Ixekizumab in Moderate to Severe Plaque Psoriasis

I had been running the psoriasis treatment center at Wake Forest University for 10 years when etanercept became available for our patients. It was a life-changing development for me and my patients who had been suffering with the skin lesions, joint pains, and other comorbidities of psoriasis. I thought I’d never see another quantum leap forward in psoriasis treatment again. Then adalimumab gave even great efficacy, and ustekinumab both greater efficacy and, as near as I can tell, greater safety…and all at only 4 shots a year!

Now we have IL-17 inhibitors, which seem to have raised the efficacy bar even further, with secukinumab showing greater efficacy than ustekinumab in a head-to-head trial.1 Wow! This article on ixekizumab reinforces the notion that IL-17 inhibitors are yet another quantum leap forward in efficacy. And it seems this has been achieved with remarkable safety; the only obvious side effect being a modest increased rate of mild to moderate candida infections. Oh, and the possibility of causing or flaring inflammatory bowel disease (IBD).

It is fascinating that there’s so much that can be said about so few cases of IBD that popped up—either new or exacerbation—in patients exposed to ixekizumab (and to the other approved IL-17 inhibitor secukinumab). First, let me say that I personally believe that the exacerbations of IBD in these patients is a real drug-induced phenomenon, not just a statistical fluke. My sense of that is rooted in data from a controlled trial of secukinumab for IBD;2 patients who received secukinumab did worse than the participants in the placebo group. It is very reminiscent of the rare cases of multiple sclerosis (MS) seen in patients on TNF inhibitors. I am convinced TNF inhibitors do cause or exacerbate MS—rarely—because the TNF inhibitor lenercept (you’ve probably never heard of it) was tested in patients with MS in a well-designed, controlled trial,3 and patients in the lenercept group did worse than the patients in the placebo group (which is why you’ve probably never heard of lenercept).

With time, we saw that the risk of MS with TNF inhibitors was quite minimal, and the risk didn’t grow over time. I suspect the same thing will happen with IL-17 inhibitors, but we won’t know for sure until we see more long-term data (so far, 2- and 3-year safety data on secukinumab seem quite reassuring). But, the most interesting aspect of all this to me is the question of how should we present this uncommon/rare risk of IBD to patients (or to ourselves). We could tell patients that about 1 in 400 patients seem to get IBD or a worsening of preexisting disease, or we could tell them 399 out of 400 don’t. While those are mathematically identical, they seem like a night and day difference to the human mind (Figures 1 and 2).

References

1. Thaçi D, Blauvelt A, Reich K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol. 2015;73(3):400-409.
2. Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012;61(12):1693-1700.
3. TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. Neurology. 1999;53(3):457-465. 

Ixekizumab for psoriasis

Ixekizumab (TaltzÒ) is the newest biologic drug approved by the FDA for use in treating moderate-to-severe psoriasis. The authors report both short-term and long-term (60 weeks) clinical efficacy and safety results across the entire phase 3 ixekizumab clinical study program. Over 3800 patients with moderate-to-severe psoriasis were enrolled in three separate, large, international studies. Approximately 90% of patients on ixekizumab achieved PASI 75 at week 12, the highest number yet recorded among all psoriasis therapies for a phase 3 program. Perhaps more importantly, approximately 80% reached clear or near clear on the Physician’s Global Assessment, 70% achieved PASI 90, and 40% were rated as PASI 100 (completely clear); these latter three measures reflect very high degrees of clearance and correspond to very high degrees of quality of life improvements for patients. Regarding safety, oral candidiasis appears to be the most common minor side effect. The possible occurrence of inflammatory bowel disease should also be noted by dermatologists and was reported at a rate of 1-2 patients out of 1,000. Importantly, systemic infections, cancer, and adverse cardiovascular outcomes were not associated with ixekizumab use. In summary, the comprehensive ixekizumab results reported in the NEJM article represent a major milestone in the area of advanced treatment for psoriasis. Because of this, this paper is an exciting “must read” for all dermatologists.

Beginning with the FDA approval of ustekinumab (StelaraÒ) in 2009, nearly all of the pipeline drugs for psoriasis since that time have targeted proteins in the interleukin 23 (IL-23)/T helper cell 17 (Th17) immunologic pathway. Ixekizumab and secukinumab (CosentyxÒ), approved in 2015, both work on this pathway by blocking IL-17A. The IL-23/Th17 pathway, which normally is involved in mucocutaneous defense against extracellular organisms (like C. albicans and S. aureus), is over-active in lesions of psoriasis. Targeting upstream (ie, by blocking IL-23), midstream (ie, by blocking IL-17A), or downstream (ie, by blocking the IL-17 receptor) has proven to be highly efficacious and highly safe for patients with psoriasis. In other words, these targeted approaches are very “psoriasis-specific” and are a step forward from less psoriasis-specific biologics, like TNF blockers, in terms of both safety and efficacy. Looking ahead, biologics that are likely to gain FDA approval in the near future will continue the trend of targeting the IL-23/Th17 pathway and include three IL-23 blockers (tildrakizumab, guselkumab, and risankizumab) and an IL-17 receptor blocker, brodalumab.

Suggested reading:

Gordon KB, Blauvelt A, Papp KA, et al. UNCOVER-1, UNCOVER-2, and UNCOVER-3 Study Groups. Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis. N Engl J Med. 2016. 

Blauvelt A. Ixekizumab: a new anti-IL-17A monoclonal antibody therapy for moderate-to severe plaque psoriasis. Expert Opin Biol Ther. 2016;16:255-263. 

Blauvelt A, Lebwohl M, Bissonnette R. Interleukin-23/interleukin-17A dysfunction phenotypes inform possible clinical effects from anti-interleukin-17A therapies. J Invest Dermatol. 2015;135:1946-1953.