The current objective criterion for primary endpoints in clinical trials for psoriasis is Psoriasis Area Severity Index 75, as defined by the Food and Drug Administration and clinical trials sponsored by pharmaceutical companies. However, with the advent of the next generation of psoriasis therapeuticsâ€”the anti-interleukin-17 agentsâ€”we have seen landmark Psoriasis Area Severity Index response rates surpassing those of the tumor necrosis factor inhibitors and the interleukin-12/23 inhibitor, stimulating us to now consider the utilization of Psoriasis Area Severity Index 90 and 100 as the new therapeutic benchmarks. In this article, we discuss the published and latest-breaking results on efficacy, safety, and patient-reported outcomes of the anti-interleukin-17 agents that justify our reasoning for dermatologists to now increase therapeutic efficacy expectations to Psoriasis Area Severity Index 90 and 100.
Major milestones in systemic biologics for psoriasis are illustrated in Figure 1. Fifteen years ago, clearance was once deemed an unrealistic expectation.1 In 2003, the United States Food and Drug Administration approved the first biologics for psoriasis: alefacept and efalizumab. These medications were known for their achievement in Psoriasis Area Severity Index (PASI) 50 response,2, 3 which has been argued to be a clinically significant endpoint in the past.4 Over the following years, the tumor necrosis factor (TNF) inhibitors etanercept, infliximab, adalimumab and the first interleukin (IL)-12,23 inhibitor ustekinumab were introduced. This generation of agents allowed for a higher expectation to what serves as the therapeutic benchmark today: PASI 75.
Now, the latest generation of biologicsâ€”the anti-IL-17 agentsâ€”are expanding our frontier in therapeutic strategy once again. Secukinumab was the first-approved in January 2015 in 300 and 150 mg doses, while ixekizumab and brodalumab are undergoing phase 3 trials. As of May 22, 2015, Amgen, Inc. has discontinued its collaboration with AstraZeneca in the co-development and commercialization of brodalumab due to events of suicidal ideation and behavior in the brodalumab program. AstraZeneca has yet to make a decision regarding the future development of brodalumab. For the purposes of this viewpoint, we continue to include brodalumabâ€™s clinical trials results as we highlight the benefits of increasing our therapeutic benchmark to PASI 90 and 100. Multiple studies have demonstrated their ability to achieve never-before-seen significant, rapid, and sustained PASI 90 and 100 response rates, while secukinumab and ixekizumab maintain favorable safety profiles similar to that of the anti-TNF and anti-IL-12,23 agents.5, 6, 7, 8 It is now time for our expectations to reflect this new attainable goal by raising the bar for therapeutic efficacy to PASI 90 and beyond. All clinical trials should begin using PASI 90 and 100 as primary endpoints, and dermatologists should now accept these new therapeutic goals to expect more highly and rapidly effective therapies for psoriasis patients. The notion of increasing to PASI 90 has been contemplated before,9, 10 but now the evidence to incorporate this new standard is compelling.
Improvement in Patient-related Outcomes
All of the anti-IL-17 agents have published results on the association between their impressive clinical responses and improved patient-reported outcomes (PROs). Secukinumab trials showed that PASI 90 response had a higher probability than PASI 75 at achieving meaningful improvements in patient-reported psoriasis symptoms.11 For ixekizumab-treated subjects, groups that achieved PASI 100 and PASI 90-<100 responses had significantly greater health-related quality of life (HRQOL) and pruritus improvements than the PASI <75 and even PASI 75-<90 groups.12 Significantly more brodalumab-treated subjects with PASI 100 compared to PASI 75-<100 response reported no psoriasis symptoms and more of the PASI 100 subjects reported no impairment in HRQOL.13 Since these results were at 12-16 weeks, we await longer duration results, but adalimumab14 and infliximab15 reports have demonstrated similar findings. Moreover, it is imperative to ensure that treatment goals are clinically relevant to patient satisfaction, which serves as a major driver in selecting therapy. There are times when a more modest, bust still clinically significant improvement in psoriasis may be acceptable to patients, given that the alternative agent is cheaper, easier to administer, or safer. Nevertheless, it is important to note that PASI 90 and 100 responses have resulted in significantly greater improvements in Dermatology Life Quality Index (DLQI) than PASI 75.14 A multicenter cross-sectional study showed that patients with clear skin were more likely to report no impact of psoriasis on quality of life than those with almost clear skin.16
Higher and Faster Response Rates Compared With the Previous Generation of Biologics
Numerous clinical trials have already completed or begun active head-to-head comparisons between anti-IL-17 agents and the previous generation of biologics, shown in Table 1. So far, published results show the superiority of secukinumab and brodalumab in PASI responses and PROs over etanercept and ustekinumab, respectively.11, 17 Additionally, preliminary results show secukinumabâ€™s superiority in achieving PASI 90 over ustekinumab.18 Trials comparing ixekizumab to etanercept are currently ongoing. All of these comparisons substantiate the importance of measuring PASI 90, as it identifies a distinct efficacy disparity between the current and new generation of biologics. These efficacy disparities demonstrate better PROs in