ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 10, October 2015, pp 2591–2600 DOI 10.1002/art.39249 C 2015, American College of Rheumatology V

The Efficacy and Safety of Subcutaneous Clazakizumab in Patients With Moderate-to-Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate Results From a Multinational, Phase IIb, Randomized, Double-Blind, Placebo/Active-Controlled, Dose-Ranging Study Michael E. Weinblatt,1 Philip Mease,2 Eduardo Mysler,3 Tsutomu Takeuchi,4 Edit Drescher,5 Alberto Berman,6 Jun Xing,7 Moshe Zilberstein,7 Subhashis Banerjee,7 and Paul Emery8 Objective. Clazakizumab is a humanized monoclonal antibody that binds to the interleukin-6 (IL-6) cytokine. This study was undertaken to evaluate the efficacy and safety of clazakizumab in combination with methotrexate (MTX) or clazakizumab monotherapy versus MTX alone in patients with rheumatoid arthritis (RA) and an inadequate response to MTX. Methods. In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging study, patients were randomized to receive 1) oncemonthly subcutaneous (SC) clazakizumab at 25, 100, or

200 mg plus MTX, 2) once-monthly SC clazakizumab at 100 mg or 200 mg as monotherapy, or 3) MTX plus placebo (i.e., MTX alone). Adalimumab (40 mg) plus MTX was included as an active reference. The primary end point was the American College of Rheumatology 20% (ACR20) improvement response rate at week 12. Secondary end points included ACR20, ACR50, and ACR70 response rates as well as protocol-defined remission rates and Health Assessment Questionnaire disability index scores at weeks 12 and 24. Results. In total, 418 patients were randomized, and baseline characteristics were balanced across the treatment groups. Patients receving clazakizumab had significantly greater ACR20 response rates at week 12 compared with patients receiving MTX alone (76.3%, 73.3%, and 60.0% of patients in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, and 55.0% and 61.0% of patients in the clazakizumab 100 and 200 mg monotherapy groups, respectively, versus

ClinicalTrials.gov identifier: NCT01373151. Supported by Bristol-Myers Squibb. 1 Michael E. Weinblatt, MD: Brigham and Women’s Hospital, Boston, Massachusetts; 2Philip Mease, MD: Swedish Medical Center and University of Washington, Seattle; 3Eduardo Mysler, MD: Organizaci on Medica de Investigaci on, Buenos Aires, Argentina; 4Tsutomu Takeuchi, MD, PhD: Keio University, Tokyo, Japan; 5Edit Drescher, MD: Csolnoky Ferenc Hospital, Veszpr em, Hungary; 6Alberto Berman, MD: Universidad Nacional de Tucuman and Centro Medico Privado de Reumatologıa, Tucuman, Argentina; 7Jun Xing, PhD, Moshe Zilberstein, MD (current address: Sanofi/Genzyme, Bridgewater, New Jersey), Subhashis Banerjee, MD: Bristol-Myers Squibb, Princeton, New Jersey; 8Paul Emery, MA, MD, FRCP: NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK. Dr. Weinblatt has received consulting fees and/or honoraria from Ablynx, Bristol-Myers Squibb, Janssen, Roche, and UCB (less than $10,000 each), and AbbVie and Amgen (more than $10,000 each). Dr. Mease has received consulting fees, speaking fees, and/or honoraria from Biogen Idec, Celgene, Covagen, Crescendo, Genentech, Janssen, Lilly, Merck, Novartis (less than $10,000 each), and AbbVie, Amgen, BristolMyers Squibb, Pfizer, and UCB (more than $10,000 each). Dr. Takeuchi has received consulting fees from AstraZeneea, Eli Lilly, Novartis, Mitsubishi Tanabe, Asahi Kasei, AbbVie, Daiichi Sankyo, Bristol-Myers K. K., and Nipponkayaku (more than $10,000 each) and has received speaking

fees from Diaichi Sankyo, Celtrion, Nipponkayaku, Pfizer Japan, and Takeda (less than $10,000 each), and AbbVie. Astellas, Bristol-Myers K. K., Chugai, Eisai, Janssen, and Mitsubishi Tanabe (more than $10,000 each), and has received grants from AbbVie, Asahikasei, Astellas Pharma, Bristol-Myers K. K., Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, Pfizer Japan, Santen, Taisho Toyama, Takeda, and Sym Bio (more than $10,000 each), and Teijin Pharma (less than $10,000 each). Drs. Xing, and Banerjee own stock or stock options in Bristol-Myers Squibb. Dr. Emery has conducted clinical trials for and provided expert advice to AbbVie, Bristol-Myers Squibb, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, and UCB. Address correspondence to Michael E. Weinblatt, MD, Rheumatology and Immunology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115. E-mail: [email protected]. Submitted for publication November 18, 2014; accepted in revised form June 11, 2015. 2591

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39.3% of patients receiving MTX alone; P < 0.05 for all comparisons). At week 24, all clazakizumab groups had higher ACR20, ACR50, and ACR70 response rates and higher remission rates compared with MTX alone. Rates of serious adverse events ranged from 8.3% to 13.6% in the clazakizumab treatment groups, compared with 3.3% in the MTX alone group. Changes in laboratory data were consistent with the pharmacologic effects of IL-6 blockade. Conclusion. In patients with RA and an inadequate response to MTX, treatment with clazakizumab in combination with MTX or clazakizumab monotherapy was well tolerated, and patients achieved significant improvements in disease activity, including higher rates of remission, as compared with patients receiving MTX alone. Interleukin-6 (IL-6) is a pleiotropic proinflammatory cytokine that regulates cellular functions both through a classic signaling process, by binding to a membranebound IL-6 receptor, and through trans-signaling, by binding to a soluble form of the IL-6 receptor (1). IL-6 dysregulation can have a pathogenic role in autoimmune disease by contributing to immunomodulatory suppression of T regulatory cells and increasing autoantibody production in B cells, and also by inducing joint damage via osteoclastmediated bone resorption (2–5). Increased IL-6 levels are found in the synovial fluid of patients with rheumatoid arthritis (RA), and this finding is correlated with the extent of disease activity and joint damage (6–8). The only agent currently approved to target and block the IL-6 and IL-6 receptor interaction is tocilizumab, a humanized antibody that binds to the IL-6 receptor (9,10). Clazakizumab (BMS945429; ALD518) is a humanized monoclonal antibody currently in development for the treatment of RA. It binds circulating IL-6 cytokine rather than the IL-6 receptor (10,11), blocking both classic signaling and trans-signaling. Clazakizumab is between 3- and 120-fold more potent than tocilizumab in vitro (10). A phase IIa, dose-ranging study demonstrated that intravenous clazakizumab was associated with rapid and significant improvements in disease activity and health-related quality of life (HRQOL) (11). Modelbased simulations of pharmacokinetic and pharmacodynamic data from the phase IIa study were used to predict efficacy responses and develop a range of subcutaneous (SC) clazakizumab doses for further investigation. In this subseqeunt phase IIb, dose-ranging study, we aimed to characterize the efficacy and safety of once-monthly SC clazakizumab, with or without methotrexate (MTX), in patients with an inadequate response to MTX. Adalimu-

WEINBLATT ET AL

mab was included as a reference arm, because it represents the current standard of care as an anti–tumor necrosis factor (anti-TNF) therapy (12). PATIENTS AND METHODS Study design. This randomized, double-blind, placebocontrolled (double-dummy), active-comparator, dose-ranging study was conducted across 115 sites in 19 countries (US, Canada, Argentina, Brazil, Mexico, The Netherlands, Belgium, France, Italy, Germany, Czech Republic, Spain, Hungary, South Africa, Russia, Poland, South Korea, Taiwan, and Japan). Data from the initial 24-week, double-blind, dose-ranging phase of this study are reported herein. This study was conducted in accordance with the Declaration of Helsinki, the ethics principles of the European Union Directive, and the US code of Federal Regulations, and was performed in accordance with the Guidelines for Good Clinical Practice. The study protocol was approved by the investigational review board at each study center. All patients provided written informed consent. Inclusion/exclusion criteria. The study included adults (ages $18 years) with moderate-to-severe active RA (meeting the American College of Rheumatology [ACR] 1987 classification criteria or the ACR/European League Against Rheumatism [EULAR] 2010 classfication criteria [13,14]) with a minimum disease duration of 16 weeks and an inadequate response to MTX. Patients were required to have an ACR global functional status class of 1–3 (15), swollen joint count (SJC) of $6 (of 66 joints assessed), tender joint count (TJC) of $6 (of 68 joints assessed), synovitis in at least 1 hand or wrist joint, and a high-sensitivity C-reactive protein (hsCRP) level of $0.8 mg/dl. Patients were required to have been receiving MTX for at least 3 months at a minimal weekly dose of 15 mg (10 mg was permitted only in those patients who did not respond to $15 mg/week, and the dose was reduced for toxicity/intolerability), and to have been receiving a stable dose for 4 weeks before randomization; other disease-modifying antirheumatic drugs (DMARDs) were to be washed out. Exclusion criteria included the following features: documented diagnosis of juvenile RA, prior exposure to other biologic treatments for RA, treatment with intramuscular (IM) or intraarticular (IA) corticosteroids within 4 days of randomization, active or recent bacterial, fungal, or viral infection, autoimmune disease other than RA, symptomatic diverticulosis/ diverticulitis, perforated diverticular diseases, or small bowel and/or upper gastrointestinal perforation, severe, progressive or uncontrolled other major medical illness, and clinically significant hepatobiliary, hematologic, or other laboratory abnormalities. Moreover, patients were excluded if they were considered to be at risk of tuberculosis (TB), including those with clinical, radiographic, or laboratory evidence of active TB or those with a history of active TB within 3 years, even if they had received treatment. The presence of latent TB was excluded at the screening visit by purified protein derivative skin testing or an interferon-g–release assay (QuantiFeron), together with a chest radiograph. Randomization. After screening, eligible patients were equally randomized and treated in 1 of 7 treatment arms: 1) clazakizumab 25 mg SC every 4 weeks plus MTX; 2) clazakizumab 100 mg SC every 4 weeks plus MTX; 3) clazakizumab

CLAZAKIZUMAB IN MODERATE-TO-SEVERE RA

200 mg SC every 4 weeks plus MTX; 4) clazakizumab 100 mg SC every 4 weeks plus placebo in place of MTX (i.e., clazakizumab monotherapy); 5) clazakizumab 200 mg SC every 4 weeks plus placebo in place of MTX (i.e., clazakizumab monotherapy); 6) adalimumab 40 mg SC every 2 weeks plus MTX; or 7) placebo plus MTX (i.e., MTX alone). Randomization was stratified by ethnicity (Japanese living in Japan versus all other patients). Following randomization, patients in the MTX treatment arms continued the dose that was being administered at the time of trial entry. Decreases in MTX dose were permitted only if there were safety concerns. All patients received concomitant folic acid therapy to minimize MTX toxicity. Patients randomized to receive clazakizumab monotherapy stopped their personal supply of MTX on day 1 and received placebo in place of MTX. Both the MTX and placebo were provided by Bristol-Myers Squibb. Stable low doses of corticosteroids were permitted, with dose changes allowed after week 12 and with a maximum allowed dosage of 10 mg/day prednisone equivalent. In addition, the following rescue therapies were allowed after week 12 but not within 4 weeks of the assessment at week 24: single IM or IA injection of a corticosteroid or addition of azathioprine, sulfasalazine, hydroxychloroquine, or chloroquine. Stable doses of nonsteroidal antiinflammatory drugs were permitted, and the dose could be changed only after week 12. Patients who did not achieve $20% reduction in the SJC and TJC, despite use of the permitted rescue therapies, were eligible to receive open-label clazakizumab 200 mg SC every 4 weeks plus MTX during weeks 13–24. Assessments. The primary objective of the study was to compare the efficacy of SC clazakizumab administered with or without MTX and the efficacy of MTX alone, with efficacy assessed as the ACR 20% (ACR20) improvement response rates (16) at 12 weeks. Additional measures of efficacy at 12 and 24 weeks for all treatment arms were as follows: ACR20, ACR50, and ACR70 improvement response rates, changes in components of the ACR core set of disease activity measures (TJC, SJC, patient’s global assessment of disease activity, pain, and physical function, physician’s global assessment of disease activity, hsCRP level) (17), Disease Activity Score in 28 joints using the CRP level (DAS28-CRP) (18), Clinical Disease Activity Index (CDAI) (19), Simplified Disease Activity Index (SDAI) (20), Boolean-defined remission rates according to the ACR/EULAR provisional definition of remission in RA clinical trials (21), and HRQOL (assessed using the Health Assessment Questionnaire [HAQ] disability index [DI] [22]). The HAQ DI response among patients with RA was defined as a reduction in the HAQ DI score of $0.22 from baseline. Protocol-defined remission cutoff thresholds were a DAS28CRP level of ,2.6 (protocol-defined DAS-based remission), CDAI score of #2.8, SDAI score of #3.3, and ACR/EULAR Boolean–based remission. Efficacy assessments were performed at weeks 1, 2, and 4, and every 4 weeks thereafter. Safety assessments included adverse event (AE) monitoring, laboratory values, physical examinations, vital signs, electrocardiograms, and immunogenicity. Laboratory abnormalities were captured and reported as AEs or serious AEs (SAEs), including those that required the patient to discontinue or interrupt the study medication or to receive specific corrective therapy. Elevations in aminotransferase levels (aspartate aminotransferase or alanine aminotransferase [ALT] level .3 times the upper limit of normal) and a concomitant total bilirubin level .2 times the

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upper limit of normal, without any other immediately apparent possible cause, were considered an SAE. All SAEs that occurred during screening, treatment, or within 6 months after treatment discontinuation were recorded. Statistical analysis. Baseline demographics and clinical characteristics were summarized according to treatment group. For statistical testing of the primary end point of the ACR20 response rate at week 12, we used the DunnettTamhane step-up testing procedure for 5 comparisons between the clazakizumab treatment arms and MTX alone in all randomized patients who had received at least 1 dose of the study medication (the modified intent-to-treat population), to control the overall Type I error rate of 0.05 (one-sided). All patients who discontinued treatment or who received rescue therapy ($1 DMARD added or $2 doses of IM or IA corticosteroids after week 12) were counted as nonresponders at all scheduled visits subsequent to the point of discontinuation or time of rescue treatment. For the primary end point of the ACR20 response rate at week 12, assuming a response rate of 30% in patients receiving MTX alone (with a 5 0.01), 58 patients per treatment arm (406 patients in total) was the sample size calculated to provide .95% power to detect an increase in treatment response of 35% over MTX alone. In general, the binary efficacy measures (e.g., ACR20/ ACR50/ACR70 response rates, remission rates) were summarized as point estimates and associated confidence intervals within and between treatment groups. The change from baseline summaries of continuous efficacy measures (e.g., ACR components, DAS28-CRP, HAQ DI scores) were provided using linear mixed model analysis, and the observed data were included in the analysis, assuming missingness at random. The evaluation of drug safety was based on the frequency of AEs, vital signs, and laboratory abnormalities (in the astreated population; i.e., all patients who received at least 1 dose of study medication). No formal statistical testing was performed on safety end points. Temporal changes in HRQOL were assessed, and descriptive statistics were provided. The study was not powered for comparisons between clazakizumab and adalimumab. A post hoc analysis was carried out to compare the efficacy of adalimumab plus MTX with MTX alone at week 12, by calculating the ACR20 response rate.

RESULTS Patient disposition. A total of 418 patients were randomly assigned to a treatment group and received at least 1 dose of study medication (Figure 1). By week 24, 371 patients remained in the study (88.8% of those initially randomized). Lack of efficacy (in 19 patients) was the main reason for discontinuation, the majority of those occurring in the MTX alone arm. Overall, the clazakizumab 25 mg plus MTX group had the fewest discontinuations, with no patients discontinuing due to AEs or lack of efficacy with this dose. Demographic and disease characteristics of the patients. Baseline demographic features were well balanced across the treatment arms (Table 1). In total, 82% of the patients were female and 77% were white.

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Figure 1. Disposition of patients. * 5 1 patient randomized to receive clazakizumab (CLZ) 25 mg plus methotrexate (MTX) and 1 patient randomized to receive clazakizumab 200 mg plus MTX completed the first 12 weeks, but did not subsequently receive study medication. These patients did not complete week 24 and were not classified as discontinuations. ADA 5 adalimumab.

The mean age was 50.4 years, and the mean disease duration was 5.9 years. Clinical characteristics were typical for this type of RA population (Table 1). The mean weekly dose of MTX at baseline was 16.4 mg (11.1 mg

Table 1.

in Japan; n 5 58). There were no major differences in disease characteristics between the treatment arms. Efficacy. Primary end point. A significantly greater proportion of patients who received clazakizu-

Baseline characteristics of the study patients* CLZ 25 mg CLZ 100 mg CLZ 200 mg 1 MTX 1 MTX 1 MTX (n 5 59) (n 5 60) (n 5 60)

Age, years Female, no. (%) Race, no. (%) White Japanese African American Other Disease duration, years TJC (68 joints assessed) SJC (66 joints assessed) Patient’s global assessment of pain, 0–100 Patient’s global assessment of disease activity, 0–100 Physician’s global assessment of disease activity, 0–100 Patient’s assessment of physical function, HAQ DI score hsCRP, mg/liter DAS28-CRP RF1, no. (%) MTX dosage, mg/week

CLZ 100 mg (n 5 60)

CLZ 200 mg (n 5 59)

ADA 1 MTX (n 5 59)

MTX (n 5 61)

Total (n 5 418) 50.4 6 12.2 343 (82.1)

47.4 6 11.0 46 (78.0)

49.9 6 14.0 53 (88.3)

46.4 6 11.9 49 (81.7)

55.0 6 12.2 52 (86.7)

50.0 6 12.5 49 (83.1)

52.8 6 11.4 48 (81.4)

51.4 6 11.0 46 (75.4)

43 (72.9) 8 (13.6) 1 (1.7) 7 (11.8) 5.0 6 5.6 23.3 6 14.76 14.0 6 9.70 63.7 6 25.25

46 (76.7) 8 (13.3) 2 (3.3) 4 (6.7) 5.6 6 6.1 24.9 6 16.30 15.0 6 8.11 59.8 6 19.63

50 (83.3) 8 (13.3) 1 (1.7) 1 (1.7) 6.0 6 7.2 25.2 6 13.61 16.9 6 10.37 64.1 6 21.52

47 (78.3) 46 (78.0) 9 (15.0) 8 (13.6) 2 (3.3) 2 (3.4) 2 (3.3) 3 (5.1) 7.4 6 6.8 5.0 6 5.5 26.5 6 14.96 29.8 6 17.75 15.9 6 9.77 17.9 6 11.86 64.1 6 24.64 65.4 6 27.18

47 (79.7) 9 (15.3) 0 2 (3.4) 6.1 6 7.5 30.0 6 16.10 18.0 6 11.14 72.1 6 18.51

43 (70.5) 322 (77.0) 9 (14.8) 59 (14.1) 5 (8.2) 13 (3.1) 4 (6.6) 24 (5.7) 6.4 6 8.1 5.9 6 6.8 28.5 6 15.69 26.9 6 15.68 18.3 6 10.95 16.5 6 10.36 65.9 6 18.68 65.0 6 22.52

58.1 6 25.33

61.6 6 19.56

61.2 6 23.06

62.5 6 23.39 62.7 6 25.94

71.5 6 18.32

64.4 6 19.05 63.1 6 22.46

58.9 6 17.46

60.2 6 17.74

61.8 6 16.85

63.8 6 17.10 64.5 6 15.40

66.3 6 17.55

62.1 6 14.10 62.5 6 16.71

1.5 6 0.78

1.5 6 0.75

1.4 6 0.77

23.0 6 25.91 5.7 6 1.01 47 (79.7) 16.6 6 3.1

22.0 6 20.65 5.8 6 0.94 45 (75.0) 16.1 6 4.4

23.5 6 20.12 5.8 6 0.90 46 (76.7) 16.7 6 3.9

1.6 6 0.70

1.7 6 0.67

25.4 6 30.27 25.1 6 29.34 5.9 6 1.06 6.1 6 1.06 51 (85.0) 53 (89.8) 15.5 6 3.5 16.3 6 4.0

1.9 6 0.64 29.6 6 29.14 6.3 6 1.11 48 (81.4) 16.3 6 4.1

1.6 6 0.60

1.6 6 0.71

24.0 6 19.95 24.6 6 25.30 6.1 6 0.91 5.9 6 1.01 47 (77.0) 337 (80.6) 17.5 6 4.2 16.4 6 3.9

* Except where indicated otherwise, values are the mean 6 SD. CLZ 5 clazakizumab; MTX 5 methotrexate; ADA 5 adalimumab; TJC 5 tender joint count; SJC 5 swollen joint count; HAQ DI 5 Health Assessment Questionnaire disability index; hsCRP 5 high-sensitivity C-reactive protein; DAS28-CRP 5 Disease Activity Score in 28 joints using CRP level; RF 5 rheumatoid factor.

CLAZAKIZUMAB IN MODERATE-TO-SEVERE RA

mab (all doses) achieved ACR20 responses at week 12 as compared with patients who received MTX alone (Figure 2A). At week 12, the ACR20 response rates were 76.3%, 73.3%, and 60.0% in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, 55.0% and 61.0% in the clazakizumab 100 and 200 mg monotherapy groups, respectively, 76.3% in the adalimumab plus MTX group, and 39.3% in the MTX alone group (P , 0.05 for all comparisons between the clazakizumab groups and MTX alone, and, in a post hoc analysis, for adalimumab plus MTX versus MTX alone). ACR response and core components. After treatment with clazakizumab, ACR20 response rates rapidly increased within 1 week. By week 24, patients receiving any of the doses of clazakizumab achieved higher ACR20, ACR50, and ACR70 response rates than did patients receiving MTX alone, although there was no clear clazakizumab dose response (Figures 2A–C). The response rates with clazakizumab plus MTX therapy and those with clazakizumab monotherapy (100 mg or 200 mg) were numerically similar at week 12, whereas at week 24, the response rates with clazakizumab plus MTX were numerically higher than those with clazakizumab monotherapy (100 mg or 200 mg). At week 24, patients receiving clazakizumab plus MTX achieved the highest ACR70 response rates of all the groups. The ACR70 responses were 27.1%, 40.0%, and 30.0% in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, 16.7% and 25.4% in the clazakizumab 100 and 200 mg monotherapy groups, respectively, 18.6% in the adalimumab plus MTX group, and 6.6% in the MTX alone group (Figure 2C). Analysis of the individual core components of the ACR core set of disease activity measures, including the HAQ DI, showed that there was a consistent and continuous reduction over the 24-week period across all clazakizumab doses (see Supplementary Figure 1, available on the Arthritis & Rheumatology web site at http://onlinelibrary. wiley.com/doi/10.1002/art.39249/abstract). Treatment with a single dose of clazakizumab was associated with rapid onset of symptom relief and a durable suppression of the hsCRP level as compared with treatment with MTX alone or with adalimumab plus MTX. At week 24, the mean changes from baseline in the HAQ DI were 20.68, 20.79, and 20.71 in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, 20.64 and 20.60 in the clazakizumab 100 and 200 mg monotherapy groups, respectively, 20.66 in the adalimumab plus MTX group, and 20.62 in the MTX alone group. The HAQ DI response rates at week 24 (defined as a reduction of $0.22 from baseline) were 72.9%, 65.0%, and 66.7% in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, 51.7%

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*

Figure 2. Change over time by visit (up to week 24) in the American College of Rheumatology 20% (ACR20) (A), ACR50 (B), and ACR70 (C) improvement response rates. The analysis was based on the modified intent-to-treat population. All patients who discontinued therapy or received rescue therapy ($1 disease-modifying antirheumatic drug added or $2 doses of intramuscular or intraarticular corticosteroids after week 12) were counted as nonresponders. CLZ 5 clazakizumab; MTX 5 methotrexate. ADA 5 adalimumab; * 5 Post hoc analysis showed a statistically significant difference at P , 0.001.

and 59.3% in the clazakizumab 100 and 200 mg monotherapy groups, respectively, 71.2% in the adalimumab plus MTX group, and 44.3% in the MTX alone group. Measures of remission. At week 24, all clazakizumab doses provided higher remission response rates than did MTX alone, as determined by multiple definitions of

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Table 2.

WEINBLATT ET AL

Remission rates at weeks 12 and 24* CLZ 25 mg 1 MTX (n 5 59)

CLZ 100 mg 1 MTX (n 5 60)

CLZ 200 mg 1 MTX (n 5 60)

CLZ 100 mg (n 5 60)

CLZ 200 mg (n 5 59)

ADA 1 MTX (n 5 59)

MTX (n 5 61)

Week 12 DAS28-CRP ,2.6† 35.6 (23.4–47.8) 35.0 (22.9–47.1) 26.7 (15.5–37.9) 21.7 (11.2–32.1) 25.4 (14.3–36.5) 20.3 (10.1–30.6) 1.6 (0.0–8.8) CDAI #2.8 11.9 (3.6–20.1) 8.3 (1.3–15.3) 3.3 (0.4–11.5) 8.3 (1.3–15.3) 3.4 (0.4–11.7) 8.5 (1.4–15.6) 3.3 (0.4–11.3) SDAI #3.3 11.9 (3.6–20.1) 8.3 (1.3–15.3) 5.0 (1.0–13.9) 8.3 (1.3–15.3) 6.8 (1.9–16.5) 10.2 (2.5–17.9) 1.6 (0.0–8.8) Boolean definition 8.5 (1.4–15.6) 10.0 (2.4–17.6) 5.0 (1.0–13.9) 6.7 (1.8–16.2) 1.7 (0.0–9.1) 5.1 (1.1–14.1) 3.3 (0.4–11.3) Week 24 DAS28-CRP ,2.6† 49.2 (36.4–61.9) 40.0 (27.6–52.4) 41.7 (29.2–54.1) 25.0 (14.0–36.0) 35.6 (23.4–47.8) 23.7 (12.9–34.6) 11.5 (3.5–19.5) CDAI #2.8 15.3 (6.1–24.4) 21.7 (11.2–32.1) 20.0 (9.9–30.1) 6.7 (1.8–16.2) 6.8 (1.9–16.5) 8.5 (1.4–15.6) 1.6 (0.0–8.8) SDAI #3.3 18.6 (8.7–28.6) 20.0 (9.9–30.1) 23.3 (12.6–34.0) 6.7 (1.8–16.2) 6.8 (1.9–16.5) 8.5 (1.4–15.6) 4.9 (1.0–13.7) Boolean definition 10.2 (2.5–17.9) 13.3 (4.7–21.9) 18.3 (8.5–28.1) 5.0 (1.0–13.9) 5.1 (1.1–14.1) 10.2 (2.5–17.9) 1.6 (0.0–8.8) * Analysis was based on all randomized patients who had received at least 1 dose of study medication (modified intent-to-treat population). All patients who discontinued treatment or received rescue therapy ($1 disease-modifying antirheumatic drug added or $2 doses of intramuscular or intraarticular corticosteroids after week 12) were counted as nonresponders. Values are the percentage of patients (95% confidence interval). CLZ 5 clazakizumab; MTX 5 methotrexate; ADA 5 adalimumab; DAS28-CRP 5 Disease Activity Score in 28 joints using C-reactive protein level; CDAI 5 Clinical Disease Activity Index; SDAI 5 Simplified Disease Activity Index. † As defined in the clinical protocol (protocol no. IM133001).

remission, including DAS-based remission (a DAS28CRP score of ,2.6), a CDAI score of #2.8, an SDAI score of #3.3, and the ACR/EULAR Boolean definition of remission (Table 2). Safety. Key safety data at week 24 are shown in Table 3. A total of 20 patients (4.8%) discontinued treatment due to AEs up to week 24, of whom 19 were in the clazakizumab 100 mg or 200 mg with or without MTX treatment arms, and 1 was in the adalimumab plus MTX treatment arm (see Supplementary Table 1, available on the Arthritis & Rheumatology web site at http://onlinelibrary. wiley.com/doi/10.1002/art.39249/abstract). There were no discontinuations due to AEs in the clazakizumab 25 mg plus MTX treatment arm. The most frequently occurring AEs leading to discontinuation were elevated transaminase levels, infections, general disorders, administration-site conditions, and skin and subcutaneous tissue disorders. The most common AE in those receiving clazakizumab was injection-site reactions (mild in 128 patients and moderate in 25 patients); these appeared to be dose related. One event of autoimmune nature occurred in the clazakizumab Table 3.

100 mg monotherapy treatment arm (psoriasis) and 1 in the clazakizumab 200 mg monotherapy treatment arm (leukocytoclastic vasculitis). The rates of SAEs ranged from 8.3% to 8.5% of patients in the clazakizumab plus MTX treatment arms, and from 8.3% to 13.6% of patients in the clazakizumab monotherapy treatment arms (9.4% overall for clazakizumab), compared with 3.3% of patients receiving MTX alone and 5.1% of patients receiving adalimumab plus MTX (Table 3). Six patients (1.4%) discontinued treatment due to SAEs; all of these patients had received clazakizumab 100 mg plus MTX or clazakizumab 100 mg or 200 mg monotherapy (1 case each of elevated transaminase levels, septic bursitis, septic tenosynovitis, and medication error, and 2 cases of new-onset pulmonary TB). Pulmonary TB occurred in 1 patient in the clazakizumab 100 mg plus MTX treatment arm and 1 patient in the clazakizumab 200 mg monotherapy treatment arm; both of these occurred in countries where TB is endemic. There were 12 serious infections in clazakizumabtreated patients, including appendicitis, cellulitis, pneu-

Summary of serious adverse events (SAEs) that occurred in .1 patient up to week 24*

SAEs Overdose Appendicitis Cellulitis Pneumonia Pulmonary tuberculosis

CLZ 25 mg 1 MTX (n 5 59)

CLZ 100 mg 1 MTX (n 5 60)

CLZ 200 mg 1 MTX (n 5 60)

CLZ 100 mg (n 5 60)

CLZ 200 mg (n 5 59)

ADA 1 MTX (n 5 59)

MTX (n 5 61)

Total (n 5 418)

5 (8.5) 1 (1.7) 0 2 (3.4) 0 0

5 (8.3) 0 2 (3.3) 0 1 (1.7) 1 (1.7)

5 (8.3) 0 0 0 0 0

5 (8.3) 0 0 0 0 0

8 (13.6) 3 (5.1) 0 0 0 1 (1.7)

3 (5.1) 0 0 0 1 (1.7) 0

2 (3.3) 0 0 0 0 0

33 (7.9) 4 (1.0) 2 (0.5) 2 (0.5) 2 (0.5) 2 (0.5)

* Analysis was based on all patients who had received at least 1 dose of study medication (as-treated population). Values are the number (%) of patients with the event. CLZ 5 clazakizumab; MTX 5 methotrexate; ADA 5 adalimumab.

CLAZAKIZUMAB IN MODERATE-TO-SEVERE RA

Table 4.

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Shifts in liver enzyme, LDL, and neutrophil levels from baseline to week 24* Laboratory test, toxicity grade

ALT No. of patients assessed .1–3 3 ULN .3–5 3 ULN .5–8 3 ULN .8 3 ULN AST No. of patients assessed .1–3 3 ULN .3–5 3 ULN .5–8 3 ULN .8 3 ULN Total bilirubin No. of patients assessed .1.0–1.5 3 ULN .1.5–2.0 3 ULN .2.0–3.0 3 ULN .3.0 3 ULN LDL No. of patients assessed ,130 mg/dl at baseline and $130 mg/dl up to 24 weeks Lowest postbaseline neutrophil level† No. of patients assessed ,0.5 3 109/liter 0.5–,1.0 3 109/liter 1.0–,1.5 3 109/liter $1.5 3 109/liter

CLZ 25 mg 1 MTX (n 5 59)

CLZ 100 mg 1 MTX (n 5 60)

CLZ 200 mg 1 MTX (n 5 60)

CLZ 100 mg (n 5 60)

CLZ 200 mg (n 5 59)

ADA 1 MTX (n 5 59)

MTX (n 5 61)

Total (n 5 418)

54 25 (46.3) 2 (3.7) 2 (3.7) 0

54 24 (44.4) 7 (13.0) 1 (1.9) 0

54 31 (57.4) 9 (16.7) 2 (3.7) 0

55 21 (38.2) 1 (1.8) 0 0

53 27 (50.9) 0 0 0

47 11 (23.4) 0 0 0

51 11 (21.6) 1 (2.0) 0 0

368 150 (40.8) 20 (5.4) 5 (1.4) 0

55 22 (40.0) 2 (3.6) 0 0

53 25 (47.2) 2 (3.8) 0 0

59 37 (62.7) 2 (3.4) 0 0

57 11 (19.3) 0 1 (1.8) 0

56 21 (37.5) 0 0 0

51 12 (23.5) 0 0 0

54 8 (14.8) 0 0 0

385 136 (35.3) 6 (1.6) 1 (0.3) 0

57 5 (8.8) 1 (1.8) 0 0

57 8 (14.0) 2 (3.5) 0 0

60 4 (6.7) 2 (3.3) 1 (1.7) 0

58 3 (5.2) 1 (1.7) 1 (1.7) 0

56 5 (8.9) 5 (8.9) 0 0

55 0 1 (1.8) 0 0

55 0 0 0 0

398 25 (6.3) 12 (3.0) 2 (0.5) 0

42 26 (61.9)

44 26 (59.1)

48 25 (52.1)

41 27 (65.9)

41 25 (61.0)

46 18 (39.1)

46 13 (28.3)

308 160 (52.0)

56 0 1 (1.8) 8 (14.3) 47 (83.9)

57 0 2 (3.5) 8 (14.0) 47 (82.5)

57 0 0 6 (10.5) 51 (89.5)

58 0 3 (5.2) 5 (8.6) 50 (86.2)

55 0 1 (1.8) 7 (12.7) 47 (85.5)

1 1 2 50

54 (1.9) (1.9) (3.7) (92.6)

53 0 0 2 (3.8) 51 (96.2)

390 1 (0.3) 8 (2.0) 38 (9.7) 343 (88.0)

* Values are the number (%) of patients in the as-treated population with normal laboratory values at baseline. LDL 5 low-density lipoprotein; CLZ 5 clazakizumab; MTX 5 methotrexate; ADA 5 adalimumab; ALT 5 alanine aminotransferase; ULN 5 upper limit of normal; AST 5 aspartate aminotransferase. † Includes only those patients with an available baseline neutrophil value and at least 1 postbaseline value; all patients in this analysis had a neutrophil level of $1.5 3 109/liter at baseline.

monia, atypical pneumonia, bursitis, tenosynovitis, influenza, sepsis, urinary tract infection, pulmonary TB, and Pneumocystis jirovecii (the latter occurring in 1 patient in Japan in the clazakizumab 200 mg plus MTX treatment arm, based on serum b-D-glucan testing). Rates of serious infections were generally comparable between the clazakizumab plus MTX and adalimumab plus MTX treatment arms, and were numerically greater than those in the MTX alone group. There were no unusual or unanticipated SAEs, and there were no deaths, malignancies, or gastrointestinal perforations. Clazakizumab treatment was associated with increased levels of transaminases (mainly when used in combination with MTX), increased levels of lipids and hemoglobin, and decreased numbers of polymorphonuclear neutrophils and platelets. In the clazakizumab plus MTX treatment arms, the mean transaminase levels increased up to days 8–15, followed by a decline and then stabilization with repeat dosing. Increases in the ALT level of .3 times the upper limit of normal were dose dependent and were lower in the clazakizumab

25 mg plus MTX treatment arm and the clazakizumab monotherapy groups than in the clazakizumab 100 mg and 200 mg combination treatment arms (Table 4). There were no cases of Hy’s law to indicate severe druginduced liver injury. In the clazakizumab treatment arms, the mean total cholesterol level increased (without changes in the high-density lipoprotein [HDL]:low-density lipoprotein [LDL] ratio), the mean platelet counts decreased (plateau after day 29), the mean total neutrophil count decreased (plateau on day 15), and the mean hemoglobin values gradually rose (data not shown). None of the patients had marked laboratory abnormalities of a low platelet count (,50 3 109/liter) or low leukocyte count (,2.0 3 109/liter). A low neutrophil count (,1.0 3 109/ liter) occurred in 1 patient (1.7%), 2 patients (3.3%), and no patients in the clazakizumab 25 mg, 100 mg, and 200 mg plus MTX groups, respectively, 3 patients (5.0%) and 2 patients (3.4%) in the clazakizumab 100 mg and 200 mg monotherapy groups, respectively, 2 patients (3.4%) in the adalimumab plus MTX group,

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WEINBLATT ET AL

and no patients in the MTX alone group. At the week 24 time point, positivity for anticlazakizumab antibodies, with respect to the findings at baseline, occurred in 3 patients, 5 patients, and 1 patient in the clazakizumab 25, 100, and 200 mg plus MTX groups, respectively, in 6 patients and 3 patients in the clazakizumab 100 and 200 mg monotherapy groups, respectively, and in no patients in the MTX alone group. DISCUSSION This phase IIb, dose-ranging study evaluated the efficacy and safety of SC clazakizumab alone or in combination with MTX in patients with RA and an inadequate response to MTX. The primary end point was met; ACR20 response rates were statistically significantly higher with all clazakizumab doses compared with MTX alone. All doses of clazakizumab resulted in greater improvements in the ACR20, ACR50, and ACR70 response rates at 12 and 24 weeks as compared with those in patients receiving MTX alone. Initial increases in the ACR20, ACR50, and ACR70 response rates with clazakizumab were rapid, occurring within 8 days. There were also improvements in the individual components of the ACR core set of disease activity measures. A rapid and sustained reduction in hsCRP levels was observed with all clazakizumab doses, which was not seen with MTX alone, and was numerically higher than with adalimumab plus MTX. Treatment with clazakizumab in combination with MTX generally resulted in higher response rates than did clazakizumab monotherapy; however, only doses of 100 mg and 200 mg of clazakizumab were assessed as monotherapy. Although no clear dose response in efficacy measures was seen with clazakizumab and the optimal dose may not yet be known, the clazakizumab 25 mg plus MTX treatment arm provided the best benefit–risk profile. It is possible that a lack of dose response with clazakizumab could be due to maximal binding and neutralization of the IL-6 molecule at the 25 mg SC dose. The doses in this study were selected based on mathematical modelings from a study previously conducted with intravenous clazakizumab (11). An ongoing clinical trial is currently evaluating additional dose ranges to determine the optimal dose for administration in future studies (ClinicalTrials.gov identifier NCT02015520). The most common AEs with the IL-6 receptor– targeted therapy tocilizumab are infections, headache, hypertension, increases in ALT enzyme levels, and increases in LDL cholesterol levels and neutropenia, whereas more serious AEs include opportunistic infec-

tions and gastrointestinal perforations (23–25). Treatment with SC clazakizumab was well tolerated, with laboratory changes consistent with the pharmacologic effects of IL-6 blockade, including elevations in liver function test results and lipid levels, and, in rare instances, occurrence of neutropenia and infections. Of note, similar increases from baseline in the total cholesterol and LDL cholesterol levels have previously been observed in patients with RA who were receiving IL-6 antagonists, including sarilumab (26), olokizumab (27), and tocilizumab (28); these findings are suggestive of a class effect. The ratio of HDL to LDL cholesterol remained relatively constant over the duration of treatment. Larger studies and long-term exposure are necessary to fully evaluate the safety profile of clazakizumab. Moreover, future studies will assess detailed changes in the lipid profiles with clazakizumab. The modest sample sizes of the treatment groups in this phase IIb study are appropriate for this stage of drug development but mean that the present study was not statistically powered to allow comparisons between clazakizumab doses. The results are, however, indicative of appropriate doses and combinations of treatment for further investigation. This study was not powered to be a head-to-head study comparing clazakizumab and adalimumab; adalimumab was included in this study as an active reference. Adalimumab response rates were as expected based on the findings from other studies with this agent (29). This study included patients who had never received treatment with biologic DMARDs; future studies will assess the efficacy and safety of clazakizumab in patients with a range of previous exposure to biologic DMARDs. A dose-ranging study in patients with a previous inadequate response to TNF inhibitors is presently ongoing (ClinicalTrials.gov identifier NCT02015520). In conclusion, all doses of clazakizumab, with or without MTX, were associated with a rapid and significant improvement in disease activity. Clazakizumab was well tolerated, with no unanticipated safety signals and with changes in laboratory data consistent with the known pharmacologic effects of IL-6 blockade. Further studies are warranted to confirm the efficacy signal with clazakizumab seen in this phase IIb trial. ACKNOWLEDGMENTS We would like to thank all of the patients who participated in the study. In addition, we thank the following investigators: Mahmood Ally, MBChB, Rieke Alten, MD, Denis Arniaud, MD, Valderilio Azevedo, MD, Sang-Cheol Bae, MD, PhD, Andre Beaulieu, MD, Francis Berenbaum, MD, Charles Birbara, MD, Francisco J. Blanco, MD, PhD, Ricardo Blanco, MD, PhD, George Bruyn, MD, Mario Cardiel, MD, Tien-Tsai Cheng, MD, Ying-Ming Chiu, MD, PhD, Jung Yoon Choe,

CLAZAKIZUMAB IN MODERATE-TO-SEVERE RA

MD, PhD, Christine Ellen Codding, MD, Ara Dikranian, MD, Anna Dudek, MD, PhD, Patrick Durez, MD, Alicia Eimon, MD, Olga Ershova, MD, PhD, Eugen Feist, MD, Ugo Fiocco, MD, Federico Galvan-Villegas, MD, Mario Garza, MD, Geoffrey Gladstein, MD, Joanna Glogowska-Szelag, MD, Juan Gomez-Reino, MD, PhD, Hitoshi Goto, PhD, Philippe Goupille, MD, Boulos Haraoui, MD, John L. Harshbarger, MD, Emily Jane Herron Box, MD, Toshihiko Hidaka, PhD, Laszlo Hodinka, MD, Chung-Ming Huang, MD, Fedra Irazoque, MD, Mitsuhiro Iwahashi, MD, Juan Angel Jover, MD, Toshihisa Kanamono, MD, Atsushi Kawakami, PhD, Mauro Keiserman, MD, Peter Keszthelyi, MD, Alan J. Kivitz, MD, Hitoshi Kohsaka, MD, Tatsuya Koike, PhD, Mariusz Korkosz, MD, PhD, Alicia Lazaro, MD, Jan Lenaerts, MD, Olga Lesnyak, MD, PhD, Ingrid C. Louw, MD, Charles L. Ludivico, MD, Shue-Fen Luo, MD, Liam Martin, MD, Tsukasa Matsubara, PhD, Ryutaro Matsumura, MD, Pier Luigi Meroni, MD, PhD, Jose Luis Cristian Moreno, MD, Leysan Myasoutova, MD, Evgeny Nasonov, MD, Federico Navarro Sarabia, MD, Savrithree Nayiager, MBChB, Debra Nel, MBChB, Michael Nurmohamed, MD, Richard Olson, MD, Dennis Ozment, MD, SungHwan Park, MD, PhD, Matthias Pierer, MD, Wieslawa Porawska, MD, PhD, Sebastiao Cezar Radominski, MD, Maria RellBakalarska, MD, PhD, Juan Rizo, PhD, Marcos Rosemffet, MD, Andrea Rubbert-Roth, MD, Carlo Salvarani, MD, Thierry Schaeverbeke, MD, Joy Schechtman, DO, Morton Scheinberg, PhD, Antonio Scotton, MD, Marie Sedlackova, MD, William Julius Shergy, MD, Seung-Cheol Shim, MD, PhD, Yoshiki Shiohira, MD, Mikhail Shostak, MD, Neal I. Shparago, DO, Jean Sibilia, MD, Daniel Alberto Siri, MD, Catherine Spargo, MBChB, Ingrid Strusberg, MD, Zoltan Szekanecz, MD, Gabriella Szucs, MD, Yoshiya Tanaka, MD, Guillermo Tate, MD, Hans-Peter Tony, MD, Jean-Luc Tremblay, MD, Seiji Tsuboi, MD, Yukitaka Ueki, PhD, Robert M. Valente, MD, Gabriele Valentini, MD, Jiri Vencovsky, MD, David Whitelaw, MBChB, Antonio Carlos Ximenes, MD, Takashi Yamada, MD, Jorge Zamudio, PhD, Cristiano Zerbini, MD, and Elena Zonova, MD. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Weinblatt had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Weinblatt, Mease, Takeuchi, Drescher, Berman, Zilberstein, Emery. Acquisition of data. Weinblatt, Mease, Drescher, Berman, Xing, Zilberstein, Emery. Analysis and interpretation of data. Weinblatt, Mease, Mysler, Takeuchi, Drescher, Berman, Xing, Zilberstein, Banerjee, Emery.

ROLE OF THE STUDY SPONSOR Professional medical writing and editorial assistance was provided by Jane Bryant at Caudex, which was funded by Bristol-Myers Squibb. Bristol-Myers Squibb facilitated the study design and reviewed and approved the manuscript prior to submission. All authors had full access to the study data, contributed to the interpretation of the results, and had ultimate control over the decision to publish and over the final version of the manuscript submitted for publication.

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