SUMMARY

• Please refer to local labeling for relevant information on the use of TREMFYA in patients with active psoriatic arthritis (PsA) and preexisting enthesitis.
• Use of TREMFYA in enthesitis among adult patients with PsA was assessed in a post hoc analysis of pooled data from DISCOVER-1 and DISCOVER-2 studies through week 24 and week 52. Significantly higher proportions of patients achieved resolution of enthesitis at week 24 in both the TREMFYA every 4 weeks (q4w) (44.9%; P=0.0301) and every 8 weeks (q8w) (49.6%; P=0.0301) groups vs placebo (29%). Leeds Enthesitis Index (LEI) entheseal count (EC) improvement was maintained from week 24 through week 52 with 52% of patients achieving enthesitis resolution in the TREMFYA q4w and q8w groups.¹
• In a post hoc analysis of DISCOVER-2, enthesitis resolution rates at week 100 were 61.8% in the TREMFYA q4w, 69.8% in the q8w groups, and 64.6% in the placebo→TREMFYA crossover group.²
• Use of TREMFYA in adult patients with active PsA and inadequate response to tumor necrosis factor inhibitors (TNFi-IRs) was evaluated in a post hoc analysis of COSMOS through week 48. Enthesitis resolution rate was higher in patients with TREMFYA vs placebo at week 24 (47% vs 23%), and this improvement sustained through week 48 (56%).³ 

CLINICAL DATA

Post hoc Analysis

McGonagle et al (2021)¹ evaluated the efficacy of TREMFYA on enthesitis from two randomized, double-blind, placebo-controlled, multicenter, phase 3 studies (DISCOVER-1 and DISCOVER-2).

Study Design/Methods

• The study designs are presented in Figure: DISCOVER-1 Study Design and in Figure: DISCOVER-2 Study Design

• Pre-specified, pooled data from both DISCOVER-1 and DISCOVER-2 were used to assess changes from baseline in the number of tender LEI sites and proportion of patients achieving enthesitis resolution at week 24 among patients with LEI EC ≥1 at baseline.
• Enthesitis was assessed using the LEI (total score: 0-6) for patients to document the absence (0) or presence (1) of painful entheses among the left and right lateral epicondyle humeri, left and right medial femoral condyle, and left and right Achilles tendon insertions.
  • Additional pre-specified endpoint included the number of LEI sites with newly developed enthesitis through week 52 among patients with no enthesitis (LEI EC=0) at baseline.
• Additional post hoc analyses of select endpoints at weeks 24 and 52 was assessed including ≥20% improvement in the American College of Rheumatology (ACR) response criteria (ACR20), mean changes from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form 36-item (SF-36) physical component summary (PCS) and mental component summary (MCS) scores, and achievement of minimal disease activity (MDA).
• At baseline, patients with enthesitis (LEI EC ≥1) were categorized by the following:
  • Mild enthesis: LEI score=1
  • Moderate enthesis: LEI score=2
  • Severe enthesis: LEI score=3 to 6
• Enthesitis resolution status through week 52 was categorized as:
  • Full: post-baseline LEI EC=0
  • Partial: post-baseline LEI EC < baseline LEI EC
  • Stable/worse: post-baseline LEI EC ≥ baseline LEI EC
• Treatment failure rules were applied as pre-specified through week 24 and as post-hoc after week 24.
• Patients meeting treatment failure criteria and missing binary data were considered non-response.

Results

Patient Characteristics

• Among 1118 patients pooled from DISCOVER-1 and DISCOVER-2, 728 patients (65%) had enthesitis at baseline (mean LEI score=2.8) and were characterized with BMI ≥30, IGA score = 4, PASI ≥20, higher mean values for indicators of more active disease and impaired physical function and consisted of more female patients compared to those without enthesitis. Baseline demographics are summarized in Table: Baseline Characteristics in Patients With or Without Enthesitis at Baseline.

Efficacy

• Significantly higher proportions of patients achieved enthesitis resolution at week 24 in both the TREMFYA q4w (44.9%, 109/243; P=0.0301 vs placebo) and q8w (49.6%, 114/230; P=0.0301 vs placebo) groups vs. placebo (29%, 75/255).
• Median time to achieve enthesitis resolution was shorter in the TREMFYA groups (16 weeks, respectively) than placebo (24 weeks).
• LEI EC improvement was maintained from week 24 through week 52 with 58% of patients achieving enthesitis resolution in the TREMFYA q4w and q8w groups.
• Least-square mean change in LEI was higher in both TREMFYA groups compared with placebo.
• Enthesitis resolution and least-square mean change in LEI through week 52 in patients with enthesitis at baseline are summarized in Table: Enthesitis Improvement through Week 24 And Week 52 in Patients with Enthesitis at Baseline.

• Treatment effect of the TREMFYA groups compared with placebo was observed by week 8 in patients with mild or moderate enthesitis and by week 16 in patients with severe enthesitis. Change in enthesitis severity from baseline through week 52 is summarized in Table: Change in Enthesitis Severity from Baseline at Week 4 and Week 52 in Patients with Enthesitis at Baseline.

• ACR20 response at week 24 (the primary endpoint of DISCOVER-1 and DISCOVER-2) was similar in TREMFYA-treated patients with enthesitis (60–61%) and without enthesitis (60–64%) at baseline.
  • Through week 52, ACR20 response rate was sustained in patients with enthesitis (68–72%) and without enthesitis (70-72%).
• Through week 52, no new on-set enthesitis was reported in the majority of patients (86.9% in TREMFYA q4w; 84.6% in TREMFYA q8w vs 82.6% in placebo).
• Improvement in HAQ-DI score and HRQoL (SF-36 PCS and MCS scores) at week 24 were also consistent between patients with and without enthesitis at baseline in patients receiving TREMFYA.
  • Through week 52, patients with enthesitis at baseline appeared to have higher numerical improvement in the SF-36 PCS score than those without (4.7–5.0 vs 3.4–3.8).
• Among patients receiving TREMFYA, MDA was achieved in 38–45% of patients without enthesitis and in 27–31% of those with enthesitis at week 52.

Rahman et al (2022)² evaluated the efficacy of TREMFYA on enthesitis resolution rates through week 100 in a post hoc analysis of DISCOVER-2.

Study Design/Methods

• For study design and inclusion/exclusion criteria, please refer to Figure: DISCOVER-2 Study Design above.
• At baseline, LEI scores (1-6) were evaluated.
• Change in LEI score and enthesitis resolution (LEI score=0) at the analysis visit among patients who had enthesitis at baseline (including 8 patients with ≥1 tender entheseal site at baseline based on only 4/6 LEI entheseal sites evaluated) were assessed through week 100.
• Nonresponder imputation was implemented for enthesitis resolution rates through week 100:
  • Weeks 0-24: patients who met treatment failure criteria were considered non-responders/having no improvement from baseline through week 24.
    • Remaining missing data used multiple imputation for continuous endpoints and were imputed as nonresponders for categorical endpoints.
  • Post-week 24 continuous data: patients with missing data due to treatment discontinuation were considered having no change from baseline; multiple imputation was used to impute remaining missing data assuming they were missing at random.
  • Post-week 24 categorical data: patients with missing data due to treatment discontinuation and remaining missing data were imputed as nonresponders.

Results

• At baseline, 69% (n=245) of all patients (N=739) had enthesitis with a mean LEI score of 2.8.
  • Proportion of patients with enthesitis was 69% in TREMFYA q4w group (mean LEI score=3.0); 64% in TREMFYA q8w group (mean LEI score=2.6); 73% in placebo group (mean LEI score=2.8).
• Least squares mean change from baseline in LEI scores and enthesitis resolution rates through week 100 among patients with enthesitis at baseline are summarized in Table: Least Squares Mean Change in LEI Scores and Enthesitis Resolution Rates (NRI) Through Week 100 From DISCOVER-2 in Patients With Manifestation at Baseline.
• Greater improvements (average decrease in LEI score) in enthesitis were achieved at week 24 and through week 100 (LEI scores of -1.9 to -2.1) among TREMFYA-treated patients.

McInnes et al (2024)³ evaluated the effect of TREMFYA through 48 weeks across various clinical outcomes, including enthesitis in patients with active PsA and TNFi-IRs from a phase 3b, randomized, double-blind, placebo-controlled clinical trial (COSMOS).

Study Design/Methods

COSMOS Study Design 

• Select inclusion criteria: patients ≥18 years of age; active PsA for ≥6 months;
  ≥3 swollen joints and ≥3 tender joints for ≥6 months; patients who met Classification Criteria for Psoriatic Arthritis (CASPAR) at screening; active (≥1 psoriatic plaque of
  ≥2 cm) or documented history of plaque psoriasis (PsO) or current nail PsO; inadequate response or intolerance to 1-2 tumor necrosis factor inhibitors (TNFis).⁷  
• Patients were randomized in a 2:1 ratio to receive either TREMFYA 100 mg or placebo subcutaneously (SC) at weeks 0, 4, and q8w thereafter through week 44. 
• The study comprised placebo-controlled (weeks 0-24) and active-treatment (weeks
  24-48) periods, with final study intervention at week 44.  
• At week 16, patients from either group who experienced <5% improvement from baseline in both swollen and tender joint counts were eligible for early escape (EE) to initiate/increase one of the permitted concomitant medications per investigator’s discretion. Patients in the TREMFYA group continued the randomized treatment and received placebo at week 16 to maintain blinding and patients in the placebo group who qualified for EE received TREMFYA at weeks 16, 20, and q8w thereafter through week 44.
• At week 24, all remaining randomized placebo patients crossed over to receive TREMFYA 100 mg at weeks 24, 28, and q8w thereafter through week 44.
• The primary endpoint was the American College of Rheumatology (ACR) 20 response at week 24.
• Efficacy response was assessed through week 48.
• Multiplicity-controlled secondary endpoints evaluated at week 24 included the following: mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQDI); ≥50% improvement from baseline in the ACR50; mean change from baseline in the 36-item Short-Form Health Survey Physical Component Summary (SF-36 PCS) score; and 100% improvement from baseline in the Psoriasis Area and Severity Index (PASI 100) score in patients with ≥3% body surface area (BSA) psoriatic involvement and an Investigator’s Global Assessment (IGA) score ≥2 at baseline.
• Safety was assessed through week 56.

Post Hoc Analysis Study Design 

• The post hoc analysis assessed the following outcomes from COSMOS trial at weeks 24 and 48:³ 
  • Effects on joints: ACR 20/50/70 response, enthesitis and dactylitis resolutions ([LEI=0] and Dactylitis Severity Score [DSS=0])
  • Skin: improvement in PASI 90/100 response in patients with ≥3% BSA and IGA ≥2 at baseline, IGA score of 0/1 response
  • Patient-report outcomes: ≥4 points improvement from baseline in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) and ≥0.35 points improvement from baseline in HAQ-DI
  • Composite outcome measures: PsA Disease Activity Score (PASDAS) low disease activity (LDA) and minimal disease activity (MDA)
• These outcomes were evaluated by baseline patient age, sex, body mass index (BMI), swollen joint count (SJC), tender joint count (TJC), PsA duration, % BSA, C-reactive protein (CRP), pain Visual Analogue Scale (VAS), number of prior TNFi and discontinuation reason, and conventional synthetic disease-modifying antirheumatic drug (csDMARD) status.

Results

Baseline characteristics

• A total of 285 patients with PsA and TNFi-IR were randomized to receive TREMFYA (n=189) or placebo (n=96).^3,7 
• Baseline demographics are summarized in Table: Summary of Patient Baseline Demographics.

Efficacy

• In the overall population, enthesitis resolution rate was higher in patients with TREMFYA than those with placebo at week 24 (47% [59/126] vs 23% [15/64]; odd ratio [OR] 2.9; 95% confidence interval [CI], 1.4-6.1) and this improvement sustained in the TREMFYA group through week 48 (56% [70/126]).³ 
• In subgroup analyses, greater proportions of patients with TREMFYA achieved enthesitis resolution rates than the placebo at week 24 in the following baselines:1.
  • Patient demographics (age, sex, and BMI): ORs =1.5-6.5
  • Disease characteristics (SJC, TJC, PsA duration, % BSA, CRP level, or pain VAS): ORs =1.0-10.5
  • Prior/ongoing therapies and reasons for discontinuing prior TNFi: ORs =1.4-5.1
• Enthesitis resolution rates at weeks 24 and 48 by baseline patient demographics, disease characteristics, prior/ongoing therapies, and reasons for prior TNFi discontinuation in Figure: Enthesitis Resolution Rates at Weeks 24 and 48 by Baseline Subgroups

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 13 January 2025.