Guselkumab for the Treatment of Psoriasis: A Review of Phase III Trials

Psoriasis is a chronic inflammatory skin disease that affects approximately 3% of the adult US population [1]. The disease is thought to be a systemic inflammatory process and is associated with comorbidities such as psoriatic arthritis, cardiometabolic diseases, gastrointestinal diseases, kidney disease, malignancy, infection, and mood disorders [2]. Psoriasis can have a significant negative impact on quality of life, including impairment in physical and mental functioning, psychological well-being, and work productivity [3‐5]. Safe and effective long-term treatment options for psoriasis are needed, not only for improving physical appearance but also for restoring quality of life and potentially decreasing the risk of comorbid diseases [6, 7].

There has been rapid development of novel psoriasis therapies over the past two decades, especially biologic agents including tumor necrosis factor (TNF)-α inhibitors, interleukin (IL)-12/23 inhibitors, and IL-17 inhibitors. A new class of biologics currently undergoing clinical trials includes the IL-23 inhibitors guselkumab, tildrakizumab, and risankizumab [8]. IL-23 is primarily produced by antigen-presenting cells and induces and maintains differentiation of T-helper (Th)-17 and Th-22 cells, which produce pro-inflammatory cytokines such as IL-17 and IL-22 that mediate the inflammation and epidermal hyperplasia of psoriasis [9]. IL-23 is composed of p19 and p40 subunits that bind to IL-23 receptor (IL-23R) and IL-12 receptor b1 (IL-12Rb1), which results in activation of pro-inflammatory Janus kinase 2 (JAK2), tyrosine kinase 2 (TYK2), and signal transducer and activator of transcription (STAT) signaling molecules [10].

Guselkumab (CNTO1959; Janssen Research & Development, Spring House, PA, USA) is a fully human IgG1 lambda monoclonal antibody that binds to the p19 subunit of IL-23. Phase I and II studies have shown promising safety and efficacy in the treatment of moderate-to-severe psoriasis [11, 12]. In the following article, the available results to date of the Phase III clinical trials establishing the efficacy and safety of guselkumab in patients with moderate-to-severe plaque psoriasis will be reviewed.

We reviewed all published results of the Phase III clinical trials for guselkumab, which we identified by performing an English language literature search using PubMed with the following search terms: “guselkumab and psoriasis” and “IL-23 and psoriasis”. References of relevant articles were hand-searched to identify other applicable publications. This article is based on published data from previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

Data from two Phase III, multicenter, randomized, double-blind, placebo- and comparator- controlled clinical trials, VOYAGE 1 and VOYAGE 2 (ClinicalTrials.gov identifiers: NCT02207231 and NCT02207231, respectively) have been published to date. Up to 48 weeks of data are included. Both studies evaluated the efficacy and safety of guselkumab compared to placebo and adalimumab in patients with moderate-to-severe psoriasis [13, 14]. VOYAGE 2 also included a randomized withdrawal and retreatment period to evaluate the effect of interrupted treatment on the safety and efficacy of guselkumab.

The primary and secondary endpoints for VOYAGE 1 and VOYAGE 2 are shown in Table 1. Table 2 shows baseline demographic information of the subjects from each trial. Efficacy data of guselkumab compared to placebo and adalimumab from both trials are shown in Tables 3 and 4.

Results from the examined Phase III clinical trials, VOYAGE 1 and VOYAGE 2, demonstrate the safety and efficacy of guselkumab in the treatment of moderate-to-severe plaque psoriasis in a diverse group of patients. At week 16, the proportions of patients achieving IGA 0/1 and PASI-90 were statistically significantly superior compared to placebo. Guselkumab’s efficacy as measured by IGA 0, IGA 0/1, PASI-90, and PASI-75 was also superior to adalimumab at weeks 12, 24, and 48. Guselkumab also showed effectiveness in treating difficult-to-treat areas including the scalp (ss-IGA), nails (f-PGA, NAPSI), hands and feet (hf-PGA). Patient reported outcomes and health-related quality of life (DLQI, PSSD) also improved and mirrored improvement in investigator-reported psoriasis measures.

The randomized withdrawal and re-treatment study in VOYAGE 2 showed that maintenance treatment with guselkumab (100 mg every 8 weeks) is superior in maintaining PASI 90 response compared to interrupted therapy. This suggests that IL-23 inhibition does not cause long-lasting remission of psoriasis. The median time to loss of PASI 90 response after discontinuing guselkumab therapy was 15.2 weeks. Guselkumab was also effective in patients who failed to respond to adalimumab.

Although head-to-head studies are lacking, compared to all biologic agents currently available for the treatment of moderate-to-severe psoriasis, Phase III studies of guselkumab report some of the highest PASI-90 rates (at week 16, 73.3% in VOYAGE 1 and 70.0% in VOYAGE 2) to date [15]. Recent studies have shown that patients who reach PASI 90 or PASI 100 experience greater improvement in quality of life compared to those who achieve PASI 75 [16]. The potential of guselkumab to achieve PASI 90 in 70% or more of patients suggests that guselkumab may have a significant positive impact on patient quality of life. Furthermore, patients maintain PASI 90 response for a median of 15.2 weeks (106.4 days) after discontinuing guselkumab. This is significantly greater than the time to relapse (defined as PGA ≥3) for etanercept 50 mg BIW of 72 days [17] and etanercept 50 mg QW of 36.9 days [18]. The median time to relapse (defined as PGA ≥3) for adalimumab 40 mg QOW is 141 days [19]. The time to loss of PASI 90 is not reported. Regardless, the development of this unique, highly effective therapy provides optimism for patients whose psoriasis remains refractory to currently available biologic agents and adds to the growing armamentarium of psoriasis therapies.

The high efficacy rate of guselkumab may be related to the mechanism of IL-23 inhibition. IL-23 is thought to induce production of TNF-α, IL-17A, and IL-22, which are all implicated in the pathogenesis of psoriasis [20‐22]. Targeting IL-23, a key cytokine driving various other effector cytokines, may be responsible for the high efficacy and durable responses up to week 48. Further long-term studies are needed to understand the long-term efficacy of guselkumab.

Overall, guselkumab appears to have a favorable safety profile: Phase III trials have found the most common AEs to include nasopharyngitis, headache, and upper respiratory tract infection. Serious infection, malignancy, and MACE do not appear to be increased in patients treated with guselkumab compared to placebo and adalimumab. ISR were more common in patients treated with adalimumab compared to guselkumab. There were five cases of NMSC, four of which were in the guselkumab group (two BCCs and three SCCs) and the other in the adalimumab group. A recent study has shown an increased risk of NMSC in psoriasis patients treated with TNF-α inhibitors [23]. However, other studies have suggested that psoriasis-related factors such as treatment with phototherapy and chronic inflammatory dysfunction of psoriasis, not biologic therapies, may be factors responsible for the observed increased risk of NMSC in psoriasis patients [24]. The details of the individual cases of NMSC in VOYAGE 1 and 2 are not publicly available to date; therefore, it is unknown whether or not these particular patients have a history of treatment with phototherapy. Guselkumab antibody formation was observed in a small percentage of patients (5.3% in VOYAGE 1, 6.6% in VOYAGE 2) but did not have any observable effect on the efficacy or safety of guselkumab. The clinical implications of these findings are unknown, and further long-term studies are necessary to determine AEs resulting from long duration of treatment with guselkumab in a larger population of patients. The favorable AE profile of guselkumab observed in Phase III studies suggest that IL-23 may be a more psoriasis-specific cytokine compared to other cytokines such as TNF-α and IL-17 [25].

Guselkumab has generated encouraging data for efficacy and safety in the treatment of moderate-to-severe chronic plaque psoriasis. The Phase III clinical trials results suggest that guselkumab is superior to placebo at week 16 and is better able to clear or almost clear psoriasis plaques compared to adalimumab. The effects are maintained through week 48. Further long-term studies are required to validate the promising long-term efficacy and safety profile of guselkumab.