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Rheumatoid Arthritis
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Interleukin 6 Inhibition in Rheumatoid Arthritis: Highlight on Olokizumab

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Published Online: Apr 6th 2023 touchREVIEWS in RMD. 2023;2(1):17–27 DOI: https://doi.org/10.17925/RMD.2023.2.1.17
Authors: Eugen Feist, Evgeny Nasonov
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Abstract:
Overview

Rheumatoid arthritis (RA) is a chronic immunoinflammatory rheumatic disease, which manifests as progressive destruction of joints, systemic inflammation of visceral organs and a wide range of comorbidities associated with chronic inflammation. Among the cytokines involved in the pathogenesis of RA and certain other immunoinflammatory rheumatic diseases, the role of interleukin (IL) 6 is of special interest. The introduction of the monoclonal antibodies tocilizumab and later sarilumab, both of which block the IL-6 receptor, into clinical practice was an important achievement in the treatment of immunoinflammatory rheumatic diseases at the beginning of the 21st century. The humanized monoclonal antibody against IL-6, olokizumab, provides a new mode of action by direct inhibition of IL-6. This article reviews new data on the efficacy and safety of olokizumab in RA and the prospects of its use in rheumatology.

Keywords

Biological disease-modifying antirheumatic drugs, disease-modifying antirheumatic drugs, interleukin 6, interleukin 6 inhibitors, monoclonal antibodies, olokizumab, rheumatoid arthritis, tocilizumab

Article:

Article highlights

  • Treatment of rheumatoid arthritis remains a challenge, and new interleukin (IL) 6 inhibitors deserve special attention.

  • IL-6 provides pleiotropic effects not only on the pathogenesis of rheumatoid arthritis but also on its comorbidities.

  • The humanized monoclonal antibody olokizumab has special mode of action by directly suppressing IL-6 (site III).

  • The safety and efficacy of olokizumab were confirmed in large international randomized trials both in biologically naïve patients and in patients with resistance to tumour necrosis factor alpha inhibitors.

Rheumatoid arthritis (RA) is a chronic immunoinflammatory rheumatic disease characterized by the progressive destruction of joints, systemic inflammation of visceral organs and a wide range of comorbidities associated with chronic inflammation.1 The RA pathogenesis is determined by complex relationship between environmental factors and genetic predisposition leading to an autoimmune response before or in parallel to the development of the clinical symptoms of the disease.2–4 Along with the development of novel drugs, the strategy of RA pharmacotherapy has been improved based on the concepts of ‘treat to target5,6 and window of opportunity7 ‘ by diagnosing RA early. This approach determines the possibility of initiating active, tightly controlled anti-inflammatory therapy with diseasemodifying antirheumatic drugs (DMARDs), primarily methotrexate and, if necessary, with subsequent biological disease-modifying antirheumatic drugs (bDMARDs).8 However, despite significant progress in the early diagnosis and treatment of RA,9 which led to a clear improvement in the prognosis for many patients, the issues with RA pharmacotherapy are far from resolved.10 This is due to heterogeneous immunopathogenic mechanisms, both at the onset and during the progression of RA, which complicates personalized therapy.

Among the cytokines involved in the pathogenesis of RA and other immunoinflammatory rheumatic diseases, interleukin (IL) 6 is of special clinical value.11-16 The introduction of the monoclonal antibodies (mAbs) tocilizumab first and then sarilumab, which inhibit the proinflammatory effects of IL-6, into clinical practice was considered a great achievement in the treatment of immunoinflammatory rheumatic diseases at the beginning of the 21st century.14

It is worth remembering that IL-6 is a protein consisting of 184 amino acids, with a molecular weight of 26 kDa, two N-glycosylated sites and four cysteine residues. IL6 was originally described as Bcell differentiation factor. The biological effects and molecular mechanisms of action of IL-6 are determined by its ability to activate the target genes regulating the differentiation, survival, apoptosis and proliferation of various immune and non-immune cells in the human body. Therefore, IL-6 acts as a pleiotropic autocrine, paracrine and hormone-like regulator of various normal and abnormal biological processes (e.g. development of all forms of acute and chronic inflammation, coordination of innate and acquired immunity, metabolism, neurodegeneration, oncogenesis)The pathogenetic effects of IL-6 and potential effects of IL-6 inhibitors are summarized in Table 117–19 and Table 2.20–40 IL-6 expression and synthesis, predominantly by myeloid cells (e.g. macrophages, dendritic cells), are regulated by various transcription factors, such as nuclear factor kappa beta, which are activated by proinflammatory cytokines (e.g. IL-1βtumour necrosis factor alpha [TNFα], IL-17) and pathogenrecognizing Toll-like receptors (Rs), and are controlled by microRNAs, RNA-binding proteins (Roquin, AT-rich interactive domain-containing 5a [Arid5a]), and RNases (Regnase-1), which are all circadian rhythm regulatorsThe physiological concentration of IL-6 is very low (15 pg/mL) but tends to increase rapidly to 1 µg/mL when inflammatory diseases (e.g. RA) or infections (e.g. sepsis, coronavirus disease 2019 [COVID-19]) are present.

Several factors determine the pleiotropic characteristics of IL-6. First, to transmit the intracellular signal, IL-6 binds to the α-chain of the heterodimeric IL-6R Cluster of Differentiation 126 (CD126)with a molecular weight of 80 kDa, forming a complex that then binds to the signal coreceptor, the transmembrane protein gp130 [130 kDa glycoprotein; IL-6Rβ]).41 Second, IL-6Rα is only expressed on the surface of certain cells (i.e. hepatocytes, neutrophils, monocytes, adipocytes, myocytes and some populations of lymphocytes), whereas gp130 is expressed by the vast majority of human cells.42 Therefore, IL-6 shows a high affinity for IL-6Rα and reacts with gp130 only as part of the IL-6IL-6Rα complex.

The existence of IL-6R in both transmembrane (membrane-bound [m]IL-6R) and soluble forms (sIL-6R) determines the three main forms of IL-6 signalling: classical signalling, trans-signalling and cluster signalling. Classical signalling is mediated by the binding of IL-6 to mIL-6R, whereas trans-signalling is mediated by the formation of the IL-6 complex with sIL-6R, which directly induces the activation of gp130 in cells not expressing mIL-6R. A new IL-6 signalling mechanism, trans-presentation (cluster signalling), has recently been characterized, whereby IL-6 binds to IL-6Rα on the membrane of specific dendritic cells and is presented to gp130 homodimer expressed on the surface of closely spaced T cells.43 This mechanism is believed to play a major role in the implementation of a pathogenic subpopulation of Th17 cells. All IL-6 signalling pathways lead to the activation of the Janus family tyrosine kinase (JAK) pathway, such as signal transducers and activators of transcription 1 (STAT 1) and STAT3, phosphoinositide 3-kinases, mitogen-activated protein kinase and AMP-activated protein kinase, regulating the synthesis of a wide range of biologically active mediators.44 Trans-signalling (and trans-presentation) is believed to be involved in the development of proinflammatory effects of IL-6, whereas classical signalling is largely involved in the physiological regulation of homeostasis and inflammation resolution.

Table 1: Pleiotropic effects of interleukin 6 potentially involved in the pathogenesis of rheumatoid arthritis and concomitant comorbidities17–19

Effects

Role in pathogenesis

Effect of IL-6 inhibition

Immune

Proinflammatory

  • Enhancement of B-cell differentiation and antibody synthesis

  • Maturation of plasmablasts to plasma cells (together with IL-10)

  • Differentiation of follicular Th cells (together with IL-21 and IL-23) activating B-cells in the germ centres

  • Differentiation of T cells towards Th2 and Th17 (together with TGFβ and IL-23), suppression of Th1 and T regulation

  • Activation of effector functions of CD8cytotoxic T cells

  • Positive and negative regulation of synthesis of acute phase proteins (e.g. CRP, SAA, fibrinogen) and body temperature

  •  Development of chronic synovitis and proliferation of fibroblast-like synoviocytes, enhancement of angiogenesis

  •  Protection against bacterial, fungal and viral infections

  •  Suppression of systemic and local inflammation and immune disorders

  •  Increased risk of infectious complications

Anti-inflammatory

  • Regulation of neutrophil traffic to inflammation site, suppression of chemokine synthesis and neutrophil apoptosis

  • Inhibition of synthesis of pro-inflammatory cytokines (TNF-α and IL-1β), enhancement of synthesis of anti-inflammatory cytokines (IL-10, IL-1Ra)

  • Polarization of macrophages towards M2 having suppressive properties (inhibition of activation and proliferation of CD4lymphocytes, formation of activated T cells)

  • Amyloidosis, fever

  • Reduced risk of amyloidosis; normalization of body temperature

  • Inadequate efficacy and development of resistance to therapy?

 Musculoskeletal

Catabolic

  •  Induction of osteoclast differentiation (induction of RANKL synthesis)

  •  Destruction of muscle fibres

Anabolic

  •  Hypertrophy of skeletal muscles by increasing proliferation and differentiation of satellite cells

  •  Destruction of cartilage, development of bone erosion and loss of bone tissue

  •  Rheumatoid cachexia

  •  Slowing down progression of cartilage destruction, bone erosion formation, BMD stabilization

  •  Building muscle mass by means of physical exercise

Haematological

  • Stimulation of synthesis of hepcidin (hormone-like peptide) inhibiting iron absorption

  • Activation of megakaryocytopoiesis by enhancing expression of thrombopoietin in hepatocytes

  • Increased neutrophil migration towards IL-8 expressing cells

  •  Anaemia of chronic inflammation

  •  Thrombocytosis

  •  Transient neutropenia

  •  Treatment of anaemia of chronic inflammation

  • Reduction of platelet count

 Neuronal

  •  Dysregulation of hypothalamuspituitaryadrenal axis (cortisol production)

  •  Increased expression of gp130 on dorsal horn neuronal cells

  •  Depression, tiredness, sleep disorders, appetite disorders

  •  Hyperalgesia

  •  Improvement in qualityoflife parameters of patients

 Cardiovascular and endocrine

  •  Activation of endothelial cells, impairment of lipid and carbohydrate metabolism

  •  Atherosclerosis, insulin resistance, risk of diabetes mellitus

  •  Increased lipid concentration

  •  Normalization of endothelium-related vasodilation and arterial stiffness

  •  Decrease in HbA1c concentration, stabilization of glucose concentration

  •  Body weight increase

BMD = bone mineral density;CRP = C-reactive protein;HbA1c = glycated haemoglobin;IL = interleukin;M2 = alternatively activated macrophage;RANKL = receptor activator of nuclear factor kappa-B ligand;SAA = serum amyloid A;TGF = Transforming growth factor;Th = T helper;TNF = tumour necrosis factor.

Table 2: The main characteristics of interleukin 6 inhibitors20–40*

Characteristics

Tocilizumab

Sarilumab

Olokizumab

Molecule

Humanized IgG1 mAb

Human mAb

Humanized IgG4 mAb

Mechanism of action

Binding to soluble and membrane IL-6R

Binding to soluble and membrane IL-6R

Binding to IL-6 site III

Routes of administration

IV, SC

SC

SC

Half-life

13 days (8 mg/kg)

10 days (200 mg)

31 days

Doses

IV

RA  8 mg/kg every 4 weeks (initial dose 4 mg/kg every 4 weeks)

pJIA – 8 or 10 mg/kg every 4 weeks

sJIA – 8 or 12 mg/kg every 2 weeks

COVID-19 – 8 mg/kg (single dose)

GCA – 6 mg/kg every 4 weeks

CRS – 8 or 12 mg/kg every 2 weeks

SC

RA, SSc-ILD and GCA – 162 mg once weekly

pJIA – 162 mg every 2 or 3 weeks

sJIA – 162 mg once weekly or every 2 weeks

150 or 200 mg every 2 weeks

64 mg every 2 or 4 weeks

Formal indications

RA, pJIA, sJIA, GCACRS against CAR-T-cell therapy, COVID-19, SSc-ILD

RA

RА, COVID-19 (approved only in Russia)

Main randomized placebocontrolled studies for RA

  • Resistance to MTX (combination therapy with MTX)

OPTION,20 LITHE,21

MOBILITY,22 KAKEHASI23

CREDO-124

CREDO 225

  • Resistance to csDMARDs (combination therapy with csDMARDs)

TOWARD,26 ROSE,27 SUMMACTA,28 BREVACTA,29

  • Resistance to TNF-α inhibitors

RADIATE30

ADACTA,31 SATORI,32 AMBITION33

U-ACT-EARLY;34 FUNCTION35

TARGET36

CREDO 3,37 Genovese et al.,§38 Takeuchi et al.§39

  • Resistance to MTX (monotherapy)

MONARCH40

  • DMARD-naïve (monotherapy)

*Sirukumab is a human monoclonal antibody designed for the treatment of RA. The clinical development programme was terminated by the manufacturer. This product was not approved by the US Food and Drug Administration due to an imbalance in mortality between sirukumab and placebo groups in phase III.

All trials listed were phase III studies except ADACTA (phase IV) and two phase II studies §(38,39).

CAR-T = chimeric antigen receptor T cell;COVID-19 = coronavirus disease 2019;CRS = cytokine release syndrome;csDMARD = conventional synthetic disease-modifying antirheumatic drugs;GCA = giant cell arteritis;Ig = immunoglobulin;IL = interleukin;IV = intravenous;mAB = monoclonal antibody;p/sJIA polyarticular/systemic juvenile idiopathic arthritis;R = receptor;RA = rheumatoid arthritis;SC subcutaneous;SSc-ILD = systemic sclerosis-associated interstitial lung disease;TNF = tumour necrosis factor.

Currently, several bDMARDs specific to IL-6R and IL-6 have been developed. The most well-characterized ones include tocilizumab (Actemra, RoActemra; F. Hoffmann-La Roche Ltd., Basel, Switzerland), which is a humanized mAb targeting IL-6R,45,46 and sarilumab (Kevzara®; Sanofi and Regeneron Pharmaceuticals, Inc.Paris, France), which is a human mAb targeting IL-6R.47,48 The mAbs that block the activity of IL-6 itself include the human mAbs sirukumab,49,50 the humanized mAbs clazakizumab and satralizumab (Enspryng®; F. Hoffmann-La Roche Ltd., Basel, Switzerland),51 and the chimeric mAb siltuximab (Sylvant®; EUSA Pharma, Hemel Hempstead, UK).52

This article focuses on the humanized mAb olokizumab, which binds to IL-6, developed by R-PHARM (Moscow, Russia) under the license agreement with UCB Pharma (Brussels, Belgium).53 The half-life of the product is 31 daysits bioavailability is 65%, and subcutaneous injection volume is 0.4 mL (for dose of 64 mg).

To understand the mechanism of action of olokizumab, it has to be highlighted that IL-6 contains three conservative conformational epitopes: site I, site II and site III (Figure 1). Site I participates in the formation of the IL-6 complex with IL-6R, and site II is a composite epitope interacting with cytokine-binding homologous gp130 site, with the formation of IL-6RIL-6gp130 trimeric complex. Subsequent interaction between IL-6 site III with the gp130 immunoglobulin-like activation domain consisting of two IL-6RIL-6–gp130 trimers leads to the formation of a complete biologically active hexamer signalling complex activating JAK-STAT. Thus, by specifically blocking site III, the mode of action of olokizumab is special, as it limits the ability of IL-6 to form a hexameric signalling complex, thereby suppressing the activation of the JAK-STAT signalling pathway.14,53

Figure 1: Characteristics of interleukin 6 inhibitors

Ab = antibody; IL = interleukin; R = receptor.

Efficacy and safety of olokizumab for rheumatoid arthritis

CREDO 1

The efficacy and safety of olokizumab were investigated in CREDO 1 (ClinicalTrials.gov identifier: NCT02760368), 24week multicentre randomized controlled trial (RCT) that enrolled 428 patients randomized 1:1:1 to groups receiving olokizumab 64 mg every 2 weeksolokizumab 64 mg every 4 weeks or placebo.24 The primary endpoint was achieving the American College of Rheumatology 20% improvement criteria (ACR20) after 12 weeks. Secondary endpoints included the number of patients with Disease Activity Score-C-reactive protein (DAS28-CRP) of <3.2 at week 12, Clinical Disease Activity Index (CDAI) of 2.8 at week 24, ACR50 response after 24 weeks and changes in Health Assessment Questionnaire-Disability Index (HAQ-DIfrom baseline to week 12.

ACR20 response was achieved in 70.4% of patients treated with olokizumab every 4 weeks, 63.6% of patients receiving olokizumab every 2 weeks and 25.9% of the placebo group (p<0.001) (Table 3).24 Olokizumab had higher efficacy than placebo after 12 weeks, which was maintained for up to 24 weeks. The frequency of DAS28 CRP decrease 3.2 was 33.6% with olokizumab every 2 weeks38.7% with olokizumab every 4 weeks and 3.5% with placebo (p<0.0001 in both comparisons). Significant improvement in physical function (HAQ-DI) was noted after 12 weeks of treatment with olokizumab compared with placebo (olokizumab every 2 weeks-0.54; olokizumab every 4 weeks0.56placebo: 0.20p<0.0001 in both cases). Minimally significant improvement in HAQ-DI (0.22) occurred in 62.2% and 66.2% of patients treated with olokizumab every 2 weeks and every 4 weeks, respectively, compared with 47.6% of patients in the placebo group. The ACR50 response after 24 weeks was reported in 42.7 % of patients receiving olokizumab every 2 weeksin 48.6% of those receiving olokizumab every 4 weeks and in 7.7% of those receiving placebo (p<0.0001 in both cases). Remission (CDAI 2.8) after 24 weeks was achieved in 8.4% of patients treated with olokizumab every 2 weeksin 7.7% of patients treated with olokizumab every 4 weeks and in no patients in the placebo group (p<0.0003 and p<0.0002, respectively). Olokizumab efficacy (ACR20) was not affected by sex, age, body mass index, initial severity of RA, duration of previous methotrexate therapy, detection of antibodies to cyclic citrullinated proteins and rheumatoid factor. In addition, there was a more pronounced positive change in the Short Form-36 mental and physical domains, the Functional Assessment of Chronic Illness Therapy – Fatigue and other qualityoflife parameters.

Table 3: Efficacy of olokizumab compared with placebo in patients with methotrexate-resistant rheumatoid arthritis (CREDO-1) (12 weeks)

Efficacy parameters

Groups of patients

OKZ (every 2 weeks)

N=143

OKZ (every 4 weeks)

N=142

Placebo

N=143

Primary endpoint

ACR20, n (%)

91 (63.6)

<0.0001

100 (70.4)

<0.0001

37 (25.9)

Secondary endpoints

ACR50, n (%)

61 (42.7)

<0.0001

69 (48.6)

<0.0001

11 (7.7)

DAS28-CRP 3.2, n (%)

48 (33.6)

<0.0001

55 (38.7)

<0.0001

5 (3.5)

CDAI 2.8, n (%)

12 (8.4)

<0.001

11 (7.7)

<0.001

0

HAQ-DI, LSM (SE)

0.54 (0.04)

0.56 (0.04)

0.20 (0.04)

ACR(20/50) = American College of Rheumatology improvement criteria (20%/50% improvement);CDAI = Clinical Disease Activity Index;DAS28-CRP = Disease Activity Score-C-reactive protein;HAQ-DI = Health Assessment Questionnaire-Disability Index;LSM = least squares mean;OKZ = olokizumab;SE = standard error.

Most adverse drug reactions (ADRs) were nosevere and occurred in about half of the patients. ADRs leading to discontinuation of treatment were reported in 4.9% of patients who received olokizumab every 2 weeks3.5% of patients who received olokizumab every 4 weeks and in 0.7% of patients who received placebo.24 Injection-related reactions were reported in two patients (1.4%) in each olokizumab group. In total, 20 serious ADRs were reported, 5.6% among patients from both olokizumab groups and 2.8% from patients in the placebo group. The most common serious ADRs were infections, which occurred in 2.8% of patients receiving olokizumab every 2 weeksin 0% of those receiving olokizumab every 4 weeks and of 1.4% in those receiving placebo. The only fatal outcome reported was in a patient receiving olokizumab every 2 weeks and was associated with staphylococcal sepsis resulting in toxic shock. As with treatment with other IL-6 inhibitors, olokizumab was associated with increased lipid levels, although no cardiovascular complications were observed. In very rare cases, moderate thrombocytopenia and neutropenia were reported. Increased serum alanine aminotransferase levels (>3 times the upper limit of normal) were observed in 9.2% of patients treated with olokizumab every 2 weeksin 11.4% of patients treated with olokizumab every 4 weeks and in 5.0% of patients treated with placebo. Antidrug antibodies were found in 4.4% of patients receiving olokizumab every 2 weeks and in 6.6% of patients receiving olokizumab every 4 weeks. Neutralizing antidrug antibodies were not detected.

CREDO 2

Among the RCTs designed to investigate the efficacy of mAb to IL-6R or IL-6, the CREDO 2 study (ClinicalTrials.gov identifier: NCT02760407) is of particular interest because it was not only placebo controlled but also active comparator controlled (adalimumab) in patients with methotrexate resistance.25 This RCT enrolled 1,648 patients with active RA (swollen joint count of 6 out of 66 joints assessedtender joint count of 6 out of 68 joints assessed) who met the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) criteria, with inadequate effect (or intolerance) of methotrexate (12 weeks) at a dose of 1525 mg/week. The patients were randomized (2:2:2:1) to four groups: olokizumab 64 mg every 2 weeks, olokizumab 64 mg every 4 weeksadalimumab 40 mg every 2 weeks or placebo, in all cases added to methotrexate therapy. The primary endpoint was ACR20 response after 12 weeksThe secondary endpoints were non-inferiority of olokizumab compared with adalimumab with respect to an ACR20 response, reduction of percentage of patients receiving olokizumab with a DAS28-CRP of 3.2 compared with both adalimumab and placebo, HAQ-DI changes, ACR50 and CDAI 2.8 (remission).

After 12 weeksthe ACR20 response was reported in 70.3% of patients treated with olokizumab every 2 weeks71.4% of patients treated with olokizumab every 4 weeks66.9% of patients in the adalimumab group and 44.4% of patients in the placebo group (p<0.0001) (Table 4).25 Differences in the efficacy of olokizumab and adalimumab compared with placebo were noticeable after 2 weeks. DAS28-CRP 3.2 was achieved in 45.3% of patients treated with olokizumab every 2 weeks45.7% of patients treated with olokizumab every 4 weeks38.3% of patients treated with adalimumab and 12.8% of patients in the placebo group (all p<0.0001). With olokizumab and adalimumabthe ACR50 response and rate of remission (CDAI 2.8) were more frequent compared with placebo.

Table 4: Efficacy of olokizumab compared with adalimumab and placebo in patients with methotrexate-resistant rheumatoid arthritis (CREDO-2)

Efficacy parameters

Groups of patients

OKZ (every 2 weeks)

N=464

OKZ (every 4 weeks)

N=479

ADA

N=462

Placebo

N=243

Primary endpoint

ACR20, 12 weeks, n (%)

326 (70.3)

<0.0001

342 (71.4)

<0.0001

309 (66.9)

<0.0001

108 (44.4)

Secondary endpoints

ACR50, 24 weeks, n (%)

234 (50.4)

<0.0001

240 (50.1)

<0.0001

214 (46.3)

55 (22.6)

DAS28-CRP 3.212 weeks, n (%)

210 (45.3)

<0.0001

219 (45.7)

<0.0001

177 (38.3)

<0.0001

31 (12.8)

CDAI 2.8, 24 weeks, n (%)

52 (11.2)

0.0008

58 (12.1)

0.0003

60 (13.0)

10 (4.1)

HAQ-DI, 12 weeks, LSM (SE)

0.64 (0.03)

0.61 (0.03)

0.61 (0.03)

0.42 (0.04)

ACR(20/50) = American College of Rheumatology improvement criteria (20%/50% improvement);ADA adalimumab;CDAI = Clinical Disease Activity Index;DAS28-CRP = Disease Activity Score-C-reactive protein;HAQ-DI = Health Assessment Questionnaire-Disability Index;LSM = least squares mean;OKZ = olokizumab;SE = standard error.

In general, ADRs were reported in 68.0% of patients. Infections (upper respiratory tract infection and urinary tract infection) were the most frequent events.25 In most cases, ADRs were mild to moderate and led to discontinuation of treatment in 4.5% of patients treated with olokizumab every 2 weeks6.3% of patients treated with olokizumab every 4 weeks5.6% of patients treated with adalimumab and 3.7% of patients treated with placebo. The incidence of serious ADRs was 4.8%, 4.2%, 5.6% and 4.9%, respectively. The most common serious ADRs were infections: 1.3% occurred in patients who received olokizumab every 2 weeks1.5% in patients who received olokizumab every 4 weeks3.5% in patients who received adalimumab and 1.6% in patients who received placebo. ADRs leading to death occurred in three patients (0.6%) treated with olokizumab every 2 weekstwo patients (0.4%) treated with olokizumab every 4 weeksone (0.2%) treated with adalimumab and one treated with placebo (0.4%). Serious adverse events leading to death were as follows: one case each of stroke, sepsis and septic shock among patients receiving olokizumab every 2 weeks (0.2%); one case each of sepsis and myocardial infarction among patients receiving olokizumab every 4 weeks (0.2%); sepsis in one patient receiving adalimumab (0.2%); and sudden death in one patient receiving placebo (0.4%). Antidrug antibodies were found in 3.8% of patients treated with olokizumab every 2 weeks and in 5.1% of patients treated with olokizumab every 4 weeks. Neutralizing antidrug antibodies were detected in two patients treated with olokizumab every 4 weeks, one of whom lacked treatment ACR20 response.

CREDO 3

The RCT CREDO-3 (ClinicalTrials.gov identifier: NCT02760433was designed to evaluate the efficacy and safety of olokizumab in patients resistant to TNF-α inhibitors.37 The study enrolled 368 patients, who were randomized (2:2:1) to three groups: olokizumab 64 mg every 2 weeksolokizumab 64 mg every 4 weeks and placebo. After 16 weeks, the patients receiving placebo were re-randomized into groups receiving olokizumab 64 mg every 2 weeks and olokizumab 64 mg every 4 weeksPatients had active RA (swollen joint count of 6 out of 66 joints considerd; tender joint count of 6 out of 68 joints considered), met the ACR/EULAR criteria (2010), had received methotrexate 1525 mg/week for 12 weeks prior to screening and had an inadequate response to at least one anti-TNF agent after 12 weeks of treatment. The primary endpoint was ACR20 response after 12 weeks. Secondary endpoints included the number of patients achieving a decrease in DAS28-CRP 2.8 after 12 weeks.

The primary efficacy endpoint (ACR20) after 12 weeks was reported in 60.9% of patients receiving olokizumab every 2 weeks59.6% of patients receiving olokizumab every 4 weeks and in 40.6% of patients receiving placebo (p<0.01 for both comparisons) (Table 5).37 The difference in therapeutic efficacy between the patients receiving olokizumab or placebo was already observed after 2 weeks and persisted for 24 weeksDifferences were also reported between patients receiving olokizumab every 2 weeksolokizumab every 4 weeks and placebo according to DAS28-CRP 3.2 (secondary endpoint) (p<0.0001 and p<0.0035, respectively). Despite the tendency for more pronounced positive changes in HAQ-DI between the patients receiving olokizumab and placebo, these differences were not statistically significant (Table 5). As in CREDO 1, the efficacy of olokizumab (ACR20) was not affected by sex, age, body mass index, initial severity of RA, duration of previous methotrexate therapy, detection of antibodies to cyclic citrullinated proteins and rheumatoid factor. During the re-randomization of patients treated with placebo to the olokizumab groups after 16 weeks, rapid positive changes were reported in all tested endpoints, reflecting therapeutic efficacy. In addition, positive changes in quality of life (mental and physical domains of the Short Form-36 index) were observed in the olokizumab groups.

Table 5: Efficacy of olokizumab compared with placebo in patients with tumour necrosis factor alpha inhibitor-resistant rheumatoid arthritis (12 weeks) (CREDO-3)

Efficacy parameters

Groups of patients

OKZ (every 2 weeks)

N=138

OKZ (every 4 weeks)

N=161

Placebo

N=69

Primary endpoint

ACR20, n (%)

84 (60.9)

<0.01

96 (59.6)

<0.01

28 (40.6)

Secondary endpoints

ACR50, n (%)

46 (33.3)

<0.01

52 (32.3)

<0.01

11 (15.9)

DAS28-CRP 3.2, n (%)

55 (39.9)

<0.001

45 (28.0)

<0.01

8 (11.6)

CDAI 2.8, n (%)

9 (6.5)

<0.001

5 (3.1)

<0.001

0

HAQ-DI, LSM (SE)

0.49 (0.05)

0.025

0.39 (0.04)

0.32 (0.07)

ACR(20/50) = American College of Rheumatology improvement criteria (20%/50% improvement);CDAI = Clinical Disease Activity Index;DAS28-CRP = Disease Activity Score-C-reactive protein;HAQ-DI = Health Assessment Questionnaire-Disability Index;LSM = least squares mean;OKZ = olokizumab;SE = standard error.

The overall incidence up to 24 weeks of treatmen- emergent adverse events (TEAEswas 64.7% in particular 64.3% of patients in the olokizumab every 2 weeks group59.7% of patients in the olokizumab every 4 weeks group and 50.7% of patients in the placebo group.37 Most TEAEs were mild, and infectious complications were the most frequent. Serious TEAEs were reported in 7.0% of patients treated with olokizumab every 2 weeks3.2% patients treated with olokizumab every 4 weeks and no patients in the placebo group. Increased (>3 the upper limit of normal) alanine transaminase levels were observed in 8.7% of patients receiving olokizumab every 2 weeks10.0% of patients receiving olokizumab every 4 weeks and 0% of patients receiving placebo. Non-neutralizing antidrug antibodies were found in 6.9% of patients; there was no association between antidrug antibody detection, efficacy of therapy and development of ADRs.

Discussion

The results of these three large-scale, international phase III randomized, placebo-controlled double-blind studies of olokizumab in RA  CREDO 1,24 CREDO 225 and CREDO 337 – have confirmed the efficacy and safety of IL-6 inhibition and have led to approval by the US Food and Drug Administration.54 It is currently unclear whether the biological and clinical effects of mAbs inhibiting IL-6R or IL-6 itself are different. For example, the administration of mAb to IL-6R while retaining IL-6 in the bloodstream leads to the increase of IL-6 serum concentrations. For mAbs to IL-6 (e.g. olokizumab) induction of IL6 expression has not been observed so far.55 According to the study results, no clear difference was evident between olokizumab and the other IL-6R antagonists for efficacy (Table 6) and safety outcomes (Table 7).20,22,24,25,30,36,37,56–58

Table 6: Comparative efficacy of interleukin 6 inhibitor therapy in rheumatoid arthritis

 

Product (trial name)

Duration, weeks

Groups of patients

Efficacy, %

ACR20

ACR50

ACR70

DAS28-CRP <2.6

CDAI 2.8

Resistance to methotrexate

Tocilizumab (OPTION, phase III)20

24

TCZ 8 mg/kg 4 weeks MTX (n=205)

TCZ 4 mg/kg 4 weeks MTX (n=213)

Placebo MTX (n=204)

58.5*

47.8

26.5

43.9*

31.4

10.8

21.9*

12.2

1.9

27.4*

13.4

0.8

Sarilumab (MOBILITY, phase III)22

52

SAR 200 mg 2 weeks MTX (n=399)

SAR 150 mg 2 weeks MTX (n=400)

Placebo MTX(n=398)

66.4*

58.0

33.4

46.0

37.0

17.0

12.8*

14.8

3.0

34.1*

27.8

10.1

13.8*

10.3

5.0

Levilimab (AURORA, phase II)56

12

LVM 162 mg + МТX1 week (n=35)

LVM 162 mg + МТX2 weeks (n=35)

Placebo MTX (n=35)

77.1*

57.1

17.1

51.4*

31.4

5.7

28.6*

20.0

2.9

11.4*

5.7

2.9

Only change of overall CDAI

Olokizumab CREDO-1 (phase III)24

24

OKZ 64 mg 2 weeks MTX (п=143)

OKZ 64 mg 4 weeks MTX (п=142)

Placebo MTX (n=143)

63.6

70.4

25.9

42.7

48.6

7.7

19.6

22.5

2.1

21.7

28.2

3.5

8.4

7.7

0.0

Olokizumab CREDO-2 (phase III)25

24

OKZ 64 mg 2 weeks MTX (п=464)

OKZ 64 mg 4 weeks MTX (п=479)

Placebo MTX (n=243)

74.1*

71.4

46.5

50.4*

50.1

22.6

28.7*

26.9

11.1

52.2*

53.9

21.8

11.2*

12.1

4.1

Sirukumab (SIRROUND-D, phase III)57

16

SRM 100 mg 2 weeks MTX (n=551)

SRM 50 mg 4 weeks MTX (n=553)

Placebo MTX (n=550)

53.5*

54.8

26.4

33.2*

30.2

12.4

16.3*

14.9

3.4

25.5

26.0

5.6

8.4

7.0

3.1

Resistance to TNF-α inhibitors

Tocilizumab (RADIATE, phase III)30

24

TCZ 8 mg/kg 4 weeks MTX (n=170)

TCZ 4 mg/kg 4 weeks MTX (n=161)

Placebo MTX (n=158)

50.0*

30.4

10.1

28.8*

16.8

3.8

12.4*

5.0

1.3

30.1*

7.6

1.6

Sarilumab (TARGET, phase III)36

24

SAR 200 mg 2 weeks MTX (n=184)

SAR 150 mg 2 weeks MTX (n=181)

Placebo MTX (n=181)

60.9*

55.8

33.7