Tildrakizumab In PsA: A Data Review

Case Study: 

A thirty-three-year-old male with body and scalp plaque psoriasis and a history of psoriatic arthritis with established duration of seven years presented with a flare of his joint disease. The patient’s previous therapy included several TNF-α inhibitors, most recently infliximab dosed at six week intervals, with the addition of leflunomide, and oral corticosteroids due to progression of his peripheral articular disease. His past medical history included depression, hypertension, and prediabetes. He is co-managed by both a dermatologist and rheumatologist who collaborate to determine the optimal treatment approach to manage his psoriatic arthritis. The case study demonstrates the ideal patient for consideration of IL-23 inhibitors for the management of psoriasis and psoriatic arthritis. 

Introduction 

Psoriasis is a prevalent skin disease with several associated comorbidities including depression, cardiovascular disease, metabolic syndrome, and psoriatic arthritis with personal and economic implications¹. The economic burden of psoriasis in the USA alone is estimated to be over $112 billion USD². Psoriatic arthritis has an estimated global prevalence of 0.2-0.3%³, and likely has a similar economic burden due to effects on physical function and quality of life. 

The pathogenesis of psoriasis is a result of dysregulation of T lymphocytes and dendritic cells contributing to aberrant keratinocyte proliferation. Particularly, T-helper 17 (Th17) cells are key to the overproduction of IL-17 and IL-22 which drive the pathogenesis of psoriasis and psoriatic arthritis. IL-22, along with TNF-α and IL-23 has been implicated in activating resident cells (chondrocytes, osteoblasts, osteoclasts) in the joint and at the enthesis ultimately upregulating RANKL and inducing osteoclast formation contributing to bone erosion and new bone formation^4,5. Upstream to Th17 activation is dendritic cell driven IL-23 production, that amplifies further differentiation of Th174. As such, targeting IL-23 can ablate aberrant production of IL-23, decreasing Th17 activation.

The American College of Rheumatology-National Psoriasis Foundation joint guidelines for the treatment of PsA recommend TNF-α inhibitors, and DMARDs prior to the initiation of IL-23 inhibitors; Currently, the only IL-23 inhibitor that has been approved by the FDA in patients with psoriatic arthritis is guselkumab⁶. Recently published GRAPPA treatment guidelines strongly recommended use of IL-23 inhibitors in line with other bDMARDs for the treatment of peripheral arthritis, enthesitis, and dactylitis7.

The reSURFACE1 and reSURFACE2 trials as well as studies investigating tildrakizumab for psoriatic arthritis demonstrated similar safety profiles for tildrakizumab. Nasopharyngitis, headache and injection site reactions were the most common treatment emergent adverse events reported^8,9. As of May 2021, tildrakizumab is Health Canada approved for the treatment of moderate-to-severe plaque psoriasis. 

Pivotal Study Design

Tildrakizumab was evaluated for the treatment of psoriatic arthritis in a recent phase IIb study conducted in 8 countries across 74 sites over 52 weeks with placebo crossover at week 24. Patients over the age of 18, with a diagnosis of PsA meeting CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria for > 6 months, with ≥ 3 tender or swollen joints as evaluated by an independent assessor were screened for study entry. Randomisation was computer-generated before the study and patients were stratified by prior anti-TNF-α therapy use (yes/no; prior anti-TNF-α use capped at 30% of total patients) and baseline body weight (≤ 90 kg/> 90 kg). Key inclusion criteria included stable use of NSAIDs, acceptable concomitant use of conventional systemic disease modifying antirheumatic drugs (csDMARDs) or prednisone, and the ability to maintain current background treatment for the first 24 weeks.⁹ Conventional systemic DMARDs allowed included methotrexate < 25 mg per week or leflunomide < 20 mg per day for > 3 months and on a stable dose for > 8 weeks prior to the start of treatment with tildrakizumab. Patients were excluded if they had more than 1 biologic treatment or any prior use of IL-18, IL24 or IL12/23 p40 biologic therapies. Patients who were on anti-TNF-α therapy, B-cell and T-cell depleting agents, or apremilast use were excluded. Five hundred patients were screened of whom 391 patients met inclusion criteria. These patients with psoriatic arthritis were randomized and assigned 1:1:1:1:1 to receive tildrakizumab 200 mg subcutaneous every 4 weeks, tildrakizumab 200 mg, 100 mg or 20 mg every 12 weeks or placebo every 4 weeks (Figure 1). At 24 weeks, patients receiving tildrakizumab 20 mg or placebo were switched to receive tildrakizumab 200mg every 12 weeks.⁹

Figure 1: Study Design illustrating randomization stratified by prior TNF-α use, baseline body weight.

The primary end point was ACR20 response at week 24. The secondary and exploratory end points were prespecified as well, notably minimal disease activity, and ACR50/70. Additional end points are listed in Table 1. Patients were allowed to enroll and continue concomitant antirheumatic medications. Patients who failed to show minimal response to treatment (<10% improvement from baseline in swollen and tender joint counts) at week 16 could have background csDMARDs or oral corticosteroids adjusted according to the maximum permitted daily dose and continue in the study as a non-responder. At baseline, demographics were matched for age, sex, body mass. Patients had psoriatic arthritis for a median range of 4.4 years since diagnosis.

Table 1: Primary and Secondary End Points

Treatment Efficacy

The primary end point, ACR20 at week 24, was achieved by 71.4-79.5% of patients receiving any dose of tildrakizumab relative to placebo-treated patients (50.6%), with more responders at 200 mg every 4 weeks and 100 mg every 12 weeks (Table 2). At 52 weeks, the response was marginally higher at 67.5-79.5% of patients achieving ACR20. Similarly, at week 24 ACR50 was achieved by 50.6-52.6% of patients receiving tildrakizumab 200 mg either every 4 weeks or every 12 weeks relative to placebo-treated patients (24.1%).⁹ Although a direct comparison cannot be made, 52.0-64.1% of patients achieved ACR 20 on guselkumab in the DISCOVER-1 and DISCOVER-2 trials.¹⁰ With respect to tildrakizumab, patients achieving ACR70 at 24 weeks displayed more modest response at 16.7-28.2% (Table 2). Patients achieving ACR70 at 52 weeks had a more robust response ranging from 35.4-50.0% across all treatment arms; tildrakizumab 200 mg dosed at 4-week intervals having the highest response rate (50.0%). 

Table 2: Review of ACR20/50/70 across all treatment arms at week 24 and week 52.

With respect to minimal disease activity (Figure 2), a composite of physician and patient global assessments as well as quality of life measures, tildrakizumab 200 mg dosed at 12-week intervals outperformed other doses across most criteria, including tender joint count, swollen joint count, PASI, BSA, and pain visual analogue scale. However, patients had limited improvement in tender entheseal points compared to the placebo-treated arm (71.8-80.3% on Tildrakizumab vs 74.4% on placebo treatment) as well as HAQ-DI <0.05 (Figure 2).¹¹ 

Figure 2: Tildrakizumab and impact on minimal disease activity composite at Week 24. Tender joint count (TJC) <1, Swollen Joint Count (SJC) <1, Psoriasis Area and Severity Index <1 or Body surface area <3%, patient pain visual analogue scale <15, patient global disease activity <1, VAS <20, HAQ-DI <0.5 and tender5 entheseal points <1.

Interestingly, exploratory analysis of patients on tildrakizumab with prior anti-TNF-α experience also demonstrated sustained response and met ACR20 relative to placebo but less than TNF-α-naive patients (Figure 3). At week 24, 52.9-70.6% of TNF-α-exposed patients with PsA had achieved ACR20 compared to patients in the placebo treated arm (36.8%) (Figure 4).⁹ 

Figure 3: Efficacy – ACR20 at Weeks 24 and 52 by Prior Anti-TNF-α Experience

Figure 4a: Efficacy – ACR50 at Weeks 24 and 52 by Prior Anti-TNF-α Experience

Figure 4b: Efficacy – ACR70 at Weeks 24 and 52 by Prior Anti-TNF-α Experience

The proportion of patients achieving very low disease activity (VLDA) (Figure 5) was higher in patients who received tildrakizumab 200 mg dosed at 4-week intervals (15.4%) and in patients who received tildrakizumab 200 mg dosed at 12-week intervals (16.5%) vs patients in the placebo group (1.3%) at week 24. Durable responses were noted at week 52, with responses seen in patients that switched from the placebo arm or the tildrakizumab 20 mg every 4 weeks arm to the tildrakizumab 200 mg every 4 weeks arm.¹² 

Figure 5: Proportion of patients achieving very low disease activity by treatment and time point.

Safety 

This study demonstrated a similar safety profile for tildrakizumab as was observed in the reSURFACE trials in plaque psoriasis. In a pooled analysis of reSURFACE 1 and reSURFACE 2 trials over a 148-week period, tildrakizumab was shown to be safe and effective with treatment emergent AEs at 35.2-37.2 per 100 patient years compared to placebo at 148.6 events per 100 patient years8. Nasopharyngitis, headache and injection site reactions were the most common treatment emergent adverse events reported. A low incidence of serious adverse events was noted in this study similar to the reSURFACE trial¹³. The safety profile of tildrakizumab compared to other IL-23 inhibitors is also similar with respect to overall adverse events including serious adverse events. In this study, there were no reports of deaths, systemic candidiasis, inflammatory bowel disease, major adverse cardiac event, or significant transaminitis through week 529. There was one case each of pyelonephritis and UTI in the tildrakizumab 100 mg arm, but none in the 200 mg every 12-week arm (Table 3). One malignancy (intraductal proliferative breast lesion) was reported in a patient who started on tildrakizumab 20 mg every 12 weeks and then crossed over to tildrakizumab 200 mg every 12 weeks. 

Table 3: Safety profile of tildrakizumab including treatment emergent adverse effects, including those of special and clinical interest.

Summary and Conclusion 

Compared with the placebo group, more patients in the tildrakizumab groups achieved an ACR20 or ACR50 response, minimal disease activity responses at week 24 and maintained their response through week 52. The molecule’s safety profile is consistent with other IL-23 inhibitors and the medication was generally well tolerated. Shortening the dosing interval from every 12 weeks to every 4 weeks for the 200 mg dose did not result in a measurable increase in skin or joint response scores. Some of the practical considerations to utilizing tildrakizumab include convenience, safety with concomitant csDMARDs, and sustained improvement in PASI scores, which make tildrakizumab a favourable option in the clinician’s therapeutic armamentarium. 

Acronyms 

PsA – Psoriatic Arthritis 

PACE – Psoriatic Arthritis Screening and Evaluation 

HAQ – Health Assessment Questionnaire 

hsCRP – high sensitivity C-reactive protein 

csDMARD – conventional systemic disease modifying antirheumatic drug 

bDMARD – biologic disease modifying antirheumatic drug 

GRAPPA – Group for Research and Assessment of Psoriasis and Psoriatic Arthritis