Jennifer Wytsma, BASc; Taylor Evart Woo, MD, MSc; Laurie Parsons, MD, FRCPC

Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Conflict of interest: The authors have no conflicts of interest to declare. Funding: None.

Abstract:
The pathogenesis of psoriasis has been linked to autoimmune and autoinflammatory traits that result in atypical cytokine and keratinocyte activation and proliferation. Many cytokine pathways are involved in the development of inflammation with interleukin-23 (IL-23) playing a significant role in plaque-type psoriasis. Biologic agents that target specific cytokines have shown to be effective therapies in the treatment of plaque-type psoriasis over other conventional treatments such as systemic retinoids. Tildrakizumab is an immunoglobulin G1-kappa monoclonal antibody that inhibits the IL-23/IL-17 pathway and has demonstrated through two three-part randomized Phase 3 clinical trials (reSURFACE 1 and reSURFACE 2) and their extension trials to be an efficacious and safe therapy for the targeted treatment of moderate-to-severe plaque-type psoriasis.

Keywords: psoriasis, tildrakizumab, IL-23/IL-17 pathway, targeted therapy, re-SURFACE trials, Ilumya®

Introduction

Psoriasis is a chronic inflammatory skin disease that affects 2% of the population. The pathogenesis of psoriasis is multifactorial and associated with a polygenic genetic predisposition and various triggers, leading to an abnormal type 1 immune response stimulating abnormal keratinocyte proliferation and differentiation.1-3 Among the various cytokines implicated in the development of psoriasis, interleukin-23 (IL-23) has shown to play a significant role via induction of IL-17 and regulation of T memory cells and activation of macrophages that contribute to chronic inflammation (Figure 1).2 The development of co-morbidities such as joint and vascular inflammation, and an increased risk of cardiometabolic, gastrointestinal, and chronic kidney diseases, can lead to psychological and quality of life impairments for many patients.1 A systematic review and meta-analysis showed that the risk of developing depression is greater in patients with psoriasis, which may result from factors such as stigma and social isolation, physical pain from pruritus and bleeding, and co-morbidities, as well as associations with pro-inflammatory biomarkers.4 An increased prevalence of depression, anxiety and suicide ideation amongst the psoriatic population reveals a high burden of disease.1

Long-Term Efficacy of Tildrakizumab in the Treatment of Psoriasis - image
Figure 1: Proposed mechanism of action for tildrakizumab in the IL-23-Th17 pathway.
Psoriasis is a chronic inflammatory condition that has been linked to type 1 cytokines stimulating keratinocyte activation and proliferation.3 IL-23 has shown to play a significant role in the pathogenesis behind plaque-type psoriasis.2 When a physical trigger activates keratinocytes, dendritic cells become activated. These plasmacytoid dendritic cells (pDCs) recruit IL cytokines (IL-23 and IL-12). The IL-23p19 subunit binds to the IL-23R receptor on Th17 and stimulates the phosphorylation of JAK2, STAT3, and TYK2, thereby, inducing gene expression of RORΥt. This results in Th17 cell differentiation that release proinflammatory cytokines (IL-17A/F) that in turn further induce keratinocyte activation and proliferation.9-11 Tildrakizumab in a high-affinity IgG1 antagonist antibody that targets the IL-23p19 subunit. Its binding to the p19 subunit on IL-23 inhibits the binding of IL-23p19 with IL-23R. This ultimately reduces the generation of IL-17A/F, thereby reducing keratinocyte activation and proliferation. Tildrakizumab specifically targets the IL-23p19 subunit and does not interact with other IL cytokines on the pathway.6
pDC, plasmacytoid dendritic cell; IL, interleukin; IL-23R, interleukin-23 receptor; Th, T helper lymphocyte; JAK2, Janus activated kinase 2; TYK2, tyrosine kinase 2; STAT3, signal transducer and activator of transcription 3; RORΥt, retinoid-related orphan receptor-gamma (t); TNFα, tumor necrosis factor alpha. BioRender was used to create Figure 1.

While phototherapy continues to be used in the sphere of psoriasis, other therapies such as immunosuppressive and immunomodulatory treatments, including methotrexate, carry long-term risk of adverse effects.5 With an improved safety and efficacy profile over conventional treatments, biologics are increasingly emerging as standard of therapy for the management of psoriasis.

Novel Therapy

In March 2018, tildrakizumab, a high-affinity, humanized immunoglobulin G1-kappa (IgG1/k) monoclonal antibody targeting the p19 unit of IL-23, was approved by the US FDA for the treatment of patients with moderate-to-severe chronic plaque psoriasis.6 Health Canada approval followed in May 2021. Data from two randomized Phase 3 trials (reSURFACE 1 and reSURFACE 2, n=772 and n=1090) and their extension trials showed favorable efficacy and tolerability of tildrakizumab.7,8

Mechanism of Action

Tildrakizumab binds to the p19 subunit on IL-23 and inhibits the binding of IL-23 with the IL-23 receptor (IL-23R) on Th-17 cells.6 When the IL-23p19 subunit binds to the IL-23 receptor, it results in tyrosine phosphorylation of JAK2 within Th-17 cells, thereby inducing phosphorylation of STAT3 and TYK2 and gene expression of RORγt, leading to Th17 cell differentiation. Th17 cell differentiation releases proinflammatory cytokines (IL-17A/F) that in turn induce keratinocyte activation and proliferation.9-11 By blocking the binding of IL-23p19 to IL-23R, the release of IL-17A/F cytokines is inhibited.

Clinical Trials

The efficacy and safety of tildrakizumab was assessed in two three-part randomized Phase 3 trials (reSURFACE 1 and reSURFACE 2).7 The two trials spanned 250 sites globally and included sites in Australia, Canada, the UK, the US, Europe, Israel, and Japan. Enrolled participants were aged 18 years or older with moderate-to-severe chronic plaque psoriasis as defined by body surface area ≥10%, Physician’s Global Assessment (PGA) score ≥3 and Psoriasis Area and Severity Index (PASI) score ≥12. Baseline characteristics were similar across all groups and included a higher percentage of male (65%-73%) and White (65%-92%) participants with average PASI scores of 19.3-20.7. Two co-primary endpoints were evaluated in the trials and included: achieving PASI 75 and PGA response (score of 0 (“clear”) or 1 (“minimal”) with ≥2 grade score reduction from baseline) at week 12. Secondary endpoints were PASI 90 and PASI 100 at week 12 in both studies. In reSURFACE 2, PASI 75 and PGA response at week 28 were also secondary endpoints. In reSURFACE 1, 772 subjects were randomized to receive 200 mg (n=308), 100 mg (n=309), or placebo (n=155). In reSURFACE 2, 1090 subjects were randomized to receive 200 mg (n=314), 100 mg (n=307), placebo (n=156), or etanercept (n=313). Tildrakizumab was administered at week 0 and 4 during part 1 and at week 16 during part 2. Etanercept was administered twice weekly in part 1 and once weekly during part 2 of the reSURFACE 2 trial.

At week 12, subjects assigned to 100 mg or 200 mg of tildrakizumab groups showed significant clinical improvement in both re-SURFACE 1 and 2 trials compared to vehicle controls. Table 1 shows efficacy results for the two co-primary efficacy endpoints and the two secondary endpoints (p<0.0001 for comparisons of both tildrakizumab groups vs. placebo in both trials).

Table 1: Week 12 co-primary efficacy endpoints of PASI 75 responses and PGA scores, and secondary endpoints of PASI 90 and PASI 100, in tildrakizumab 100 mg, 200 mg, and vehicle groups according to reSURFACE trials.
Overall, both trials achieved the two co-primary efficacy endpoints (week 12 PASI 75 and PGA score of “clear” or “minimal”) and the week 12 PASI 90 and PASI 100 secondary endpoints, demonstrating that both the 100 mg and 200 mg tildrakizumab doses were efficacious compared with vehicle groups.7
PASI, Psoriasis Area and Severity Index; PGA, Physician’s Global Assessment

Two extension studies of the reSURFACE 1 and 2 Phase 3 trials were conducted up until 148 weeks (2 years) and 244 weeks (5 years). In the 148-week extension, efficacy was assessed for responders (PASI 75) to 100 mg and 200 mg tildrakizumab, partial responders (PASI 50-75) to 100 mg and 200 mg tildrakizumab, and partial/non-responders (PASI 50-75/PASI 0-50) to etanercept at week 28. Tildrakizumab responders (100 mg, n=329; 200 mg, n=227) and partial responders (100 mg, n=40; 200 mg, n=201) were maintained on the same dose and partial/non-responders to etanercept 50 mg were switched to tildrakizumab 200 mg dosing (n=121), administered every 12 weeks, until week 148.8 In the 244-week extension study, the tildrakizumab 100 mg and 200 mg week 28 responders (100 mg, n=302; 200 mg, n=213) and partial/non-responders to etanercept who were switched to tildrakizumab 200 mg at week 28 (n=107) were maintained on the same dose, administered every 12 weeks, until week 244.12 The efficacy results for both extension studies are shown in Table 2.

Table 2: Week 148 and Week 244 PASI 75, 90, and 100 responses to tildrakizumab 100 mg and 200 mg by response group.
PASI, Psoriasis Area and Severity Index

Overall, the reSURFACE trials 2-year extension study demonstrated that 80% of patients who initially responded to tildrakizumab maintained PASI 75 efficacy up to week 148 with continued tildrakizumab treatment.8 The 5-year extension study showed improved PASI 75, 90, and 100 responses from week 128 to week 244 across tildrakizumab responders and etanercept partial/nonresponders groups, demonstrating sustained psoriasis control with tildrakizumab treatment in moderate-to-severe psoriasis patients.12

Safety Profile

Phase 3 trials of tildrakizumab showed an overall safety profile similar to vehicle. The most common adverse event in these investigations was nasopharyngitis (200 mg 6%, 100 mg 8%, and vehicle 5% in reSURFACE 1; 200 mg 11%, 100 mg 13%, and vehicle 8% in reSURFACE 2) and upper respiratory tract infection (200 mg 5%, 100 mg 3%, and vehicle 6% in reSURFACE 1). The proportion of patients with serious adverse events or who discontinued were low across both reSURFACE 1 and 2 trials (2%, 1% in the 200 mg tildrakizumab group; 0%, 1% in the 100 mg tildrakizumab group; 1%, 1% in the placebo group for reSURFACE 1 and reSURFACE 2, respectively). Notably, many side effects associated with other psoriasis medications, such as Candida infections, commonly seen in anti-IL 17A antibodies medications, were infrequent in reSURFACE trials. No new cases of inflammatory bowel disease or exacerbation of pre-existing disorders was reported in these studies. Suicidal ideation and behavior that have been observed with brodalumab, an IL-17A antibody, were not reported in any of the reSURFACE trials. Only one major adverse cardiovascular (CV) event, a side effect that has been linked to briakinumab, an IL-12 and IL-23p40 antibody, was reported in the trials.7

In the 2-year and 5-year extension study, there were no apparent dose-dependent safety signals or unexpected adverse events. Nasopharyngitis remained the most common treatment-emergent adverse event. The safety profile for 2- and 5-year extension trials for adverse events occurring in greater than 5% of patients is shown in Table 3.8

Table 3: Numbers and exposure-adjusted incidence rates of treatment-emergent adverse events occurring in greater than 5% of patients for the reSURFACE 2- and 5-year extension trials.
Data is shown as patients with events per 100 patient-years (PYs) of exposure.

In the 5-year extension study, the cumulative incidence for major adverse CV events (0.5, 0.7 per 100 PYs for tildrakizumab 100 mg and 200 mg, respectively), malignancy excluding non-melanoma skin cancer (0.7, 0.6 per 100 PYs for tildrakizumab 100 mg and 200 mg, respectively), and severe infections (1.2, 1.3 per 100 PYs for tildrakizumab 100 mg and 200 mg, respectively) were generally comparable with Psoriasis Longitudinal Assessment and Registry (0.22, 0.55, 1.45 per 100 PYs). No dosage-related differences in frequency of severe infections or malignancies were noted.12

An additional pooled analysis of the 5-year extension study data compared the safety profile of tildrakizumab in younger (<65 years: 100 mg, n=303; 200 mg, n=211) and older (≥65 years: 100 mg, n=26; 200 mg, n=16) patients with psoriasis. Both age groups showed similar profiles, with nasopharyngitis and upper respiratory tract infections being the most common treatment-emergent adverse events. While older patients showed higher incidence than younger patients of CV events (100 mg/200 mg 14/21 per 100 PYs vs. 1/3 per 100 PYs), nonmelanoma skin cancer (6/10 vs. 8/6), and other malignancies (17/11 vs. 4/6), these increases were likely attributable to aging and longer psoriatic disease duration, and not as a result of psoriasis treatment. Overall, tildrakizumab demonstrated similar efficacy across both age groups, with comparable improvements in quality of life, and without major safety issues.13 These results further support the favorable safety profile of tildrakizumab.

Conclusion

Tildrakizumab is a promising target therapy to treat moderate-to-severe plaque psoriasis. Evidence from the Phase 3 clinical investigations and their extension trials has demonstrated that tildrakizumab is efficacious and well-tolerated by patients and maintains a reassuring safety profile. The most common side effects from the trials (up to 5 years), were nasopharyngitis and upper respiratory tract infection. Adverse effects that have been linked to other biologic agents, such as Candida infections, CV events, and suicide ideation, were not identified or were uncommon in the 5-year trials. While the reSURFACE 1 and 2 trials and their extensions have provided evidence of the longer-term safety profile of tildrakizumab, pharmacovigilance remains important through real-world and/or prolonged experience.

References



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