Key evidence on psoriasis treatments

Fumaric acid esters - key clinical trials in psoriasis

Dimethyl fumarate

The European Medicines Agency's (EMAs) decision to approve a new formulation dimethyl fumarate (DMF) across Europe in 2017 was based on a Phase III, double-blind, placebo-controlled, non-inferiority trial (BRIDGE), which assessed the efficacy and safety of the new formulation DMF, compared with placebo, and an older DMF². 

The BRIDGE study²

In the BRIDGE trial, patients were randomised to receive a new formulation DMF, an older formulation DMF, or placebo (2:2:1) for 16 weeks, up-titrating to a maximum daily DMF dose of
720 mg, depending upon individual response².

At Week 16: 

LAS410008, a new formulation DMF.

Most treatment‐related adverse events were classed as ‘mild’².

PDE4 inhibitor key psoriasis clinical trials

Apremilast

Key efficacy and safety findings

ESTEEM 1: Apremilast 30 mg twice daily versus placebo³

• PASI 75 (Week 16): 33.1% of patients receiving apremilast achieved PASI 75 vs. 5.3% of placebo-treated patients (P<0.0001)
• PASI 50 (Week 52): 61% of patients re-randomised to apremilast at Week 32 achieved PASI 75 at Week 52 vs. 11.7% re-randomised to placebo
• Pruritis: ~30% reduction in pruritis visual analogue scale scores
• PASI 50 in PASI 75 non-responders: ~50% of patients who were PASI 75 non-responders achieved PASI 50 at Weeks 32 and 52 
• Adverse events (AEs): 69.3% of patients reported at least one adverse event with apremilast vs. 55.7% of placebo-treated patients

ESTEEM 2: Apremilast 30 mg twice daily versus placebo (re-randomisation of patients achieving PASI 50)⁴

PASI 50 at Week 52: 80% of patients re-randomised to apremilast versus 11.7% re-randomised to placebo achieved PASI 50 at Week 52⁴.

The LIBERATE trial⁵

The Phase IIIb trial LIBERATE evaluated the efficacy and safety of apremilast vs. placebo in biologic-naïve patients with moderate-to-severe plaque psoriasis, and the safety of switching from etanercept to apremilast. 

It demonstrated that the efficacy of apremilast was sustained over 52 weeks both in patients who continued on apremilast and also in patients who switched from etanercept to apremilast⁵.

Switching from etanercept to apremilast did not result in any new or clinically significant safety signals.

The UNVEIL trial⁶

Meanwhile, the Phase IV UNVEIL trial assessed the efficacy and safety of apremilast in systemic- and biologic-naïve patients with moderate plaque psoriasis over 52 weeks. In the initial 16-week randomised, double-blind, placebo-controlled phase of the study, patients receiving apremilast achieved a significantly greater change from baseline in the product of Static Physicians Global Assessment (sPGA) and body surface area (BSA) scores (PGA x BSA) than placebo (–48.1% vs. –10.2%, P<0.0001)⁶. 

Patients receiving apremilast also experienced a significantly greater improvement in Dermatology Life Quality Index (DLQI) score than patients given placebo (–4.8 vs. –2.4; P=0.0008)⁶. 

UNVEIL extension phase

In the UNVEIL extension phase all patients received apremilast and were followed for up to 52 weeks. Among those patients that completed the study, all efficacy improvements observed at Week 16 were maintained at Week 52⁷.

In a pooled analysis of ESTEEM 1 and 2^80,81, LIBERATE¹⁷⁷, and UNVEIL¹⁷⁸, greater achievement of PASI ≤2 was observed in patients with more moderate than more severe skin disease⁸

TNF-α inhibitor - key clinical trials in psoriasis

Infliximab for psoriasis

Approval of infliximab for psoriasis was based on the two Phase III EXPRESS clinical studies^9,10. 

Key efficacy findings

EXPRESS: infliximab 5 mg/kg vs. placebo⁹

EXPRESS II: infliximab 3 mg and 5 mg/kg vs. placebo¹⁰

PASI scores at Week 50: Better PASI responses were obtained with 5 mg/kg and with continuous maintenance vs. intermittent treatment.

The REALITY health-related quality of life study¹¹

REALITY was a prospective, observational, real-world, open-label study, of infliximab in moderate-to-severe psoriasis that demonstrated substantial improvements in health-related quality of life (HRQoL)¹¹. 

• At Week 50, the mean DLQI improved (decreased) from 12.7 at baseline, to 4.7
• 64% of infliximab patients improved by ≥5 DLQI points
• At Week 98 mean DLQI was 2.8 
• 68.8% of infliximab patients improved by ≥5 DLQI points
• 47.5% of patients achieved a DLQI of 0

The PIECE (Psoriasis Infliximab vs. Etanercept Comparison Evaluation) study¹²

The PIECE study was a non-pharmaceutical sponsored prospective randomised controlled trial comparing infliximab and etanercept in moderate-to-severe psoriasis.

PIECE demonstrated that although infliximab is associated with a rapid and significantly higher level of short-term efficacy compared to etanercept (at Week 24, PASI 75 was achieved in 72% infliximab vs. 34.8% etanercept, P=0.01), there was no significant difference with longer term maintenance treatment¹²:

• At Week 48, PASI 75 was achieved in 66.7% infliximab patients vs. 50% etanercept patients (P=0.65)

Key safety results

Infliximab was generally well tolerated in most patients in the EXPRESS trials. 

Etanercept for psoriasis

Key efficacy findings

Approval of etanercept for psoriasis was based on the results of two Phase III studies described below.

Etanercept low (25 mg weekly), medium (25 mg twice weekly) or high dose (50 mg twice weekly) vs. placebo¹³

Patients received either:

• Etanercept low dose (25 mg weekly)
• Etanercept medium dose (25 mg twice weekly)
• Etanercept high dose (50 mg high dose)
• Placebo

At Week 24, PASI 90 was achieved by:

• 25% of patients receiving etanercept low dose
• 44% of patients receiving etanercept medium dose
• 59% of patients receiving etanercept high dose

PASI responses were paralleled by improvements in PGA and QoL. 

Etanercept 25 mg or 50 mg twice weekly vs. placebo¹⁴

At Week 24, PASI 75 was achieved by:

• 54% of patients with dose reduction 50 mg to 25 mg bi-weekly
• 45% of patients with continuous 25 mg bi-weekly dosing
• 28% of placebo-treated patients who subsequently received 25 mg bi-weekly dosing

Key safety results

Etanercept was generally well tolerated in the etanercept pivotal clinical trials¹⁴. 

Adalimumab for psoriasis

REVEAL¹⁵

In REVEAL, patients received either 40 mg of adalimumab or placebo once every two weeks.

Key efficacy findings

Key safety findings

In REVEAL, <2% of patients discontinued the study.

CHAMPION¹⁶

In CHAMPION, patients were assigned to receive either adalimumab (80 mg at Week 0, then 40 mg once every two weeks) or methotrexate (7.5–25 mg weekly).

Key efficacy findings 

Key safety findings

In CHAMPION, AEs were similar across treatment groups; discontinuation was greatest with methotrexate.

ESPRIT: long-term observational registry¹⁷

ESPRIT is an ongoing, 10-year, observational registry evaluating long-term safety and efficacy of adalimumab in moderate-to-severe psoriasis in routine clinical practice¹⁷. 

Initial (5-year) results demonstrate that efficacy remains stable over five years with no new safety signals¹⁷. The study is due to be completed in September 2022.

Certolizumab pegol for psoriasis

Phase III development of certolizumab pegol involved two studies that enrolled approximately 1,000 patients, including patients with and without prior treatment experience with biologic products^18,19.

CIMPASI-1²⁰

In CIMPASI-1, patients received either placebo or a 400 mg certolizumab pegol (CPZ) loading dose at Weeks 0, 2 and 4, then certolizumab pegol 200 mg or 400 mg every two weeks.

Key efficacy findings

* Secondary endpoint.

Key safety findings

TEAE, treatment-emergent adverse events.

CIMPASI-2²⁰

CIMPASI-2 was a replicate study run in parallel to CIMPASI-1.

Key efficacy findings

* Secondary endpoint.

Key safety findings

TEAE, treatment-emergent adverse events.

CIMPACT²¹

In CIMPACT, up until Week 16 patients received either:

• A 400 mg certolizumab pegol loading dose at Weeks 0, 2 and 4, then 200 mg certolizumab pegol every two weeks
• A 400 mg certolizumab pegol loading dose at Weeks 0, 2 and 4, then 400 mg certolizumab pegol every two weeks
• Etanercept twice weekly
• Placebo

Patients who were re-randomised and were PASI 50 non-responders at any visit during the maintenance period were entered into the open-label safety extension and received certolizumab pegol 400 mg every two weeks.

Key efficacy findings

Sustained superiority versus placebo:

Superiority versus etanercept for certolizumab pegol 400 mg every two weeks, and non-inferiority for certolizumab pegol 200 mg every two weeks:

Etanercept PASI 75 responders who were switched to certolizumab pegol or placebo at Week 16:

Etanercept non-responders (<PASI 50 at Week 12) who were switched to certolizumab pegol 400 mg every two weeks:

In 3-year results from CIMPASI-1 and CIMPASI-2, at Week 144, PASI 75/90 was achieved by 70.6%/48.7% patients randomised to certolizumab pegol 200 mg, and 72.9%/42.7% randomised to certolizumab pegol 400 mg²².

Key safety findings

TEAE, treatment-emergent adverse events.

IL-12 and IL-23 inhibitors – key clinical trials in psoriasis

Ustekinumab (IL-12/23 inhibitor) for psoriasis

Approval of ustekinumab in psoriasis was based on the efficacy and safety data from two Phase III clinical trials, PHOENIX 1 and PHOENIX 2.

Comparable efficacy of ustekinumab (standard dose) has been demonstrated in both adults and psoriasis patients aged 12–17 with no unexpected AEs²³.

PHOENIX 1²⁴

In this study, ustekinumab was administered at a dose of either 45 mg or 90 mg at Weeks 0 and 4, then every 12 weeks versus placebo. 

Key efficacy findings

Key safety findings

During the placebo-controlled phase, AEs and serious adverse events (SAEs) occurred in 54.5%, and 1.2% of ustekinumab-treated patients vs. 48.2% and 0.8% of placebo-treated patients.

PHOENIX 2^25,26

In this study, ustekinumab was administered at a dose of either 45 mg or 90 mg at Weeks 0 and 4, then every 12 weeks versus placebo. 

Key efficacy findings

Key safety findings

Ustekinumab vs. other psoriasis treatments (PSOLAR registry data)

Efficacy and safety of ustekinumab and other psoriasis treatments in a real-world setting was assessed using the PSOLAR registry data^27,28. 

Analyses concluded that ustekinumab in people with psoriasis:

• is more effective than infliximab, etanercept and adalimumab, with no increased risk of malignancy, major adverse cardiovascular events (MACE), serious infection, or mortality^27,28
• presents a lower risk of infections compared to methotrexate treatment (hazard ratio [HR] 0.65; 95% CI, 0.47–0.89)²⁹
• offers superior drug survival compared with infliximab, adalimumab and etanercept³⁰

The PSOLAR efficacy findings were confirmed by data from the prospective, BioCAPTURE registry comparing one- and five-year efficacy of adalimumab, etanercept and ustekinumab in people with psoriasis in daily clinical practice. BioCAPTURE suggested that after one year, PASI 75 is more often achieved with adalimumab and ustekinumab than etanercept, and that after five years, ustekinumab has the highest efficacy (P=0.019)³¹.

Guselkumab (IL-23 inhibitor) for psoriasis

VOYAGE-1³²

In VOYAGE-1, patients received one of three dosing regimens:

• Guselkumab (GUS) 100 mg at Weeks 0 and 4, and then every 8 weeks thereafter
• Placebo at Weeks 0, 4 and 12, then guselkumab at weeks 16 and 20, and then every 8 weeks thereafter 

• Adalimumab (ADA) 80 mg at Week 0, 40 mg adalimumab at Week 1, and then every 2 weeks thereafter

Key efficacy findings

Improvement in DLQI:

• At Week 16, change in DLQI was
• –11.2 for guselkumab (P<0.001 vs. placebo; not stated vs. adalimumab)
• –9.3 for adalimumab
• –0.6 for placebo
• At Week 24, change in DLQI was
• –11.6 for guselkumab (P<0.001 vs. adalimumab)
• –9.5 for adalimumab
• At Week 48, change in DLQI was
• –11.8 for guselkumab (P<0.001 vs. adalimumab)
• –9.2 for adalimumab

Open-label extension study

VOYAGE-1 continues with an open-label extension study, running from Week 48 to Week 100. At Week 52, all patients began receiving  guselkumab 100 mg every 8 weeks. Patients initially randomised to adalimumab at Week 0 entered a washout period after their final dose of adalimumab at Week 47 and initiated guselkumab 100 mg at Week 52 and every 8 weeks thereafter.

The study is due to be completed in 2022³³. 

Overall, PASI 75, PASI 90, and Investigator’s Global Assessment (IGA) response rates at Weeks 52 and 100 remained consistent.

Key safety findings

Key safety findings

Drug survival at Week 48:

• Discontinuation for any reason was 8.5% guselkumab vs. 15.6% adalimumab (P=0.0053)
• HR 1.88 (95% CI, 1.19–2.98) P=0.007
• Discontinuation due to lack of efficacy/worsening psoriasis was 0.9% guselkumab vs. 5.1% adalimumab (P=0.0017)
• HR 5.71 (95% CI, 1.68–19.5) P=0.0054
• Discontinuation due to AEs was 3.0% guselkumab vs. 2.8% adalimumab (P=0.297)

In the open-label extension study, rates of AEs, SAEsand infections per 100 patient-years were consistent with those recorded for VOYAGE-1 up to Week 48.

VOYAGE-2³⁴

The VOYAGE-2 study addressed whether benefits observed in patients who responded to guselkumab would be maintained following withdrawal³⁴. 

Key efficacy findings

Clinical outcomes were significantly better in patients who were maintained with treatment compared with those who received placebo.

VOYAGE-2 efficacy and safety at 4 years

Results of continuous guselkumab treatment through 4 years from VOYAGE 2 revealed efficacy was maintained through 4 years of continuous guselkumab treatment for moderate-to-severe psoriasis, and comparable with patients who crossed over from adalimumab to guselkumab³⁵. Guselkumab showed a favourable safety profile through 4 years, with no new safety signals observed³⁵.

PASI Scores at Week 204

Patient‐Reported Outcome Scores at Week 204

GUS, patients receiving GUS 100 mg every 8 weeks. A>GUS, ADA non-responders switched to GUS 100 mg, receiving GUS at or after Week 28.

VOYAGE-1 and 2 - 5-year efficacy and quality of life

In 5-year results, the proportions of patients in the guselkumab group who achieved clinical responses at Week 252 in VOYAGE 1 and VOYAGE 2, respectively, were 84.1% and 82.0% (≥90% improvement in PASI; 82.4% and 85.0% (IGA 0 or 1); 52.7% and 53.0% (100% improvement in PASI), and 54.7% and 55.5% (IGA 0)³⁶.

Health-related QoL (HRQoL) endpoints were 72.7% and 71.1% of patients (DLQI 0 or 1: no effect on patient’s life); 42.4% and 42.0% (Psoriasis Symptoms and Signs Diary [PSSD] symptom score=0), and 33.0% and 31.0% (PSSD sign score=0). As measured in VOYAGE 2 only, approximately 45% of patients achieved ≥5-point reduction in Short Form-36 physical and mental component scores, and 80% reported no anxiety or depression (Hospital Anxiety and Depression Scale scores <8). Similar findings were reported for adalimumab crossovers. These effects were maintained from Week 52 in VOYAGE 1 and Week 100 in VOYAGE 2³⁶.

Key safety findings at Week 204

In 5-year safety results from VOYAGE-1 and 2, AEs rates were low, and generally remained stable over time with continuous guselkumab exposure through 5 years³⁷.

ECLIPSE³⁴

ECLIPSE is the first head-to-head study to compare efficacy between guselkumab and secukinumab³³. 

Patients received either:

• Guselkumab 100 mg by subcutaneous injection at Weeks 0 and 4, followed by a maintenance dose every 8 weeks, or
• Secukinumab 300 mg (2 subcutaneous injections of 150 mg) at Weeks 0, 1, 2, 3 and 4 followed by monthly maintenance dosing

Key safety findings

Safety profiles were consistent with the known safety profiles seen in the respective registration trials and the current prescribing information.

POLARIS³⁸

A completed Phase IIIb national, multicentre, randomised, open-label, assessor-blinded, active comparator trial (POLARIS; NCT02951533) compared the efficacy of guselkumab to fumaric acid esters (FAE) in people with moderate-to-severe psoriasis who are candidates for, and naïve to, systemic treatment in Germany³⁸.

In this study, 82% of patients receiving guselkumab achieved PASI 90 versus 14% receiving FAE at Week 24 (P<0.001)³⁸.

While 28% of patients receiving FAE discontinued due to AEs, no patients receiving guselkumab had to discontinue for this reason³⁸.

Tildrakizumab (IL-23 inhibitor) for psoriasis

In Phase III studies outlined below, tildrakizumab was associated with significantly higher proportions of people with moderate-to-severe psoriasis achieving PASI 75 and clear or minimal PGAs than placebo.

ReSURFACE long-term data – expert opinion

Watch the short video clips, featuring Professor Diamant Thaçi (Director, Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Germany), to learn more about tildrakizumab and why long-term safety and efficacy data for biologics is so important.

reSURFACE 1³⁹

In reSURFACE 1, patients were randomised to one of the following at Weeks 0 and 4, and then every 12 weeks thereafter they received tildrakizumab 100 mg or 200 mg, or placebo.

Placebo-treated patients were re-randomised to tildrakizumab at either 100 mg or 200 mg at Weeks 12 and 16. Dosing continued to Week 64.

Key efficacy findings

ReSURFACE 2 (tildrakizumab versus etanercept)

ReSURFACE 2 also showed that tildrakizumab 200 mg was associated with significantly higher proportions of patients achieving PASI 75 and PGA responses at Week 12 than etanercept, an effective anti-TNF-α treatment for psoriasis³⁹. 

In patients who were non-responders or partial responders to etanercept in the reSURFACE 2 study, who joined a 2-year extension phase, tildrakizumab 200 mg resulted in PASI 75 responses in almost 9 out of 10 patients after 3 doses and these responses were maintained at Week 148⁴⁰.

ReSURFACE extension (long-term response of tildrakizumab)

All patients enrolled on an extension study achieved at least PASI 50.

In the long-term extension to reSURFACE 1 and reSURFACE 2, PASI 75 and PASI 100 were maintained at Week 148 in etanercept non- or partial responders who were switched to tildrakizumab 200 mg⁴⁰. Tildrakizumab demonstrated maintenance efficacy for at least 3 years:

ReSURFACE 1 and 2 five-year efficacy and safety data⁴¹

Pooled from the reSURFACE 1 and reSURFACE 2 Phase III studies, tildrakizumab is the first anti-interleukin (IL)-23p19 treatment for which five-year efficacy and safety data are reported for patients with moderate-to-severe psoriasis who respond at week 28⁴¹.

Efficacy analyses included 329 and 227 Week 28 responders to tildrakizumab 100 mg and tildrakizumab 200 mg, respectively, and 121 etanercept partial responders/non-responders switched to tildrakizumab 200 at Week 28. Safety was assessed from AEs in all treated patients⁴¹.

Key efficacy findings

Key safety findings

Notable adverse events

Risankizumab (IL-23 inhibitor) for psoriasis

UltIMMa-1⁴²

Patients were randomised to either:

• Risankizumab (RIS) 150 mg at baseline, and then at Weeks 4, 16, 28, and 40
• Ustekinumab (UST) 45 mg or 90 mg (based on screening weight) at baseline, then at Weeks 4, 16, 28, and 40
• Placebo

At Week 28, patients who achieved sPGA 0/1 were re-randomised to either:

• Risankizumab (maintenance)
• Placebo (withdrawal)

Treatment continued until Week 104; however, from Week 32, patients who relapsed (sPGA ≥3) were re-treated with risankizumab.

Key efficacy findings

Key safety findings

From baseline to Week 16, at least one adverse event occurred in:

• 49.7% of risankizumab-treated patients
• 50.0% of ustekinumab-treated patients
• 51.0% of placebo-treated patients

Through to Week 16, SAEs occurred in:

• 2.3% of risankizumab-treated patients
• 8.0% of ustekinumab-treated patients
• 2.9% of placebo-treated patients

UltIMMa-2⁴²

A replicate study of ultIMMa-1.

IMMhance⁴³

Patients were randomised to either:

• Risankizumab 150 mg at baseline, at Week 4 and then every 12 weeks thereafter
• Placebo

At Week 28, patients who achieved sPGA 0/1 were re-randomised to either:

• Risankizumab (maintenance)
• Placebo (withdrawal)

Treatment continued until Week 104; however, from Week 32, patients who relapsed (sPGA ≥3) were retreated with risankizumab.

At Week 52, 87% of risankizumab-treated patients (maintenance group) achieved sPGA 0 or 1, versus 61% of the maintenance group.

Key safety findings

From baseline to Week 16, at least one adverse event occurred in:

• 45.5% of risankizumab-treated patients
• 48.0% of placebo-treated patients

Through to Week 16, SAEs occurred in:

• 2% of risankizumab-treated patients
• 8% of placebo-treated patients

IMMvent⁴⁴

Patients were randomised to either:

• Risankizumab 150 mg at baseline, at Week 4, and then every 12 weeks thereafter
• Adalimumab (ADA) 80 mg at baseline, followed by 40 mg every other week starting at Week 1

Dose modification at Week 16:

• Adalimumab-treated patients with a <50 PASI response were switched to risankizumab
• Adalimumab-treated PASI 90 responders continued with adalimumab
• Adalimumab-treated PASI 50 responders with a <90 PASI response were re-randomised to risankizumab or adalimumab 

Key safety findings

From baseline to Week 16, at least one adverse event occurred in:

• 55.8% of risankizumab-treated patients
• 56.9% of adalimumab-treated patients

Through to Week 16, SAEs occurred in:

• 3.3% of risankizumab-treated patients
• 3.0% of adalimumab-treated patients

IL-17 inhibitors - key clinical trials in psoriasis

Ixekizumab for psoriasis

UNCOVER-1⁴⁵

Patients received either:

• Ixekizumab (IXE) 80 mg every two weeks 
• Ixekizumab 80 mg every four weeks 
• Placebo

UNCOVER-2 and UNCOVER-3⁴⁶

Patients received either:

• Ixekizumab 80 mg every two weeks 
• Ixekizumab 80 mg every four weeks
• Etanercept 
• Placebo

 In the UNCOVER trials, ixekizumab treatment also resulted in⁴⁶:

• High levels of response in etanercept non-responders
• High efficacy in biologic naïve and experienced patients
• Greater improvements in nail psoriasis versus etanercept and placebo
• Sustained improvement in scalp psoriasis versus etanercept and placebo

• Significant and clinically meaningful improvements in itch (P<0.001)

Key safety findings

SAEs were observed in:

• 1.9% of patients receiving ixekizumab 2 weekly
• 1.9% of patients receiving ixekizumab 4 weekly
• 1.9% of patients receiving etanercept
• 1.9% of patients receiving placebo (P<0.0001)

The safety profile at Week 60 was similar to that at Week 12.

IXORA-S⁴⁷

Patients received either:

• Ixekizumab 160 mg given as a loading dose, followed by 80 mg at Week 2, 4, 6, 8, 10, and 12, and 80 mg ixekizumab every four weeks thereafter
• 40 mg or 90 mg ustekinumab at Weeks 0 and 4, then every 12 weeks thereafter

Head-to-head studies

IXORA-R (ixekizumab versus guselkumab)^48,49

The IXORA-R head-to-head trial, designed to evaluate superiority between ixekizumab and guselkumab was the first head-to-head trial between an anti-IL-17 and anti-IL-23 therapy using the PSAI 100 score as a primary endpoint.

The results showed that:

• The primary end point of PASI 100 at Week 12 was achieved in 41% of patients in the ixekizumab group compared to 25% with guselkumab (P<0.001)
• Serious adverse event frequency was 3% for each group with no new safety signals identified
• At Week 24, ixekizumab was noninferior to guselkumab (50% vs. 52%, respectively) with no significant difference in PASI 100 (P=0.41)

Ixekizumab versus fumaric acid esters and methotrexate

The efficacy of ixekizumab was compared to fumaric acid esters (FAEs) and methotrexate in a head-to-head Phase III trial of 162 patients with moderate-to-severe psoriasis who were naïve to systemic treatment⁵⁰. Patients were randomised 1:1:1 to ixekizumab, FAE or methotrexate for 24 weeks of treatment⁵⁰. The primary outcome was the proportion of patients who achieved PASI75, while key secondary outcomes included 24-week PASI 90 and 100, static Physician’s Global Assessment (sPGA) score (0 or 1), and Dermatology Life Quality Index (DLQI) score (0 or 1)⁵⁰.

At week 24, the results showed⁵⁰:

• Significantly more patients treated with ixekizumab achieved PASI75, PASI 90 and PASI 100 than those who received FAEs or methotrexate (91% vs 22% vs 70%; 80% vs 9% vs 39%; 41% vs 4% vs 13%, respectively)
• Results for sPGA (0,1) in patients with baseline sPGA ≥3 and DLQI (0,1) were superior for ixekizumab versus methotrexate or FAEs
• The safety profile of all treatments were consistent with previous studies

Bimekizumab for psoriasis

Bimekizumab received EMA approval for moderate-to-severe psoriasis in 2021⁵¹. Overall, the safety and efficacy of bimekizumab has been evaluated in patients with moderate-to-severe plaque psoriasis across four Phase III multicentre, randomised, placebo and/or active comparator-controlled clinical trials^51–56.

• In BE READY (n = 435), more participants treated with bimekizumab achieved PASI90 (91%) and Investigator’s Global Assessment (IGA) success (response of 0 or 1 in 93%), than those who received placebo (1% for both; P<0.0001 for both) after 16 weeks⁵⁵
• In BE VIVID (n = 567), more participants treated with treated with bimekizumab (85%) achieved PASI90 than those who received either ustekinumab or placebo (50% and 15%, respectively; P<0.0001 for both); and IGA success (84%) versus ustekinumab and placebo (53% and 5%, respectively; P<0.0001 for both) after 16 weeks⁵⁶
• In BE SURE (n = 478), more participants treated with bimekizumab (86.2%, pooled analysis) achieved PASI90, than those who received adalimumab (47.2%, P<0.001); and IGA score of 0/1 (85.3%, pooled analysis) versus adalimumab (57.2%, P<0.001)⁵⁴
• In BE RADIANT (n = 743), more participants treated with bimekizumab (61.7%) achieved PASI100, than those who received secukinumab (48.9%, P<0.001) after 16 weeks⁵³

Efficacy of bimekizumab was maintained for up to 56 weeks of treatment in BE READY, BE RADIANT and BE VIVID^52,53,55,56.

In the BE READY trial, AEs were reported more frequently in participants who received bimekizumab than those who received placebo up to week 16 (61% versus 41%)⁵⁵. The most common AEs with bimekizumab were nasopharyngitis (9%), oral candidiasis (9%) and upper respiratory tract infections (3%)⁵⁵. In a meta-analysis of six randomised bimekizumab trials, pooled analysis revealed no obvious differences in treatment-emergent AEs (TEAEs) and serious TEAEs between the bimekizumab and placebo groups (RR 1.17; 95%CI 0.93–1.47; P>0.05; and RR 0.67; 95%CI 0.28–1.61; P>0.05, respectively)⁵⁷.

In the head-to-head trials, similar rates of AEs were reported for bimekizumab and secukinumab up to 48 weeks (86.1% versus 81.4%)⁵³), adalimumab up to 24 weeks (70.9-72% versus 69.8%)⁵⁴), and ustekinumab up to 16 weeks (56% vs 51%)⁵⁶.

Brodalumab for psoriasis 

Phase III development for brodalumab consists of one placebo-controlled trial (AMAGINE-1) and two head-to-head studies comparing brodalumab (BROD) to ustekinumab (AMAGINE-2 and 3)^58,59. Based on the results of the AMAGINE studies, brodalumab was submitted to regulatory authorities in Europe and the USA in late 2015/early 2016.

AMAGINE-1⁵⁸                                                           

Patients received either:

• Brodalumab 140 mg 
• Brodalumab 210 mg 
• Placebo

AMAGINE-2 and AMAGINE-3⁵⁹

During the induction phase, patients received either:

• Brodalumab 140 mg 
• Brodalumab 210 mg 
• Ustekinumab 45 mg or 90 mg (weight-based dosing)

Following the induction phase, patients receiving brodalumab at Week 12 were re-randomised to receive either:

• Brodalumab 210 mg every two weeks
• Brodalumab 140 mg every two weeks
• Brodalumab 140 mg every four weeks
• Brodalumab 140 mg every eight weeks

Patients who originally received placebo were switched to brodalumab every two weeks. 

At Week 52, those patients still receiving ustekinumab were switched to brodalumab 210 mg every two weeks for the extension phase.

PASI 100 was achieved in 50% of patients at 14 weeks for brodalumab and at 44 weeks for ustekinumab.

AMAGINE-2 long-term extension study⁶⁰

Efficacy data was reported for patients who received brodalumab 210 mg every two weeks through to Week 120 of the long-term extension phase. 

Secukinumab (IL-17 inhibitor) for psoriasis

ERASURE⁶¹

Patients received either 150 mg or 300 mg secukinumab (SEC) (once weekly for 5 weeks, then monthly) or placebo.

In addition:

• The proportion of patients achieving PASI 75 and IGA 0/1 increased to Week 16 and was maintained 
• Secukinumab 150 mg and 300 mg was superior to placebo with respect to the PASI 90 and PASI 100 responses at Week 12 (P<0.001)

FIXTURE⁶¹

Patients received either:

• Secukinumab 150 mg or 300 mg (once weekly for 5 weeks, then monthly) 
• Etanercept (ETN) 50 mg (twice weekly for 3 months, then once weekly)
• Placebo

In addition, rates of PASI 90 and PASI 100 were higher among patients receiving secukinumab than those receiving etanercept at Week 12 to Week 52 (P<0.001).

Additional analyses found that efficacy obtained at week 16 was sustained for 2 years.

FEATURE⁶²

Patients received either:

• Secukinumab 150 mg or 300 mg (once weekly for 5 weeks, then monthly) 
• Etanercept 50 mg (twice weekly for 3 months, then once weekly)
• Placebo

100% of subjects successfully self-administered treatment at Week 1.

JUNCTURE⁶³

Patients received either:

• Secukinumab 150 mg or 300 mg 
• Placebo

IL-36 inhibitor - key clinical trials in psoriasis

Spesolimab for psoriasis

The key trial that supported the EMA’s conditional approval of spesolimab for generalised pustular psoriasis was a randomised, double-blind, placebo-controlled Phase II study (Effisayil 1), conducted in 53 adult patients with flares of generalised pustular psoriasis⁶⁴.

In this study, 53 patients were randomised to receive a single intravenous dose of spesolimab 900 g or placebo. Both groups could receive an open-label dose of spesolimab on day 8 or as a rescue medication after day 8, or both, and were followed to week 12.

At the end of week 1:

• A total of 54% of patients in the spesolimab group achieved the primary endpoint, which was a Generalised Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (no visible pustules), compared with 6% in the placebo group (P<0.001)
• A total of 43% in the spesolimab achieved the secondary end point of 0 or 1 (clear or almost clear skin) as their GPPGA total score, compared with 11% in the placebo group (P=0.02)

The treatment effect was observed irrespective of the mutation status of IL-36RN, the gene that encodes IL-36 receptor inhibitor^64,65.

Key safety findings

Within the first week after treatment, AEs were reported in 66% of patients who received spesolimab, versus 56% in the placebo group; while 29% of participants in the spesolimab group had AEs that were considered by the investigator as drug-related, compared to 28% in the placebo group ⁶⁵. By the end of the first week, infections were reported in 17% of participants in the spesolimab group versus 6% in placebo, and in this reached 47% of participants at week 12⁶⁵.

At the end of week 1, serious AEs (SAEs) had been reported in 6 participants treated with spesolimab and none in the placebo group ⁶⁵. Of these SAEs, drug reactions with eosinophilia and systemic symptoms (DRESS) were reported in 2 patients treated with spesolimab, one of which occurred at the same time as a drug-induced hepatic injury⁶⁵.

Overall, results of this study indicate spesolimab is associated with infections and systemic drug reactions ⁶⁵. However, data from larger and longer term trials of spesolimab are needed in patients with pustular psoriasis ⁶⁵.

TYK2 inhibitor – key clinical trials in psoriasis

Deucravacitinib

The 2023 EMA approval of deucravacitinib for the treatment of moderate-to-severe plaque psoriasis^66,67 was based on the efficacy and safety results of two multicentre, randomised, double-blind trials: POETYK PSO-1 and POETYK PSO-2 ^67–70.

In both trials, patients with moderate-to-severe plaque psoriasis were randomised to deucravacitinib 6 mg once daily, apremilast 30 mg twice daily, or placebo^67–69.

• Participants assigned to placebo were switched to deucravacitinib at week 16, which was continued up to week 52 ^67–69
• Participants assigned to apremilast who did not achieve a PASI 50 (POETYK PSO-1) or PASI 75 (POETYK PSO-2) response at week 24 were switched to deucravacitinib, continued until week 52 ^67–69.
• For the deucravacitinib arms:
  • In POETYK PSO-1, patients who were randomised to deucravacitinib continued treatment up to week 52^67,68
  • In POETYK PSO-2, patients who were randomised to deucravacitinib and achieved PASI 75 at week 24 were re-randomised 1:1 to continue deucravacitinib (maintenance) or were switched to placebo (withdrawal) ^67,69

In both studies, the co-primary endpoints were the proportions of patients who achieved the following at week 16 ^67–69:

• ≥75% improvement in PASI scores (PASI 75) from baseline, and
• a static Physician’s Global Assessment (PGA) score of clear or almost clear (0 or 1) versus placebo

Key results for the co-primary endpoints are summarised in Table 1.

Table 1. Results for co-primary endpoints at week 16 from the POETYK PSO-1 and POETYK PSO-2 trials ^67–69. PASI75, ≥75% reduction from baseline in Psoriasis Area and Severity Index; sPGA, static Physician’s Global Assessment.
^*P≤ 0.0001 for comparison between deucravacitinib and placebo or deucravacitinib and apremilast. ^†Co-primary endpoint comparing deucravacitinib with placebo. ^‡p <0.001 for comparison between deucravacitinib and apremilast.

In both POETYK PSO-1 and PSO-2 trials, PASI 75 response was maintained for up to 52 weeks in the majority of patients (≥80%) who continued deucravacitinib treatment^67–69.

Key safety findings

Deucravacitinib was considered well tolerated⁶⁸, and adverse event (AE) rates were considered similar to those with placebo and apremilast across the POETYK PSO-1 and POETYK PSO-2 trials^68,69. The most frequent AEs in the deucravacitinib group were nasopharyngitis and upper respiratory tract infection up to week 52 ^68,69.

However, across both trials, there was a higher incidence of serious infections and herpes zoster infections up to week 52 in the group that received deucravacitinib, compared with those who received apremilast or placebo^68,69. All cases of herpes zoster were mild to moderate in severity, localised and did not lead to discontinuation^68,69.

Comparative data on treatments for psoriasis

There are a limited number of head-to-head trials that have directly compared efficacy and safety profiles between psoriasis treatments^71,72. These include Phase III comparisons of the efficacy ± safety profiles between^71,72:

• TNF-α inhibitors versus IL-17, IL-12/23 or IL-23 inhibitors
• TNF-α inhibitors versus the PDE4 inhibitor, apremilast
• IL-12/23 inhibitor versus IL-17 inhibitors
• IL-23 inhibitors versus IL-17 inhibitors
• Types of TNF-α inhibitors

In addition, several systematic reviews and network meta-analyses have also indirectly compared the relative efficacy of treatments for moderate-to-severe psoriasis^72–79. Results of indirect comparisons are considered to fill an important evidence gap, as it is not feasible to undertake head-to-head comparisons of all treatments for psoriasis⁸⁰.

For example, Armstrong and collagues (2021) incorporated results of the head-to-head IXORA-R, ECLIPSE, CLARITY, IMMerge clinical trials into a network meta-analysis, which assessed short-term and long-term PASI response rates across trials of FDA- and EMA-approved treatments in moderate-to-severe plaque psoriasis⁷². This analysis indirectly compared results across Phase II–IV randomised controlled trials, using a Bayesian network meta-analysis approach to estimate PASI 75/90/100 response rates from treatment in the short-term (i.e. 10–16 weeks from baseline) or long-term (i.e. 48–52 weeks from baseline)⁷². Compared to other approved treatments for moderate-to-severe psoriasis, results of this meta-analysis indicated⁷²:

• PASI response rates were highest for ixekizumab, risankizumab and brodalimumab in the short-term (n=71 trials)
• PASI response rates were highest for risankzumab in the long-term (n=11 trials)

However, it is important to note the results of this indirect comparison (and others) are limited by differences in study design, conduct and patient populations across trials included in the analysis⁷² .

Also of note, rankings for most biologic treatments for psoriasis have been reported to vary across indirect comparisons⁸⁰. This may be due to differences in methodologies for comparisons, variations in treatments that were included in each analysis, as well as treatment dosing, during, outcome definitions and effect measures between indirect comparisons⁸⁰

When considering results and the clinical relevance of indirect comparisons, treatment rankings should not be considered in isolation, and rather should be considered alongside actual differences in outcomes⁸⁰

Further head-to-head trials are required to more accurately rank psoriasis treatment options according to their risk/benefit ratio⁷¹, and more long-term analyses are needed to better understand the comparative long-term efficacy of treatment options for psoriasis and inform clinical decision-making ⁸⁰.

Read about real-world evidence for biologics in psoriasis

Explore effective treatment selection in psoriasis

Expert opinion on real-world evidence for psoriasis

Join Professor of Dermatology, Ulrich Mrowietz, in this discussion on the real-world evidence for the efficacy and safety of biologic treatments for psoriasis.

• Compare phase III clinical trial and real-world evidence data for psoriasis
• Evaluate if biologic treatments meet patient and practitioner expectations

Does real-world data demonstrate comparative efficacy and safety to phase III clinical trial data when evaluating biologic treatments?

Does real-world data inform us about biologic drug survival and relapse rates in people with psoriasis?

Is real-world evidence for biologic treatment efficacy sufficient to aid practitioners and patients in shared decision making?

Key findings from real-world evidence on biologics for psoriasis

Cohort and registry data have confirmed the real-world effectiveness and safety profile of various biologics for psoriasis, and have provided further information on the association between treatment history and patient characteristics with treatment response, and potential safety risks.

Numerous real-world studies have confirmed the effectiveness and safety profile of various IL-17^85–87, IL-23⁸⁸, IL-12/23^89–92 and TNF-α inhibitors ^83,93 in patients with psoriasis in clinical practice. These real-world populations include patients with comorbidities, multiple prior treatment failures, and the elderly.

Key findings include:

• Response rates in the real-world can be lower when compared with data from clinical trials^83,94
• Higher response rates have been reported in patients who are biologic-naive, compared with those who are biologic-experienced^84,87,94

In addition, registry data have also been used as a basis to analyse biologic effectiveness according to prior biologic exposure⁹⁵, and the effectiveness of within-class switches between biologics (e.g. for IL-17 inhibitors⁹⁶) in patients with psoriasis.

Read on to learn more about key safety findings from real-world evidence, as well as evidence for use of biologics in specific populations, and comparative data between different types of biologics.

Key real-world safety findings for biologics in psoriasis

Risk of infections

Clinical trials that indicated an increased incidence of candidiasis in patients treated with IL-17 inhibitors, and real-world safety data from WHO, EMA, registry and cohort populations also support an association between treatment with IL-17 inhibitors and an increased risk of oropharyngeal, esophageal and cutaneous candidiasis⁹⁷.

In addition, results of a retrospective cohort study of patents with psoriasis or psoriatic arthritis (n = 9305) in the US indicated ⁹⁸:

• the risk of serious infections in biologic-naive patients treated with IL-12/23 inhibitors was lower than those treated with TNF-α or IL-17 inhibitors
• no difference in infection across TNF-α, IL-17 or IL-12/23 inhibitors in biologic-experienced patients

Risk of IBD

Phase III clinical trials have indicated an association between IL-17 inhibitors treatment and exacerbation or new-onset inflammatory bowel disease (IBD) in patients with psoriasis⁹⁹. However, results of a nationwide, population-based study using the French National Health Data System has indicated no increased risk of developing IBD in patients with psoriasis and psoriatic arthritis/ankylosing spondylitis who initated IL-17 inhibitor treatment, compared with etanercept⁹⁹. A small study of the French national registry (MISSIL) also reported that new-onset IBD events were uncommon with IL-17 inhibitor treatment in patients with psoriasis or spondyloarthritis¹⁰⁰.

Risk of tuberculosis reactivation

Guidelines recommend screening for tuberculosis (TB) prior to starting treatment with a biologic^101–103.

In patients with psoriasis and latent TB, use of TNF-α inhibitors has been associated with an increased risk of TB reactivation across both clinical trials and real-world studies^103,104. However, the incidence of conversion to positive TB in real-world patients with psoriasis treated with IL-17, IL-23 and IL-12/23 inhibitors appears to be low^105–108, although there is limited long-term data available¹⁰⁶.

In a pooled cohort study of over 12,000 patients with psoriasis, psoriatic arthritis or ankylosing spondylitis, spontaneously reported new latent TB infection during secukinumab treatment was rare¹⁰⁶. No cases of active TB or latent TB activation were reported¹⁰⁶.

In an Italian retrospective chart review of 59 patients with moderate-to-severe psoriasis who were positive for TB and treated with secukinumab, no cases of TB reactivation were reported after up to 84 weeks of treatment¹⁰⁵. This included patients who did not receive prior prophylaxis for TB, and no unexpected safety signals were reported¹⁰⁵.

Biologics in specific patient populations

Older patients with psoriasis

Considering older patients are often excluded from clinical trials, a study of the Netherlands BioCAPTURE registry compared drug survival (i.e. the probability of remaining on therapy), safety and effectiveness of biologics in older (≥ 65 years) versus younger patients (<65 years) with psoriasis⁸². In the drug survival analysis, treatment discontinuation due to ineffectiveness, AEs, ineffectiveness and AEs combined, other reasons, and death were considered events⁸².

In this cohort, ~65% were biologic-naive (~65%), while around ~20% had used 1 previous biologic and ~8% had used 2 previous biologics. Overall,  ~66% were on TNF-α inhibitors, 22.8% on the IL-12/23 inhibitor ustekinumab, and the remaining ~11% were on IL-17 inhibitors⁸².

After correcting for confounders, similar trends were observed in the drug survival outcomes between the older and younger patient groups⁸².

Results of a BioCAPTURE registry study indicated biologics were well tolerated and effective in older patients; although they reported discontinuing biologics more often because of ineffectiveness compared with younger patients, no clear differences in PASI were observed between the two groups⁸²In addition, treatment discontinuation due to AEs were no more frequent in older patients compared to younger patients⁸².

Asian versus non-Asian patients with psoraisis

An analysis of the US and Canadian CorEvitas Psoriasis Registry compared the 6-month effectiveness of biologic therapy between Asian (n = 293) and non-Asian patients with plaque psoriasis (n = 2,314)¹⁰⁹, using PASI response, disease activity measures and patient-reported outcomes. After adjustment for confounders, results were similar between groups, except for Dermatology Life Quality Index (DLQI) – there was a 33% lower odds of achieving a DLQI score of 0/1 in Asian versus non-Asian patients¹⁰⁹.

Although results of a CorEvitas Psoriasis Registry study indicated that responses to biologic treatment for psoriasis were similar between Asian and non-Asian patients, DLQI analysis indicated Asian patients may experience lesser responses in skin-related quality of life after biologic treatment, when compared to non-Asian patients with psoriasis¹⁰⁹

Real-world comparative data on biologics in psoriasis

Comparative effectiveness of TNF-α inhibitors, IL-17 and IL-23 inhibitors

The first-year effectiveness of etanercept, adalimumab, ustekinumab, secukinumab, ixekizumab and guselkumab was compared across 700 patients with psoriasis in a prospective, multicentre cohort study using data from the BioCAPTURE registry⁸³. In this cohort, >30% had psoriatic arthritis, and ~62% were biologic-naive.

Based on PASI 90 and PASI75 data (correcting for baseline PASI, biologic naivety and weight), results indicated⁸³:

• Patients treated with adalimumab, ustekinumab, secukinumab, ixekizumab or guselkumab had significantly higher overall odds of reaching PASI90 than those treated with etanercept
• Patients treated with ixekizumab or guselkumab also had higher probabilities of reaching PASI90 than those treated with adalimumab, ustekinumab or secukinumab

The authors concluded that ixekizumab and guselkumab showed high effectiveness in daily practice, whereas etanercept appeared to be least effective⁸³.

In this cohort study based on BioCAPTURE Registry data, a 90% reduction in baseline PASI was reached less often in this real-world population with TNF-α, IL-17, IL-12/23 and IL-23 inhibitors than that expected based on results from randomised controlled trials⁸³

Comparative drug survival

In real-world studies, drug survival (i.e. the probability of remaining on therapy) is often used as a proxy measure for effectivess⁸⁴. It reflects the time from initiation to discontinuation of a treatment, and helps to predict the likelihood of a patient remaining on a specific treatment¹¹⁰.

Numerous real-world drug survival studies have demonstrated biologic-naive patients are more likely to have an adequate response to treatment, and have higher drug survival when compared with biologic-experienced patients⁸⁴.

In patients with psoriasis, drug survival rates at one year and after four years were 69% and 47% respectively for adalimumab, and 82% and 56% for ustekinumab⁸⁴. Drug survival for IL-17 inhibitors ixekizumab, guselkumab and secukinumab has been reported as 75%, 80% and 76%, respectively, after one year, and can vary with biologic experience⁸⁴.

In a retrospective, multi-country study of 4,187 patients with psoriasis, the cumulative probability of drug survival for both IL-17 and IL-23 inhibitors was higher than 75% at 24 months, and IL-23 inhibitors had the highest drug survival rates during the entire study period¹¹⁰

Risankizumab and guselkumab demonstrated overall cumulative probabilities of ≥90%, and the likelihood of discontinuation was lower for isankizumab, guselkumab and ixekizumab, compared with secukinumab¹¹⁰. Predictors for drug discontinuation included the type of biologic, prior exposure to biologic agents, higher baseline body mass index (BMI) and PASI values, and absence of family history of psoriasis¹¹⁰.

However, it has been suggested that drug survival may not be sufficiently captured if other indicators of relative treatment failure (e.g. dose escalation) are not reflected⁸⁴. An analysis of the Danish DERMBIO registry included dose escalation or drug discontinuation in their measure of biologic drug survival in patients with psoriasis during the first 3 years of treatment⁸⁴. Results indicated ⁸⁴:

• secukinumab was associated with the lowest risk of the composite endpoint of either off-label dose escalation or discontinuation, compared with ustekinumab and adalimumab
• a lower risk of this composite endpoint in biologic-naive versus biologic-experienced patients

Read about the place in therapy of psoriasis treatments

Explore effective treatment selection in psoriasis

Refresh your knowledge on European and US guidelines for psoriasis