Journal of Clinical and Aesthetic Dermatology

Plaque-type Psoriasis Supplement 2016

An evidence-based, peer-reviewed journal for practicing clinicians in the field of dermatology

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A Novel Paradigm for Treatment of Moderate-to-severe Plaque-type Psoriasis [JUNE 2016 • VOLUME 9 • NUMBER 6 • SUPPLEMENT 1] SUPPLEMENT TO THE JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY S11 m ore common with secukinumab than with etanercept; however, none resulted in discontinuation of therapy or chronic mucocutaneous candidiasis. A higher rate of candidiasis was observed with the 300mg secukinumab group (4.7%) compared to the 150mg secukinumab g roup (2.3%); all cases of candidiasis resolved on their own or with standard therapy. Of note, very low rates of neutropenia were observed in both the secukinumab groups (1% with Grade 3 neutropenia) and etanercept (0.3% with Grade 4 neutropenia). Finally, anti-secukinumab antibodies were observed in 0.4% of the secukinumab-treated patients. The anti- secukinumab antibodies were not neutralizing, and the antibody presence did not appear to be associated with reduced efficacy or adverse events. Secukinumab versus Ustekinumab: the CLEAR Study Thaci et al 10 published the 16-week analysis from the CLEAR study, a Phase 3b study comparing the efficacy and safety of secukinumab with ustekinumab. Primary objective. The primary objective of the CLEAR study was to determine superiority of secukinumab versus ustekinumab using PASI 90 response at Week 16. Study design and study population. CLEAR is a 52-week, randomized, double-blind, active comparator, parallel-group, superiority Phase 3b study that began in February 2014. The inclusion criteria were adult patients with moderate-to-severe plaque psoriasis who had been inadequately controlled by topical treatments, phototherapy, and/or previous systemic therapy. The key exclusion criteria were prior exposure to any biologics directly targeting IL-17 inhibitors or ustekinumab. The eligible participants were randomized 1:1 to secukinumab 300mg or ustekinumab (per-label dosing of 45mg for patients ≤100kg and 90mg for patients >100kg). In the CLEAR study, a total of 676 subjects were randomized. The baseline demographic and clinical characteristics were balanced between the two study groups. The patients were on average 45 years old, with BMI of 29; approximately 67 percent of patients have had prior systemic treatment. Slight numeric imbalance was observed in the proportion of patients with psoriatic arthritic, with 21 percent and 16 percent in secukinumab and ustekinumab groups, respectively. Outcomes: Coprimary endpoints and key secondary endpoints. With regard to the primary endpoint, at Week 16, 79 percent of patients randomized to the secukinumab and 58 percent of those randomized to the ustekinumab group achieved PASI 90 response (P<0.0001). Several key secondary endpoints were also examined. A significantly greater proportion of secukinumab-treated patients achieved PASI 100 r esponse compared to ustekinumab group at Week 16 (44.3% vs. 28.4%, respectively, p<0.0001). Furthermore, a significantly greater proportion of secukinumab-treated patients achieved PASI 75 and IGA 0 or 1 at Week 16 compared to ustekinumab. W ith respect to efficacy during the initial treatment period, 50 percent of secukinumab-treated patients achieved PASI 75 at Week 4 compared to 21 percent in the ustekinumab arm (P<0.0001). The superiority in efficacy of secukinumab to ustekinumab was also observed with PASI 90, PASI 100, or IGA 0 or 1 at Week 4. Furthermore, the proportion of patients achieving DLQI 0 or 1 was significantly higher in the secukinumab-treated patients compared to ustekinumab-treated patients. Safety. The duration of 16-weeks used in this analysis was likely not long enough to detect rare events or events with long latency periods. Nevertheless, the 16- week safety analysis showed that, overall, secukinumab exhibited a safety profile similar to that of ustekinumab. In addition, the investigators did not observe new or unexpected safety signals that were not observed in the prior Phase 3 trials. Discussion The aforementioned studies showed that IL-17A appears to be critical in the pathogenesis of psoriasis. Blocking IL-17A ligand leads to excellent clearance of plaque psoriasis and is associated with an acceptable safety profile. A few notable observations remain with the FIXTURE and ERASURE studies. First, compared to the pivotal trials for previously approved biologics, the study population in these secukinumab studies enrolled patients with overall lower average body weight than prior biologic trials. Second, compared to previous pivotal studies with other biologics, the patient population in these two trials has higher baseline BSA involvement and lower rates of psoriatic arthritis. In the real world where clinical decisions are made in the context of choosing among multiple available agents, it is important to obtain comparative effectiveness data to help guide our clinical decision-making. Randomized controlled studies comparing secukinumab to etanercept and to ustekinumab are highly informative to clinical decision-making. In conclusion, secukinumab is the first of the IL-17 inhibitor class of biologics to become available to our psoriasis patients. Its efficacy has been demonstrated to be outstanding based on its clinical trial data, and its role in treating moderate-to-severe psoriasis is critical. Determining how secukinumab impacts other aspects of the patients' well-being using patient-reported outcomes is also as important as examining the traditional outcomes assessments based on morphology and BSA alone. The safety of secukinumab appears to be acceptable at this time, but continued surveillance will be necessary to determine its long-term safety.

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