IL-23 blockade with guselkumab potentially modifies psoriasis pathogenesis: rationale and study protocol of a phase 3b, randomised, double-blind, multicentre study in participants with moderate-to-severe plaque-type psoriasis (GUIDE)

Abstract

Background: Guselkumab is an interleukin (IL)-23 pathway blocker with proven efficacy in patients with moderate-to-severe plaque psoriasis. Early intervention with guselkumab may result in changes to the clinical disease course versus later intervention.

Methods and analysis: Here we present the rationale and design of a phase 3b, randomised, double-blind, multicentre study (GUIDE), comparing treatment effects of guselkumab in patients with short (≤2 years) or longer (>2 years) duration of plaque-type psoriasis, measured from first appearance of psoriatic plaques. Participants achieving skin clearance (Psoriasis Area and Severity Index (PASI)=0) by week 20 and maintaining complete clearance at week 28 visit ('super-responders' (SRe)) will be randomised to continue approved maintenance dosing every 8 weeks (q8w) versus an investigational maintenance dosing interval of 16 weeks (q16w) until week 68. Primary endpoint: proportion of participants in the q8w vs q16w arms with absolute PASI <3 at week 68. Participants with PASI <3 at week 68 will be withdrawn from guselkumab treatment for up to 48 weeks. Participants not achieving SRe criteria (non-SRe) will remain in the study with q8w guselkumab dosing through week 68. Additional to serum samples obtained from all patients, skin biopsies and whole-blood samples will be taken from SRe and non-SRe participants at various time points in optional substudies. Analyses include: genetics; immunophenotyping (fluorescence-activated cell sorting); gene and protein expression profiling; immunohistology. By merging clinical endpoints with mechanistic findings, this study aims to elucidate how IL-23 blockade with guselkumab can modify the disease course by altering molecular and cellular drivers that cause relapse after treatment withdrawal, particularly among SRe.

Ethics and dissemination: Approval obtained from ethics committee Medical Council Hamburg, Germany (PVN5925). GUIDE is compliant with the Declaration of Helsinki.

Trial registration number: Registered at ClinicalTrials.gov (NCT03818035). All primary endpoint results (prespecified analyses) will be submitted to peer-reviewed, international journals within 18 months after primary completion date.

Keywords: adult dermatology; protocols & guidelines; psoriasis.

Figure 1

Current pathogenic model of psoriasis. (A) T cell subsets in psoriasis, their differentiation, function and phenotype. High TGF-β concentration promotes IL-10 and IL-17 producing T_reg differentiation, while the presence of IL-6, TGF-β, IL-1-β and IL-21 promote dominant Th17 cell differentiation expressing an IL-17/IFN-γ cytokine signature. (B) In early psoriasis, environmental stimuli in combination with a loss of tolerance activate the innate immune system, leading to the production of IL-23 by dermal DCs and macrophages. IL-23 then drives activation and expansion of T17 cells which subsequently generate a cytokine milieu that promotes a feedforward inflammatory cascade in epidermal keratinocytes, leading to parakeratosis and psoriatic lesions. IL-17 autoamplifies its signal by triggering the production of chemokines by activated keratinocytes, which subsequently recruits more T17 cells and other immune cells (eg, neutrophils, DCs and macrophages). Persistent high levels of IL-23 in psoriatic skin sustain IL-17 production, thus fuelling the self-amplifying inflammatory process. As psoriasis progresses to a more chronic state, sustained high levels of IL-23 in combination with low concentrations of TGF-β promotes IL-23R expression, favouring T17 cell differentiation and supressing T_reg differentiation. T_RM are a subset of non-circulating memory T cells that persist long-term in peripheral tissues and are characterised by the markers CD69 and CD103. (C) Inhibition of the regulatory cytokine IL-23 is hypothesised to lead to long-lasting therapeutic effects by restoring a ‘physiological’ T_reg/T_RM balance. This is in contrast to the blockade of an effector cytokine, which leads to reduction of inflammatory cells but has less effect on the relative numbers of proinflammatory and anti-inflammatory T cells. Ahr, aryl hydrocarbon receptor; CCR, chemokine receptor; CD, cluster of differentiation; CXCR, CXC chemokine receptor; DC, dendritic cell; IFN, interferon; IL, interleukin; RORγt, retinoic acid receptor-related orphan receptor transcription factor; T17, IL-17 producing T cells; T-bet, T box protein expressed in T cells; TGF, transforming growth factor; Th17, T helper 17; T_reg, regulatory T cell; T_RM, tissue-resident memory T cell.

Figure 2

Study setup and design. SRe are defined as participants who receive on-label GUS treatment until W20 and respond with a score of PASI=0 at W20 and W28. *Blinded treatment. Group 1: All participants who are enrolled and scheduled to receive GUS 100 mg at W0, W4, then q8w until W28 (study part 1). Group 2a: SRe (PASI score=0 at W20 and W28) randomised to GUS 100 mg q8w at W28–W60 (study part 2). Group 2b: SRe randomised to GUS 100 mg q16w at W28–W60 (study part 2). Group 2c: non-SRe with a PASI score >0 at W20 and/or W28 who will receive GUS 100 mg q8w at W28–W60 (study part 2). Group 2d: SRe with loss of disease control between W28 and W68, who will enter the retreatment arm and receive GUS 100 mg at R0, R8 and R16 calculated from the date of loss of disease control (study part 2). Group 3a: SRe randomised to GUS 100 mg q8w in study part 2 with withdrawal of GUS at W68 (study part 3). Group 3b: SRe randomised to GUS 100 mg q16w in study part 2 with withdrawal of GUS at W68 (study part 3). Group 3c: SRe with fluctuating disease (PASI score 3–5) at W68 or loss of disease control (PASI score >5) at any other visit after W68, who will enter the retreatment arm and receive GUS 100 mg at R0, R8 and R16 calculated from the date of loss of disease control (study part 3). GUS, guselkumab; PASI, Psoriasis Area and Severity Index score; q8w, every 8 weeks; q16w, every 16 weeks; R, retreatment week; SRe, super-responder; W, week.