SUMMARY

• Please refer to local labeling for relevant information regarding the occurrence of elevated liver enzymes in patients receiving TREMFYA. Summarized in this response is relevant data on the topic of elevated gamma-glutamyltransferase (GGT) only.
• The company cannot recommend any practices, procedures, or usages that deviate from the approved labeling.
• In VOYAGE 1 and VOYAGE 2, elevated gamma-glutamyltransferase was reported in adult patients with moderate to severe plaque psoriasis (PsO) treated with TREMFYA through week 264.¹
• In DISCOVER-1 and DISCOVER-2, elevated GGT was not reported in adult patients with active psoriatic arthritis (PsA) treated with TREMFYA through 1 year.²
• Retrospective studies and a case report summarized real-world data on TREMFYA treatment and the occurrence of elevated GGT.^3-6

CLINICAL DATA in Plaque psoriasis

VOYAGE 1 and VOYAGE 2

Blauvelt et al (2017)⁷, Griffiths et al (2020)⁸, Reich et al (2017)⁹, and Reich et al (2021)¹⁰ reported results from two phase 3, multicenter, randomized, double-blind, placebo and active comparator-controlled studies evaluating the efficacy and safety of TREMFYA compared to placebo and adalimumab in adult patients with moderate to severe plaque PsO.

Study Design/Methods

• Patients with plaque PsO were randomized to receive TREMFYA 100 mg subcutaneous (SC) at weeks 0, 4, 12, and then every 8 weeks (q8w) thereafter; placebo (PBO) SC at weeks 0, 4, 12 followed by TREMFYA 100 mg SC at weeks 16 and 20 and then q8w thereafter; or adalimumab (ADA) 80 mg SC at week 0, 40 mg at week 1, and then every 2 weeks (q2w) through week 47 (VOYAGE 1) or week 23 (VOYAGE 2).
• In VOYAGE 1, all patients received open-label TREMFYA 100 mg q8w through the open label extension (OLE) period from weeks 52 to 252. VOYAGE 2 incorporated a randomized withdrawal study design during weeks 28 to 76, followed by open-label treatment with TREMFYA from weeks 76 to 252.
• Safety was analyzed through week 264 (5 years) for both VOYAGE 1 and VOYAGE 2.^8,10

Results

Pooled VOYAGE 1 and VOYAGE 2 Data Through Week 264

• The proportion of patients who developed elevated GGT, a treatment-emergent adverse event (TEAE), among TREMFYA-treated patients, is shown in Table: VOYAGE 1 and VOYAGE 2 Proportion of Elevated Gamma-glutamyltransferase through Week 264.

Retrospective Studies

Megna et al (2022)³ reported long-term, real-life data on TREMFYA safety and efficacy in psoriasis management through 3 years.

Study Design/Methods

• The study included patients with moderate to severe plaque PsO who were treated with TREMFYA from October 2018 to March 2022.
• At each follow-up, eventual adverse events (AE), PsO severity scores (psoriasis area and severity index [PASI], body surface area [BSA]), routine blood tests, and safety (physical examinations, laboratory monitoring, treatment-emergent AEs [TEAE]) were evaluated.

Results

• A total of 31 patients (18 males and 13 females) with a mean age of 55.0 ± 6.9 years completed the study period. Mean PsO duration was 18.3 ± 9.7 years and PsA was assessed in 17/31 (54.8%) patients.
• All patients had been treated with at least 1 conventional systemic treatment prior to TREMFYA (cyclosporine, methotrexate, acitretin, and/or narrow band ultraviolet (UV)-B phototherapy).
• Most patients were previously treated with biologics (n=26, 83.9%), of which, included anti-tumor necrosis factor (TNF), anti-interleukin (IL)-17, and ustekinumab.
• Routine blood tests showed alterations in 5 patients: hyperglycemia (n=2), hypertriglyceridemia (n=2), and elevated liver enzymes (n=1). None of the patients required treatment interruption.
  • The patient with elevated liver enzymes presented with glutamic pyruvic transaminase (GPT), 77 units/liter (U/L; normal: 0-46 U/L); glutamic oxaloacetic transaminase (GOT), 152 (normal 0-39 U/L); and GGT, 44 (normal 11-40 U/L).

Megna et al (2022)⁴ was a single-center study that evaluated the efficacy and safety of TREMFYA through 52 weeks in psoriasis patients who failed anti-IL-17 treatment.

Study Design/Methods

• The study included patients with moderate to severe plaque PsO who were treated with TREMFYA from June 2019 to December 2021, after previously failing one or more anti-IL-17 treatments (brodalumab, ixekizumab, and/or secukinumab).
• At each follow-up, psoriasis severity indexes, routine blood tests, and AEs were recorded. Safety was assessed by TEAEs, physical examinations, and laboratory monitoring.

Results

• A total of 44 patients (28 males and 16 females) with a mean age of 59.0 ± 10.2 years completed the study. Mean PsO duration was 37.5 ± 10.7 years.
• All patients had been treated with at least 1 systemic treatment (cyclosporine, methotrexate, acitretin, apremilast, and narrow band UVB phototherapy).
• Previous biologic treatment failures included: anti-TNF (n=40, 91.0%), ustekinumab (n=12, 27.3%), and anti-IL-17 (n=44, 100%).
• Routine blood tests showed alterations in 7 patients (15.9%): hyperglycemia (n=2), hypertriglyceridemia (n=2), leukocytosis (n=2), and elevated liver enzymes (n=1).
  • The patient with elevated liver enzymes presented with GOT 229 U/L (normal: 0-37 U/L); GPT 123 U/L (normal 0-45 U/L); and GGT 47 (normal 10-39 U/L).

Megna et al (2022)⁵ was a single-center study that evaluated the effectiveness, safety, tolerability, and drug-persistence of TREMFYA in psoriasis patients through 44 weeks.

Study Design/Methods

• The study included patients with moderate to severe plaque PsO who had a wash-out period of at least 2 weeks from topical treatment and 4 weeks from systemic or UV treatment and were treated with TREMFYA from October 2018 to January 2020.
• Patients were treated with TREMFYA 100 mg SC at weeks 0, 4, and q8w through week 44.
• At every follow-up, efficacy measures (PASI, BSA, and DLQI), routine blood tests, and adverse events were evaluated. Safety was assessed by TEAEs, physical examinations and laboratory monitoring.

Results

• A total of 23 patients with a mean age of 49.7 ± 17.9 years were enrolled in the study (15 males and 8 females). Mean psoriasis duration was 49.7 ± 17.9 years.
• Six patients also reported psoriatic arthritis with a mean duration of 7 ± 6.3 years.
• All patients were treated with at least 1 conventional systemic treatment. Previous conventional systemic treatments included cyclosporine, methotrexate, acitretin, and/or narrow band UVB phototherapy.
• More than half of patients (65.2%, n=15) were treated with a biologic such as secukinumab, adalimumab, ustekinumab, ixekizumab, etanercept, golimumab, and/or infliximab.
• During the follow-up period, 4 (17.4%) patients experienced blood test alterations: hyperglycemia (n=1); hypertriglyceridemia (n=1); elevated erythrocyte sedimentation rate (ESR, n=1); and elevated liver enzymes (n=1; GOT, 419 U/L [normal: 0-37 U/L]; GPT, 321 U/L [normal: 0-45 U/L]; GGT: 58 U/L [normal: 10-39 U/L]).
• The patient who experienced elevated liver enzymes discontinued TREMFYA treatment. It was noted the patient had a history of chronic hepatitis C.
  • Liver enzymes decreased to lower values (aspartate transaminase [AST], 160; alanine transaminase [ALT], 117) 3 weeks after TREMFYA discontinuation.
  • The patient was eventually lost to follow-up.

Case Report

Megna et al (2022)⁶ summarizes a case of TREMFYA treatment in a severe PsO patient with chronic HCV infection.

• A 48-year-old Caucasian male presented with a 15-year history of severe plaque PsO.
• Medication history included topicals, cyclosporine, methotrexate, adalimumab, and infliximab), with partial and transient disease improvement.
• Blood tests confirmed chronic HCV infection with positive anti-HCV and HCV-RNA tests.
• Etanercept was initiated without significant liver enzyme changes: ALT, 59 U/L (normal: 0-45 U/L); AST, 45 U/L (normal: 0-37 U/L); and GGT, 107 U/L (normal: 10-38 U/L).
• The following year, ustekinumab was initiated due to worsening psoriasis. Liver profile screening at the time showed: ALT, 78 U/L; AST, 109 U/L; GGT, 59 U/L; and HCV-RNA 2.35 log UI/mL.
• Treatment was switched to golimumab after a diagnosis of PsA. Due to worsening of PsO and PsA, treatment with secukinumab, certolizumab, and ixekizumab followed.
• After ixekizumab discontinuation, dermatological examination showed widespread erythmato-desquamative plaques (PASI, 18; BSA, 38%).
• Transaminases were within normal range, and HCV-RNA clearance was achieved with pegylated interferon and ribavirin. TREMFYA 100 mg SC at weeks 0, 4 and q8w thereafter was then initiated.
• After three months, blood tests showed increased liver enzymes (ALT, 321 U/L; AST, 419 U/L; GGT, 58 U/L) and positive HCV-RNA serum levels (2.3 log UI/mL).
• TREMFYA was temporarily discontinued to treat HCV reactivation with sofosbuvir and ribavirin treatments. Normal liver enzyme levels and HCV-RNA clearance were achieved after 4 and 6 months, respectively.
• The patient was lost to follow-up.

CLINICAL DATA in Psoriatic Arthritis

DISCOVER-1 AND DISCOVER-2

Rahman et al (2020)¹¹ and Rahman et al (2021)¹² 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 two phase 3, randomized, controlled studies.

Study Design/Methods

• Patients with PsA were randomized to receive TREMFYA 100 mg SC at weeks 0 and 4, and then q8w through week 52; TREMFYA 100 mg SC at week 0 and then every 4 weeks (q4w) through week 52; or PBO at week 0 and then q4w through week 20. Patients randomized to receive PBO were crossed over to TREMFYA 100 mg SC at week 24 and then every q4w through week 52 (DISCOVER-1) or week 100 (DISCOVER-2).
• Adverse events 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 (end of the study) and through week 52 in DISCOVER-2.

Results

Pooled DISCOVER-1 and DISCOVER-2 Data Through 1 Year

• No occurrence of elevated GGT or TEAE, per 100 patient-years of follow-up through 1 year were found as shown in the following table: DISCOVER 1 and DISCOVER Number of Elevated Gamma-glutamyltransferase Per 100 Patient-Years of Follow-up through 1 Year.

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and DERWENT^® (and/or other resources, including internal/external databases) was conducted on 28 June 2024.