Two interleukin (IL)-17A inhibitors are now approved for the treatment of psoriatic arthritis (PsA). Secukinumab was approved by the US FDA and the EMA in 2015, while the indication for ixekizumab was expanded to include PsA in the USA and Europe in 2017. Both secukinumab and ixekizumab are recommended for the treatment of active PsA in the USA, while the EMA recommends their use for adult patients with active PsA and an inadequate response or intolerance to one or more DMARDs. Brodalumab, an antibody that binds to the IL-17 receptor subunit A, is approved for plaque psoriasis in a number of settings and for PsA in Japan.
Here, medwireNews summarizes the phase 3 trials supporting the efficacy and safety profiles of IL-17A inhibitors in patients with PsA.
Secukinumab
FUTURE 1
Patient population | Treatment groups | Status |
Active PsA and an inadequate response or intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs), conventional DMARDs, or tumor necrosis factor (TNF) inhibitors | Subcutaneous secukinumab 150 mg every 4 weeks (n=202) or 75 mg every 4 weeks (n=202) following an intravenous loading dose of 10 mg/kg at weeks 0, 2, and 4, or placebo (n=202) | Published |
The results of the FUTURE 1 trial, published in The New England Journal of Medicine in 2015, demonstrated that participants treated with the 150 mg or 75 mg doses of secukinumab had significantly higher ACR20 response rates at week 24 than those given placebo, at 50.0% and 50.5% versus 17.3%, respectively. ACR50 response rates were also significantly greater among patients in the secukinumab arms versus those in the placebo group, as were PASI75 and PASI90 response rates and average improvements in DAS28-CRP scores. Rates of radiographic progression were significantly lower with secukinumab versus placebo treatment.
A total of 64.9%, 60.4%, and 58.4% of patients in the secukinumab 150 mg, secukinumab 75 mg, and placebo groups, respectively, experienced adverse events (AEs) during the 16-week placebo-controlled period. The most common AEs were nasopharyngitis, headache, and upper respiratory tract infection, and these AEs occurred more commonly in patients treated with secukinumab compared with placebo.
FUTURE 2
Patient population | Treatment groups | Status |
Active PsA despite treatment with NSAIDs, conventional DMARDs, and/or TNF inhibitors | Subcutaneous secukinumab 300 mg (n=100), 150 mg (n=100), or 75 mg (n=99) every week for 4 weeks and every 4 weeks thereafter, or placebo (n=98) | Published |
As reported in The Lancet in 2015, The FUTURE 2 investigators found that ACR20 response rates at week 24 were significantly higher among patients treated with secukinumab 300 mg, 150 mg, or 75 mg versus placebo, at 54%, 51%, and 29%, respectively, versus 15%. Patients treated with the 300 mg and 150 mg doses of the IL-17A inhibitor, but not those in the secukinumab 75 mg group, had significantly higher PASI75 response rates than participants in the placebo arm.
In the safety analysis, upper respiratory tract infections and nasopharyngitis were the most frequently reported AEs, and the investigators said that the AE profile was consistent with that reported previously for secukinumab.
FUTURE 3
Patient population | Treatment groups | Status |
Active PsA despite treatment with NSAIDs, conventional DMARDs, and/or TNF inhibitors | Subcutaneous secukinumab 300 mg (n=139) or 150 mg (n=138) once weekly at weeks 0–4 and every 4 weeks thereafter, or placebo (n=137), self-administered by autoinjector | Published |
FUTURE 3 aimed to investigate the efficacy and safety of secukinumab that was self-administered by patients using an autoinjector. Overall ACR20 response rates at week 24 were 48.2% and 42.0% in the secukinumab 300 mg and 150 mg groups, respectively, compared with 16.1% for the placebo arm.
At least 88% of participants reported being satisfied or very satisfied with the autoinjector, and no new safety concerns were identified.
The FUTURE 3 results were published in Arthritis Research & Therapy in 2018.
FUTURE 4
Patient population | Treatment groups | Status |
Active PsA despite treatment with NSAIDs, conventional DMARDs, and/or TNF inhibitors | Subcutaneous secukinumab 150 mg every 4 weeks with (n=114) or without (n=113) a 150 mg/week loading dose (LD) from baseline to week 4, or placebo (n=114) | Published |
This trial evaluated the efficacy and safety of subcutaneous secukinumab 150 mg every 4 weeks with or without a LD. As reported in Rheumatology and Therapy in 2019, week 16 ACR20 response rates were significantly higher among patients treated with secukinumab with and without the LD versus placebo (41.2 and 39.8%, respectively, vs 18.4%). The study authors described “[e]arlier and numerically higher” responses rates among patients given secukinumab with versus without a LD for endpoints such as ACR50 (22.8 vs 16.8%), PASI90 (36.4 vs 20.4%), and minimal disease activity (MDA; 14.0 vs 10.6%) at week 16.
The investigators report that these responses were maintained at the 52- and 104-week follow-up visits, and patients who were switched to a higher secukinumab dose of 300 mg, as used in FUTURE 3 after week 36, at their physician’s discretion experienced improved efficacy. There were no unexpected safety results reported in FUTURE 4.
FUTURE 5
Patient population | Treatment groups | Status |
Active PsA despite treatment with NSAIDs, conventional DMARDs, and/or TNF inhibitors | Subcutaneous secukinumab 300 mg every 4 weeks with a 300 mg/week loading dose (LD) at weeks 0–4 (n=222), 150 mg every 4 weeks with (n=220) or without (n=222) a 150 mg/week LD at weeks 0–4, or placebo (n=332) | Published |
The FUTURE 5 study – published in the Annals of the Rheumatic Diseases in 2018 – investigated the impact of secukinumab on clinical disease and radiographic progression in patients with PsA, as well as the short-term benefits of using a LD.
At week 16, ACR20 response rates were significantly higher among patients in the secukinumab 300 mg plus LD, 150 mg plus LD, and 150 mg with no LD groups compared with those in the placebo arm, at 62.6%, 55.5%, and 59.5%, respectively, versus 27.4%. Treatment with the higher (300 mg) dose of secukinumab resulted in numerically better responses than the 150 mg dose, and the investigators say that use of the loading dose resulted in earlier onset of action, particularly for high efficacy endpoints including ACR50/70 and PASI75/90 response rates, and the percentage of patients achieving MDA.
Participants in all secukinumab groups also experienced significantly less radiographic progression as measured by changes in mTSS score from baseline to week 24 compared with patients given placebo, and the safety profile of secukinumab was consistent with that reported previously.
Related news story: FUTURE 5 supports subcutaneous secukinumab for PsA
MAXIMISE
Patient population | Treatment groups | Status |
PsA with axial manifestations and an inadequate response to at least two NSAIDs over a 4-week period | Subcutaneous secukinumab at a dose of 300 mg every 4 weeks with a 300 mg/week LD for 4 weeks (n=167) or 150 mg every 4 weeks with a 150 mg/week LD for 4 weeks (n=165), or placebo (n=166) | Published |
The findings from the MAXIMISE trial were presented at the EULAR 2019 congress in Madrid, Spain, and demonstrated that ASAS20 response rates among patients with axial manifestations were significantly higher in the secukinumab 300 mg and 150 mg versus placebo groups, at corresponding rates of 63.1% and 66.3% versus 31.3%. The trial results were published in the Annals of the Rheumatic Diseases in 2021.
Related news story: Positive secukinumab results for axial manifestations in PsA
EXCEED
Patient population | Treatment groups | Status |
Biologic-naïve active PsA with an inadequate response or intolerance to conventional DMARDs | Subcutaneous secukinumab 300 mg every 4 weeks after an LD of 300 mg/week at weeks 0–4, or subcutaneous adalimumab 40 mg every 2 weeks | Published |
EXCEED was designed to compare the efficacy and safety profiles of secukinumab with those of adalimumab in PsA patients with no prior exposure to biologics and an inadequate response or intolerance to conventional DMARDs.
The results were published in The Lancet in 2020, demonstrating no significant difference in the primary endpoint of ACR20 response rates at 1 year among patients treated with secukinumab versus adalimumab, with rates of 67% and 62%, respectively.
However, rates of treatment discontinuation were lower with secukinumab versus adalimumab (14 vs 24%), and a prespecified exploratory analysis demonstrated that a higher proportion of patients in the secukinumab arm achieved a simultaneous ACR50 and PASI 100 response (31 vs 19%). No new safety signals were reported.
ACHILLES
Patient population | Treatment groups | Status |
PsA or axial spondyloarthritis with active enthesitis including one Achilles tendon site and an inadequate response to NSAIDs, conventional DMARDs, and/or TNF inhibitors | Secukinumab 300 mg or 150 mg every 4 weeks following a weekly LD for 4 weeks, or placebo | Results reported; not yet published |
The ACHILLES trial results were presented at the ACR Convergence 2020 virtual meeting. At the 24-week follow-up, the proportion of patients with clinical resolution of Achilles tendon enthesitis was numerically higher in the secukinumab than the placebo arm, at 42.2% versus 31.4%, but the between-group difference did not reach statistical significance and the primary endpoint was not met.
However, average heel enthesopathy, physician and patient global assessment of disease activity scores, and quality of life improved to a significantly greater degree among patients treated with secukinumab versus placebo, and the investigators reported that heel pain was “notably reduced” in the secukinumab arm.
Related news story: Secukinumab may reduce the burden of Achilles tendon enthesitis in patients with spondyloarthritis
ULTIMATE
Patient population | Treatment groups | Status |
Active PsA and synovitis with no prior biologic exposure and an inadequate response to conventional DMARDs | Subcutaneous secukinumab 150 mg or 300 mg/week (depending on disease severity) or placebo | Results reported; not yet published |
| https://clinicaltrials.gov/ct2/show/NCT02662985 | ||
Also presented at the ACR Convergence 2020 virtual meeting, the ULTIMATE trial found that patients treated with secukinumab experienced a significantly greater reduction in synovitis from baseline to week 12 compared with those given placebo. Average reductions in global EULAR-OMERACT synovitis score – an ultrasonography composite scoring system – were 9 points and 6 points, respectively.
Related news story: ULTIMATE trial: Secukinumab reduces synovitis in patients with PsA
Ixekizumab
SPIRIT-P1
Patient population | Treatment groups | Status |
PsA and no prior biologic treatment | Subcutaneous ixekizumab 80 mg every 2 weeks (n=103) or 80 mg every 4 weeks (n=107), adalimumab 40 mg every 2 weeks (n=101), or placebo (n=106) | Published |
As reported in the Annals of the Rheumatic Diseases in 2016, a significantly higher proportion of patients treated with ixekizumab every 2 weeks or every 4 weeks compared with placebo achieved an ACR20 response at week 24, with corresponding rates of 62.1% and 57.9% versus 30.2%. The ACR20 response rate for adalimumab-treated patients was 57.4%. Ixekizumab-treated patients also experienced significantly greater mean improvements in DAS28-CRP and less radiographic progression than those given placebo.
In all, 65.7% of patients treated with ixekizumab every 2 weeks and 66.4% of patients given ixekizumab every 4 weeks experienced treatment-emergent adverse events (TEAEs), compared with 47.2% of participants in the placebo group. The most commonly reported TEAEs were injection site reaction, injection site erythema, and nasopharyngitis, and the majority of adverse events were mild or moderate in severity.
SPIRIT-P2
Patient population | Treatment groups | Status |
Active PsA and an inadequate response or intolerance to prior treatment with TNF inhibitors | Subcutaneous injections of ixekizumab at a starting dose of 160 mg followed by 80 mg every 2 weeks (n=123) or every 4 weeks (n=122), or placebo (n=118) | Published |
The SPIRIT-P2 results were reported in The Lancet in 2017. The investigators found that a significantly higher proportion of patients treated with ixekizumab versus placebo achieved an ACR20 response at week 24, with rates of 48% for patients given ixekizumab every 2 weeks, 53% for those in the ixekizumab every 4 weeks group, and 20% for participants receiving placebo.
Improvements in Health Assessment Questionnaire-Disability Index scores at week 24 were also significantly greater among patients in both ixekizumab groups compared with those given placebo, as were PASI75, 90, and 100 response rates.
A total of 7% of patients receiving ixekizumab every 2 weeks, 3% of those given the drug every 4 weeks, and 3% of placebo-treated patients experienced serious adverse events. The most frequently reported adverse events were injection site reaction, upper respiratory tract infection, and nasopharyngitis. No new safety concerns were identified.
Related news story: SPIRIT-P2 results support ixekizumab for PsA patients with inadequate anti-TNF response
SPIRIT-P3
Patient population | Treatment groups | Status |
Active PsA, no prior biologic exposure, and a previous inadequate response to conventional DMARDs | Patients achieving stable MDA on ixekizumab (160 mg LD followed by 80 mg every 2 weeks) were randomly assigned to continue on the same treatment (n=79) or switch to placebo (n=79) for up to 68 weeks | Results reported; not yet published |
This withdrawal trial aimed to evaluate the long-term efficacy and safety profiles of ixekizumab in patients who achieved sustained MDA during treatment with the IL-17A inhibitor.
Forty weeks after participants with MDA were randomly assigned to continue treatment with ixekizumab or switch to placebo, those still receiving the IL-17A inhibitor were significantly less likely to relapse than those in the withdrawal arm, at rates of 34% versus 73%.
Ixekizumab was reintroduced for patients who flared while receiving placebo, and the investigators report that the “vast majority” of these people regained MDA after switching back to ixekizumab. The safety profile of ixekizumab was consistent with that reported in previous studies.
Related news story: Continuing ixekizumab superior to withdrawal for stable psoriatic arthritis patients
Brodalumab
AMVISION-1 and AMVISION-2
Patient population | Treatment groups | Status |
Active PsA and an inadequate response or intolerance to conventional treatment with NSAIDs or DMARDs | Subcutaneous brodalumab 140 mg (N=318), brodalumab 210 mg (N=322), or placebo (N=322) once every 2 weeks following loading doses at weeks 0 and 1 | Published |
| https://clinicaltrials.gov/ct2/show/NCT02029495 https://clinicaltrials.gov/ct2/show/NCT02024646 | ||
As reported in the Annals of the Rheumatic Diseases in 2020, pooled analysis of data from both trials indicated that patients treated with brodalumab 140 mg or 210 mg had significantly higher ACR20 response rates at week 16 than those given placebo, at 45.8% and 47.9% versus 20.9%, respectively.
ACR50 and ACR70 response rates were also significantly greater among participants treated with either dose of brodalumab versus placebo, as were improvements in skin, enthesitis, and dactylitis endpoints.
The AMVISION-1 and AMVISION-2 trials were terminated early after suicidal ideation and behavior (SIB) was identified as a potential risk during the drug’s development, and patients with SIB were excluded from the trials. The investigators say that the rates of SIB were comparable in the brodalumab 140 mg, brodalumab 210 mg, and placebo arms (0.3 vs 0 vs 0%).
Related news story: Brodalumab shows promise for psoriatic arthritis
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