SUMMARY

• Please refer to local labeling for relevant information regarding the occurrence of elevated liver enzymes in patients receiving TREMFYA.
• In VOYAGE 1 and VOYAGE 2, elevated liver enzymes (increased alanine aminotransferase [ALT] and increased aspartate aminotransferase [AST]) were reported in adult patients with moderate to severe plaque psoriasis (PsO). Through week 264, most of the abnormal liver function laboratory results, including ALT, AST, total bilirubin (TBIL), alkaline phosphatase (ALP), and albumin were National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) toxicity Grade 1 for both TREMFYA and adalimumab→TREMFYA crossover groups.¹
• Elevated liver enzymes were also reported in NAVIGATE through week 60 and in ORION through week 40.^2-4
• Through week 24, in an integrated safety analysis of the DISCOVER-1 and DISCOVER-2 studies in adult patients with active psoriatic arthritis (PsA), adverse events (AEs) of increased ALT and increased AST were reported slightly more frequently in the combined TREMFYA group (6.8% and 4.9%, respectively) than in the placebo group (3.8% and 2.4%, respectively).⁵
• In pooled safety analyses of DISCOVER-1 and DISCOVER-2 studies, increases in serum ALT and AST through week 24 were mostly grade 1, generally transient and did not result in study drug discontinuation. They were not associated with clinically significant increases in bilirubin.^5,6
  • Through 1 year, increases in serum ALT and AST were consistent with those observed through week 24.⁶
• In pooled safety analyses of a phase 2 study, DISCOVER-1, and DISCOVER-2, the majority of elevated ALT, AST, or bilirubin levels were NCI-CTCAE grade 1 or 2 with no grade 4 events through 2 years of treatment with TREMFYA.⁷
• In the COSMOS trial, elevated liver enzymes were reported as serious adverse events (SAEs) through week 56 in patients with PsA. Majority of the ALT and AST elevations were NCI-CTCAE grade 1.⁸

CLINICAL DATA - Moderate to severe Plaque Psoriasis

VOYAGE 1

Blauvelt et al (2017)⁹ and Griffiths et al (2020)¹⁰ reported results from a phase 3, multicenter, randomized, double-blind, placebo and active comparator-controlled study evaluating the efficacy and safety of TREMFYA compared to placebo and adalimumab in 837 patients with moderate to severe plaque PsO.

Study Design/Methods

• Eligible patients were randomized in a 2:1:2 ratio to 1 of 3 treatment arms:
  • TREMFYA 100 mg at weeks 0 and 4, then every 8 weeks (q8w; n=329)
  • Placebo through week 16, then TREMFYA 100 mg at weeks 16 and 20, then q8w (n=174)
  • Adalimumab 80 mg at week 0, 40 mg at week 1, then every 2 weeks (q2w; n=334)
• All patients received open-label TREMFYA 100 mg q8w from week 52 through week 252. Safety was analyzed through week 264 (5 years).¹⁰

VOYAGE 2

Reich et al (2017)¹¹ and Reich et al (2021)¹² reported results from 992 moderate to severe plaque PsO patients in a phase 3, multicenter, randomized, double-blind, placebo and active comparator-controlled study evaluating the efficacy and safety of TREMFYA compared to placebo and adalimumab.

Study Design/Methods

• Eligible patients were randomized in a 2:1:1 ratio to 1 of 3 treatment arms:
  • TREMFYA 100 mg at weeks 0 and 4, then q8w (n=496)
  • Placebo through week 16, then TREMFYA 100 mg at weeks 16 and 20, then q8w (n=248)
  • Adalimumab 80 mg at week 0, 40 mg at week 1, then q2w (n=248)
• At week 28:
  • TREMFYA-treated patients who achieved ≥90% improvement in Psoriasis Area and Severity Index (PASI 90) (responders) were rerandomized in a 1:1 ratio to TREMFYA or placebo, and upon loss of 50% or more of their week-28 PASI 90 response were retreated with TREMFYA, another dose 4 weeks later, then q8w thereafter. TREMFYA nonresponders continued TREMFYA treatment.
  • Placebo→TREMFYA responders received placebo q8w beginning at week 28, and upon loss of 50% or more of their week-28 PASI 90 response were retreated with TREMFYA, another dose 4 weeks later, then q8w thereafter. Placebo→TREMFYA nonresponders at week 28 continued TREMFYA q8w.
  • Adalimumab responders received placebo and upon loss of 50% or more of week-28 PASI 90 response, initiated TREMFYA, another dose 4 weeks later, then q8w thereafter, and adalimumab nonresponders initiated TREMFYA at week 28 (5 weeks after the last dose of adalimumab), another dose 4 weeks later, then q8w thereafter.
• All patients received open-label TREMFYA 100 mg q8w from week 76 through week 252. Safety was analyzed through week 264 (5 years).¹²

Results

Pooled VOYAGE 1 and VOYAGE 2 Data through Week 16 and Week 48

VOYAGE 1 And VOYAGE 2 Data through Week 264

• Through week 264, most of the abnormal liver function laboratory results, including ALT, AST, TBIL, and ALP, were NCI-CTCAE toxicity Grade 1 for both TREMFYA and adalimumab→TREMFYA groups.¹ See Table: Cumulative Proportion of Patients with Highest Post-BL Liver Laboratory US NCI-CTCAE Grade in VOYAGE 1 and VOYAGE 2 through Week 264
• Among patients with analyzed ALT and AST data at both baseline and week 264, more than 85% of patients with normal ALT and AST levels at baseline had normal levels at week 264.¹
  • Among patients with high ALT levels at baseline (VOYAGE 1, n=86; VOYAGE 2, n=108), 44% of patients in VOYAGE 1 and 53% of patients in VOYAGE 2 had normal ALT levels at week 264.
  • Among patients with high AST levels at baseline (VOYAGE 1, n=46; VOYAGE 2, n=57), 52% of patients in VOYAGE 1 and 72% of patients in VOYAGE 2 had normal AST levels at week 264.

NAVIGATE

Langley et al (2017)¹³ reported results from a phase 3, randomized, double-blind, active comparator-controlled study evaluating the efficacy and safety of TREMFYA compared to ustekinumab in 268 patients with moderate to severe plaque PsO with an inadequate response (IR) to ustekinumab.

Study Design/Methods

• A total of 871 patients received open-label ustekinumab (45 mg [patients weighing ≤100 kg] or 90 mg [patients weighing >100 kg]) at weeks 0 and 4.
• At week 16, patients with an IR to ustekinumab (Investigator’s Global Assessment [IGA] score ≥2) were randomized to:
  • TREMFYA 100 mg at weeks 16, 20, and q8w thereafter through week 44 (n=135)
  • Continue ustekinumab at week 16 and every 12 weeks thereafter through week 40 (n=133)
• Patients with an IGA of 0 or 1 continued receiving open-label ustekinumab at week 16 and every 12 weeks thereafter through week 40 (n=585).

Results

NAVIGATE Data from Week 16 through Week 60

ORION

Ferris et al (2019)¹⁴ reported results from a phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy, safety and pharmacokinetics of TREMFYA compared to placebo, both administered via the One-Press patient-controlled injection device, in adults with moderate-to-severe plaque PsO.

Study Design/Methods

• A total of 78 eligible patients were randomized in a 4:1 ratio to receive SC TREMFYA 100 mg at weeks 0, 4, 12, 20, and 28 (n=62) or SC placebo at weeks 0, 4, and 12 with crossover to TREMFYA 100 mg at weeks 16, 20 and 28 (n=16), both delivered by the One-Press patient-controlled injection device. Patients randomized to TREMFYA received placebo at week 16 to maintain the blinding.
• Safety was assessed continuously through week 40.

Results

ORION Data through Week 40

CLINICAL DATA - active PSoriatic Arthritis

Rahman et al (2020)⁵ and Rahman et al (2021)⁶ assessed the safety of TREMFYA in the treatment of adult patients with active PsA using pooled safety results through week 24 and 1 year, respectively, from 2 phase 3, randomized, controlled studies (DISCOVER-1 and DISCOVER-2).

Study Design/Methods

• In DISCOVER-1, approximately 31% of patients were previously treated with up to 2 tumor necrosis factor inhibitor (TNFi) agents whereas in DISCOVER-2, all patients were biologic-naive.
• Patients 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 every 4 weeks (q4w) or
  • Placebo through week 20, then TREMFYA 100 mg at week 24, then q4w
• AEs and clinical laboratory test results were assessed in an integrated safety analysis through week 24 (placebo-controlled phase) in both studies, and in a pooled safety analysis through week 60 in DISCOVER-1 and through week 52 in DISCOVER-2.

Results

• Through week 24, increases in serum ALT and AST were mostly grade 1. See Table: Incidence of ALT/AST Increases by Grade in DISCOVER-1 and DISCOVER-2 (Pooled) through Week 24. Grade 2 and 3 ALT and AST elevations were more common in the q4w group than in the q8w group; however, most events were transient, did not result in study drug discontinuation, and were not associated with clinically significant increases (>2 times the upper limit of normal [ULN]) in bilirubin.⁶
• Grade 1 and higher ALT and AST increases were slightly more frequent in patients receiving methotrexate (MTX) at baseline than in those patients not receiving MTX.⁶

• Through 1 year, increases in serum ALT and AST were consistent with those observed through week 24 (Table: Incidence of ALT/AST Increases by Grade in DISCOVER 1 and DISCOVER 2 (Pooled) through 1 Year).
• Through 1 year, most patients with grade 2 or 3 ALT/AST elevations had other contributing factors such as medical history, obesity, concomitant alcohol use, latent tuberculosis treatment, or use of disease-modifying antirheumatic drugs (DMARDs) or nonsteroidal anti-inflammatory drugs (NSAIDs) that are associated with liver injury.
• Through 1 year, in the TREMFYA q4w treatment group, 4 patients discontinued study treatment due to hepatobiliary AEs or elevated transaminases; all 4 patients had other contributing factors.¹⁵

Rahman et al (2021)⁷ assessed the safety of TREMFYA in the treatment of patients with active PsA using pooled data from the phase 2 study, DISCOVER-1, and DISCOVER2 through 2 years.

Study Design/Methods

• In the Phase 2 study, approximately 20% of patients were previously treated with 1 TNFi.
• Patients in the Phase 2 study were randomly assigned 2:1 to:
  • TREMFYA 100 mg at week 0 and 4, then q8w or placebo
• Patients in the DISCOVER1 and DISCOVER2 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 or
  • Placebo through week 20, then TREMFYA 100 mg at week 24, then q4w

Results

• Through up to 2 years of treatment with TREMFYA, the majority of elevated ALT, AST, or bilirubin levels were NCI-CTCAE grade 1 or 2 with no grade 4 events. See Table: Occurrence of AEs of Increased ALT, AST, or Bilirubin in a Phase 2 Study, DISCOVER-1, and DISCOVER-2 (Pooled) through 2 Years.
• The proportion of patients with elevated ALT or AST was higher at week 24 with TREMFYA q4w dosing than with q8w dosing and remained consistent through 2 years with no unexpected increase.

• Elevated ALT, AST, or bilirubin levels were more common in patients with than in those without concomitant use of MTX at baseline through 2 years. See Table: Occurrence of AEs of Increased ALT, AST, or Bilirubin Among Patients with or Without MTX Use at Baseline in a Phase 2 Study, DISCOVER-1, and DISCOVER-2 (Pooled) through 2 Years.

Coates et al (2022)⁸ reported the results of a phase 3b, randomized, placebo-controlled study (COSMOS) that assessed the efficacy and safety of TREMFYA through 1 year in patients with PsA with an IR (inadequate efficacy or intolerance) to TNFi.

Study Design/Methods

• Patients with a diagnosis of active PsA (according to ClASsification criteria for Psoriatic ARthritis [CASPAR]; ≥3 swollen; ≥3 tender joints), active (≥1 psoriatic plaque of ≥2 cm) or documented history of plaque PsO or current nail PsO, and who had shown lack of benefit or intolerance to 1-2 TNFi were included.
• At week 0, patients were randomized 2:1 as follows:
  • TREMFYA 100 mg at weeks 0 and 4, then q8w through week 44
  • Placebo at weeks 0, 4, 12, and 20, then TREMFYA 100 mg at weeks 24, 28, 36, and 44
• Safety assessment was done at week 56.

Results

COSMOS Data through Week 56

• Through week 56, increased ALT level was reported as an AE in 11 (3.9%) TREMFYA-treated patients, of whom, 3 were initially randomized to receive placebo and crossed over to TREMFYA at week 24.
• The majority of ALT and AST elevations were NCI-CTCAE grade 1.
• ALT elevations were reported as SAEs in 2 TREMFYA-treated patients as follows:
  • The first patient, who had elevated liver enzymes at baseline and was diagnosed with autoimmune hepatitis on biopsy and imaging studies, discontinued treatment. Following discontinuation, ALT levels normalized by week 24, while jaundice and nausea persisted.
  • The second patient, who had elevated ALT and AST levels at week 48 and was diagnosed with steatohepatitis, recovered after being treated with ademetionine.
• ALT and AST elevations were observed in 37% and 28% of patients, respectively, who received concomitant MTX and in 28% and 24% of patients, respectively, who did not receive concomitant MTX.
• For the proportion of patients who developed ALT and AST elevations through week 56, see Table: Occurrence of Increased ALT and AST Levels in COSMOS through Week 56.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 30 September 2024.

Summarized in this response are relevant data from phase 2 and phase 3 clinical studies describing the occurrence of elevated liver enzymes in patients receiving TREMFYA.