Summary

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• The effect of TREMFYA on radiographic progression in adult patients with active psoriatic arthritis (PsA) was evaluated in a randomized, double-blind, placebo-controlled, multicenter, phase 3 study (DISCOVER-2).^1-6
  • In the first and second reading sessions, the least squares mean (LSM) change from baseline at week 24 in the PsA-modified van der Heijde-Sharp (vdH-S) score in the TREMFYA 100 mg every 4 weeks (q4w) group vs the placebo group was 0.29 vs 0.95 (P=0.011), and in the TREMFYA 100 mg every 8 weeks (q8w) group vs the placebo group was 0.52 vs 0.95 (P=0.072).
  • The LS mean change from baseline at week 52 in the PsA-modified vdH-S score in the TREMFYA 100 mg q4w and q8w groups was 1.10 and 1.13, respectively.
  • The mean change from baseline at week 100 in the PsA-modified vdH-S score in the TREMFYA 100 mg q4w and q8w groups was 1.68 and 1.50, respectively.
  • Through week 24, serious infections were reported in 1 and 3 patients in the TREMFYA 100 q8w and q4w groups, respectively, and 1 patient in the placebo group. From week 24 through week 52, the rate of serious infection did not increase in patients treated with TREMFYA and no additional malignancies or major cardiovascular events were reported after week 24. Through week 112, death was reported in 1 patient from the placebo to TREMFYA q4w crossover group due to road traffic accident.
  • In the third reading session, the mean change from baseline in the total PsAmodified vdH-S score in the TREMFYA 100 mg q4w and q8w groups from weeks 52 to 100 was 0.8 and 0.5, respectively.⁶ 
• APEX is a phase 3b study designed to evaluate the efficacy and safety of TREMFYA in biologic-naïve patients with active PsA and known risk factors for radiographic progression.⁷
  • Results are not currently available.

CLINICAL DATA

Phase 3 Study – DISCOVER-2

Mease et al (2020)^1,8, McInnes et al (2020)², McInnes et al (2021)³, Mease et al (2024)^4,9, Mease et al (2024)⁵, and Gottlieb et al (2023)^6,10 evaluated the effect of TREMFYA on radiographic progression using the PsAmodified vdH-S score in biologic-naïve adult patients with active PsA who had inadequate response to or intolerance of standard therapies (nonbiologic disease-modifying antirheumatic drugs [DMARDs], apremilast, and nonsteroidal anti-inflammatory drugs [NSAIDs]) in a randomized, doubleblind, placebo-controlled, multicenter, phase 3 study (DISCOVER-2).

Study Design/Methods

• The study design is presented in Figure: DISCOVER-2 Study Design.

• The primary endpoint was the proportion of patients achieving ≥20% improvement in the American College of Rheumatology criteria (ACR20) at week 24.
• Secondary endpoints adjusted for multiplicity included change from baseline in PsAmodified vdH-S score at week 24.
• Radiographs of the hands (posteroanterior) and feet (anteroposterior) were obtained at weeks 0 and 24 for the first reading session and at weeks 0, 24, and 52 for the second reading session and were evaluated independently by 2 central readers (masked to the order of radiographs and clinical data) using the PsA-modified vdH-S score. A third reader was used for adjudication and was blinded to treatment group and time point.
  • The total PsA-modified vdH-S score (range, 0-528) included addition of the following scores:
    • Joint erosion score (range 0-320; 0 for no erosions to 5 for extensive loss of bone from >50% of the articulating bone)
    • Joint space narrowing score (range 0-208; 0 for no joint space narrowing to 4 for complete loss of joint space, bony ankylosis, or complete luxation)
  • The average of the joint erosion and the joint space narrowing scores was used in the analysis.
• For radiographic data, treatment failure rules, including discontinued study treatment, terminated study participation, initiated or increased DMARD or oral corticosteroid doses, or initiated protocol-prohibited PsA treatment, were not applied, and missing data were assumed to be missing at random and were imputed using multiple imputations.

Results

Patient Characteristics

• A total of 739 patients were randomized to receive TREMFYA 100 mg q8w (n=248), TREMFYA 100 mg q4w (n=245), or placebo (n=246). Of the randomized patients, 93% and 88% completed 1 year and 100 weeks of treatment, respectively.
• Baseline demographics were generally similar between the treatment groups and are summarized in Table: Baseline Demographic and Disease Characteristics.
• The majority of patients in the overall population (n=713; 96%), including those who received TREMFYA 100 mg q8w (n=234/248; 94%), TREMFYA 100 mg q4w (n=241/245; 98%), or placebo (n=238/246; 97%), had a PsA-modified vdH-S score >0.

Efficacy in Radiographic Reading

• A significantly greater proportion of patients achieved ACR20 at week 24 in the TREMFYA 100 mg q4w (64%) and q8w (64%) groups vs the placebo (33%) group (P<0.0001 for both TREMFYA groups).
• At week 24, significantly less progression of structural damage, as reflected by smaller changes from baseline in the PsA-modified vdH-S score, was observed in the TREMFYA 100 mg q4w group vs the placebo group (LS mean [95% confidence interval (CI)], 0.29 [0.05 to 0.63] vs 0.95 [0.61 to 1.29]; P=0.011), whereas a nonsignificant decrease in radiographic progression was observed in the TREMFYA 100 mg q8w group vs the placebo group (LS mean [95% CI], 0.52 [0.18 to 0.86] vs 0.95 [0.61 to 1.29]; P=0.072).
• At week 52, the estimated LS mean changes in the TREMFYA 100 mg q4w and q8w groups, respectively, were 1.10 (95% CI, 0.48-1.71) and 1.13 (95% CI, 0.52-1.73), and the LS mean differences compared with placebo were -1.06 (95% CI, -1.89 to -0.23) and -1.03 (95% CI, -1.85 to -0.20).
• At week 100, low rates of radiographic progression were observed across both the TREMFYA 100 mg q4w (1.68) and q8w (1.50) groups. Overall, mean changes in the total PsA-modified vdH-S score showed less radiographic progression from weeks 52 to 100 compared with weeks 0-52 in the 3 groups.
• For the third reading session, patients continuing study treatment at week 52 underwent assessments at weeks 0, 24, 52, and 100 (or at discontinuation after week 52). Readers were blinded to the treatment group and time point.⁶ 
  • Mean changes in the total PsA-modified vdH-S score, joint space narrowing, and erosion scores were reported.
  • Among patients who did and did not achieve clinical response at week 100, changes in the total vdH-S scores from weeks 0-100 were determined by ≥20%/≥50%/≥70% improvement in the American College of Rheumatology criteria (ACR20/50/70), low disease activity (LDA) based on Disease Activity in PsA (DAPSA) score (≤14) or PsA Disease Activity Score (PASDAS; ≤3.2), minimal disease activity (MDA), and normalized Health Assessment Questionnaire-Disability Index (HAQ-DI) score (<0.5).
• From weeks 0-24, the mean changes in radiographic scores indicated that the rates of radiographic progression of joint damage were numerically lower in TREMFYA-treated vs placebo-treated patient.
• For mean changes in radiographic scores, see Table: Change in PsA-Modifed vdH-S Score Through Weeks 24, 52, and 100.

• For association between radiographic changes and measures of clinical outcomes, see Table: Changes in PsA-Modified Total vdH-S Score from Baseline Through Week 100 by Clinical Responses at Week 52 and Week 100.

• For clinical response in patients with or without radiographic progression, see Table: Proportions of Patients Achieving MDA Components at Week 24, 52, and 100 by Treatment Groups and Progression Status.

Correlation of Baseline PsA-Modified vdH-S Scores With Baseline PsA Parameters

• For correlation between baseline PsA parameters with PsA-modified vdH-S Score among patients randomized to receive TREMFYA q4w or q8w (n=449), see Table: Correlation Between Baseline PsA-Modified vdH-S Score and Radiographic Progression Risk Factors.

Impact on Total PsA-Modified vdH-S Scores Through Week 100

• The impact on the total PsA-modified vdH-S scores among patients randomized to receive TREMFYA (n=440) is presented in Table: Multivariate Associations of DAPSA Endpoints at Week 8 and Baseline Risk Factors of Radiographic Progression Through Week 100.

• For data on the impact of achieving DAPSA endpoints at week 8 on time-averaged LSM changes from baseline to week 52 and 100, see Table: Time-Averaged LSM Change in Total PSA-Modified vdH-S Score by DAPSA Endpoints.

• The data on effect of clinical Disease Activity Index for psoriatic arthritis (cDAPSA) LDA/remission (REM) are presented in Table: LSM Change in Total PSA-Modified vdH-S Score by cDAPSA LDA/REM at Week 52 and Week 100

Safety

• Safety results summarized below are from patients enrolled in DISCOVER-2 and are not limited to patients with radiographic progression.
• The safety results through week 24 are presented in Table: Summary of Safety Results Through Week 24.

• From week 24 through week 52, the rate of serious infection did not increase in patients treated with TREMFYA and no additional malignancies or major cardiovascular events were reported after week 24.²
• Through week 112³:
  • Death was reported in 1 patient from the placebo to TREMFYA q4w crossover group due to road traffic accident.
  • Opportunistic infections, including fungal esophagitis and disseminated herpes zoster, were reported in 2 patients in the TREMFYA q8w group, and listeria meningitis was reported in 1 patient from the placebo to TREMFYA q4w crossover group.
  • Patients treated with TREMFYA did not report any inflammatory bowel disease.
  • Patients did not report any anaphylactic or serum sickness reactions or active tuberculosis.

Phase 3b Study – APEX

Ritchlin et al (2023)⁷  described APEX, a phase 3b, multicenter, randomized, double-blind, placebo-controlled study to assess the efficacy and safety of TREMFYA compared with placebo in biologic-naïve patients with active PsA and known risk factors for radiographic progression (N~950). Results are not currently available.

Study Design/Methods

• Select inclusion criteria included patients ≥18 years old with active PsA despite previous treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), apremilast, and/or nonsteroidal anti-inflammatory drug (NSAID) therapy; diagnosis of PsA for ≥6 months prior to first administration of the study medication and meeting ClASsification Criteria for Psoriatic ARthritis (CASPAR) at screening; active PsA (≥3 swollen and ≥3 tender joints and C-reactive protein [CRP] level ≥0.3 mg/dL); ≥2 joints with erosions on the baseline radiographs of the hands and feet; active plaque psoriasis (PsO) with ≥1 psoriatic plaque of ≥2 cm diameter and/or psoriatic nail changes; ≥1 of the following PsA subsets:
  • distal interphalangeal joint involvement
  • polyarticular arthritis with absence of rheumatoid nodules
  • arthritis mutilans¹¹
  • asymmetric peripheral arthritis
  • spondylitis with peripheral arthritis
• Select exclusion criteria included, current use of ≥3 csDMARDs, previous use of biologic therapy or Janus kinase (JAK) inhibitors for PsA or PsO, prior use of systemic immunosuppressants or apremilast within 4 weeks of the first administration of the study medication, systemic lupus erythematosus, and presence of other inflammatory diseases (including rheumatoid arthritis, axial spondyloarthritis, non-radiographic axial spondyloarthritis, and Lyme disease).^7,11
• Findings from DISCOVER-2 informed the design of APEX. Sample sizes of 350, 250, and 350 for placebo, TREMFYA q4w, and TREMFYA q8w treatment groups, respectively, are expected to provide adequate power to detect a significant difference in vdH-S score change at week 24; and a significant difference in the American College of Rheumatology (ACR) 20% improvement in response rates (ACR20) between each TREMFYA group and placebo at week 24.
• The study design is summarized in Figure: APEX Study Design.

• Primary endpoint:
  • Proportion of patients who achieve the ACR20 response at week 24.
    • An improvement of ≥20% from baseline in swollen joint count (66 joints) and tender joint count (68 joints).
    • An improvement of ≥20% from baseline in 3 of the following assessments: patient’s assessment of pain (Visual Analog Scale [VAS]), Patient’s Global Assessment of Disease Activity (arthritis, VAS), Physician’s Global Assessment (PGA) of Disease Activity, HAQ-DI, serum C reactive protein (CRP) level.
• Major secondary endpoint:
  • Mean change from baseline in the PsA-modified vdH-S score at week 24.
• Other secondary endpoints:
  • Safety through week 60 (through week 168 for patients who enter the long-term extension [LTE]).
    • Frequency and type of adverse events (AEs), serious AEs, reasonably related AEs, AEs leading to discontinuation of treatment, infections, and injection-site reactions.
    • Frequency of laboratory (chemistry, hematology) abnormalities and maximum toxicity grades based on the Common Terminology Criteria for Adverse Events (CTCAE 5.0).
  • Pharmacokinetics and immunogenicity through week 60 (through week 168 for patients who enter the LTE).
    • Serum guselkumab concentration
    • Incidence of antibodies to TREMFYA
  • Select other endpoints through week 156¹²:
    • Change from baseline through week 156 in the following:
      • ACR 50% improvement (ACR50) in response rate
      • ACR 70% improvement (ACR70) in response rate
      • HAQ-DI
      • Disease Activity Score 28 (DAS28; CRP)
      • Modified Psoriatic Arthritis Response Criteria (mPsARC)
      • Dactylitis
      • Enthesitis
      • Investigator’s Global Assessment (IGA)
      • Psoriasis Area and Severity Index (PASI)
      • Dermatology Life Quality Index (DLQI)
      • Modified Nail Psoriasis Severity Index (mNAPSI)
      • Work Productivity and Activity Impairment Questionnaire (WPAI)
      • Modified Composite Psoriatic Disease Activity Index (mCPDAI)
      • Psoriatic Arthritis Impact of Disease 12-item Questionnaire (PsAID12)
      • Disease Activity Index for Psoriatic Arthritis (DAPSA)
      • Minimal Disease Activity (MDA)
      • Very Low Disease Activity (VLDA)
      • Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F)

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 February 2025.