ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1735

A Phase IIb Study Of The Efficacy and Safety Of Subcutaneous Clazakizumab (anti-IL-6 monoclonal antibody) With Or Without Methotrexate In Adults With Moderate-To-Severe Active Rheumatoid Arthritis and An Inadequate Response To Methotrexate

M Weinblatt1, Philip Mease2, E Mysler3, T Takeuchi4, E Drescher5, A Berman6, M Zilberstein7, J Xing7 and P Emery8, 1Brigham and Women's Hospital, Boston, MA, 2Swedish Medical Center and University of Washington, Seattle, WA, 3Organización Médica de Investigación, Buenos Aires, Argentina, 4Keio University, Tokyo, Japan, 5Csolnoky Ferenc Hospital, Veszprém, Hungary, 6Centro Médico Privado de Reumatología, Tucuman, Argentina, 7Bristol-Myers Squibb, Princeton, NJ, 8University of Leeds, Leeds, United Kingdom

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Rheumatoid Arthritis Treatment - Small Molecules, Biologics and Gene Therapy: Efficacy and Safety of Novel Entities

Session Type: Abstract Submissions (ACR)

Background/Purpose: Clazakizumab (claza) is a humanized anti-interleukin-6 (IL-6) monoclonal antibody that potently neutralizes IL-6 signaling. This study evaluated the safety and efficacy of subcutaneous claza with or without MTX versus placebo (pbo) or adalimumab (ada). Methods: Patients with moderate-to-severe RA and an inadequate response to MTX were randomized equally to receive pbo + MTX; 25, 100 or 200 mg claza + MTX; 100 or 200 mg claza without MTX; and ada 40 mg every other week + MTX for 24 weeks. The primary endpoint was ACR 20 response rate at Week 12. Key secondary endpoints at Week 24 were ACR 20, ACR 50 and ACR 70 response rates, Health Assessment Questionnaire-Disability Index (HAQ-DI) improvements and remission defined as Disease Activity Score (DAS)28 (C-reactive protein, CRP) <2.6, Clinical Disease Activity Index (CDAI) <2.8 and Simplified Disease Activity Index (SDAI) <3.3. Results: 418 patients were randomized and received treatment. Baseline characteristics were balanced across the arms; 82% female, mean age 50 years, mean duration of RA 5.9 years, mean DAS28 (CRP) 5.94, and 80% rheumatoid-factor positive. The primary endpoint was met; ACR 20 response rates were statistically significantly higher in all claza arms versus pbo + MTX. All claza treatment groups were associated with improved ACR 20/50/70 response rates, HAQ-DI and remission versus pbo + MTX through Week 24. Rates of remission per DAS28 (CRP) <2.6, SDAI <3.3 and CDAI <2.8 were numerically higher in the claza + MTX arms compared with ada + MTX. Treatment with claza in combination with MTX resulted in higher response rates than monotherapy. However, no clear dose response for efficacy was noted. The rates of serious adverse events ranged from 8.3 to 13.3% in claza arms versus 3.3% for pbo + MTX and 5.1% for ada + MTX. Rates of serious infections were similar as reported for all claza arms and ada versus none in pbo. Claza was associated with mostly mild injection-site reactions, few of which led to discontinuation. As expected based on its mode of action, claza treatment was associated with increased transaminases (mainly in combination with MTX), increased lipids and hemoglobin, and decreased polymorphonuclear neutrophils and platelets.
  Pbo + MTX
(n=61) 		Claza
25mg + MTX
(n=59) 		Claza
100mg + pbo
(n=60) 		Claza 100mg + MTX
(n=60) 		Claza 200mg + pbo
(n=59) 		Claza 200mg + MTX
(n=60) 		Ada
+ MTX
(n=59)
Week 12
ACR 20 (primary endpoint), % (95% CI)
p-value versus pbo 		39.3
(27.1, 51.6)   		78.0
(67.4, 88.5)
<0.001 		55.0
(42.4, 67.6)
0.042 		71.7
(60.3, 83.1)
0.001 		61.0
48.6, 73.5)
0.015 		60.0
(47.6, 72.4)
0.015 		76.3
(65.4, 87.1)
Week 24
ACR 20, % (95% CI) 39.3
(27.1, 51.6) 		83.1
(73.5, 92.6) 		58.3
(45.9, 70.8) 		63.3
(51.1, 75.5) 		57.6
(45.0, 70.2) 		66.7
(54.7, 78.6) 		67.8
(55.9, 79.7)
ACR 50, % (95% CI) 18.0
(8.4, 27.7) 		47.5
(34.7, 60.2) 		36.7
(24.5, 48.9) 		45.0
(32.4, 57.6) 		33.9
(21.8, 46.0) 		43.3
(30.8, 55.9) 		49.2
(36.4, 61.9)
ACR 70, % (95% CI) 6.6
(1.8, 15.9) 		27.1
(15.8, 38.5) 		16.7
(7.2, 26.1) 		38.3
(26.0, 50.6) 		25.4
(14.3, 36.5) 		30.0
(18.4, 41.6) 		18.6
(8.7, 28.6)
DAS 28 (CRP) <2.6, % (95% CI) 13.1
(4.6, 21.6) 		49.2
(36.4, 61.9) 		28.3
(16.9, 39.7) 		41.7
(29.2, 54.1) 		35.6
(23.4, 47.8) 		41.7
(29.2, 54.1) 		23.7
(12.9, 34.6)
CDAI remission, % (95% CI) 1.6
(0.0, 8.8) 		15.3
(6.1, 24.4) 		6.7
(1.8, 16.2) 		20.0
(9.9, 30.1) 		6.8
(1.9, 16.5) 		20.0
(9.9, 30.1) 		8.5
(1.4, 15.6)
SDAI remission, % (95% CI) 4.9
(1.0, 13.7) 		18.6
(8.7, 28.6) 		6.7
(1.8, 16.2) 		20.0
(9.9, 30.1) 		6.8
(1.9, 16.5) 		23.3
(12.6, 34.0) 		8.5
(1.4, 15.6)
HAQ-DI mean change from baseline (SE) –0.6 (0.1) –0.7 (0.1) –0.7(0.1) –0.8 (0.1) –0.6 (0.1) –0.7 (0.1) –0.7 (0.1)
  Conclusion: Claza as monotherapy or in combination with MTX demonstrated efficacy in controlling the signs and symptoms of RA. At Week 24, remission rates with claza + MTX trended higher than with ada + MTX. Its safety profile was consistent with the known pharmacology of IL-6 blockade. Claza is a promising future treatment for RA that warrants further investigation.

Disclosure:

M. Weinblatt,

Bristol-Myers Squibb,

2,

Bristol-Myers Squibb, Roche/Genentech, UCB, Janssen,

5;

P. Mease,

AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Celgene, Crescendo, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, Vertex,

2,

AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Celgene, Crescendo, Genentech, Janssen, Lilly, Merck, Novartis, Pfizer, UCB, Vertex,

5,

AbbVie, Amgen, Biogen Idec, Bristol-Myers Squibb, Crescendo, Genentech, Janssen, Lilly, Pfizer, UCB,

8;

E. Mysler,
None;

T. Takeuchi,

Abott Japan Co., Astellas Pharma, Bristol-Myers K.K., Chugai ,

8;

E. Drescher,
None;

A. Berman,
None;

M. Zilberstein,

Bristol-Myers Squibb,

3;

J. Xing,

Bristol-Myers Squibb,

1,

Bristol-Myers Squibb,

3;

P. Emery,

AbbVie, BMS, Pfizer, UCB, MSD,

5,

AbbVie, BMS, Pfizer, UCB, MSD,

8.

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