Summary

• The company cannot recommend any practices, procedures, or usage that deviate from the approved labeling.
• Clinical practice guidelines have described an association between cardiovascular (CV) disease and psoriatic diseases (plaque psoriasis [PsO] and psoriatic arthritis [PsA]).^1-3
• Patients with unstable CV disease were excluded from the following TREMFYA phase 2 and 3 clinical trials:
  • Moderate to severe plaque PsO: X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, Japan Registration^4-10
  • Active PsA: Phase 2, DISCOVER 1, DISCOVER 2, COSMOS^11-14
  • Unstable CV disease was defined as recent clinical deterioration (eg, unstable angina, rapid atrial fibrillation) in the last 3 months or a cardiac hospitalization in the last 3 months^4-13
• The VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, DISCOVER 1 and DISCOVER 2 clinical trials included patients with baseline medical history of comorbid CV disease characteristics, such as coronary artery disease, myocardial infarction, and stroke; and comorbid CV disease risk factors, such as hypertension, hyperlipidemia, and diabetes mellitus.^15-21
• Outcomes and medical history related to major adverse cardiovascular events (MACE; CV death, nonfatal myocardial infarction, or nonfatal stroke) in TREMFYA-treated patients were reported in plaque PsO and PsA clinical trials.^22-31
  • An integrated pooled safety analysis evaluated the incidence rates of MACE from 11 phase 2 and 3 clinical trials in patients with plaque PsO and PsA³¹:
    • During the placebo (PBO)-controlled period, the exposure-adjusted incidence rates (EAIR) of MACE was 0.35 per 100 patient-years (PYs) in the combined-TREMFYA group (patients with PsO on TREMFYA every 8 weeks [Q8W] and patients with PsA on TREMFYA Q8W and TREMFYA every 4 weeks [Q4W]; N=2257). Through the end of the reporting period, EAIR of MACE was 0.31 per 100 PYs in the all-TREMFYA group (patients with PsO on TREMFYA Q8W [including patients originally randomized to PBO or adalimumab→TREMFYA] and patients with PsA on TREMFYA Q8W and TREMFYA Q4W [including patients originally randomized to PBO→TREMFYA at week 24]; N=4399).

PRACTICE GUIDELINES ON CARDIOVASCULAR DISEASE AND PSORIATIC DISEASES

• It is recommended that healthcare providers should inform patients regarding the association between CV disease and psoriatic disease (PsO and PsA). Patients should engage with their primary care provider or cardiologist with physical screening and clinical lab monitoring to confirm diagnoses and establish a treatment plan with lifestyle modification efforts.^1-3

Clinical TRIAL Data in moderate to severe Plaque Psoriasis

Study Design/Methods

VOYAGE 1 and VOYAGE 2

Blauvelt et al (2017)³² and Reich et al (2017)³³ summarized two phase 3, randomized, double-blind, PBO- and adalimumab comparator-controlled studies designed to evaluate the safety and efficacy of TREMFYA in patients with moderate to severe plaque PsO.

• VOYAGE 1 (n=837) and VOYAGE 2 (n=992) included a PBO-controlled period (weeks 0-16).
• Safety was assessed through week 264, including patients originally randomized to adalimumab at baseline who crossed over and were treated with TREMFYA.

NAVIGATE

Langley et al (2018)²³ evaluated the safety and efficacy of TREMFYA in NAVIGATE, a phase 3, randomized, double-blind, active-comparator controlled study in patients with moderate to severe plaque PsO with an inadequate response to ustekinumab.

• Eligible patients (n=871) received open-label ustekinumab at weeks 0 and 4.
• At week 16, patients with an inadequate response to ustekinumab (Investigator’s Global Assessment [IGA] score ≥2) were randomized to TREMFYA 100 mg through week 44 or to continue ustekinumab through week 40. Patients with an IGA of 0 or 1 continued receiving open-label ustekinumab at week 16 through week 40.
• Safety was assessed during weeks 16-60.

ORION

Ferris et al (2020)²⁴ reported results from a phase 3, randomized, double-blind, PBO-controlled study evaluating the efficacy, safety and pharmacokinetics of TREMFYA compared to PBO, both administered via the One-Press patient-controlled injection device.

• Eligible patients (n=78) were randomized in a 4:1 ratio to receive subcutaneous (SC) TREMFYA 100 mg or SC PBO with crossover to TREMFYA 100 mg, both delivered by the One-Press patient-controlled injection device. Patients randomized to TREMFYA received PBO at week 16 to maintain the blinding.
• Safety was assessed through week 40.

ECLIPSE

Reich et al (2019)³⁴ reported results from ECLIPSE, a head-to-head study of TREMFYA and secukinumab in adult patients with moderate to severe PsO.

• Eligible patients (n=1048) were randomized at week 0 in a 1:1 ratio to TREMFYA 100 mg SC or secukinumab 300 mg SC through week 44.
• Safety was assessed through week 56.

Pooled Safety Analysis: X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, and Japan Registration

Lebwohl et al (2023)²⁵ summarizes pooled safety data of TREMFYA treatment for up to 5 years in patients with moderate to severe PsO across 7 phase 2/3 clinical trials
(X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, and Japan Registration).

• All studies, including the X-PLORE, a phase 2 clinical trial (n=293), and Japan phase 3 registration (n=192) had a PBO-controlled period, except for NAVIGATE (active comparator: ustekinumab) and ECLIPSE (active comparator: secukinumab).
• Long-term safety included data from all patients treated with ≥1 dose of TREMFYA.
• The safety reporting periods for TREMFYA exposure were defined as: X-PLORE, week 0-52; VOYAGE 1 and VOYAGE 2, week 0-264; NAVIGATE, week 16-60; ORION, week 0-40; ECLIPSE, week 0-56; Japan registration, week 0-156.
• These studies included patients originally randomized to adalimumab (VOYAGE 1 and VOYAGE 2) or PBO (X-PLORE, VOYAGE 1, VOYAGE 2, ORION, Japan registration) at baseline who crossed over and were treated with TREMFYA.

Baseline Medical History of Select Comorbid CV Disease Characteristics and CV Disease Risk Factors

VOYAGE 1, VOYAGE 2, NAVIGATE, ORION and ECLIPSE

• Select baseline medical history from TREMFYA clinical trials for the treatment of moderate to severe plaque PsO is summarized in Table: Summary of Baseline Medical History of Select CV Disease Characteristics in VOYAGE 1, VOYAGE 2, NAVIGATE, ORION and ECLIPSE.^15-19

• In the pooled safety analysis across 7 phase 2/3 PsO clinical trials, baseline medical history of select CV risk factors for all randomized patients were reported: hypertension (24.3%-40.6%), hyperlipidemia (12.4%-26.6%), and diabetes mellitus (8.1%-
  17.9%).²⁵

Results for MACE

VOYAGE 1 AND VOYAGE 2

Pooled Safety Data from VOYAGE 1 and VOYAGE 2 through 5 Years

• The rates of MACE in TREMFYA-treated patients per 100 PYs of follow-up through week 264 are summarized in Table: Rates of MACE per 100 PYs of Follow-Up Across Pooled VOYAGE 1 and VOYAGE 2 Data of Patients Treated with TREMFYA through Week 264.

• The rates of MACE per 100 PYs of follow-up by year are summarized across pooled VOYAGE 1 and VOYAGE 2 data for patients in the combined TREMFYA group, see Table: Pooled VOYAGE 1 and VOYAGE 2 Rates of MACE in Patients Treated with TREMFYA per 100 PYs of Follow Up by Year.

NAVIGATE

• No MACE occurred during weeks 0-16 (open-label ustekinumab run-in).²³
• During weeks 16-60, in the randomized TREMFYA and ustekinumab groups, 3 patients had a myocardial infarction (TREMFYA group: 1 female, aged 69 years and 1 male, aged 52 years; ustekinumab group: 1 male, aged 66 years); all 3 patients had at least 2 known CV risk factors.²³
• During weeks 16-60, in the nonrandomized ustekinumab continuation group, 1 patient had an acute myocardial infarction; the patient had a history of multiple known risk factors.²³

ORION

• No cases of MACE were reported through week 40.²⁴

Pooled Safety Analysis: X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, and Japan Registration

• Through week 16, 1 TREMFYA-treated patient in VOYAGE 1 reported a nonfatal myocardial infarction (0.26 [0.01-1.47]/100 PYs). The patient had a history of hyperlipidemia, hypertension and a body mass index (BMI) of 35.4 kg/m².²⁵
• Through the long-term reporting period, 28 TREMFYA-treated patients experienced 29 MACE events (0.33 [0.22-0.48]/100 PYs). Most patients had ≥3 CV risk factors at baseline (n=19/28).²⁵
  • Nonfatal myocardial infarctions (n=19; 0.22 [0.13-0.34]/100 PYs)
    • All patients had ≥1 of the following risk factors: hypertension, hyperlipidemia, obesity, or current/former smoker.
  • Nonfatal strokes (n=6; number of MACE events=7; 0.08 [0.03-0.17]/100 PYs)
    • One patient in the Japan registration study had 2 nonfatal strokes.
    • Two patients had previous stroke history, including the patient who had 2 strokes during the Japan registration study.
  • CV deaths (n=3; 0.03 [0.01-0.10]/100 PYs)
    • All patients had a ≥3 CV risk factors at baseline.

Clinical TRIAL Data in ACtive Psoriatic Arthritis

Study Design/Methods

DISCOVER-1 and DISCOVER-2

Rahman et al (2021)²⁶ evaluated the safety of TREMFYA in the treatment of 1120 adult patients with active PsA through week 24 and 1 year from two phase 3, randomized, controlled studies (DISCOVER-1 and DISCOVER-2). McInnes et al (2022)²⁷ evaluated the long-term safety of TREMFYA in 739 adult patients with active PsA through week 112 from the phase 3 DISCOVER-2 study.

• Pooled population (n=1120) in the studies were randomized 1:1:1 to TREMFYA 100 mg at week 0 and 4, then Q8W; TREMFYA 100 mg at week 0, then Q4W; and PBO through week 20, then TREMFYA 100 mg at week 24, then Q4W.²⁶
• Adverse events and clinical laboratory test results were assessed in an integrated safety analysis through week 24 (PBO-controlled phase) in both studies, and in a pooled safety analysis through week 60 in DISCOVER-1 (end of the study) and through week 52 in DISCOVER-2.²⁶
• Safety was further assessed through week 112 in the DISCOVER-2 study.²⁷

Kavanaugh et al (2023)²⁸ evaluated the efficacy and safety of TREMFYA for the treatment of patients with active PsA and concurrent CV risk factors from DISCOVER-1 and DISCOVER-2 in a post-hoc analysis.

• Patients included had ≥1 of the following CV risk factors: obesity; smoking; or history of hypertension, hyperlipidemia, or diabetes mellitus.

Pooled Safety Analysis PsA: Phase 2, DISCOVER-1, DISCOVER-2, and COSMOS

Rahman et al (2023)²⁹ summarizes pooled safety data of TREMFYA treatment for up to 2 years in patients with active PsA across 4 phase 2/3 clinical trials (Phase 2, DISCOVER 1, DISCOVER 2, and COSMOS).

• Patients in the Phase 2 and COSMOS clinical trials were randomized to receive either TREMFYA 100 mg Q8W or PBO with crossover to TREMFYA 100 mg Q8W.
• Long-term safety included data from all patients treated with ≥1 dose of TREMFYA.
• The safety reporting periods for TREMFYA exposure were defined as: Phase 2 and COSMOS, week 0-56; DISCOVER 1, week 0-60; DISCOVER 2, week 0-112.
• Safety data were assessed in an integrated safety analysis through week 24 (PBO-controlled period) and through the end of each study.

Baseline Medical History of Select Comorbid CV Disease Characteristics and CV Disease Risk Factors

DISCOVER-1 and DISCOVER-2

• Select baseline medical history for DISCOVER-1 and DISCOVER-2 are summarized in Table: Summary of Baseline Medical History of Select Comorbid CV Disease Characteristics in DISCOVER-1 and DISCOVER-2.^20,21

• In the pooled DISCOVER-1 and DISCOVER-2 post-hoc analysis, 758/1120 had ≥1 CV risk factor (TREMFYA Q4W 259, TREMFYA Q8W 252, PBO 247).²⁸
• Of the 758 patients, 448 (59%) were obese, 315 (42%) were smokers, 420 (55%) had hypertension, 171 (23%) had hyperlipidemia, and 103 (14%) had diabetes mellitus.²⁸

Results for MACE

DISCOVER-1 and DISCOVER-2

• Through week 24, 2 patients (1 in the PBO group from DISCOVER-1 and 1 in the TREMFYA 100 mg Q4W group from DISCOVER-2) reported MACE.²⁶
• Through 1 year, there was no increase in incidence of MACE.²⁶
  • The patient in the TREMFYA 100 mg Q4W group previously reported ischemic stroke through week 24. The patient had a history of hypertension, hyperlipidemia, and diabetes at baseline.

DISCOVER-2

• Through week 112, 3 patients in the TREMFYA 100 mg Q4W group (n=245) reported nonfatal MACE, including:
  • Ischemic stroke (n=2): 1 patient had a history of hypertension, hyperlipidemia, and diabetes (reported at week 20); 1 patient had a history of hypertension, stroke, and smoking.^27,30
  • Myocardial infarction (n=1): the patient had a history of smoking, hypertension, and hyperlipidemia.²⁷

Phase 2, DISCOVER-1, DISCOVER-2, and COSMOS

• Through week 112, there were 6 reports of MACE in 5 TREMFYA-treated patients (myocardial infarction, n=3; ischemic stroke, n=2) and 1 death secondary to cardiac failure in the PBO group. All patients had multiple CV risk factors.²⁹
• The number of MACE per 100 PYs within select TREMFYA phase 2/3 clinical trials for the treatment of PsA are reported in Table: MACE Per 100 PYs for All TREMFYA-treated Patients with Active PsA in Phase 2, DISCOVER-1, DISCOVER-2, and COSMOS.

Clinical Trial Data - Plaque psoriasis and psoriatic arthritis

Pooled Safety Analysis: X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, Japan Registration, Phase 2 PsA, DISCOVER-1, DISCOVER-2 AND COSMOS

Strober et al (2024)³¹ evaluated the safety of TREMFYA in an integrated pooled analysis of data from 11 randomized, double-blind, phase 2 and 3 plaque PsO and PsA studies.

Study Design/Methods

• All plaque PsO studies (X-PLORE, VOYAGE 1, VOYAGE 2, ORION, Japan Registration) included a PBO-controlled period (weeks 0-16), except NAVIGATE (active comparator: ustekinumab) and ECLIPSE (active comparator: secukinumab).
• All active PsA studies (Phase 2, DISCOVER-1, DISCOVER-2, COSMOS) included a PBO-controlled period (weeks 0-24).
• This long-term safety analysis included a total of 4399 patients (PsO, n=2891; PsA, n=1508) who received ≥1 administration of TREMFYA (age, years, mean±standard deviation [SD], 45.4±12.5) for a total follow-up of 10,787 patient-years (PYs); see Table: Safety Reporting Period for Clinical Studies Included in the Integrated Analysis.
• The median duration of TREMFYA exposure was 1.7 years, 3.5 years, and 1.2 years in the pooled population, PsO group, and PsA group, respectively.
• The short-term safety dataset included 1061 patients who received PBO (395 PYs) and 2257 patients who received TREMFYA (856 PYs).

Results for MACE

• During the pooled PBO-controlled period, MACE exposure-adjusted incidence rates (EAIRs) remained low and similar between the PBO (0.25/100 PYs; 1 CV death) and TREMFYA groups (0.35/100 PYs; 2 nonfatal myocardial infarctions [MIs], 1 nonfatal stroke).
• A total of 34 events (0.31/100 PYs) were reported among 33 TREMFYA-treated patients.
  • Twenty-two nonfatal MI (0.20/100 PYs)
  • Nine nonfatal strokes (0.08/100 PYs); 1 patient had 2 non-fatal strokes in the Japan registration study
  • Three CV deaths (0.03/100 PYs)
• Most patients with MACE (including the 3 patients with CV death) had ≥3 CV risk factors at baseline.
• Among the 8 patients with nonfatal strokes, 3 had a prior stroke history, including the patient with 2 nonfatal strokes in the Japan registration study.
• EAIRs during the PBO-controlled period are presented in Table: Exposure Adjusted Incidence Rates of MACE Per 100 Patient-Years of Follow-Up (95% CI) During the Placebo-Controlled Period.

• EAIRs of events per 100 PYs of follow-up through the end of the reporting period are presented in Table: Exposure-Adjusted Incidence Rates of MACE Per 100 PYs of Follow-Up (95% CI) through the End of the Reporting Period.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 08 August 2024.