• Rheumatoid Arthritis Clinical Trials

Evidence from both animal and human models regarding the proinflammatory cytokine interleukin-17 (IL-17) and the T-helper cell (Th17) that secretes it provides a compelling rationale for therapeutic targeting of IL-17 in rheumatoid arthritis (RA). Ixekizumab (LY2439821) is a humanized monoclonal antibody that is used in the treatment of autoimmune diseases [Peck A and Mellins ED. Infect Immun 2010; Sarkar S and Fox DA. Rheum Dis Clin North Am 2010].

Mark C. Genovese, MD, Stanford University, Palo Alto, California, USA, presented results from an international (75 locations in the United States, Europe, South America, and Asia) Phase 2, 2 Dose-Ranging Study of Multiple Subcutaneous Doses of LY2439821 (an Anti-IL-17 Antibody) in Patients With Active Rheumatoid Arthritis on Concomitant DMARD Therapy [NCT00966875]. Two patient populations were evaluated: biologic disease modifying anti-rheumatic drug [bDMARD]-naïve patients and tumor necrosis factor alpha-inadequate responder [TNFα-IR] patients. To satisfy the TNFα-IR requirement, patients must have been treated with at least one biologic TNFα-inhibitor and had either an insufficient response to at least 3 months of treatment or have been intolerant to treatment, regardless of the treatment duration. All subjects were required to have at least 6 swollen and 6 tender joints and an elevated C-reactive protein (CRP) level. Baseline demographics and clinical characteristics are shown in Table 1.

In this randomized, double-blind study, bDMARD-naïve patients (n=260) received subcutaneous placebo or ixekizumab (3, 10, 30, 80, or 180 mg), and TNFα-IR patients (n=188) received placebo or ixekizumab (80 or 180 mg) at Weeks 0, 1, 2, 4, 6, 8, and 10 with concomitant DMARD therapy. The objectives of the study were to determine the dose-response relationship of ixekizumab in bDMARD-naïve patients, based on the ACR20 response rate (primary) by logistic regression at Week 12. Secondary endpoints included ACR50, ACR70, and ACR20 responders at Week 12 in the TNFα-IR group, Disease Activity Score (DAS) 28 and EULAR28 responses, safety, and tolerability compared with placebo.

“All patients had active disease, significant disability, elevated acute-phase proteins, and fairly high (∼6.0) DAS28-CRP scores,” Dr. Genovese noted.

There was a significant dose-response relationship in bDMARD-naïve patients at Week 12 (p=0.031 using ACR20; p<0.001 using DAS28-CRP). At Week 12, significant ixekizumab-versus-placebo differences were seen for DAS28 and EULAR28 responses in bDMARD-naïve patients and in TNFα-IR patients for all doses, with a rapid onset of efficacy within 1 week after the first dose and with increasing magnitude of reductions with increasing doses. A rapid onset of clinical efficacy (ACR20, DAS28, and CRP values dropped) occurred within 3 days. Clinical disease activity index (CDAI) responses indicated the effects of ixekizumab extend beyond the acute-phase proteins.

There were no deaths. The frequency of treatment-emergent adverse events (AEs) was similar across treatment arms (range: 45% to 62%). More patients experienced infections in the treatment arms (37% combined) compared with placebo (18%), with no observed dose relationship. Treatment-emergent serious AEs occurred in 2 patients in the placebo group (1.7%) and 16 ixekizumab-treatment patients (4.8%). Upper respiratory tract infection, urinary tract infection, systemic allergic/hypersensitivity reaction, injection-site pain, and headache were the most frequent treatment-emergent AEs in both groups. No mycobacterial or systemic fungal infections were observed. Most patients had grade 1 neutrophil counts through Week 12. The safety profile was comparable with that of other biologic therapies.

“It appears that ixekizumab results in significant improvements in symptoms and signs, in both the biologic DMARD-naïve patients as well as the anti-TNF inadequate-responder groups,” Dr. Genovese said.

• © 2012 MD Conference Express®