IL-23 Antagonists in the Treatment of Plaque Psoriasis

By Clinical Content Hub

Approximately 3.2% of American adults aged ≥20 years are affected by psoriasis, and the prevalence of the condition has remained largely stable throughout the past 15 years.1 Valuable insights gained from numerous studies aimed at understanding the pathophysiology of this chronic skin condition have led to the development of targeted immune therapies based on the inhibition of proinflammatory cytokines implicated in the development of psoriatic plaques. Cytokines identified as the drivers of plaque formation include tumor necrosis factor (TNF)-a, interleukin (IL)-17A, IL-12, and IL-23.5

Accordingly, the biologic armamentarium currently available for the treatment of plaque psoriasis includes 4 TNF-a antagonists (adalimumab, certolizumab pegol, etanercept, and infliximab), 3 inhibitors of IL-17 (brodalumab, ixekizumab, and secukinumab), three IL-23 inhibitors (guselkumab, risankizumab, and tildrakizumab), and an agent targeting both IL-12 and IL-23 (ustekinumab),6 all of which have been determined by the US Food and Drug Administration (FDA) to be safe and effective treatment options. Almost half of patients treated with these targeted therapies have been reported to achieve full skin clearance.7

The Role of IL-23 in Psoriasis

The central role of IL-23 in psoriasis has been elucidated as a result of the rapidly evolving understanding of the underlying disease pathogenesis.6,8  IL-23 was discovered in 2000; it is a heterodimeric cytokine consisting of a p19 subunit and a p40 subunit that is shared with IL-12, another cytokine implicated in the development of psoriasis.9 IL-12 consists of p40 and p35 and has been shown to promote the development of T-helper (Th) type 1 cells needed for cell-mediated immune response. 9 Analysis of skin from patients with psoriatic lesions has uncovered increased levels of p40 and p19 messenger RNA (mRNA) compared with skin from patients without lesions.10 Furthermore, in murine skin models, intradermal injections of IL-23 have led to the development of psoriatic lesions.11

“IL-23 has been viewed, in a sense, as an overarching master cytokine in psoriasis,” says Cleveland Clinic dermatologist and clinical researcher Anthony Fernandez, MD, PhD. “We know that IL-23 is required not only for terminal differentiation of Th17 cells but also for their survival.”

Once activated, Th17 cells produce other central proinflammatory cytokines such as IL-17A, resulting in a self-perpetuating inflammatory cascade. Research has shown that activated Th17 cells also secrete IL-22, IL-21 and TNF-a which further contribute to the development of psoriatic plaques.9,12

IL-23 Antagonists for the Treatment of Psoriasis

Inhibition of IL-23 may have added benefits in the treatment of psoriasis, notes Dr Fernandez. “Because we know that IL-23 is important for the survival of Th17 cells, perhaps by inhibiting IL-23 we can actually reduce the overall number of pathogenic Th17 cells over time, which may allow for better long-term control of psoriasis,” he explains.

Ustekinumab, the first biologic agent targeting IL-23, also targets IL-12 through their shared p40 subunit. Approved by the FDA in 2009 for treating moderate to severe plaque psoriasis, the agent is still in use today for the treatment of psoriasis. The rationale behind developing additional agents that selectively target IL-23 was based on the redefined central role of IL-23 in the pathogenesis of psoriasis, as well as an attempt to address safety by not interfering with the IL-12-mediated Th1 response.9,13

Three selective IL-23 inhibitors are currently approved for the treatment of plaque psoriasis:  guselkumab, risankizumab, and tildrakizumab.

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Guselkumab

Guselkumab is a fully human monoclonal antibody that binds to the p19 subunit of IL-23.9 Guselkumab was the first IL-23 antagonist to receive FDA approval for the treatment of moderate to severe plaque psoriasis in adults who are candidates for phototherapy or systemic therapy. The monoclonal antibody was approved in 2017 based on results from 2 double-blind, placebo-controlled clinical trials that included participants with moderate to severe psoriasis in the United States, Europe, Canada, Australia, Russia, Korea, and Taiwan. Most recently, in July of 2020, guselkumab also received FDA approval for the treatment of adults with active psoriatic arthritis.

The 2 clinical trials (VOYAGE 1 [ClinicalTrials.gov Identifier: NCT02207231] and VOYAGE 2 [ClinicalTrials.gov Identifier: NCT02207244]) compared guselkumab 100 mg (at weeks 0 and 4, then every 8 weeks), placebo followed by guselkumab 100 mg at week 16,  and adalimumab (80-mg loading dose at week 0, followed by 40 mg at week 1 and then every 2 weeks). The trials demonstrated that treatment with guselkumab provided superior skin clearance, as evaluated by Psoriasis Area and Severity Index (PASI) 75 and PASI 90. 14-16

Guselkumab is formulated as a subcutaneous 100-mg/mL injection and is available in a single-dose, prefilled syringe or autoinjector. The guselkumab prescribing information (PI) outlines a dosing schedule that includes administration of a single dose at week 0, week 4, and every 8 weeks thereafter.16 It also includes warnings about potential hypersensitivity reactions, increased risk of infection, and a recommendation for tuberculosis evaluation prior to treatment initiation.16

In clinical studies of patients with plaque psoriasis, those treated with guselkumab experienced a slightly higher rate of infections (23%) compared with those receiving placebo (21%), but the rate of serious infections was low in both groups (≤0.2%).16 The most common adverse events reported through week 16 included upper respiratory tract infections (14.3%), headache (4.6%), injection site reactions (4.5%), and arthralgia (2.7%).16

Tildrakizumab

Tildrakizumab — a humanized monoclonal antibody that selectively inhibits the p19 subunit of IL-239 — was the second IL-23 antagonist to receive FDA approval for the treatment of psoriasis. It was approved in 2018 for the treatment of moderate to severe plaque psoriasis in adults who may benefit from systemic therapy or phototherapy.  The approval of tildrakizumab was based on the results from 3 multicenter, international clinical trials (NCT01225731, NCT01722331, and NCT01729754) that included 1060 study participants with moderate to severe plaque psoriasis.

Tildrakizumab is formulated as a 100-mg/mL subcutaneous injection and is available in a single-dose, prefilled syringe. The tildrakizumab PI outlines a dosing schedule that includes administration of a single dose at week 0, week 4, and every 12 weeks thereafter.17 It also includes warnings about potential hypersensitivity reactions (angioedema and urticaria), increased risk for infection, and a recommendation for tuberculosis evaluation and treatment, if needed, prior to starting treatment.17

In the aforementioned multicenter, randomized, double-blind, placebo-controlled trials (reSURFACE 1 [ClinicalTrials.gov Identifier: NCT01722331] and reSURFACE 2 [ClinicalTrials.gov Identifier: NCT01729754]), study participants who received tildrakizumab 100 mg achieved significantly greater skin clearance rates at week 12 (PASI 75: 64% and 61%, PASI 90: 35% and 39%, and PASI 100: 14% and 12%, respectively) compared with those who received placebo (PASI 75: 6% in both trials, PASI 90: 3% and 1%, and PASI 100: 1% and 0%, respectively).17,18 PGA scores of 0 and 1 were also achieved by more than one-half of patients receiving tildrakizumab in both trials compared with only 7% and 4%, respectively, of patients receiving placebo.17

Risankizumab

Risankizumab is the latest IL-23 antagonist to receive FDA approval for use in plaque psoriasis. Risankizumab is a humanized monoclonal immunoglobulin G1 (IgG1) class antibody that exerts action by binding to the p19 subunit of IL-23, thereby blocking its proinflammatory activity.19 In 2019, risankizumab was approved for the treatment of moderate to severe plaque psoriasis in adults who may benefit from systemic therapy or phototherapy.  FDA approval was based on results from 5 clinical trials including 1606 participants with moderate to severe plaque psoriasis.

The UltIMMa-1 (ClinicalTrials.gov Identifier: NCT02684370) and UltIMMa-2 (ClinicalTrials.gov Identifier: NCT02684357) trials compared the safety and effectiveness of risankizumab with ustekinumab and placebo in a group of patients with moderate to severe plaque psoriasis.20  At week 16 in UltIMMa-2, 74.8% of patients receiving risankizumab achieved a PASI 90 response compared with 2% of patients receiving placebo and 47.5% of patients receiving ustekinumab.20

Similarly, at week 16 in UltIMMa-1, 75.3% of patients receiving risankizumab achieved a PASI 90 response compared with 4.8% of patients receiving placebo and 42% of patients receiving ustekinumab. In UltIMMa-1, 87.8% of patients receiving risankizumab achieved a static Physician’s Global Assessment (sPGA) score of 0 or 1 compared with 7.8% of patients receiving placebo and 63% of patients receiving ustekinumab.20

Risankizumab is administered as a subcutaneous injection at a recommended dose of 150 mg (two 75-mg injections) delivered at week 0 and week 4, followed by 150 mg every 12 weeks thereafter.21 The risankizumab PI recommends that clinicians evaluate patients for tuberculosis infection prior to initiating treatment. The medication also carries warnings about possible increased risk for infections.21 In clinical studies, participants treated with risankizumab had a higher rate of infections compared with participants receiving placebo (22.1% vs 14.7%, respectively), but the rate of serious infections was low (≤0.4%) in both groups.21

[Editor’s Update: Additionally, although studies have shown that in-class biologic switching can be effective in the treatment of psoriasis, the efficacy of an in-class IL-23 inhibitor switch had not been previously explored.22,23 In a recent observational retrospective study, patients with moderate-to-severe psoriasis who were treated with risankizumab after a guselkumab failure experienced a similar improvement to individuals who were only treated with risankizumab.24 Psoriasis severity was measured by multiplying the physician’s global assessment by the affected body surface area (PGA*BSA). The results revealed that individuals who had switched to risankizumab from guselkumab experienced a 79.3% average decrease in PGA*BSA after treatment. Individuals who were naive to anti-IL-23 treatments experienced an 84.3% decrease in PGA*BSA after treatment.24]

Risankizumab
Side Effects
Flip
Side Effects
Adverse events most commonly reported include upper respiratory infections, headache, fatigue, injection site reaction, and tinea infections.

“These are very good medications, no question,” states Dr Fernandez. “The data in the clinical trials, in terms of efficacy and safety, have looked as good as anything we have available to us.” In terms of their use in the clinic, he believes that “right now the preferred patients are going to be patients with moderate to severe psoriasis who do not have psoriatic arthritis.  However, as we have just seen guselkumab attain FDA approval for psoriatic arthritis, the population of patients who will be prescribed these agents is expected to broaden over the next few years.”

“I think that these medications have been available to us long enough where most clinicians who treat psoriasis commonly feel very comfortable using them as first-line treatments,” he concludes.

Refer to the full Prescribing Information for additional details about Tremfya®, IlumyaTM,and SkyriziTM.

Disclosure

Dr Fernandez reports receiving honoraria for consulting and speaking from AbbVie, Novartis, and Mallinckrodt. He has received research funding from Novartis and Mallinckrodt, and consulting honoraria from UCB.

References

  1. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United States. J Am Acad Dermatol. 2014;70(3):512-516.
  2. Griffiths CEM, van der Walt JM, Ashcroft DM, et al. The global state of psoriasis disease epidemiology: a workshop report. Br J Dermatol. 2017;177(1):e4-e7.
  3. Parisi, R, Symmons DPM, Griffiths CEM, Ashcroft DM; on behalf of the Identification and Management of Psoriasis and Associated ComorbidiTy (IMPACT) project team.  Global epidemiology of psoriasis: A systematic review of incidence and prevalence. J Invest Dermatol. 2013;133(2);377-385.
  4. Icen M, Crowson CS, McEvoy MT, Dann FJ, Gabriel SE, Kremers HM. Trends in incidence of adult-onset psoriasis over three decades: a population-based study. J Am Acad Dermatol. 2009;60(3);394-401.
  5. Grine L, Dejager L, Libert C, Vandenbroucke RE. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev. 2015;26(1):25-33.
  6. Yang EJ, Smith MP, Ly K, Bhutani T. Evaluating guselkumab: an anti-IL-23 antibody for the treatment of plaque psoriasis. Drug Des Devel Ther. 2019;13:1993-2000.
  7. Chan TC, Hawkes JE, Krueger JG. Interleukin 23 in the skin: role in psoriasis pathogenesis and selective interleukin 23 blockade as treatment. Ther Adv Chronic Dis. 2018;9(5):111-119.
  8. Fitch E, Harper E, Skorcheva I, Kurtz SE, Blauvelt A. Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines. Curr Rheum Rep. 2007;9(6):461-467.
  9. Fotiadou C, Lazaridou E, Sotiriou E, Ioannides D. Targeting IL-23 in psoriasis: current perspectives. Psoriasis (Auckl). 2018;8:1-5.
  10. Lee E, Trepicchio WL, Oestreicher JL, et al. Increased expression of interleukin 23p19 and p40 in lesional skin of patients with psoriasis vulgaris. J Exp Med. 2004;199(1):125-130.
  11. Nakajima K, Kanda T, Takaishi M, et al. Distinct role of IL-23 and IL-17 in the development of psoriasis-like lesions in a mouse model. J Immunol. 2011;186(7):4481-4489.
  12. Di Meglio P, Nestle FO. The role of IL-23 in the immunopathogenesis of psoriasis. F1000 Biol Rep. 2010;2:40.
  13. Levin AA, Gottlieb AB. Specific targeting of interleukin-23p19 as effective treatment for psoriasis. J Am Acad Dermatol. 2014;70(3):555-561.
  14. 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. 2017;76(3):405-417.
  15. 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, placebo- and active comparator-controlled VOYAGE 2 trial. J Am Acad Dermatol. 2017;76(3):418-431.
  16. Tremfya. Prescribing Information. Janssen Biotech; July 2017. Accessed July 22, 2020. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/TREMFYA-pi.pdf
  17. Ilumya. Prescribing Information. Sun Pharma Global FZE, Inc; August 2018. Accessed July 22, 2020. https://www.ilumyapro.com/wp-content/uploads/sites/9/Sun_Pharma_ILUMYA_US_Prescribing_Information.pdf
  18. Reich K, Papp KA, Blauvelt A, et al. Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE1 and reSURFACE 2): results from two randomised controlled, phase 3 trials. Lancet. 2017;390(10091):276-288.
  19. Banaszczyk K. Risankizumab in the treatment of psoriasis – literature review. Rheumatologia. 2019;57(3):158-162.
  20. Gordon KB, Strober B, Lebwohl M, et al. Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials. Lancet. 2018;392(10148):650-661.
  21. Skyrizi. Prescribing Information. AbbVie Inc.; March 2020. Accessed July 22, 2020. https://www.rxabbvie.com/pdf/skyrizi_pi.pdf
  1. Sherman S, Solomon-Cohen E, Amitay-Laish I, Hodak E, Pavlovsky L. IL-17A inhibitor switching-efficacy of ixekizumab following secukinumab failure. A single-center experience. Acta Derm Venereol. 2019;99(9):769-773.
  2. Georgakopoulos JR, Phung M, Ighani A, Lam K, Yeung J. Biologic switching between interleukin 17A antagonists secukinumab and ixekizumab: a 12-week, multicenter, retrospective study. J Eur Acad Dermatol Venereol. 2019; 33(1):e7-e8.
  3. Reddy R, Pannu S, Fiumara K, Khan J, Rosmarin D. Efficacy of in-class IL-23 inhibitor switching: Risankizumab following guselkumab failure in moderate-to-severe psoriasis treatment. Br J Dermatol. Published online September 30, 2020. doi:10.1111/bjd.19575

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Dermatology Advisor had no role in this content’s preparation.

Reviewed April 2021

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