JAMA Dermatology

<jats:sec><jats:title>Importance</jats:title><jats:p>Psoriasis is a chronic inflammatory skin disease with unmet needs for tailored treatment and therapy de-escalation strategies.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To evaluate early intervention with and prolonging the dosing interval for guselkumab, a p19 subunit-targeted interleukin (IL)-23 inhibitor, in patients with moderate to severe psoriasis.</jats:p></jats:sec><jats:sec><jats:title>Design, Setting, and Participants</jats:title><jats:p>The GUIDE clinical trial is an ongoing phase 3b, randomized, double-blinded trial conducted across 80 centers in Germany and France comprising 3 parts evaluating the impact of early disease intervention, prolonged dosing interval, and maintenance of response following treatment withdrawal among adults with moderate to severe plaque psoriasis. In study part 2, reported herein, first and last patient visits were September 2019 and March 2022, respectively.</jats:p></jats:sec><jats:sec><jats:title>Interventions</jats:title><jats:p>In GUIDE part 1 (week [W]0-W28), patients received guselkumab, 100 mg, at W0, W4, W12, and W20. Those achieving a Psoriasis Area and Severity Index (PASI) of 0 at both W20 and W28 were termed <jats:italic>super responders</jats:italic> (SRes). In part 2 (W28-W68), SRes were randomized to guselkumab, 100 mg, every 8 weeks or every 16 weeks; non-SRes continued open-label guselkumab every 8 weeks.</jats:p></jats:sec><jats:sec><jats:title>Main Outcomes and Measures</jats:title><jats:p>Primary objective was to demonstrate noninferiority (with a 10% margin) of guselkumab every 16 weeks vs every 8 weeks dosing among SRes for maintenance of disease control (PASI &amp;amp;lt;3 at W68). Biomarker substudies assessed immunologic effects in skin and blood.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Overall, 822 patients received guselkumab in part 2 (297 [36.1%] SRes [every 8 weeks/every 16 weeks; n = 148/n = 149] and 525 [63.9%] non-SRes). Among SRes, mean (SD) age was 39.4 (14.1) years, 95 (32.0%) were female, and 202 (68.0%) were male. The primary end point of noninferiority for guselkumab every 16 weeks vs every 8 weeks in SRes was met (<jats:italic>P</jats:italic> = .001), with 91.9% (137/149; 90% CI, 87.3%-95.3%) of SRes receiving every 16 weeks and 92.6% (137/148; 90% CI, 88.0%-95.8%) of SRes receiving dosing every 8 weeks having PASI lower than 3 at W68. Clinical effects corresponded with immunologic changes; skin CD8-positive tissue-resident memory T (TRM)–cell count decreased quickly from baseline, remaining low in both dosing groups. Similarly, serum IL-17A, IL-17F, IL-22, and β defensin (BD)–2 levels decreased significantly from baseline, remaining low in both dosing groups to W68. Guselkumab was well-tolerated; no new safety signals were identified.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Relevance</jats:title><jats:p>Psoriasis treatment guidelines lack or provide inconsistent advice on patient stratification and treatment de-escalation. We present the first randomized trial providing evidence that, in patients with early complete skin clearance at 2 consecutive visits (W20 and W28), extending the guselkumab dosing interval may control disease activity.</jats:p></jats:sec><jats:sec><jats:title>Trial Registration</jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://classic.clinicaltrials.gov/ct2/show/NCT03818035">NCT03818035</jats:ext-link></jats:p></jats:sec>

Psoriasis.

Nat Rev Dis Primers

Lancet

Resident memory T cells in psoriasis: key to a cure?

J Psoriasis Psoriatic Arthritis

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).

BMJ Open

National consensus on biologic dose reduction in psoriasis: a modified eDelphi procedure.

J Dermatolog Treat

Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis: results from the phase III, double-blinded, placebo- and active comparator-controlled VOYAGE 1 trial.

J Am Acad Dermatol

Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial.

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

Early disease intervention with guselkumab in psoriasis leads to a higher rate of stable complete skin clearance (‘clinical super response’): week 28 results from the ongoing phase IIIb randomized, double-blind, parallel-group, GUIDE study.

J Eur Acad Dermatol Venereol

Differential changes in inflammatory mononuclear phagocyte and T-cell profiles within psoriatic skin during treatment with guselkumab vs. secukinumab.

J Invest Dermatol

Guselkumab efficacy after withdrawal is associated with suppression of serum IL-23-regulated IL-17 and IL-22 in psoriasis: VOYAGE 2 study.

Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin.

Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis.

J Allergy Clin Immunol

German S3-Guideline on the treatment of Psoriasis vulgaris, adapted from EuroGuiDerm - part 1: treatment goals and treatment recommendations.

J Dtsch Dermatol Ges

Psoriasis treat to target: defining outcomes in psoriasis using data from a real-world, population-based cohort study (the British Association of Dermatologists Biologics and Immunomodulators Register, BADBIR).

Br J Dermatol

ß-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis.

Population pharmacokinetic modeling of guselkumab, a human IgG1? monoclonal antibody targeting IL-23, in patients with moderate to severe plaque psoriasis.

J Clin Pharmacol

An international Delphi consensus to define a clinically appropriate definition of disease modification for plaque psoriasis.

Secukinumab dosing optimization in patients with moderate-to-severe plaque psoriasis: results from the randomized, open-label OPTIMISE study.

Dose tapering of biologics in patients with psoriasis: a scoping review.

Drugs

Extension of ustekinumab maintenance dosing interval in moderate-to-severe psoriasis: results of a phase IIIb, randomized, double-blinded, active-controlled, multicentre study (PSTELLAR).

Real-world performance of a new strategy for off-label use of guselkumab in moderate to severe psoriasis: super-responder patients as the epitome of efficacy and optimisation.

Clin Drug Investig

Significance of IL-17A-producing CD8+CD103+ skin resident memory T cells in psoriasis lesion and their possible relationship to clinical course.

J Dermatol Sci

CD8 resident memory T cells with interleukin 17A-producing potential are accumulated in disease-naïve nonlesional sites of psoriasis possibly in correlation with disease duration.

Therapeutics targeting the IL-23 and IL-17 pathway in psoriasis.

Super-response to guselkumab treatment in patients with moderate-to-severe psoriasis: age, body weight, baseline Psoriasis Area and Severity Index, and baseline Investigator’s Global Assessment scores predict complete skin clearance.

Psoriasis is a chronic inflammatory skin disease with unmet needs for tailored treatment and therapy de-escalation strategies.
To evaluate early intervention with and prolonging the dosing interval for guselkumab, a p19 subunit-targeted interleukin (IL)-23 inhibitor, in patients with moderate to severe psoriasis.
The GUIDE clinical trial is an ongoing phase 3b, randomized, double-blinded trial conducted across 80 centers in Germany and France comprising 3 parts evaluating the impact of early disease intervention, prolonged dosing interval, and maintenance of response following treatment withdrawal among adults with moderate to severe plaque psoriasis. In study part 2, reported herein, first and last patient visits were September 2019 and March 2022, respectively.
In GUIDE part 1 (week [W]0-W28), patients received guselkumab, 100 mg, at W0, W4, W12, and W20. Those achieving a Psoriasis Area and Severity Index (PASI) of 0 at both W20 and W28 were termed super responders (SRes). In part 2 (W28-W68), SRes were randomized to guselkumab, 100 mg, every 8 weeks or every 16 weeks; non-SRes continued open-label guselkumab every 8 weeks.
Primary objective was to demonstrate noninferiority (with a 10% margin) of guselkumab every 16 weeks vs every 8 weeks dosing among SRes for maintenance of disease control (PASI <3 at W68). Biomarker substudies assessed immunologic effects in skin and blood.
Overall, 822 patients received guselkumab in part 2 (297 [36.1%] SRes [every 8 weeks/every 16 weeks; n = 148/n = 149] and 525 [63.9%] non-SRes). Among SRes, mean (SD) age was 39.4 (14.1) years, 95 (32.0%) were female, and 202 (68.0%) were male. The primary end point of noninferiority for guselkumab every 16 weeks vs every 8 weeks in SRes was met (P = .001), with 91.9% (137/149; 90% CI, 87.3%-95.3%) of SRes receiving every 16 weeks and 92.6% (137/148; 90% CI, 88.0%-95.8%) of SRes receiving dosing every 8 weeks having PASI lower than 3 at W68. Clinical effects corresponded with immunologic changes; skin CD8-positive tissue-resident memory T (TRM)-cell count decreased quickly from baseline, remaining low in both dosing groups. Similarly, serum IL-17A, IL-17F, IL-22, and β defensin (BD)-2 levels decreased significantly from baseline, remaining low in both dosing groups to W68. Guselkumab was well-tolerated; no new safety signals were identified.
Psoriasis treatment guidelines lack or provide inconsistent advice on patient stratification and treatment de-escalation. We present the first randomized trial providing evidence that, in patients with early complete skin clearance at 2 consecutive visits (W20 and W28), extending the guselkumab dosing interval may control disease activity.
ClinicalTrials.gov Identifier: NCT03818035.

Noninferiority of 16-Week vs 8-Week Guselkumab Dosing in Super Responders for Maintaining Control of Psoriasis: The GUIDE Randomized Clinical Trial.

Noninferiority of 16-Week vs 8-Week Guselkumab Dosing in Super Responders for Maintaining Control of Psoriasis

Noninferiority of 16-Week vs 8-Week Guselkumab Dosing in Super Responders for Maintaining Control of Psoriasis

Clinical Summary

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