Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials

Summary

Background

Tildrakizumab is a high-affinity, humanised, IgG1 κ antibody targeting interleukin 23 p19 that represents an evolving treatment strategy in chronic plaque psoriasis. Previous research suggested clinical improvement with inhibition of interleukin 23 p19. We did two phase 3 trials to investigate whether tildrakizumab is superior to placebo and etanercept in the treatment of chronic plaque psoriasis.

Methods

We did two three-part, parallel group, double-blind, randomised controlled studies, reSURFACE 1 (at 118 sites in Australia, Canada, Japan, the UK, and the USA) and reSURFACE 2 (at 132 sites in Europe, Israel, and the USA). Participants aged 18 years or older with moderate-to-severe chronic plaque psoriasis (body surface area involvement ≥10%, Physician's Global Assessment [PGA] score ≥3, and Psoriasis Area and Severity Index [PASI] score ≥12) were randomised (via interactive voice and web response system) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo in reSURFACE 1 (2:2:1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2). Randomisation was done by region and stratified for bodyweight (≤90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Assigned medication was identical in appearance and packaging. Tildrakizumab was administered subcutaneously at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomised from placebo to tildrakizumab; etanercept was given twice weekly in part 1 of reSURFACE 2 and once weekly during part 2). The co-primary endpoints were the proportion of patients achieving PASI 75 and PGA response (score of 0 or 1 with ≥2 grade score reduction from baseline) at week 12. Safety was assessed in the all-participants-as-treated population, and efficacy in the full-analysis set. These trials are registered with ClinicalTrials.gov, numbers NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). These studies are completed, but extension studies are ongoing.

Findings

reSURFACE 1 ran from Dec 10, 2012, to Oct 28, 2015. reSURFACE 2 ran from Feb 12, 2013, to Sept 28, 2015. In reSURFACE 1, 772 patients were randomly assigned, 308 to tildrakizumab 200 mg, 309 to tildrakizumab 100 mg, and 155 to placebo. At week 12, 192 patients (62%) in the 200 mg group and 197 patients (64%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). 182 patients (59%) in the 200 mg group and 179 patients (58%) in the 100 mg group achieved PGA responses, compared with 11 patients (7%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). In reSURFACE 2, 1090 patients were randomly assigned, 314 to tildrakizumab 200 mg, 307 to tildrakizumab 100 mg, 156 to placebo, and 313 to etanercept. At week 12, 206 patients (66%) in the 200 mg group, and 188 patients (61%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group and 151 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p<0·0001 for 200 mg vs etanercept and p=0·0010 for 100 mg vs etanercept). 186 patients (59%) in the 200 mg group, and 168 patients (55%) in the 100 mg group achieved a PGA response, compared with 7 patients (4%) in the placebo group and 149 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p=0·0031 for 200 mg vs etanercept and p=0·0663 for 100 mg vs etanercept). Serious adverse events were similar and low in all groups in both trials. One patient died in reSURFACE 2, in the tildrakizumab 100 mg group; the patient had alcoholic cardiomyopathy and steatohepatitis, and adjudication was unable to determine the cause of death.

Interpretation

In two phase 3 trials, tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate-to-severe chronic plaque psoriasis.

Funding

Merck & Co.

Introduction

Chronic plaque psoriasis is an immune-mediated disease with a prevalence of around 2% in Europe and North America.¹ Symptoms include painful, pruritic, well demarcated, scaly, and erythematous plaques, which lead to detrimental physical effects and reduced psychological wellbeing.2, 3 Comorbid disorders associated with psoriasis can limit social interactions, impair school or work productivity, and lead to suicidality.2, 4, 5 Thus, psoriasis can lead to substantial disability and reduced quality of life.⁶

Research in context

Evidence before this study

We searched PubMed with the terms “psoriasis”, “IL-23p19”, “IL-12/23p40”, “IL-17”, “ustekinumab”, “briakinumab”, “secukinumab”, “ixekizumab”, “guselkumab”, “tildrakizumab”, “risankizumab”, “BI 655066”, “etanercept”, and “adalimumab” for studies published in English on or before Oct 12, 2016, the date of our final search. Antibodies targeting interleukins 12 and 23 p40 were an efficacious treatment for psoriasis in several phase 3 studies. However, subsequent research identified interleukin 23, rather than interleukin 12, as the more important driver of psoriasis pathogenesis, leading to a focus on specifically blocking the interleukin 23–interleukin–17 inflammatory pathway. Phase 1 and 2 studies have shown the potential to treat psoriasis by specifically targeting interleukin 23 with anti-interleukin 23 p19 antibodies, without affecting interleukin 12 signalling.

Added value of this study

We report the results of two phase 3 studies of the anti-interleukin 23 p19 treatment tildrakizumab, reSURFACE 1 and reSURFACE 2. With a combined population of 1862 patients with moderate-to-severe psoriasis, these data provide evidence of efficacy and safety of tildrakizumab in the largest psoriasis population (so far) treated with anti-interleukin 23 p19 antibodies.

Implications of all the available evidence

Our results support the therapeutic potential of anti-interleukin 23 p19 antibodies. No apparent reduction of efficacy was noted with specific targeting of interleukin 23 and sparing of interleukin 12, which is consistent with the hypothesis that interleukin 23–interleukin 17 inflammatory pathway is critical in pathogenesis of psoriasis. Adverse events, including malignancy, cardiovascular events, serious infections, and drug-related hypersensitivity were rare in this large patient sample over 28 weeks. Open-label extension data showing multi-year clinical experience in reSURFACE 1 and 2 are forthcoming. These studies and additional randomised and observational studies will help to further characterise the efficacy profile of tildrakizumab and to further investigate adverse events.

T-helper 17 (Th17) cells, the major effector cells present in psoriatic lesions, stimulate activation and proliferation of surrounding keratinocytes and endothelial cells via production of interleukin 17A and other pro-inflammatory cytokines.⁷ The introduction of biological treatments, initially with anti-tumour necrosis factor α (TNFα) agents, led to improved outcomes in psoriasis when compared with previous treatments.8, 9, 10, 11 Specific targeting of interleukins 12 and 23 p40 with ustekinumab resulted in further improved clinical outcomes.12, 13 Subsequent research showed that interleukin 23 is a key regulatory cytokine in psoriasis that stimulates differentiation, proliferation, and survival of Th17 cells; interleukin 12 is not. Specific targeting of the interleukin 23–interleukin 17 inflammatory pathway has become an effective therapeutic approach.14, 15 Initial phase 1 and 2 clinical studies16, 17, 18, 19, 20 have shown that targeting interleukin 23 alone via antibodies directed against the p19 subunit is at least as effective in the treatment of psoriasis as is inhibition of both interleukins 12 and 23.

Tildrakizumab is a high affinity, humanised IgG1 κ monoclonal antibody that targets the p19 subunit of interleukin 23. We did two large, randomised, controlled, three-part, phase 3 studies, reSURFACE 1 and reSURFACE 2 to assess the efficacy, safety and tolerability of tildrakizumab compared with placebo and etanercept.