Psoriasis – ixekizumab
Psoriasis causes real quality of life issues for sufferers and is not easy to treat, but a new monoclonal antibody therapy from Lilly addresses an alternative target
The autoimmune disease psoriasis is not easy to treat, and causes real quality of life issues for patients, with the uncontrolled proliferation of skin keratinocytes often causing scaly plaques to form on the skin. Some symptomatic improvements can be achieved using topical treatments, adherence and side-effects both limit their effectiveness.
Early systemic treatments focused on suppressing the immune response, including cyclosporin and methotrexate, do sometimes have a positive effect, but efficacy is rarely that good, and side-effects are once more an issue. The availability of monoclonal antibody drugs with a disease modifying effect, such as the tumour necrosis factor alpha blockers etanercept, adalimumab and infliximab, means there are now more effective treatment options, but not all patients respond, and in some cases efficacy is lost over time.
An alternative target for monoclonal antibody therapy, Lilly’s ixekizumab, works by interfering with the activity of interleukin-17A, a pro-inflammatory cytokine that has an important role in driving the proliferation and activation of keratinocytes.1 In contrast to another IL-17A antibody that is currently in development, brodalumab, which binds to the IL-17A receptor, ixekizumab binds to IL-17A itself, effectively neutralising the cytokine and preventing it from binding to its receptor.
In a double-blind, placebo-controlled Phase II trial, 142 patients were given subcutaneous injections of 10, 25, 75 or 150mg of ixekizumab or placebo at 0, 2, 4, 8, 12 and 16 weeks.2 After 12 weeks, all doses apart from the lowest gave a significantly greater improvement in psoriasis area and severity index score than placebo – 76–82% of treated patients (excluding the 10mg group) had at least a 75% reduction compared with 7.7% with placebo; 90% and 100% improvements were also good in the treated group, with none achieving these reductions on placebo. Significant differences were observed as early as the first week, and were sustained through 20 weeks. There were no serious adverse events, and adverse event profiles were similar across treated patients and those given placebo.
An open label study has also been carried out to evaluate its long-term efficacy and safety.3 Following the Phase II trial, patients who had achieved less than 75% improvement in PASI score were given open label 120mg doses of ixekizumab every four weeks, and those who had achieved this reduction entered a 12-week treatment-free period, followed by entering the open label extension once response criteria were met.
In all, 103 of the 120 patients who entered the open label extension completed at least 52 weeks of treatment. Those who had responded in Phase II maintained their response; each group had similar response rates at 52 weeks, regardless of the dose they had received during the initial Phase II trial.
It is also being assessed as a potential treatment for rheumatoid arthritis. In a Phase II trial, 260 patients who had not received biologic therapy and 188 who had not responded well to TNF-α were given ixekizumab or placebo at weeks 0, 1, 2, 4, 6, 8 and 10 alongside disease-modifying antirheumatic drugs.4
Response rates as measured by the American College of Rheumatology 20% improvement criteria were significantly better than placebo at week 12 in the TNF-α blocker non-responders, and there was a statistically significant dose-response relationship in those patients who were biologics-naïve.
References
1. M.C. Genovese et al. Arthritis Rheum. 2010, 62, 929
2. C. Leonardi et al. N. Engl. J. Med. 2012, 366, 1190
3. K.B. Gordon et al. J. Am. Acad. Dermatol. 2014, epub ahead of print, DOI: 10.1016/j.jaad.2014.07.048
4. M.C. Genovese et al. Arthritis Rheum. 2014, 66, 1693
