Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


ALD518 (BMS945429), a High Affinity Monoclonal Antibody Directed Against Interleukin-6, Reduces Disease Activity and Achieves Remission in Patients with Rheumatoid Arthritis and Inadequate Response to Methotrexate.

Mease5,  Philip, Strand4,  Vibeke, Shalamberidze6,  Levan, Dimic3,  Aleksandar, Aranda2,   Richard, Smith1,  Jeff

Alder Biopharmaceuticals Inc., Bothell, WA
Bristol-Myers Squibb, Princeton, NJ
Institute of Rehabilitation and Treatment, Niska Banja, Serbia
Stanford University, Palo Alto, CA
Swedish Medical Center and University of Washington, Seattle, WA
V. Tsitlanadze Scientific Practical Centre of Rheumatology, Tbilisi, Georgia

Background:

Interleukin-6 (IL-6) plays a key role in the inflammatory cascade in rheumatoid arthritis (RA). ALD518 (BMS945429) is an asialated, humanized, anti-IL-6 monoclonal antibody with a half-life of ~30 days. ALD518 binds to IL-6 with high affinity, preventing interaction and signaling mediated via soluble and membrane-bound IL-6R. Here, we report the impact of ALD518 on disease activity and DAS28 remission over 16 weeks.

Methods:

Patients with active RA and an inadequate response to MTX were randomized 1:1:1:1 to intravenous ALD518 80, 160 or 320 mg or placebo during this 16-week, double-blind, placebo-controlled Phase II study. Patients received two IV infusions of ALD518 (Day 1 and Week 8), while continuing on stable doses of MTX. The primary efficacy endpoint was ACR 20 responders at Week 12. Disease activity was assessed via DAS28 (CRP) as a secondary endpoint, including mean change from baseline and DAS28-defined remission (score <2.6). Efficacy data were assessed for the modified intent-to-treat population. Safety was monitored throughout. P values for ACR responses are based on Fisher's exact test and for DAS28 classes are based on chi-square tests.

Results:

Of 127 randomized and treated patients, 116 completed the trial. At baseline, mean age was 52.3 years and RA duration was 6.8 years. Mean baseline DAS28 (CRP) scores were 6.3, 6.2, 6.2 and 6.1 in the ALD518 80, 160, 320 mg and placebo groups, respectively. Reductions in DAS28 score and the proportion of patients achieving Low Disease Activity State (LDAS; DAS28 [CRP]<=3.2), remission and ACR 20, 50 and 70 responses were rapidly achieved and greater than placebo for all ALD518 doses at each time point (Table). For all assessments, there was a trend toward greater responses with higher ALD518 doses.

 Time pointALD518 80 mg (N=32)ALD518 160 mg (N=34)ALD518 320 mg (N=28)Placebo (N=33)
DAS28, mean reduction from baseline (see text)Week 4-2.0 (1.2)-2.0 (0.8)-2.4 (1.1)-0.6 (1.0)
 Week 12-2.7 (1.2)-2.5 (1.0)-2.9 (1.3)-0.9 (1.3)
 Week 16-2.7 (1.2)-2.7 (1.0)-3.2 (1.2)-1.1 (1.1)
LDAS (%)Week 410.023.5*28.6*0
 Week 1220.6*33.3*46.1*6.6
 Week 1620.7*50.0*52.0*3.4
DAS28-defined remission (%)Week 410.08.8*17.9*0
 Week 1217.2*21.2*34.6*3.3
 Week 1613.8*28.1*44.0*0
ACR 20 (%)Week 450.0*55.9*71.4*24.2
 Week 1281.3*70.6*82.1*27.3
 Week 1675.0*64.7*82.1*36.4
ACR 50 (%)Week 49.414.728.6*3.0
 Week 1234.4*26.5*50.0*9.1
 Week 1640.6*41.2*50.0*15.2
ACR 70 (%)Week 46.3010.70
 Week 1212.511.825.0*3.0
 Week 1621.917.642.9*6.1
* p<0.05 vs placebo.

Through 16 weeks, serious AEs were reported in two ALD518 patients (both had significant increases in liver enzymes, and discontinued treatment). Increases in ALT >3x upper limit of normal occurred in 12, 6 and 29% of patients in the ALD518 80, 160 and 320 mg groups, respectively. Modest increases in total cholesterol were observed; mean levels at Week 16 were 6.5, 6.4 and 6.0 mmol/L in the ALD518 80, 160 and 320 mg groups, versus 5.4 mmol/L in the placebo group. Nine ALD518 patients had transient Grade II (five in the ALD518 80 mg group and four in the 160 mg group) and two had transient Grade III neutropenia (both in the 80 mg group). There were no serious infections or infusion reactions in any treatment group, and no evident immunogenicity.

Conclusions:

In this Phase II study, the IL-6 inhibitor ALD518 resulted in rapid and significant improvements in disease activity sustained over 16 weeks of assessment in patients with RA and an inadequate response to MTX. ALD518 was well tolerated, with a safety profile consistent with the biology of IL-6 blockade.

Reference:

1Mease, P, et al. Ann Rheum Dis 2010;69(Suppl3):98. Abstract OP013

To cite this abstract, please use the following information:
Mease, Philip, Strand, Vibeke, Shalamberidze, Levan, Dimic, Aleksandar, Aranda,  Richard, Smith, Jeff; ALD518 (BMS945429), a High Affinity Monoclonal Antibody Directed Against Interleukin-6, Reduces Disease Activity and Achieves Remission in Patients with Rheumatoid Arthritis and Inadequate Response to Methotrexate. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :2168
DOI: 10.1002/art.29932

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