rate during first 12 weeks after switching (online supplemental table S4).

Deaths

The ER of deaths was similar for both dosing arms—0.76/100 PY and 0.69/100 PY for every 2 weeks and every 4 weeks, respectively (table 2). There were 32 deaths in patients treated with OKZ. Most common causes of death were infections (11 cases), which occurred more commonly in the every 2 weeks OKZ arm and MACE (8 cases), which occurred more frequently in the every 4 weeks OKZ arm. Events of deaths occurred throughout the study at the same rate over time (online supplemental figure S2).

Major adverse cardiac event

The number of patients with adjudicated MACE was 11 (1.0%) in OKZ every 2 weeks arm and 17 (1.5%) in OKZ every 4 weeks arm. The ER per 100 PY was 0.58 and 0.83, respectively. There was one CV death in OKZ every 2 weeks group and seven deaths in OKZ every 4 weeks group. Other MACE events reported in OKZ every 2 weeks and OKZ every 4 weeks groups included 5 cases of non-fatal myocardial infarction (MI), 12 non-fatal strokes and 3 non-fatal coronary revascularisation procedures (table 2). The rate of MACE was consistent across the entire treatment period (figure 2). In the core studies, MACE ER was 0.49 per 100 PY for PBO-treated patients, and 0.91 per 100 PY for ADA-treated patients.

Venous thromboembolism

VTE events occurred with an ER of 0.58/100 PY in OKZ every 2 weeks and 0.37/100 PY in OKZ every 4 weeks group. The majority of these events were deep vein thrombosis (table 2).

Laboratory abnormalities

Neutropenia of any grade was seen in 413 (36.9%) and 378 (33.90%) patients in OKZ every 2 weeks and every 4 weeks groups, respectively. Thrombocytopaenia developed in 130 (11.5%) patients in OKZ every 2 weeks group and in 121 (10.6%) in OKZ every 4 weeks group. ER of cytopenias (neutropenia, thrombocytopaenia, leucocytopenia and pancytopenia) per 100 PY trended to dose-dependency: 24.15 in OKZ every 2 weeks and 22.31 in OKZ every 4 weeks. There were three cases of grade 4 neutropenia; but only one was reported as a SAE in OKZ every 2 weeks and improved to grade 1 after treatment discontinuation. The majority of neutropenias resolved spontaneously—OKZ was discontinued at the visit for this reason only in 16.8% and 15.6% of cases in OKZ every 2 weeks and OKZ every 2 weeks groups accordingly (online supplemental table S5). The rate of development of neutropenia did not increase with prolonged exposure (figure 3). Further analysis showed that there were no persistent grade 3 or 4 cases; grade 2 neutropenia was registered only in 10 (7.6%) OKZ every 2 weeks and 9 (6.7%) OKZ every 4 weeks—treated patients during 30 weeks after maximal neutropenia was observed (V0) (online supplemental figure S3). Detailed information on time to normalisation and therapy withdrawal related to cytopenias is shown in online supplemental table S6.

Figure 3

Exposure-adjusted rate of laboratory abnormalities by 12-week interval: ALT≥3×ULN and ANC<1×109/L. ALT, alanine aminotransferase; ANC, absolute neutrophil count; CI, confidence interval; OKZ, olokizumab; PY, patient-year; ULN, upper limit of normal.

The rate of infections and SI was similar in patients with and without a recorded event of neutropenia at any time during the study. Absolute neutrophil count (ANC) values were normal at the last ANC assessment (usually within 12 weeks) before the infection in the majority of events (OKZ every 2 weeks 803/915 (87.8%) and OKZ every 4 weeks 812/900 (90.2%). There was neither an increase in the proportion of patients with infections after neutrophil decrease was observed, nor there was an association between neutropenia grade and number of infections (online supplemental table S7). Similar results were observed for SI: ANC values were normal at the last ANC assessment before SI in 51/56 (91.1%) and 37/41 (90.2%) SI occurring usually within 12 weeks of an ANC assessment. Rate of infections cases and SIs was higher after absolute lymphocytes counts decrease <0.5×109/L compared with normal lymphocyte counts or mild decrease (online supplemental table S8).

ALT grade 3 increase (>5 to 10×ULN) was observed in 19 (1.9%) cases in OKZ every 2 weeks group and in 28 (2.8%) cases in OKZ every 4 weeks group (online supplemental table S9). ALT increase >10× ULN (grade 4) was identified in 3 (0.3%) patients in each dosing regimen. AST grade 3 elevation occurred in 12 (1.2%) and 14 (1.4%) patients in OKZ every 2 weeks and every 4 weeks arms, respectively. One OKZ every 4 weeks patient showed AST increase >10× ULN (online supplemental table S9). ALT and AST elevation did not correlate with bilirubin increase (online supplemental figure S4). Elevated levels of ALT above 3×ULN, accompanied by increased levels of bilirubin (above 2×ULN), were observed in two cases. In most instances of patients with less severe hepatic dysfunction, the grade of ALT increase dropped at the next visit after peak level (online supplemental figure S5). Among 48 (during V+1) patients with grade 3 or 4 (>5.0 ULN) ALT increase, at the next visit ALT dropped to normal in 15 patients and was <3 ULN in 22 patients. In two visits (mean time 74 days) after ALT peak, grade 2 elevation was registered in 4 patients (2.2%), in others ALT was normal or <3 ULN (online supplemental table S10). In the vast majority of subjects elevations of ALT resolved with discontinuation or adjustment of dose of MTX. During the episode of ALT elevation of any grade, MTX therapy was discontinued or reduced in 337 patients: 178 (21.6%) in the OKZ every 2 weeks group and 159 (20.2%) in the OKZ every 4 weeks group. OKZ was discontinued due to hepatotoxicity in 31 (3.8%) patients in the OKZ every 2 weeks group and 26 (3.3%) in the OKZ every 4 weeks group (online supplemental table S11). Details of ALT/AST increase above 3×ULN normalisation and related therapy withdrawal can be found in online supplemental table S6. We did not see correlations between ALT elevations and body mass index.

AE of potential hepatotoxicity occurred with the same frequency in both dosing regimens – 6.71 and 7.07 per 100 PY for OKZ every 2 weeks and every 4 weeks, respectively (table 2). ER of elevation in liver enzymes did not increase with time (figure 3).

Patients with baseline Hb value <lower limit of normal (LLN), observed in 391 (17.4%) of all patients randomised, showed an increase in Hb to normal values—173 (88.7%) patients in OKZ every 2 weeks and 179 (91.3%) patients in every 4 weeks group. Normal Hb baseline values (1834 (81.7%) patients) decreased <LLN in 79 (8.5%) patients in OKZ every 2 weeks group and in 94 (10.4%) patients in OKZ every 4 weeks group (online supplemental figure S6 and table S9).

A similar proportion of patients in each OKZ group showed shifts in cholesterol, both LDC and HDC, and triglycerides. Among patients with low levels of HDC, elevation to normal value was observed in 29.5% and 27.2% of patients (online supplemental table S9). Elevation of blood lipids was reported as an AE with a dose-dependent rate of 14.94/100 PY with OKZ every 2 weeks and 11.94/100 PY with OKZ every 4 weeks (table 2), with the maximum rate observed during first 12 weeks of core RCTs (figure 2). Mean lipoprotein(a) (Lp(a)) value decreased during treatment (online supplemental table S12).

Other laboratory AEs included the following (ER per 100 PY in OKZ every 2 weeks and OKZ every 4 weeks): creatinine (0.89 and 0.96) and bilirubin (1.07 and 1.24) increase, haemoglobin decrease (0.49 and 0.73), mycobacterium tuberculosis test positive (0.94 and 0.64) and APTT prolonged (0.13 and 0.55) (table 2).

Clinical response

Efficacy assessments demonstrated that OKZ is an effective treatment for active RA with both clinical and functional improvements observed in many patients.

Clinical response rates were comparable between the two OKZ dosing regimens. In the RCT treatment period, ACR20/50/70 response rates were higher with OKZ and ADA compared with PBO, and the rates remained stable up to week 106 of the OLE. Patients who switched from PBO achieved ACR20 and ACR50 response rates and DAS28 (CRP) similar to the patients who initially received OKZ and ADA by 12 weeks (figure 4). For the more stringent responses, namely ACR70, HAQ-DI (decrease in score of 0.22 units), CDAI remission and LDA, patients switched from PBO achieved rates similar to OKZ groups by 24 weeks. In patients who were switched from ADA to OKZ, there were improvements in efficacy scores as well (figure 4). As expected, efficacy results in the completer population were higher compared with the ITT population (figure 4, online supplemental table S13). Of note, even when using these most stringent assessment methods, by the end of OLE ACR70 response rates stabilised at 28%–41%, CDAI LDA at 48%–69% and CDAI remission at 15%–27%, and the Boolean 2.0 remission definition at 15%–25%, depending on the group and analysis, a remarkable result given the preceding treatment history of this pooled population (online supplemental table S13).

Figure 4

Efficacy assessments response dynamics. ACR, American College of Rheumatology; ADA, adalimumab; CDAI, Clinical Disease Activity Index; CRP, C-reactive protein; DAS-28, Disease Activity Score-28; HAQ-DI, Health Assessment Questionnaire Disability Index; OKZ, olokizumab.

Discussion

This report is a pooled safety and efficacy data analysis of OKZ in combination with MTX evaluated in three phase 3 RCTs and the long-term OLE study. The data show that (1) no new safety issues arose during the OLE period when compared with the RCT period and (2) no safety issues were found that had not been seen with other agents inhibiting the IL-6 pathway during the OLE period.6 7 Similar to tocilizumab and sarilumab, we observed infections, lipid elevation, neutropenia, GI perforations. Differences in incidence rates of these AEs between OKZ, tocilizumab and sarilumab programmes cannot be accurately assessed because of the differences in study design, patient characteristics and relevant comorbidities, time of study and other variables. Importantly, no increase in ER of AEs or SAEs was observed with prolonged exposure to OKZ and no new safety signals were identified. The rate of AEs leading to study discontinuation was comparable to that of other IL-6 inhibitors.6 8 However, since direct IL-6 inhibition is a relative new mechanism of action, long-term observation is needed to fully clarify the safety profile.

Patients with RA are known to have an increased risk of infections and therapy with immunosuppressive drugs may increase this risk.9 10 Infections were the most frequently reported AEs and SAEs with OKZ with no difference between dosing regimens. There was no increase in the rate, severity or change in nature of infections with time. The observed ER for SI (2.95/100 PY in OKZ every 2 weeks and 2.34/100 PY in OKZ every 4 weeks) was slightly lower than that reported for tocilizumab (3.5–4.9/100 PY) and sarilumab (3.7/100 PY in combination with csDMARDs)8 11 and was in line with long-term studies of other biological or targeted synthetic DMARDs (b/tsDMARDs).12–14 This suggests that blocking the IL-6 ligand does not appear to increase the risk of infections compared with blocking its receptor.

A decrease in neutrophil counts and an increase in hepatic enzymes as well as dyslipidaemia are the most common laboratory changes observed with IL-6 inhibitors. ERs of elevated hepatic enzymes for OKZ-treated patients were comparable with data from sarilumab-treated patients in the OLE studies.15 Similar data for these laboratory variables were obtained for tocilizumab16 (online supplemental table S14). Serious ALT elevations occurred rarely. Neutropenia was a relatively common AE with no significant difference between every 2 weeks or every 4 weeks dosing regimens, and the rate was similar to previously reported results for sarilumab.11 17 It has been shown that IL-6 inhibition affects neutrophil trafficking to the bone marrow with no influence on neutrophil function, activation or apoptosis, making the association of neutropenia and infections with IL-6 inhibition unlikely.11 18–20 The lack of an association between decreased neutrophil counts during OKZ treatment and the occurrence of infections supports this hypothesis.

IL-6 inhibition has been shown to increase Hb in many RA patients with anaemia, and our data support this: Hb values returned to normal level in the majority of patients with initially low Hb values. This is in line with most other anti-inflammatory agents; only JAK-inhibitors do not improve anaemia of chronic diseases,21–23 with the exception of filgotinib.24

Although inflammation leads to a decrease in lipid levels, RA patients with continued disease activity are at increased risk of CV diseases25; this is referred to as the ‘lipid paradox’26 and reflects the complex interactions of lipids, lipoproteins and inflammation. IL-6 inhibitors are known to increase total and LDС blood levels in RA, however, this is not associated with increased MACE risk.27 28 Based on the available studies data, MACE incidence varies from 0.2 to 3.5 per 100 PY in RA patients.29 A well-controlled CV safety study of tocilizumab versus etanercept showed no increased risk of MACE with the IL-6 inhibition.30 In this pooled dataset, MACE events were observed infrequently and the rate did not increase with time while lipid elevations were relatively frequent, which is in line with the observations for tocilizumab and sarilumab in RA.8 11 In TCZ-treated patients, incidence rate of stroke (0.19 per 100 PY) and MI (0.25 per 100 PY) were comparable with data obtained for OKZ (table 2).7 For other drugs with IL-6 inhibitory mechanism, MACE incidence was 0.4–0.8 per 100 PY in RA patients based on the pooled studies data.17 31 32 MACE occurred relatively more frequently in the every 4 weeks dosing group of OKZ, suggesting these events were not dose-dependent. In the core studies of OKZ, the incidence of MACE in ADA-treated and PBO-treated patients was similar to the rates observed for both OKZ groups. The difference in CV mortality could be due to the following: difference in family history of CV diseases which is of some importance and wasn’t captured; difference in degree of control of the modifiable risk factors, such as difference in haemoglobin A1c levels or differences in blood pressure control or extent of chronic kidney disease; potential difference in the number of risk factors per patient in each group. Overall, the death rate is similar to those observed for tocilizumab8 or ADA33 and comparable with other new RA treatments (online supplemental table S15). Also, given the similarity of MACE rates among the two OKZ groups differences in mortality may be due to underlying healthcare access or even chance. The CREDO 4 study was completed during the COVID-19 pandemic and some MACE events occurred during the pandemic which also could influence the overall rates. There was also a decrease of Lp(a) levels observed. Lp(a) is a known risk factor for atherosclerotic CV diseases,34 its decrease may indicate lowering of CV risk during IL-6 inhibition withOKZ.

GI perforations are rare life-threating events observed more frequently in patients with RA treated with glucocorticoids and NSAIDs and during treatment with drugs that directly or indirectly inhibit the IL-6 pathway.35 36 GI perforations were observed in three patients (ER 0.09/100 PY and 0.05/100 PY in OKZ every 2 weeks and OKZ every 4 weeks, respectively). This observation is in line with the reported ER of GI perforations with tocilizumab (0.28/100 PY) and sarilumab (0.1/100 PY).

Malignancies were rare and the ER /100 PY was comparable to sarilumab (0.6–0.7/100 PY) and tocilizumab (1.4 and 0.7/100 PY depending on dosage).8 11 Thromboembolic events were also rare and in line with sarilumab ERs in RA (0.4–0.8 per 100 PY).11 17 37

The results showed a sustained clinical response to OKZ during 106 weeks of treatment. Similar response rates in most measures of efficacy (ACR20/50 responses, DAS28 (CRP)<3.2, CDAI≤10 and ≤2.8) were observed between both every 2 weeks and every 4 weeks treatment groups by weeks 12–24 of treatment with OKZ and were sustained over time. The efficacy for patients who switched from PBO to OKZ was in line with the core studies for patients who initiated OKZ treatment. It should be noted that response rate trends were similar with both non-responder imputation and as observed methods. Combination of all bDMARDs with MTX, including other IL-6 inhibitors, has been shown to elicit better outcomes than monotherapy2 38–41 and is also highly recommended in the EULAR RA management recommendations.42

This study has several limitations. This is a pooled analysis of different studies with different patient populations. Second, the patients received an active comparator or PBO during the RCT part of observation only, which precludes the possibility to provide a comparative analysis in the OLE period. Third, the safety results are observational and cannot be directly compared with properly powered studies of safety. Lastly, as there is no head-to-head study comparing the safety of OKZ to other IL-6 inhibitors, the comparison of safety is conjectural.

Conclusions

The safety findings of long-term OKZ exposure were consistent with those seen in the shorter-term assessments and also those seen with IL-6R inhibitors.8 The efficacy of OKZ was maintained through week 106.

Supplemental material

Data availability statement

Data are available on reasonable request. On request by email to SG, sa.grishin@rpharm.com, R-Pharm will provide access to individual deidentified participant data from R-Pharm-sponsored global interventional clinical studies. R-Pharm will also consider requests for the protocol, data dictionary and statistical analysis plan. Data may be requested from R-Pharm trials 24 months after study completion.

Ethics statements

Patient consent for publication

Ethics approval

Studies were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines, along with applicable local country regulations and laws. The study protocol and informed consent form (ICF)were approved by the Institutional Review Boards/Independent Ethics Committee of each investigational site. All patients provided written informed consent.

Acknowledgments

The authors would like to thank Alina Egorova (R-Pharm) for statistical support. Medical writing support, under the guidance of the authors, was provided by Anna Karpenko, PhD (funded by R-Pharm).

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • Handling editor David S Pisetsky

  • Collaborators The authors would like to thank Alina Egorova (R-Pharm) for statistical support. Medical writing support, under the guidance of the authors, was provided by Anna Karpenko, PhD (funded by R-Pharm).

  • Contributors R-Pharm, JSC was involved in the study design, collection and analysis, interpretation of data and checking of information provided in the manuscript. MS, SG, SF and SK were involved with study conceptualisation and conducted the data analysis. All authors had unrestricted access to study data and contributed to the interpretation of the results. The authors received no honoraria related to the development of this publication. All authors were responsible for all content and editorial decisions. The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE).Medical writing assistance, under the direction of the authors, and editorial support was provided by Anna Karpenko, PhD (JSC R-Pharm, RMF) according to CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials (https://www.bmj.com/content/340/bmj.c332) and Good Publication Practice guidelines (http://annals.org/aim/article/2424869). SG as a guarantor.

  • Funding NCT03120949RCT was funded by JSC R-Pharm.

  • 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; RF: Consultant for AbbVie, Arthrosi, BMS, Galvani, Genentech, Gilead, GSK, InventisBio, Janssen, Eli Lilly, Novartis, Pfizer, Proviant, Recor, UCB, Vyne; Clinical Study grants: AbbVie, Acceleron, Arthrosi, Biosplice, BMS, Cugene, Flexion, Galvani, Gilead, GSK, Horizon, Idorsia, Janssen, LG Chem, Eli Lilly, Novartis, Pfizer, Proviant, Sankyo, UCB, Viela. 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; DB, SG, SK and MS: employee of R-Pharm, with no R-Pharm stock; JS: Editor-in-Chief of ARD, 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; 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.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.