Key evidence from clinical trials for secukinumab

Introduction

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

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has recommended the marketing authorization of secukinumab.

Secukinumab is a human IgG1 monoclonal antibody that selectively binds to the cytokine interleukin-17A (IL-17A) by 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. plates.

The approval of secukinumab is based on the effectiveness and safety results from 10 Phase II and III studies that included more than 3,990 patients with moderate to severe plaque psoriasis. These trials included four pivotal Phase III trials, ERASURE, FIXTURE, FEATURE, and JUNCTURE, detailed below.

ERASURE study - efficacy

• ERASURE (Ukinumab REgimens Fixed Two Second Safety and Response Efficiency in Psoriasis) was randomized, double-blind, placebocontrolled, multicenter, phase III parallel group study of 738 patients with poorly controlled moderate to severe plaque psoriasis with current treatments, phototherapy, systemic therapy (methotrexate, acitretin, cyclosporine), or a combination of these therapies [1].
• All patients were followed up for 52 weeks after the first administration of study medication.
• The aim 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 than base in Psoriasis Severity and Area Index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator global assessment scale.
• The key secondary efficacy endpoints 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 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 itching climbing in psoriasis Symptom Daily at week 12; maintenance of PASI 75 from week 12 to week 52; and maintenance of a response of 0 or 1 on the modified investigator's global assessment from week 12 to week 52.
• The authors randomized 738 patients to subcutaneous secukinumab at a dose of 300 mg or 150 mg (given once weekly for 5 weeks, then every 4 weeks until week 48) or placebo.
• Secukinumab was shown to be higher placebo with respect to all key co-primary and secondary end points (P <0.001 vs placebo).
• Table 1 summarizes the efficacy endpoints in the ERASURE study.

Security - 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 summarized in Table 2.

Fixation study - efficacy

• FIXTURE (Full Year Round Investigation Review of secukinumab versus eTanercept using 2 dosing regimens to determine efficacy in psoriasis) was a randomized, double-blind, placebo, active-controlled, multicenter, phase III, parallel group study involving to 1306 patients with moderate to very severe plaque psoriasis [1].
• Patients randomized to secukinumab received either two 150 mg subcutaneous injections of secukinumab (i.e. 300 mg total) or one 150 mg injection plus one injection of placebo, with both injections given once weekly at baseline and within weeks 1, 2, 3, and 4 and then every 4 weeks until week 48.
• Patients randomized to etanercept received 50 mg administered subcutaneously twice weekly from baseline through week 12 and then once weekly through week 51, according to the standard dosing regimen.
• The placebo group received placebo injections corresponding to the secukinumab and etanercept regimens, and the secukinumab and etanercept groups received placebo injections corresponding to the other active drug regimen, to maintain a double dummy design.
• The objective in the FIXTURE study was to assess the superiority of secukinumab over placebo with respect to PASI 75 co-primary efficacy endpoints and a response of 0 or 1 on the modified investigator global assessment at week 12.
• Key secondary endpoints in the FIXTURE study included evaluations 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 PASI 75 criteria at week 12.
• Efficacy endpoints (at week 12) in FIXTURE are summarized in Table 3.

Security - FIXTURE study

The most common Adverse reactions (in> 2% of patients) at week 12 are summarized in Table 4.

CHARACTERISTICS Study

• CHARACTERISTIC (First study of sEcukinumAb in prefilled syringes in subjects with chronic plaque-type psoriasis (response) was a randomized, double-blind, placebo-controlled, multicenter, phase III study that enrolled 177 subjects with moderate to severe plaque psoriasis [2].
• In this study, prefilled syringes (PFS) were introduced into the secukinumab clinical program.
• 59 patients were randomized 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 a total of up to 12 weeks.
• The safety, tolerability, and usability of secukinumab self-administration via a pre-filled syringe were evaluated after 12 weeks.
• End points 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) in the 2011 Modified Investigator's Global Assessment. (IGA).
• Patients were successfully self-administered and reported high acceptability of the pre-filled syringe according to the SIAQ (self-injection assessment questionnaire) throughout the trial.
• The efficacy results (at week 12) are summarized in Table 5.

Adverse reactions that occurred at a higher incidence (> 2%) in patients treated with secukinumab versus placebo up to week 12 included nasopharyngitis, diarrhea, and upper respiratory tract infections.

JUNCTURE study

• JUNCTURE (Judging the Efficacy of secUkinumab in Psoriasis Patients Using Autoinjector: A Clinical Trial Evaluating Treatment Outcomes) was a phase III, double-blind, placebo-controlled, multicentre study involving 182 subjects with plaque psoriasis. moderate to severe [3].
• In this study, the autoinjector / pen (AI) was introduced into the secukinumab clinical program.
• 60 patients were randomized 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.
• The safety, tolerability and usability of secukinumab self-administration via Sensoready pen for 12 weeks were evaluated.
• End points 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) in the 2011 Modified Investigator's Global Assessment. (IGA).
• All subjects were successfully self-administered with no critical hazards related to use.
• Subject acceptability of the autoinjector was high for 12 weeks.
• The efficacy results (at week 12) are summarized in Table 6.

Adverse reactions that occurred with a higher incidence (> 2%) in patients treated with secukinumab versus placebo up to week 12 included nasopharyngitis, diarrhea, and upper respiratory tract infections.

Secukinumab Efficacy - Real World Analysis

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

The PROSPECT study evaluated the effectiveness and safety of secukinumab in the context of previous and concomitant treatments. [4]. This study is an ongoing 24-week simple cohort non-interventional study that included 1988 patients with moderate to severe psoriasis who received 300 mg of secukinumab.

The mean psoriasis area severity index and severity index (PASI) score was 17.7 ± 12.5. The 90.9% of the subjects had previous systemic treatment. Concomitant treatment was recorded in 44.3% of the subjects. The median duration of the transition period was 14.0, 30.0 and 44.5 days from previous conventional topical, systemic and biological treatments. PASI75 / 90/100 was achieved at week 24 in 86.1%, 68.5%, and 39.7% of the subjects who began treatment with secukinumab at baseline. No unexpected safety signs were observed.

The safety and efficacy of secukinumab were similar to those seen in the phase III clinical trial program.

Guselkumab vs secukinumab - ECLIPSE study

In this phase 3, multicenter, double-blind, randomized, comparator-controlled trial [5] at 142 outpatient clinical sites in nine countries, eligible patients were randomized to receive guselkumab (100 mg at weeks 0 and 4 and 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 main objective of this study was to show the superiority of the clinical response at week 48 for guselkumab versus secukinumab.

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

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

The proportions of patients with adverse events, infections and serious adverse events were similar between the two treatments and, in general, the safety results were consistent with the observations from the registry trials.

Ustekinumab vs secukinumab - CLEAR study - long-term sustained efficacy

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

Among 676 randomized 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] ); The PASI 100 responses were 46% versus 36% (P = .0103) and the Investigator Global Assessment responses of fair / almost fair skin were 80% versus 65% (P <.0001). Subjects receiving secukinumab reported greater reductions in psoriasis-related pain, itching, and scaling, and greater improvement in all assessed quality of life measures (Dermatologic Quality of Life Index [[DLQI], 5-dimensional EuroQoL 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 in the secukinumab arm who completed 52 weeks of treatment and consented to continue for a open the extension phase received secukinumab 300 mg at week 52, followed by dosing every 4 weeks at week 100.

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

The psoriasis area and severity index 75 (89.6%), 90 (74.7%) and 100 (47.4%), and the response rates of Investigator's Global Assessment 2011 version 0/1 modified (68.8%) with secukinumab were maintained through year 2. A A similar trend was observed for the 0/1 response of the dermatology quality of life index and mean scores for the patient's assessment of psoriasis-related pain, itching, and scale severity up to year 2 of secukinumab treatment. A high proportion of patients achieved complete relief (score 0) of sustained psoriasis-related pain, itching, and scaling through year 2.

Subgroup analysis: CLARO study

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

Similar to the central study, secukinumab showed sustained and superior efficacy with a faster response versus ustekinumab, and there were 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 years) safety and efficacy of subcutaneous secukinumab 150 and 300 mg in 205 subjects with moderate to severe palmoplantar psoriasis (ppPsO).

Palmo's primary end point Plant Investigator Global Assessment was maintained for 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 groups mg, respectively, achieving clear or almost clear palms and soles (ppIGA 0/1).

At 2 to 5 years, the mean palmoplantar psoriasis area and severity index were reduced with both secukinumab 300 mg (-74 · 7%) and 150 mg (-61 · 6%).

The safety profile was favorable and similar to previous studies.

The above results were also confirmed in study 2PRECISE [9] which was a multicenter, randomized, double-blind, placebo-controlled, parallel group phase 3b study comparing treatment with 300 mg of secukinumab (n = 79), 150 mg 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 Palmo75 plantar area severity index responses for 52 weeks and improved quality of life.

Secukinumab: efficacy in psoriasis of the scalp

In this 24-week, double-blind phase 3b study [10], 102 patients with scalp psoriasis were randomized 1: 1 to 300 mg of subcutaneous secukinumab or placebo at baseline, weeks 1, 2, and 3, and then every 4 weeks from week 4 to 20. The primary efficacy endpoint was an improvement in the psoriasis 90% 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 changed the 2011 scalp responses to 0 or 1 (secukinumab 300 mg vs. placebo, 56.9% vs 5.9%) were significantly higher 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 previous phase 3 studies.

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

Secukinumab: efficacy in nail psoriasis

The TRANSFIGURE trial [11] evaluated 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, through week 132.

In this double-blind, randomized, placebo-controlled study in patients with moderate to severe nail and plaque psoriasis, the primary goal of NAPSI was met with both doses of secukinumab, which was superior to placebo at week 16 (NAPSI improvements of -453%, -379% and -108% for secukinumab 300 mg and 150 mg and placebo, respectively, P <0 · 001).

Significant improvements were observed in the quality of life of the patients: the NAPPA (Evaluation of nails in psoriasis and psoriatic). Arthritis ) -The mean decrease in total quality of life score at week 16 was 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 through 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 maintained in most patients through week 52 with continuous therapy with secukinumab every 4 weeks.
• The FIXTURE study showed the superior efficacy of secukinumab over the TNF inhibitor etanercept over a period of 52 weeks.
• The incidence of adverse events in the secukinumab groups during induction (baseline up to 12 weeks) and the full treatment period of 52 weeks in the FIXTURE study were similar to the incidence with etanercept.
• However, the incidence of adverse events, especially infectious adverse events, were higher in the secukinumab groups than in the placebo group.
• Continuous surveillance for the potential for candida infection will be necessary for patients undergoing treatment with interleukin-17A inhibitors.