Zeena Nawas, MD1; Michael Hatch, MD2; Elmira Ramos1; Melinda Liu3; Yun Tong, MD1,4; Andrew Peranteau, MD1; Stephen Tyring, MD, PhD1,5
1Center For Clinical Studies, Houston, TX, USA
2Texas Tech School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, USA
3Baylor College of Medicine, Houston, TX, USA
4Department of Dermatology, University of California San Diego, La Jolla, CA, USA
5Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA
Conflicts of Interest:
Dr. Tyring has been an investigator for clinical trials sponsored by Abbvie, Amgen, Boehringer Ingelheim, Celgene, Coherus, Contravir, Cutanea, Dermira, Galderma, Genocea, Innovaderm, Janssen, Eli Lilly and Company, Leo Pharma, Merck, MSD, Medimmune, Novan, Novartis, Pfizer, Promius, Regeneron, Tolmar, Vitae, Watson-Actavis, and Xoma. Drs. Nawas, Tong and Peranteau have been sub-investigators on clinical trials sponsored by the same companies listed above. Hatch, Ramos, and Liu have no conflicts of interest to disclose.
Psoriasis is a chronic inflammatory skin disorder that affects 2% of the population. Evidence suggests that interleukin (IL)-23 plays a pivotal role in the pathogenesis of psoriasis. Guselkumab is a subcutaneously administered, humanized anti-IL23 monoclonal antibody indicated for the treatment of moderate-to-severe plaque psoriasis. Data from Phase I-III trials in this patient population reveal that guselkumab has proven to be superior to placebo or adalimumab based on achieving a Psoriasis Area and Severity Index (PASI) 90% reduction, or a static Physician Global Assessment (sPGA) score of 0 or 1 from baseline. This article reviews the current status of guselkumab as a therapy for moderate-to-severe plaque psoriasis.
biologics, cytokine, IL-23, interleukin-23 inhibitor, monoclonal antibody, psoriasis, Th17
Psoriasis is the most common chronic autoimmune skin condition affecting about 2% of the population.1 This disease has a significant impact on quality of life, mental health and work productivity, and it is linked to other comorbid conditions such as cardiovascular disease, metabolic syndrome, and arthritis.2,3 Psoriasis is thought to arise from a combination of pathogenic factors including genetic susceptibility and environmental exacerbation, which results in activation of dendritic cells in the skin and differentiation of T cells.4 In turn, these T cells produce cytokines that induce keratinocyte hyperproliferation and result in characteristic raised, well-demarcated erythematous lesions of psoriasis.
Accumulating evidence suggests that the proinflammatory cytokine interleukin (IL)-23 and its resulting T helper 17 (Th17) pathway play a more important role in mediating psoriasis than IL-12.5,6 IL-23 induces differentiation and maintenance of Th17 cells, which produce the effector cytokines IL-17, IL-22, and tumor necrosis factor-alpha (TNFα).7,8 IL-23 is a heterodimer composed of two subunits, p40 and p19.8 While p40 is also present in IL-12, p19 is specific for IL-23.8 Levels of IL-23p19 and IL-12/23p40 messenger RNA (mRNA) are upregulated in psoriatic plaques and decrease with effective treatment.7-11
This paper focuses on guselkumab, a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits intracellular IL-23 and downstream signaling by targeting the p19 subunit.12,13 Guselkumab decreases blood and skin lesion levels of effector IL-17A and decreases epidermal hyperplasia and inflammation by downregulating T cells and myeloid dendritic cells.12 This evidence further establishes the IL-23/Th17 axis as the primary driver of psoriatic inflammation. Additionally, another goal for guselkumab is increased safety by maintaining the IL-12/Th1 axis, an important regulator of immune function, unlike the previous medications that targeted both IL-12 and IL-23. IL-12 is required for appropriate Th1 response and defense against intracellular pathogens due to its role in the production of interferon gamma (INFγ) by T- and natural killer (NK)-cells.14 Animal studies have demonstrated that anti-p40 antibodies enhance mycobacterial growth, but that p19-deficient mice are indistinguishable from wild type animals as long as IL-12 is functional.6 In contrast, patients deficient in the p40 subunit are more susceptible to low virulence nontuberculous Mycobacterium and Salmonella.6
Additional monoclonal antibodies targeting both IL-12/23 have been investigated for the treatment of psoriasis. Briakinumab, has been found to be associated with a significantly higher rate of major adverse cardiovascular events, infections, and nonmelanoma skin cancers as compared with placebo. Resultantly, this drug has been withdrawn from the market.15 Conversely, ustekinumab, has shown a safer profile with a similar rate of adverse events in comaparison to placebo.12
This first-in-human, randomized, double-blind, placebocontrolled Phase I study showed that a single dose of guselkumab results in a significant clinical response. In this trial, 24 patients with moderate-to-severe plaque psoriasis received a single dose of guselkumab consisting of either 10 mg, 30 mg, 100 mg or 300 mg or a placebo. At week 12, Psoriasis Area and Severity Index (PASI) 75 was achieved in 50%, 60%, 60% and 100% of patients, respectively, as compared with 0% in the placebo group. In addition, the trial reported a decrease in both psoriasis gene expression and serum IL-17A levels in the guselkumab-treated group. The overall incidence of adverse reactions was similar in the treatment (65%) and placebo arms (50%).16
Phase II – Efficacy
The efficacy of guselkumab was evaluated in a Phase II randomized, double-blind, placebo controlled, active-comparator trial (X-PLORE).17 In this trial, the efficacy of guselkumab was compared with adalimumab, a TNFα inhibitor used to treat plaque psoriasis. Two hundred and ninety-three patients were randomized to receive either gusekumab, adalimumab, or placebo. A total of 39 patients in the placebo group were crossed over to receive guselkumab at week 16. After 16 weeks of treatment, the percentage of patients achieving a physician’s global assessment(PGA, primary endpoint) of 0 or 1 was significantly higher in each guselkumab group than placebo (34% for 5 mg, 61% for 15 mg, 79% for 50 mg, 86% for 100 mg, 83% for 200 mg, and 7% for placebo). Likewise, the percentage of patients with at least a 75% improvement from baseline in PASI score was significantly higher in each guselkumab group.
The percentage of patients with a PGA score of 0 or 1 reached a maximum at week 20 in most guselkumab groups, which was maintained through week 40. In addition, the group that crossed over from placebo to guselkumab at week 16 achieved similar PGA scores as the group that received 100 mg guselkumab. Finally, at both weeks 16 and 40, the percentage of patients with a PGA score of 0 or 1 was higher in most guselkumab groups (50 mg, 100 mg, and 200 mg) compared to the adalimumab group.
Phase II – Safety
Up to week 16, the proportion of patients with adverse events was similar in the different treatment groups (52% for placebo, 50% for guselkumab, 56% for adalimumab), and there was no demonstrable relationship between the guselkumab dose and rate of adverse events through to termination of the study. However, through week 52, a higher proportion of patients in the adalimumab group (61%) experienced an adverse event compared with guselkumab groups (49%). Of note, two serious infections, one case of grade 3 cervical intraepithelial neoplasia, and three major adverse cardiovascular events, including one death from myocardial infarction, occurred in the guselkumab group.
Preliminary results for the VOYAGE 1 and VOYAGE 2 trials have been published. In the VOYAGE 1 trial, patients were randomly assigned to three arms: guselkumab 100 mg at weeks 0 and 4, then every 8 weeks; placebo at weeks 0, 4 and 12 then guselkumab at week 16 and 20, then every 8 weeks; or adalimumab 80 mg at week 0, 40 mg week 1, then 40 mg every 2 weeks. At week 16, the patients exhibited improved responses to guselkumab as compared with placebo (PASI 90 response of 73.3% vs. 2.9%) and adalimumab at week 16 (73.3% vs. 49.7%). Furthermore, guselkumab comparisons to adalimumab were also significantly superior at weeks 24 and 48 (80.2% vs. 53%, and 76.3% vs. 47.9%, respectively). Adverse events were similar among all groups.
In the VOYAGE 2 trial, patients were randomized to identical comparison arms, however at week 28 PASI 90 responders were re-randomized to guselkumab or placebo with further crossover for those who lost response. The results showed that at week 16, 70.0% of patients receiving guselkumab had a PASI 90 as compared with 2.4% in placebo. When compared to adalimumab, guselkumab demonstrated 75% and 100% of PASI 90 improvement at 16 and 24 weeks, respectively. In addition, guselkumab showed improved outcomes in those who were adalimumab nonresponders.
Currently a Phase III, multicenter, randomized, double-blind study evaluating the efficacy and safety of guselkumab is ongoing.16 This study examines patients with moderate-to-severe plaque-type psoriasis who experienced an inadequate response to ustekinumab. Results from the study are planned for presentation at upcoming scientific meetings according to a Janssen press release. Other Phase III trials of guselkumab are also currently underway (Table 1).17-19
|Trial ID||Title of Study||Primary Outcome Measure||Status|
|NCT02207231||A Study of Guselkumab and Active Comparator in the Treatment of Participants With Moderate to Severe Plaque-Type Psoriasis (VOYAGE 1)||Percentage of participants with an Investigator’s Global Assessment (IGA) score of 0 or 1 comparing the guselkumab group and the placebo group on week 16|
Percentage of participants with a PASI 90 response comparing the guselkumab group and the placebo group at week 16
|NCT02207244||A Study of Guselkumab in the Treatment of Participants With Moderate to Severe Plaque-Type Psoriasis With Randomized Withdrawal and Retreatment (VOYAGE 2)||Percentage of participants with an IGA score of 0 or 1 comparing the guselkumab group and the placebo group on week 16|
Percentage of participants with a PASI 90 response comparing the guselkumab group and the placebo group at week 16
|NCT02343744||An Efficacy and Safety Study of CNTO1959 (Guselkumab) in the Treatment of Participants With Generalized Pustular Psoriasis or Erythrodermic Psoriasis||Percentage of participants with treatment success (â€œvery much improvedâ€ in the Clinical Global Impression [CGI] scale) at week 16||Ongoing|
|NCT02325219||An Efficacy and Safety of CNTO 1959 (Guselkumab) in Participants With Moderate to Severe Plaque-Type Psoriasis||Number of participants who achieve an IGA score of 0 or 1 at week 16 comparing 50 mg, 100 mg of CNTO1959 or placebo||Ongoing|
|NCT02203032||A Phase 3, Multicenter, Randomized, Double-blind Study to Evaluate the Efficacy and Safety of Guselkumab for the Treatment of Subjects With Moderate to Severe Plaque-type Psoriasis and an Inadequate Response to Ustekinumab||The number of visits at which participants achieve an IGA response of 0 or 1 and at least a 2 grade improvement (from week 16) among randomized participants with an inadequate (IGA ≥2) response to ustekinumab at week 16||Completed – pending results|
|Table 1. Phase III clinical trials of guselkumab in psoriasis|
Guselkumab is a monoclonal IL-23 antibody that treats psoriasis. Targeting IL-23 is believed to block a specific mediator of psoriatic inflammation. Data from a Phase II study shows that guselkumab is safe and efficacious. Preliminary results have demonstrated superiority of guselkumab over placebo and adalimumab. Guselkumab was superior to both placebo and adalimumab (p<0.001 for all comparisons of guselkumab with placebo and adalimumab). Further data from Phase III trials is expected to be available in the summer 2018.
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- Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol. 2014 Mar;70(3):512-6.
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- Levin AA, Gottlieb AB. Specific targeting of interleukin-23p19 as effective treatment for psoriasis. J Am Acad Dermatol. 2014 Mar;70(3):555-61.
- Toichi E, Torres G, McCormick TS, et al. An anti-IL-12p40 antibody downregulates type 1 cytokines, chemokines, and IL-12/IL-23 in psoriasis. J Immunol. 2006 Oct 01;177(7):4917-26.
- Di Meglio P, Nestle FO. The role of IL-23 in the immunopathogenesis of psoriasis. F1000 Biol Rep. 2010 May 24;2.
- D’Elios MM, Del Prete G, Amedei A. Targeting IL-23 in human diseases. Expert Opin Ther Targets. 2010 Jul;14(7):759-74.
- Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23 p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004 Jan 05;199(1):125-30.
- Piskin G, Sylva-Steenland RM, Bos JD, et al. In vitro and in situ expression of IL-23 by keratinocytes in healthy skin and psoriasis lesions: enhanced expression in psoriatic skin. J Immunol. 2006 Feb 01;176(3):1908-15.
- Papp KA, Langley RG, Lebwohl M, et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial(PHOENIX 2). Lancet. 2008 May 17;371(9625):1675-84.
- Kopp T, Riedl E, Bangert C, et al. Clinical improvement in psoriasis with specific targeting of interleukin-23. Nature. 2015 May 14;521(7551):222-6.
- Gaspari AA, Tyring S. New and emerging biologic therapies for moderate-tosevere plaque psoriasis: mechanistic rationales and recent clinical data for IL-17 and IL-23 inhibitors. Dermatol Ther. 2015 Jul-Aug;28(4):179-93.
- Gordon KB, Langley RG, Gottlieb AB, et al. A phase III, randomized, controlled trial of the fully human IL-12/23 mAb briakinumab in moderate-to-severe psoriasis. J Invest Dermatol. 2012 Feb;132(2):304-14.
- Sofen H, Smith S, Matheson RT, et al. Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-tosevere psoriasis. J Allergy Clin Immunol. 2014 Apr;133(4):1032-40.
- Gordon KB, Duffin KC, Bissonnette R, et al. A phase 2 trial of guselkumab versus adalimumab for plaque psoriasis. N Engl J Med. 2015 Jul 09;373(2):136-44.
- Blauvelt A, Papp KA, Griffiths CE, et al. 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. 2016 Dec 29. [Epub ahead of print] doi: 10.1016/j.jaad.2016.11.041.
- Reich K, Armstrong AW, Foley P, et al. 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, placeboand active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2016 Dec 29. [Epub ahead of print] doi: 10.1016/j.jaad.2016.11.042.