Elsevier

The Lancet

Volume 394, Issue 10201, 7–13 September 2019, Pages 831-839
The Lancet

Articles
Guselkumab versus secukinumab for the treatment of moderate-to-severe psoriasis (ECLIPSE): results from a phase 3, randomised controlled trial

https://doi.org/10.1016/S0140-6736(19)31773-8Get rights and content

Summary

Background

Antibodies targeting interleukin (IL)-23 and IL-17A effectively treat moderate-to-severe psoriasis. ECLIPSE is the first comparator study of an IL-23p19 inhibitor, guselkumab, versus an IL-17A inhibitor, secukinumab. The primary objective of this study was to show superiority of clinical response at week 48 for guselkumab versus secukinumab.

Methods

In this phase 3, multicentre, double-blind, randomised, comparator-controlled trial at 142 outpatient clinical sites in nine countries (Australia, Canada, Czech Republic, France, Germany, Hungary, Poland, Spain, and the USA), eligible patients were aged 18 years or older, had moderate-to-severe plaque-type psoriasis, and were candidates for phototherapy or systemic therapy. Eligible patients were randomly assigned with permuted block randomisation using an interactive web response system to receive either guselkumab (100 mg at weeks 0 and 4 then every 8 weeks) or secukinumab (300 mg at weeks 0, 1, 2, 3, and 4, and then every 4 weeks). The primary endpoint, the proportion of patients in the intention-to-treat population who achieved 90% reduction or more from baseline of Psoriasis Area and Severity Index (PASI 90 response) at week 48, and major secondary endpoints (the proportions of patients in the guselkumab group and in the secukinumab group who achieved a PASI 75 response at both weeks 12 and 48, a PASI 90 response at week 12, a PASI 75 response at week 12, a PASI 100 response at week 48, an Investigator's Global Assessment [IGA] score of 0 [cleared] at week 48, and an IGA score of 0 or 1 [minimal] at week 48) were to be tested in a fixed sequence to control type I error rate. Safety was evaluated in patients who received one or more doses of study drug from week 0 to 56. The study is registered with ClinicalTrials.gov, NCT03090100.

Findings

This study was done between April 27, 2017, and Sept 20, 2018. 1048 eligible patients were enrolled and, of these, 534 were assigned to receive guselkumab and 514 to receive secukinumab. The proportion of patients with a PASI 90 response at week 48 was greater in the guselkumab group (451 [84%]) than in the secukinumab group (360 [70%]; p<0·0001). Although non-inferiority (margin of 10 percentage points) was established for the first major secondary endpoint (452 [85%] of patients in the guselkumab group vs 412 [80%] of patients in the secukinumab group achieving a PASI 75 response at both weeks 12 and 48), superiority was not established (p=0·0616). Consequently, formal statistical testing was not done for subsequent major secondary endpoints. Proportions of patients with adverse events, infections, and serious adverse events were similar between the two treatments and, in general, safety findings were consistent with registrational trial observations.

Interpretation

Guselkumab showed superior long-term efficacy based on PASI 90 at week 48 when compared with secukinumab for treating moderate-to-severe psoriasis. This finding could assist health-care providers in their decision making process when selecting a biologic for treating moderate-to-severe psoriasis.

Funding

This study was funded by Janssen Research & Development.

Introduction

Psoriasis, a chronic, systemic inflammatory disease with prominent skin involvement, affects approximately 2–4% of the world's population1, 2 and profoundly impairs patients' health-related quality of life.3, 4, 5 Over the past 15 years, substantial improvements in the efficacy of biologics to treat moderate-to-severe psoriasis have been achieved.6 As a result, at least a 90% reduction of the baseline Psoriasis Area and Severity Index (PASI 90 response) is replacing PASI 75 as the standard response for measuring successful treatment of psoriasis.7, 8, 9

Multiple psoriasis comparator studies have been done to evaluate relative efficacy among biologic therapies. These trials have shown superior efficacy for interleukin (IL)-23 blockade versus a tumour necrosis factor (TNF) inhibitor,10, 11, 12 as well as improved responses for IL-17A neutralisation13, 14 and selective blockade of the p19 subunit of IL-23 (IL-23p19)15 versus an inhibitor of the p40 subunit of IL-12 and IL-23 (IL-12/23p40). Of note, the primary endpoints of these comparator studies focused on only short-term responses (up until weeks 12 or 16). Because psoriasis is a chronic disease, longer-term endpoints to evaluate sustainability of responses and safety are more clinically relevant.10, 11, 13, 14, 15, 16

Research in context

Evidence before this study

We searched PubMed for publications of clinical trials and review articles using combinations and variations of the search terms “psoriasis”, “biologics”, “guselkumab and psoriasis”, “secukinumab and psoriasis”, “quality of life”, “efficacy standards for psoriasis”, “comparator or head-to-head psoriasis studies”, “psoriasis cytokines”, “interleukin (IL)-17 and psoriasis”, “IL-23 and psoriasis”, “IL-12/23 and psoriasis”, and “safety of biologics in psoriasis”. We also used other public search engines to retrieve relevant package inserts from companies. We did the searches from Oct 22 to Dec 4, 2018, and included materials published from Jan 1, 1999, to Dec 4, 2018. We observed from this search that although significant improvements in the efficacy of biologics for the treatment of moderate-to-severe psoriasis have been made, patients' desire for clear skin, and stable, long-term control is generally of greater relevance than an early response.

Until the past 4 years, dermatologists have had access to anti-tumour necrosis factor drugs and the IL-12/23p40 inhibitor, ustekinumab, for the treatment of moderate-to-severe psoriasis. Two novel classes of targeted biologic therapies are now available, the IL-17A inhibitors (first-in-class drug approved in 2015) and the IL-23p19 inhibitors (first-in-class drug approved in 2017), which are generally more effective. The first approved and available representatives of these classes are secukinumab (an IL-17A inhibitor) and guselkumab (an IL-23p19 inhibitor). Until now, there has been no comparison of these two novel classes in a head-to-head study. This information might also have relevance to a broader scope of health-care providers given the differential effects of these drug classes in other immune-mediated diseases such as inflammatory bowel disease and ankylosing spondylitis.

Added value of this study

The ECLIPSE study is the first head-to-head comparator trial between guselkumab and secukinumab. This study showed that guselkumab was superior to secukinumab for patients achieving an improvement of 90% or more in the Psoriasis Area and Severity Index (PASI 90) from baseline at week 48 (p<0·0001). This primary endpoint was assessed considerably later than was done in most pivotal phase 3 psoriasis trials. The proportions of patients with a response for other stringent longer-term efficacy endpoints (PASI 100, Investigator's Global Assessment [IGA] score of 0, and IGA score of 0 or 1 at week 48) were also numerically higher for guselkumab than for secukinumab, although formal statistical testing was not done. This report also provides a comprehensive assessment of efficacy over time in which clear differences were observed. Between week 3 and week 12, the proportions of patients achieving a PASI 90 response were higher in the secukinumab group than in the guselkumab group; at weeks 16 and 20 they were similar in the two groups; and from week 28 to 48 they were higher in the guselkumab group.

Both guselkumab and secukinumab were well tolerated. Although the proportion of overall adverse events and serious adverse events were similar in the two groups, some safety differences were observed. A higher proportion of patients with Crohn's disease was reported with secukinumab than with guselkumab, consistent with previous study findings and the approved label. A higher proportion of patients with non-melanoma skin cancers was reported for guselkumab than with secukinumab, which was not a known safety risk for guselkumab.

Implications of all the available evidence

The ECLIPSE study provides a comparison between the most effective classes of biologics used for treating moderate-to-severe psoriasis—generating valuable data for understanding the timeline and extent of efficacy of targeting IL-23p19 versus IL-17A—as well as a comparative safety profile, for a duration of nearly 1 year. This first ever head-to-head comparison of an IL-23p19 inhibitor (guselkumab) versus an IL-17A inhibitor (secukinumab), reported superior long-term efficacy for guselkumab at week 48. These findings should assist health-care providers in their decision making process when selecting a biologic for treating moderate-to-severe psoriasis.

In the past 4 years, two newer classes of biologics, IL-17 inhibitors14, 17, 18, 19 and IL-23 inhibitors,10, 11, 15 have elevated the standards by achieving even higher levels of efficacy than did previously available treatments for patients with moderate-to-severe psoriasis. Here, we report the results of the ECLIPSE study, the first head-to-head comparator trial between an IL-23p19 inhibitor, guselkumab, and an IL-17A inhibitor, secukinumab, for treatment of psoriasis. The primary endpoint of the study was based on PASI 90 response at week 48, to focus on longer-term response in this chronic disease.

The primary objective of the ECLIPSE study was to demonstrate superiority of clinical response at week 48 for guselkumab versus secukinumab.

Section snippets

Study design and patients

A phase 3, multicentre, randomised, double-blind, comparator-controlled study (ECLIPSE) was done at 142 outpatient clinical sites in nine countries (Australia, Canada, Czech Republic, France, Germany, Hungary, Poland, Spain, and the USA).

Eligible patients (aged ≥18 years) had moderate-to-severe plaque-type psoriasis (PASI ≥12, Investigator's Global Assessment [IGA] score ≥3, body surface area involvement ≥10% for ≥6 months) and were candidates for phototherapy or systemic therapy. Patients were

Results

This study was done between April 27, 2017, and Sept 20, 2018. 1048 of 1200 patients assessed for eligibility were randomly assigned at baseline to receive either guselkumab 100 mg (n=534) or secukinumab 300 mg (n=514). Three patients in the secukinumab group were not treated because of violations of the inclusion or exclusion criteria; all other patients received their assigned treatment. Between week 0 and week 44, 27 (5%) of 534 patients in the guselkumab group and 48 (9%) of 514 patients in

Discussion

Biologics that selectively target IL-23p1910, 11, 12, 15 or IL-17A,14, 16, 17, 18, 19, 22 the most recently approved for psoriasis, are generally more effective than biologics targeting TNF or IL-12/23p40. In ECLIPSE, the first comparator study between an anti-IL-23p19 drug and an anti-IL-17A drug, guselkumab was superior to secukinumab in treating moderate-to-severe plaque psoriasis 48 weeks after the start of treatment. A significantly greater proportion of patients in the guselkumab group

Data sharing

Requests for access to the study data can be submitted through the Yale Open Data Access Project site as per the data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson.

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