SUMMARY

• Please refer to the local labeling for relevant information regarding tuberculosis (TB) infection.
• In a pooled safety analysis of 11 phase 2 and 3 clinical trials (X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, Japan Registration, Phase 2 psoriatic arthritis [PsA], DISCOVER-1, DISCOVER-2, and COSMOS), no cases of active TB infections were reported.¹
• In a pooled safety analysis of 7 phase 2 and 3 clinical trials (X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, and Japan Registration) through 5 years, no cases of active TB infections were reported.²
• In a pooled safety analysis of VOYAGE 1 and VOYAGE 2 clinical studies through 5 years (week 264), no events of TB infections were reported.^3,4
• In the NAVIGATE, ORION, and ECLIPSE clinical studies, there were no reported cases of active TB through week 40, 60, and 56, respectively.^5-7
• In the DISCOVER-1 and DISCOVER-2 clinical studies, no cases of active TB were reported through weeks 60 and 112, respectively.^8-12
• Two case reports have been published describing patients who developed active TB infection while receiving treatment with TREMFYA.^13,14

CLINICAL DATA in Plaque psoriasis and ACTIVE psoriatic arthritis

Strober et al (2023)¹ evaluated the safety of TREMFYA in an integrated pooled analysis of data from 11 randomized, phase 2 and 3 plaque psoriasis (PsO) and PsA studies.

Study Design/Methods

• All plaque PsO studies (X-PLORE, VOYAGE 1, VOYAGE 2, ORION, Japan Registration) included a placebo-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 placebo-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 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.

Results

• No cases of active TB were reported in TREMFYA-treated patients across all studies.

clinical data in MODERATE TO SEVERE plaque psoriasis

Placebo- and Active Comparator-Controlled Trials

The safety and efficacy of TREMFYA in patients diagnosed with moderate to severe plaque PsO were evaluated in a phase 2 (X-PLORE) and 5 phase 3 (VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, and Japan Registration) multicenter, randomized, double-blind studies.^{2,3,5-7,15-18}

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

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

• All studies, including X-PLORE, a phase 2 clinical trial (n=293), and Japan phase 3 registration (n=192) had a placebo-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 placebo (X-PLORE, VOYAGE 1, VOYAGE 2, ORION, Japan Registration) at baseline who crossed over and were treated with TREMFYA.

Results

• There were no cases of active TB.
• At baseline, 173 TREMFYA-treated patients had latent tuberculosis infection (LTBI) across studies. There were no cases of LTBI reactivation in any TREMFYA-treated patients through the end of long-term follow-up.

VOYAGE 1 and VOYAGE 2

Blauvelt et al (2022)³ evaluated the safety of TREMFYA using pooled data from the VOYAGE 1 and VOYAGE 2 studies through 5 years.

Study Design/Methods

• In the VOYAGE 1 and VOYAGE 2 studies, patients were screened for LTBI prior to being randomized to TREMFYA, adalimumab, or placebo.⁴
• Eligible patients had no history of LTBI or active TB.
  • Patients with LTBI based on positive TB test during screening (QuantiFERON-TB Gold or Purified Protein Derivative testing) were eligible if active TB was ruled out and appropriate LTBI treatment was initiated prior to or simultaneously with the first study agent administration, or if appropriate LTBI treatment was completed within 5 years prior to first administration.
• Placebo-treated patients crossed over to TREMFYA at week 16, and all patients received open-label TREMFYA treatment q8w through week 264, beginning at week 52 (VOYAGE 1) or week 76 (VOYAGE 2).

Results

• No events of TB infection were reported through 5 years (week 264).

Puig et al (2020)⁴ evaluated safety of TREMFYA, adalimumab, or placebo in patients with moderate to severe PsO with LTBI receiving LTBI treatment (LTBI+) and patients without LTBI (LTBI-) using pooled data from the VOYAGE 1 and VOYAGE 2 studies through week 100.

Results

• A total of 1721 patients were randomized in the VOYAGE 1 and VOYAGE 2 studies, and, of these, 130 patients (TREMFYA, n=69; adalimumab, n=36; placebo, n=25) tested positive for LTBI and received concomitant LTBI treatments (LTBI+). See Table: Baseline Demographics, Previous Medication Treatments, and LTBI Treatments Among LTBI+ Patients in VOYAGE 1 and VOYAGE 2 through Week 100.
  • A total of 13 patients who started LTBI treatment after initiating study drug (mean of 70 days), of which 9 patients were QuantiFERON-TB Gold positive at baseline but did not start LTBI treatment, were classified as major protocol deviations.
  • Three of the 13 patients were QuantiFERON-TB Gold negative at baseline but received LTBI treatment during the study (1 TREMFYA-treated patient received rifabutin for H. pylori, 1 adalimumab-treated patient initiated LTBI treatment during the trial, and 1 adalimumab-treated patient developed new onset active TB and was treated accordingly).
  • One additional placebo-treated patient with missing QuantiFERON-TB Gold results at baseline was treated with LTBI prior to discontinuing the study after week 3.

• No cases of TB were reported among TREMFYA-treated patients through week 100, as shown in Table: Safety of Patients Treated with and without Concomitant LTBI Medications in VOYAGE 1 and VOYAGE 2 through Week 100.

NAVIGATE

Langley et al (2018)⁵ evaluated efficacy (through week 52) and safety (during weeks 16-60) 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.

Results

• There were no reported cases of active TB in TREMFYA-treated patients during week 16 through week 60.

ORION

Ferris et al (2019)⁶ reported results from a phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy, safety, and pharmacokinetics of TREMFYA through week 40 compared to placebo, both administered via the One-Press patient-controlled injection device.

Results

• There were no reported cases of active TB reported through week 40.

ECLIPSE

Reich et al (2019)⁷ reported results from ECLIPSE, a head-to-head study of TREMFYA and secukinumab in adult patients with moderate to severe PsO up to week 56.

Results

• There were no reported cases of TB in TREMFYA-treated patients through week 56.

CLINICAL DATA in ACTIVE psoriatic arthritis

Placebo-controlled Clinical Trials

The safety and efficacy of TREMFYA in patients diagnosed with active PsA were evaluated in 2 phase 3 (DISCOVER-1 and DISCOVER-2) multicenter, randomized, double-blind studies.^5,8

DISCOVER-1 and DISCOVER-2

Deodhar et al (2020)⁸ and Mease et al (2020)¹⁰ conducted the phase 3, randomized, double-blind, multicenter, placebo-controlled DISCOVER-1 and DISCOVER-2 studies, respectively.

• DISCOVER-1 was conducted in adult patients with active PsA who were biologic-naïve or had a prior biologic experience of ≤2 anti-tumor necrosis factor alpha (anti-TNFα) treatments and had inadequate response to or intolerance of standard therapies, including nonbiologic disease modifying antirheumatic drugs (DMARDs), apremilast, and nonsteroidal anti-inflammatory drug (NSAIDs).⁸
• DISCOVER-2 was conducted in adult patients with active PsA who were biologic-naïve and had inadequate response to or intolerance of standard therapies, including nonbiologic DMARDs, apremilast, and NSAIDs.¹⁰

Study Design/Methods

• In DISCOVER-1 and DISCOVER-2, patients were screened for TB prior to being randomized to TREMFYA 100 mg q8w, TREMFYA 100 mg q4w, or placebo.^8,10
• Patients were considered eligible according to the following TB screening criteria^19,20:
  • No history of LTBI or active TB prior to screening. Patients with LTBI based on a positive TB test during screening (QuantiFERON^®-TB Gold or tuberculin skin test conducted within 8 weeks prior to the first administration of study agent) were eligible if active TB was ruled out and appropriate LTBI treatment was initiated prior to the first administration of study agent or if appropriate LTBI treatment was completed within 5 years prior to the first administration.
    • Patients with persistently indeterminate QuantiFERON^®-TB Gold test results were enrolled without treatment for LTBI if active TB was ruled out, chest radiograph showed no abnormality suggestive of TB (active or old, inactive TB), and no additional risk factors for TB, as determined by the investigator.
  • No signs or symptoms suggestive of active TB upon medical history and/or physical examination.
  • No recent close contact with a person with active TB or, if there had been such contact, were referred to a physician specializing in TB to undergo additional evaluation and, if warranted, received appropriate treatment for LTBI prior to the first administration of study agent.
  • Chest radiograph (posterior-anterior view) obtained within 3 months prior to the first administration of study agent, with no evidence of current, active TB or old, inactive TB.

Results

• In DISCOVER-1, 624 patients were screened, of whom 18 did not meet the criteria for TB and 381 were randomized to receive TREMFYA 100 mg q8w (n=127), TREMFYA 100 mg q4w (n=128), or placebo (n=126). Of the 381 patients, 90% completed treatment through 1 year.^8,9
  • No cases of active TB were reported through week 60.^8,9
• In DISCOVER-2, 1153 patients were screened, of whom 32 did not meet the criteria for TB and 739 were randomized to receive TREMFYA 100 mg q8w (n=248), TREMFYA 100 mg q4w (n=245), or placebo (n=246). A total of 93% and 88% of these patients completed 1 year and 100 weeks of treatment, respectively.^10-12
  • No cases of active TB were reported through week 112.

Case ReportS

Cerejeira et al (2022)¹³ described the case of a 38-year-old male patient with plaque and ungueal PsO who presented with active TB infection while receiving treatment with TREMFYA.

• The patient presented with concomitant chronic hepatitis B infection being treated with tenofovir.
• Before initiating immunosuppressive treatment, tuberculin skin test and interferon gamma release assay were negative; however, due to a family history of pulmonary TB, the patient received isoniazid for 6 months.
• While receiving treatment with TREMFYA, the patient complained of fatigue, night sweats, and weight loss; chest computed tomography revealed cavities in both lungs, multiple centrilobular micronodules in a tree-in-bud pattern, and enlarged lymph nodes.
• Mycobacterium tuberculosis was identified by both culture and polymerase chain reaction, leading to the diagnosis of cavitary pulmonary TB.
• Anti-TB treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol was started, and TREMFYA was discontinued.
• TB improved over the next 2 months; however, PsO worsened with the development of exuberant erythroderma. A decision to resume treatment with TREMFYA was made while continuing anti-TB treatment.
• After 12 weeks, both TB and psoriatic lesions improved.

Takeda et al (2022)¹⁴ described the case of a 64-year-old male with plaque and nail PsO, and PsA, who developed pulmonary TB while receiving TREMFYA.

• The patient had stage IIIC lung cancer and developed PsO and PsA after 6 cycles of durvalumab.
• Durvalumab was discontinued and prednisolone (20 mg/day), celecoxib, and calcipotriol/ betamethasone dipropionate ointment were started for PsO and PsA.
• Over the next month, symptoms worsened and the patient was started on TREMFYA to treat PsA.
• Improvement in PsA symptoms were reported at week 3 of TREMFYA therapy. After 2 months, complete improvement of all symptoms except nail PsO were reported.
• Two months into TREMFYA treatment, the patient developed pulmonary TB (of note he had a negative interferon-gamma release test before initiation).
• TREMFYA was temporarily stopped and anti-TB treatment was given and authors noted the treatment of pulmonary TB was successful.
• The patient was restarted on TREMFYA and continuedfor 8 months, after which PsA symptoms resolved but residual toenail PsO was still evident.
• The patient had been receiving prednisolone 15-20 mg/day for up to 4 months before it was tapered down to 2 mg/day after 8 months of TREMFYA therapy.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 07 March 2024.

Data included in this response are from the phase 2 and 3 clinical trials of TREMFYA in patients with plaque PsO or PsA (X-PLORE, VOYAGE 1, VOYAGE 2, NAVIGATE, ORION, ECLIPSE, Japan Registration, Phase 2 PsA, DISCOVER-1, DISCOVER-2, and COSMOS). Additional information from pooled safety analyses across PsO or PsA and case reports are also included.