Key clinical-trial evidence for secukinumab

Introduction

In January 2015, the US Food and Drug Administration (FDA) approved secukinumab (Cosentyx™, Novartis, USA) for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.

The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorisation for secukinumab.

Secukinumab is a human IgG1 monoclonal antibody that selectively binds to the cytokine interleukin-17A (IL-17A) inhibiting its pro-inflammatory effects.

IL-17A is a key cytokine (messenger protein) involved in the development of plaque psoriasis and is found in high concentrations in psoriasis plaques.

The approval of secukinumab is based on the efficacy and safety outcomes from 10 Phase II and III studies which included over 3,990 patients with moderate-to-severe plaque psoriasis. These trials included four pivotal Phase III trials, ERASURE, FIXTURE, FEATURE and JUNCTURE studies detailed below.

ERASURE study – efficacy

• ERASURE (Efficacy of Response And Safety of two fixed secUkinumab REgimens in psoriasis) was a randomised, double-blind, placebo-controlled, multicentre, parallel-group phase III study involving 738 patients with moderate-to-severe plaque psoriasis poorly controlled with topical treatments, phototherapy, systemic therapy (methotrexate, acitretin, ciclosporin), or a combination of these therapies [1].
• All patients were followed up to 52 weeks after the first administration of study medication.
• The objective of the study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area–and–severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5–point modified investigator's global assessment scale.
• Key secondary efficacy objectives in the ERASURE study were to determine the superiority of secukinumab over placebo with respect to the proportion of patients who met the criteria for a reduction of 90% or more in the PASI score from baseline at week 12 (PASI 90); the superiority of secukinumab over placebo with respect to patient-reported psoriasis-related itching, pain, and scaling on the Psoriasis Symptom Diary at week 12; maintenance of PASI 75 from week 12 through week 52; and maintenance of a response of 0 or 1 on the modified investigator's global assessment from week 12 through week 52.
• Authors randomly assigned 738 patients to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks up until week 48) or placebo.
• Secukinumab was shown to be superior to placebo with respect to all the coprimary and key secondary end points (P< 0.001 vs placebo).
• Table 1 summarises the efficacy endpoints in the ERASURE study.

Safety — ERASURE study

• The most common adverse events in the induction period (week 1–12) and the entire treatment period (week 1–52) in this study were nasopharyngitis, headache, and upper respiratory tract infection.
• Adverse events from baseline to 12 weeks are summarised in Table 2.

FIXTURE study – efficacy

• FIXTURE (the Full year Investigative eXamination of secukinumab vs. eTanercept Using 2 dosing Regimens to determine Efficacy in psoriasis) was a randomised, double-blind, placebo and active-controlled, multicentre, parallel-group phase III study involving 1306 patients with moderate-to-severe plaque psoriasis [1].
• Patients randomly assigned to secukinumab received either two 150-mg subcutaneous secukinumab injections (i.e.300 mg total) or one 150-mg injection plus one placebo injection, with both injections administered once weekly at baseline and at weeks 1, 2, 3, and 4 and then every 4 weeks until week 48.
• Patients randomly assigned to etanercept received 50 mg administered subcutaneously twice weekly from baseline until week 12 and then once weekly through week 51, in accordance with the standard dosing regimen.
• The placebo group received placebo injections corresponding to the secukinumab and the etanercept regimens, and the secukinumab and etanercept groups received placebo injections corresponding to the other active-drug regimen, in order to maintain a double-dummy design.
• The objective in the FIXTURE study was to assess the superiority of secukinumab over placebo with respect to the coprimary efficacy endpoints of PASI 75 and a response of 0 or 1 on the modified investigator's global assessment at week 12.
• The key secondary objectives in the FIXTURE study included assessments of the superiority of secukinumab over placebo with respect to the proportion of patients who met the criteria for PASI 90 at week 12; the superiority of secukinumab over etanercept with respect to the proportion of patients who met the criteria for PASI 75 at week 12.
• Efficacy endpoints (at week 12) in FIXTURE are summarised in Table 3.

Safety – FIXTURE study

The most common adverse reactions (occurring in > 2% of patients) at week 12 are summarised in table 4.

FEATURE study

• FEATURE (First study of sEcukinumAb in prefilled syringes in subjecTs with chronic plaqUe-type psoriasis REsponse) was a randomised double-blind, placebo-controlled, multicentre, phase III study involving 177 subjects with moderate-to-severe plaque psoriasis [2].
• In this study, prefilled syringes (PFS) were introduced into the secukinumab clinical programme.
• 59 patients were randomised to secukinumab 300 mg, 59 to secukinumab 150 mg, and 59 to placebo.
• Subjects received subcutaneous treatment at Weeks 0, 1, 2, 3, and 4, followed by the same dose every 4 weeks for up to 12 weeks total.
• Safety, tolerability, and usability of secukinumab self-administration via prefilled syringe were assessed after 12 weeks.
• The endpoints were the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline to week 12 and treatment success (clear or almost clear) on the Investigator’s Global Assessment modified 2011 (IGA).
• Patients successfully self-administered treatment and reported high SIAQ (Self-Injection Assessment Questionnaire) -assessed acceptability of the pre-filled syringe throughout the trial.
• Efficacy results (at week 12) are summarised in Table 5.

Adverse reactions that occurred at a higher incidence (> 2%) in secukinumab-treated patients vs placebo through to week 12 included nasopharyngitis, diarrhoea and upper respiratory tract infections.

JUNCTURE study

• JUNCTURE (Judging the efficacy of secUkinumab in patients with psoriasis using autoiNjector: a Clinical Trial evalUating treatment REsults) was a double-blind, placebo-controlled, multicentre, phase III study involving 182 subjects with moderate-to-severe plaque psoriasis [3].
• In this study, the autoinjector/pen (AI) was introduced into the secukinumab clinical program.
• 60 patients were randomised to secukinumab 300 mg, 61 to secukinumab 150 mg, and 61 to placebo.
• Patients received subcutaneous secukinumab at weeks 0, 1, 2, 3, and 4, followed by the same dose every 4 weeks for up to 12 weeks.
• Safety, tolerability, and usability of secukinumab self-administration via Sensoready pen for 12 weeks were assessed.
• The endpoints were the proportion of subjects who achieved a reduction in PASI score of at least 75% (PASI 75) from baseline to week 12 and treatment success (clear or almost clear) on the Investigator’s Global Assessment modified 2011 (IGA).
• All subjects successfully self-administered treatment without critical use-related hazards.
• Subject acceptability of autoinjector was high throughout 12 weeks.
• Efficacy results (at week 12) are summarised in Table 6.

Adverse reactions that occurred at a higher incidence (> 2%) in secukinumab-treated patients vs placebo through to week 12 included nasopharyngitis, diarrhoea and upper respiratory tract infections.

Efficacy of secukinumab — real-world analysis

Non-trial data are needed in the efficacy and safety of secukinumab in routine clinical practice as most trial protocols prohibit concomitant psoriasis medication and specify transition periods.

The effectiveness and safety of secukinumab in the context of previous and concomitant treatments was assessed in the PROSPECT study [4]. This study is an ongoing 24-week single cohort non-interventional study which included 1988 patients with moderate to severe psoriasis receiving secukinumab 300 mg.

Mean baseline Psoriasis Area and Severity Index (PASI) score was 17.7±12.5. 90.9% of subjects had prior systemic treatment. Concomitant treatment was recorded in 44.3% of subjects. The median duration of the transition period was 14.0, 30.0, and 44.5 days from prior topical, conventional systemic, and biologic treatments. At Week 24 PASI75/90/100 was reached by 86.1%, 68.5%, and 39.7% of subjects who started secukinumab treatment at baseline. No unexpected safety signals were observed.

The safety and effectiveness of secukinumab were similar to that observed in the phase III clinical trial programme.

Guselkumab vs secukinumab — ECLIPSE study

In this phase 3, multicentre, double-blind, randomised, comparator-controlled trial [5] at 142 outpatient clinical sites in nine countries, eligible patients were randomly assigned to receive either guselkumab (100 mg at weeks 0 and 4 then every 8 weeks; n =534) or secukinumab (300 mg at weeks 0, 1, 2, 3, and 4, and then every 4 weeks; n = 514).

The primary objective of this study was to show the superiority of clinical response at week 48 for guselkumab versus secukinumab.

The proportion of patients with a PASI 90 response at week 48 was greater in the guselkumab group (451 [84%]) than in the secukinumab group (360 [70%]; p < 0·0001).

However, no superiority was shown in favour of secukinumab for the major secondary endpoint of PASI 75 at both weeks 12 and 48.

Proportions of patients with adverse events, infections, and serious adverse events were similar between the two treatments and, in general, safety findings were consistent with registrational trial observations.

Ustekinumab vs secukinumab - CLEAR study — long term sustained efficacy

The CLEAR study [6] was a phase 3b, head-to-head, randomised, double-blind study on the efficacy and safety of secukinumab compared with ustekinumab over 52 weeks of treatment in adult patients with moderate-to-severe psoriasis.

Among 676 randomised subjects, secukinumab demonstrated superiority to ustekinumab at week 52 in the proportion of subjects with ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) (76% vs 61% [P < .0001]); PASI 100 responses were 46% versus 36% (P = .0103) and Investigator's Global Assessment responses of clear/almost clear skin were 80% versus 65% (P < .0001). Subjects on secukinumab reported greater reductions in psoriasis-related pain, itching, and scaling, and greater improvement across all quality-of-life measures evaluated (Dermatology Life Quality Index [DLQI], EuroQoL 5-Dimension Health Questionnaire, Work Productivity and Activity Impairment Questionnaire-Psoriasis, and Health Assessment Questionnaire-Disability Index). The safety profile of secukinumab was comparable to that of ustekinumab.

In the long term sustained efficacy study, patients from the secukinumab arm who completed 52 weeks of treatment and consented to continue in an open-label extension phase received secukinumab 300 mg at week 52, followed by dosing every 4 weeks to week 100.

303 patients entered the extension phase and 277 patients completed the 2-year extension study.

Psoriasis Area and Severity Index 75 (89.6%), 90 (74.7%), and 100 (47.4%), and Investigator's Global Assessment 2011 modified version 0/1 response rates (68.8%) with secukinumab were sustained up to year 2. A similar trend was seen for the Dermatology Life Quality Index 0/1 response and the mean scores for patient assessment of psoriasis-related pain, itching, and scaling severity up to year 2 of secukinumab treatment. A high proportion of patients achieved complete relief (score 0) of psoriasis-related pain, itching, and scaling sustained up to year 2.

Sub-group analysis – CLEAR study

The 52-week results from the CLEAR study [6] showed high and superior efficacy of secukinumab versus ustekinumab in clearing skin and improving patient-reported outcomes, with a comparable safety profile in subjects with moderate to severe psoriasis.

Similar to the core study, secukinumab showed sustained and superior efficacy with faster response versus ustekinumab, and no new or unexpected safety concerns in Asian subjects with moderate to severe plaque psoriasis [7].

Secukinumab — efficacy in palmoplantar psoriasis

The GESTURE study [8] investigated the long-term (2·5 year) safety and efficacy of subcutaneous secukinumab 150 and 300 mg in 205 subjects with moderate-to-severe palmoplantar psoriasis (ppPsO).

The primary endpoint of the Palmo Plantar Investigator’s Global Assessment was sustained over 2·5 years with 59·2% (95% CI: 43·5-74·1) and 52·5% (35·1-69·6) of subjects in the secukinumab 300 and 150 mg groups, respectively, achieving clear or almost clear palms and soles (ppIGA 0/1).

At 2·5 years, the mean palmoplantar Psoriasis Area and Severity Index was reduced with both secukinumab 300 mg (-74·7%) and 150 mg (-61·6%).

The safety profile was favourable and similar to previous studies.

Above results were also confirmed in the 2PRECISE study [9] which was a phase 3b multicentre, randomised, double-blind, placebo-controlled, parallel-group study comparing treatment with 300 mg of secukinumab (n = 79), 150 mg of secukinumab (n = 80), and placebo (n = 78) in subjects with moderate-to-severe palmoplantar psoriasis over a period of 52 weeks. Patients with PPP who were treated with secukinumab, 300 mg, showed benefit in terms of Palmo Plantar Area Severity Index75 responses over 52 weeks and improved quality of life.

Secukinumab — efficacy in scalp psoriasis

In this 24-week, double-blind, phase 3b study [10], 102 patients with scalp psoriasis were randomised 1:1 to subcutaneous secukinumab 300 mg or placebo at baseline, weeks 1, 2, and 3, and then every 4 weeks from week 4 to 20. The primary efficacy variable was 90% improvement of Psoriasis Scalp Severity Index (PSSI) score from baseline to week 12.

At week 12, PSSI 90 (secukinumab 300 mg vs placebo, 52.9% vs 2.0%) and Investigator's Global Assessment modified 2011 scalp responses of 0 or 1 (secukinumab 300 mg vs placebo, 56.9% vs 5.9%) were significantly greater with secukinumab 300 mg than placebo (p < 0.001 for both).

The median time to 50% reduction in PSSI score was 3.29 weeks with secukinumab 300 mg. The safety profile of secukinumab was consistent with the previous phase 3 studies.

One of the study limitations was that there was no active comparator arm.

Secukinumab — efficacy in nail psoriasis

The TRANSFIGURE trial [11] assessed the superiority of secukinumab over placebo in clearing nail psoriasis as assessed by the Nail Psoriasis Severity Index (NAPSI) at week 16 and over time, up to week 132.

In this double-blind, randomised, placebo-controlled study in patients with moderate-to-severe plaque and nail psoriasis, the primary objective of NAPSI was met with both doses of secukinumab which was superior to placebo at week 16 (NAPSI improvements of -45·3%, -37·9% and -10·8% for secukinumab 300 mg and 150 mg and placebo, respectively, p < 0·001).

Significant improvements were seen in patients' quality of life: the NAPPA (Nail Assessment in Psoriasis and Psoriatic Arthritis )-Quality of Life total score median decreases at week 16 were 60·9%, 49·9% and 15·8% for secukinumab 300 mg and 150 mg and placebo, respectively (p < 0·001). Improvement in nail psoriasis continued to week 32. The most common adverse events were nasopharyngitis, headache and upper respiratory tract infections.

Future directions for secukinumab

• The results of these phase 3 studies validate interleukin-17A as an important therapeutic target in moderate-to-severe plaque psoriasis.
• Responses at week 12 were sustained in the majority of patients through to week 52 with continued secukinumab therapy every 4 weeks.
• The FIXTURE study showed the superior efficacy of secukinumab over the TNF inhibitor etanercept over a period of 52 weeks.
• The incidences of adverse events in the secukinumab groups during induction (baseline to 12 weeks) and the entire 52-week treatment period in the FIXTURE study were similar to the incidence with etanercept.
• However, the incidences of adverse events, notably infectious adverse events, were higher in the secukinumab groups than in the placebo group.
• Continued vigilance with respect to the potential for candida infection will be necessary for patients undergoing treatment with interleukin-17A inhibitors.