Guselkumab is a human monoclonal antibody that binds selectively to the regulatory cytokine IL-23, levels of which are elevated in the skin of patients with plaque psoriasis.
IL-23 affects the differentiation, expansion and survival of T-cell and innate immune cell subsets responsible for the production of pro-inflammatory cytokines including IL-17A, IL-17F and IL-22. By binding to IL-23, guselkumab prevents its interaction with cell-surface receptors, blocking the IL-23 pathway and normalising production of these cytokines.
Clinical trial programme
VOYAGE 1 and 2 were randomised placebo- and active-controlled studies involving 1,829 patients with moderate to severe plaque psoriasis for at least 6 months who were candidates for systemic therapy or phototherapy.
The VOYAGE 1 study (n=837) comprised an active comparator part, comparing guselkumab (100mg at weeks 0, 4, 12 and every 8 weeks up to week 44; n=329) with adalimumab (80mg at week 0, then 40mg at week 1 and every 2 weeks up to week 47; n=334), and a placebo-controlled part (placebo at weeks 0, 4 and 12 followed by guselkumab 100mg at weeks 16 and 20, and every 8 weeks up to week 44; n=174).
The co-primary endpoints were the proportions of patients achieving an Investigator Global Assessment (IGA) score of cleared/minimal disease (IGA 0/1) and 90% or greater improvement in Psoriasis Area and Severity Index (PASI) score from baseline (PASI 90) at week 16 in the guselkumab group compared with the placebo group. Major secondary endpoints included PASI 75 at 16 weeks, change from baseline in Dermatology Life Quality Index (DLQI) and Psoriasis Symptoms and Signs Diary (PSSD) scores at 16 weeks, and the proportion of patients achieving a PSSD symptom score of 0 at 24 weeks.
Superiority to adalimumab
Guselkumab was found to be superior to placebo and/or adalimumab for the co-primary endpoints and all major secondary endpoints (all p<0.001). A significantly greater proportion of patients achieved an IGA score of 0/1 and a PASI 90 response at week 16 in the guselkumab group than in the placebo group (85.1% vs 6.9% and 73.3% vs 2.9%, respectively).
Similarly, compared with adalimumab, guselkumab was associated with a significantly greater proportion of patients achieving IGA 0/1 (85.1% vs 65.9%) and a PASI 90 response (73.3% vs 49.7%).
Patient-reported outcomes (DLQI and PSSD) were also significantly improved in patients receiving guselkumab up to week 48.
The ongoing VOYAGE 2 study (n=992) is of similar design to VOYAGE 1 and has produced similar findings but incorporates a randomised withdrawal and re-treatment period. The study results at week 48 revealed a better persistence of response in the guselkumab maintenance groups versus the withdrawal groups (p<0.001). They also showed effective treatment with guselkumab among adalimumab non-responders, with 66.1% achieving a PASI 90 response at week 48.
Efficacy in ustekinumab non-responders
In the NAVIGATE study (n=871) all patients received open-label treatment with ustekinumab at weeks 0 and 4. Those with an inadequate response to treatment at week 16 (IGA score ≥2) were then randomised to receive guselkumab at weeks 16, 20 and every 8 weeks up to week 44 or to continue with ustekinumab at week 16 and every 12 weeks up to week 40.
Patients who did not achieve an IGA score of 0/1 by week 16 on ustekinumab treatment derived significant benefit from switching to guselkumab. Among randomised patients the guselkumab group had a significantly higher mean number of visits at which patients had an IGA score of 0/1 and at least a two-grade improvement, relative to week 16, from weeks 28 to 40 (primary endpoint) compared with the ustekinumab group (1.5 vs 0.7; p<0.001). All major secondary endpoints, including the mean number of visits at which patients had a PASI 90 relative to baseline, between weeks 28 and 40, were also met (2.2 vs 1.1 for the guselkumab and ustekinumab groups, respectively; p<0.001).
Adverse event rates
Guselkumab was well tolerated in clinical trials with upper respiratory tract infection the most commonly reported adverse effect.