BERLIN – The interleukin-17 blocker ixekizumab demonstrated significant clinical benefit and noteworthy rapid onset of efficacy in a phase II clinical trial in rheumatoid arthritis patients.
The anti-IL-17 monoclonal antibody proved effective both in patients naive to biologic therapy and in prior inadequate responders to tumor necrosis factor (TNF) inhibitors, reported Dr. Mark Genovese, who is professor of medicine at Stanford (Calif.) University.
Dr. Mark Genovese
"We saw ACR 20 responses and DAS28 and C-reactive protein values decrease within 3 days," he observed.
The randomized, double-blind study included 260 biologic-naive subjects and 188 others with an inadequate response to one or more TNF inhibitors. The biologic-naive patients were randomized to subcutaneous ixekizumab at 3, 10, 30, 80, or 180 mg at weeks 0, 1, 2, and every 2 weeks thereafter or to placebo. The TNF inhibitor–refractory patients received ixekizumab at 80 or 180 mg or placebo on the same dosing schedule. Everyone also received methotrexate or another nonbiologic disease-modifying antirheumatic drug.
The prespecified primary end point required by the Food and Drug Administration was the ACR 20 response at week 12. Although all patients in the biologic-naive group had higher ACR 20 response rates than did the placebo-treated controls, there was no clear dose-response effect. Only in subjects on ixekizumab at 30 mg did the difference from placebo attain statistical significance; their ACR 20 rate of 70% was twice than in controls.
In patients with prior inadequate response to anti-TNF agents, both the 80- and 180-mg doses of the anti-IL-17 biologic resulted in ACR 20 response rates of about 40%, roughly twice the rate with placebo.
For the secondary end points of Disease Activity Score based on 28-joint counts (DAS28), Clinical Disease Activity Index, and C-reactive protein titers, moderate to good responses were seen at multiple doses. For example, mean CRP levels remained essentially unchanged over time in the placebo group but dropped by 10.2-11.0 mg/L from a baseline of about 20 mg/L in biologic-naive patients on 30, 80, or 180 mg of ixekizumab. Mean CRP dropped by 5.7 and 8.1 mg/L, respectively, in patients with prior inadequate response to anti-TNF therapy who were assigned to ixekizumab at 80 and 180 mg.
Asked later about the somewhat muddy ACR 20 findings, Dr. Genovese replied, "This isn’t the only trial to date that’s been able to show a much nicer dose-response curve with DAS28 as opposed to ACR 20. While it’s only my personal opinion, it appears to me that the DAS scoring system seems to be a more robust and clinically applicable scoring system for use in outcomes in a dose-response study."
Ixekizumab’s safety profile in the phase II study was "comparable to other biologic therapies," the rheumatologist continued. Attrition was low, with only three treatment discontinuations because of adverse events in the active-treatment arm. Serious treatment-emergent adverse events occurred in 1.7% of controls and 4% of patients on the IL-17 inhibitor. Upper respiratory and urinary tract infections were slightly more frequent in ixekizumab-treated patients; however, no mycobacterial or systemic fungal infections occurred. Neutrophil counts were modestly lower in the ixekizumab group but were unrelated to infection risk.
Dr. Genovese reported receiving research grants from and serving as a consultant to Eli Lilly, which is developing ixekizumab for treatment of rheumatoid arthritis and psoriasis.