Reimbursement Review

Secukinumab (Cosentyx)

Sponsor: Novartis Pharmaceuticals Canada Inc.

Therapeutic area: Hidradenitis suppurativa

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

Submission Update Provided by the Sponsor Dated April 24, 2024

The review of secukinumab was accepted as a pre–Notice of Compliance submission and the Clinical Report was initially drafted based on the draft product monograph. In consideration of the revisions included in the final product monograph, specifically the indication and dosage and administration sections for hidradenitis suppurativa (HS) (summarized in Table 1), additional information relevant to the updated product monograph was extracted from the SUNSHINE and SUNRISE studies (collectively referred to as the SUNNY trials) and the indirect treatment comparison (ITC) submitted by the sponsor. This included results on the comparison between the secukinumab 300 mg every 4 weeks dosage group versus placebo from the SUNNY trials and versus adalimumab from the ITC for the outcomes of interest to this review.

Table 1: Summary of the Revisions to the Product Monograph of Secukinumab

Note: Notice of Compliance was issued on May 17, 2024.

Source: Product monograph for secukinumab.¹

Systematic Review Evidence on the Monthly Maintenance Dose of Secukinumab

Detailed outcome data to address the revisions made to the product monograph are presented in Appendix 2.

Results

Sixteen-Week Placebo-Controlled Treatment Period 1

Overall, the direction of treatment effect based on the key efficacy results was consistent between the biweekly and monthly maintenance dosing of secukinumab versus placebo. Statistical significance cannot be claimed for the primary analysis results at week 16 for the abscesses and inflammatory nodules (AN) count and at least a 30% reduction and at least a 2-unit reduction from baseline in skin pain at its worst as measured by a numerical rating scale (NRS30 skin pain response) at week 16, despite the P value being less than 0.005, from the SUNSHINE trial for the secukinumab monthly maintenance dosage group versus placebo because the result for the primary end point (at least a 50% decrease in AN count with no increase in the number of abscesses and/or in the number of draining fistulas [HiSCR50 response]), which was a prior end point in the testing hierarchy, was not statistically significant. Results for these end points should be considered as supportive evidence. Overall, no notable differences in the frequency of adverse events (AEs) between the study drug groups were identified in each study.

Entire Study Period

The entire study period consisted of a 16-week placebo-controlled treatment period (treatment period 1), a 36-week treatment period (treatment period 2), and an 8-week follow-up. The results at week 52 were noncomparative and presented descriptively. Overall, the direction of treatment effect based on the key efficacy results was consistent between the biweekly and monthly maintenance dosing of secukinumab. Additionally, no notable differences in the frequency of AEs between the study drug groups were identified in each study.

Critical Appraisal

In general, no notable differences in the study population between the 3 study drug groups (i.e., secukinumab 300 mg every 2 weeks, secukinumab 300 mg every 4 weeks, and placebo) was identified in each study. As such, the limitations discussed for the primary and exploratory efficacy analyses at week 16 and week 52 of the biweekly maintenance dosing are applicable to the corresponding analyses of the monthly maintenance dosing. Overall, no concerns of serious risk of bias and no major issues with the generalizability of the results to the target population and Canadian practice were identified in the appraisal of the SUNNY trials. Notably, there was no active or placebo comparator group for the assessments made at week 52. As such, the ability to draw causal conclusions about the 52-week results is limited because the noncomparative design does not facilitate distinguishing between the effect of treatment, placebo effects, and natural history.

Network Meta-Analyses on the Monthly Maintenance Dose of Secukinumab

Detailed outcome data to address the revisions made to the product monograph are presented in Appendix 2.

The primary evidence network was informed by 4 studies (PIONEER 1, PIONEER 2, SUNSHINE, and SUNRISE) and was limited to patients who were biologic-naive. All results were based on the induction phase of the trials (12 to 16 weeks). Overall, the results for the secukinumab every 4 weeks dosage group were similar to the secukinumab every 2 weeks dosage group. The findings for the secukinumab every 4 weeks dosage group were inconclusive, showing 95% credible intervals (CrIs) that were wide and included the null for secukinumab versus adalimumab in biologic-naive patients. The results of the sensitivity analyses that included biologic-naive and biologic-experienced patients were also inconclusive. These analyses shared the same limitations as discussed for the secukinumab every 2 weeks comparison in the indirect evidence section of this report.

Pharmacoeconomic Review on the Monthly Maintenance Dose of Secukinumab

Economic Impact

The economic review compared secukinumab 300 mg every 2 weeks with standard of care and adalimumab. At the committee meeting, it was noted that the comparison with adalimumab was more relevant, and this informed the pricing condition. As no robust evidence was provided that indicated secukinumab produced better health outcomes than adalimumab, the pricing condition was: “Secukinumab should be negotiated so that it does not exceed the drug program cost of treatment with the least costly form of adalimumab reimbursed for the treatment of HS.” This statement is not unique to 2-week dosing. The same pricing condition would apply to the new draft monograph, which also allows for 4-week dosing, unless the committee felt the 4-week dose would result in better or worse health outcomes for patients relative to adalimumab.

Budget Impact

The budget impact analysis (BIA) was conducted assuming twice-weekly dosing. If dosing every 4 weeks were implemented, this would reduce the drug costs associated with secukinumab and therefore lower the BIA. However, it is unclear how many patients would be placed on this dosing schedule and how many would remain on this schedule. It is also uncertain whether a less frequent dose schedule would increase the size of the market of patients willing to try a biologic; if so, this would increase the budget impact. Overall, there was considerable uncertainty around the size of the original BIA, with the estimate by Canada’s Drug Agency (CDA-AMC) being substantially lower than the sponsor’s submitted BIA (CDA-AMC 3-year BIA: $9,547,349; sponsor-submitted 3-year BIA: $76,542,993). As such, a reimbursement condition was added to the recommendation text stating that uncertainty associated with the BIA must be addressed (refer to reimbursement condition 10). The presence of a different dosing schedule would further increase the uncertainty associated with the BIA.

Executive Summary Before Submission Update

The following report reflects the draft product monograph before the aforementioned revisions were made, hence the focus on the maintenance dose of 300 mg of secukinumab administered every 2 weeks, unless otherwise specified.

An overview of the submission details for the drug under review is provided in Table 2.

Table 2: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

^aSecukinumab (Cosentyx) 75 mg/0.5 mL solution for injection is not applicable to the indication for hidradenitis suppurativa.

^bThe single-use vial is not available in Canada.

Introduction

HS is a chronic, debilitating skin condition characterized by abscesses that lead to tissue destruction and scarring on the skin, particularly in the skin folds such as the axillae, groin, and perineum.^2,3 HS is thought to involve a combination of factors, including immune and endocrine dysregulation, genetics, and bacterial infection.^4-10 Key symptoms of HS are pain, itch, malodorous discharge, burning sensations, and local warmth.^2,11 The onset of HS typically occurs after puberty, mostly occurring in the second or third decade of life.¹² The estimated prevalence of HS in North America and Europe is approximately 1% of the population.^13-17 A study of patients with HS living in Canada suggested that approximately 44% of patients have stage 2 disease and 12% of patients have stage 3 disease.¹⁸

The clinical experts consulted by CDA-AMC for this review indicated that systemic antibiotics are the first-line systemic therapies in the treatment of HS. The experts indicated that tetracyclines are the most commonly utilized antibiotic class, with prescriptions for doxycycline and tetracycline exceeding those for minocycline. The experts further indicated that clindamycin combined with rifampin and IV ertapenem are used much less frequently than tetracyclines. In general, the North American clinical management guidelines for HS¹⁹ (published in 2019) indicate that systemic antibiotics are used as adjunctive therapy in advanced disease because they result in lower response rates and increased recurrence. The experts indicated that patients with moderate to severe HS that has not responded to systemic antibiotic therapy would be eligible for adalimumab, the only biologic therapy currently approved by Health Canada for use in HS. This is aligned with the guidelines,¹⁹ which advise on treatment with adalimumab in patients with moderate to severe disease. Other biologics that are not approved for use in HS but are discussed in the guidelines¹⁹ for the treatment of moderate to severe HS include infliximab, anakinra, and ustekinumab. The experts indicated that topical therapy that has resulted in a partial response in a patient with moderate to severe HS may be continued as adjunct therapy before starting systemic therapy. More specifically, the guidelines¹⁹ reference treatment with topical clindamycin and resorcinol.

When considering the unmet need in HS, the clinician group, Canadian Hidradenitis Suppurativa Foundation, which provided input for this review, and the experts indicated that not all patients experience a response to the currently available treatment options, including adalimumab. The clinician group and the experts also agreed that HS becomes refractory to systemic therapies, including adalimumab, and up-dosing of adalimumab is common to maintain response in clinical practice. The clinician group also indicated that the current management options for HS are not effective in inducing remission.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of secukinumab 150 mg/1 mL and 300 mg/2 mL solution by subcutaneous (SC) injection in the treatment of HS in adult patients with moderate to severe HS.

Note that secukinumab was previously reviewed by CADTH for psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.

Patient Group and Clinician Group Perspectives

The information in this section is a summary of input provided by the patient and clinician groups who responded to our call for input and from the clinical experts consulted by CDA-AMC for the purpose of this review.

Patient Input

The Canadian Skin Patient Alliance, HS Heroes, and Hidradenitis and Me Support Group collaboratively provided input for this review. Patient input was gathered from the results of a survey (N = 547) published in the 2020 National Report of Patients’ Experiences Living with Hidradenitis Suppurativa and a patient survey hosted by the patient groups from March 28 to May 23, 2023 (N = 15). Of note, 4 patients from the 2023 patient survey reported prior experience with secukinumab. All respondents indicated their HS lesions are chronic, with the majority being active lesions.

More than 80% of respondents to the 2020 survey reported HS negatively impacted their work performance, social interactions, and intimacy with their partner. Respondents to the 2020 survey reported being worried about odour, staining of clothes, and the unpredictable onset of painful disease flares. Nearly all respondents to the 2020 survey reported experiencing some degree of moderate pain daily; only 11% of survey respondents considered their pain to be well controlled and 46% considered their pain to be poorly controlled. Similarly, respondents to the 2023 survey reported that HS has a severe impact (drainage, severe pain, and lesions) on their day-to-day life. Respondents to the 2023 survey highlighted the high costs associated with wound care and treatment for HS and the high level of anxiety and irritation due to living with HS. When considering unmet needs, 1 respondent to the 2020 survey described their experience with HS as “so painful, so disgusting, and so life-altering.”

In the 2020 survey, respondents reported trying an average of 15 different medications, surgical procedures, home treatments, and lifestyle modifications to manage symptoms, with only a few reporting any significant improvement. Eighty-two percent of survey respondents reported receiving a long course of antibiotics, with 11% reporting improvement in symptoms. Twenty-seven percent of survey respondents reported using biologics, with 38% reporting symptomatic improvement. Other treatments reported by the survey respondents were corticosteroid injections, carbon dioxide lasers, radiotherapy, incision and drainage, and surgical intervention. Overall, 13% of survey respondents reported satisfaction with their current treatments. Respondents reported the following side effects with currently available treatments: back pain, headache, intestinal problems, and fatigue.

The main treatment goals described by the 2020 survey respondents were to achieve symptom control, cure HS, and be able to enjoy personal relationships. Moreover, based on input from the patient groups, patients expressed that they would derive emotional, physical, and daily life benefits with effective therapy. While describing their experience with the current drug under review, 2 of 4 respondents indicated secukinumab to be effective in reducing HS lesions, pain, and the need for wound care. One respondent reported achieving complete resolution of HS lesions and disease remission, while 1 reported treatment discontinuation due to ineffectiveness.

Clinician Input

Input From Clinical Experts Consulted by CDA-AMC

The clinical experts indicated that not all patients respond to currently available treatment options, including adalimumab. The experts estimated that 40% to 60% of patients would experience a partial response to adalimumab and 20% of patients experience a good response to adalimumab. The experts also indicated that HS becomes refractory to systemic therapies, including adalimumab. The experts anticipated secukinumab to be an alternative to adalimumab as a second-line systemic drug used after the failure of systemic antibiotics. The experts anticipated secukinumab would be offered to patients with HS that has not responded to, developed AEs to, or have contraindications to adalimumab. The experts indicated that secukinumab can be offered as the patient’s first biologic therapy. As such, the experts concluded that it may cause a slight shift in the current treatment paradigm. According to the experts, the patient population best suited for treatment with secukinumab are patients with moderate to severe HS that has not responded to systemic antibiotic therapy or antibiotic therapy and adalimumab and who are eligible for adalimumab (i.e., as an alternative to adalimumab).

The experts identified the following as outcomes used in clinical practice to assess response to treatment: lesion count (abscess, nodule, and fistula), pain scale, number of sites involved, extent of disease, and patient-reported outcomes such as the Dermatology Life Quality Index (DLQI), activities of daily living, and health-related quality of life (HRQoL). The experts highlighted the importance of the number of sites involved — a reduction in lesion count with new sites of involvement would likely be interpreted by the patient as treatment failure. The experts indicated that outcomes are typically assessed every 3 to 6 months. When deciding to discontinue treatment with secukinumab, the experts indicated they would consider the following: disease progression, less than 50% improvement after 6 months of treatment, and severe AEs related to secukinumab, such as severe inflammatory bowel disease.

Clinician Group Input

One clinician group, Canadian Hidradenitis Suppurativa Foundation, provided input for this review, with 2 clinicians contributing to this input. When considering unmet needs, the clinician group indicated that current management options are not able to completely control the disease and are not effective in inducing remission; furthermore, some patients may lose benefit with treatment. The clinician group further indicated that a higher dose of the medication (i.e., adalimumab) may be required in patients with severe disease to maintain efficacy. The clinician group noted that adalimumab is the only biologic option approved in Canada for the treatment of HS. According to the clinician group, off-label alternative biologics include infliximab, ustekinumab, interleukin (IL) 17 (IL-17) inhibitors, and IL-1 inhibitors; however, these alternative treatments are offered to patients depending on coverage and compassionate programs.

The clinician group suggested that secukinumab may be an alternative treatment option for patients who would have not demonstrated efficacy with the current standard of care (i.e., secukinumab should be offered as a biologic alternative when treatment with systemic antibiotics after 12 weeks have failed). When considering patients who would be best suited for treatment with the drug under review, the clinician group identified patients with moderate to severe HS (i.e., Hurley stage 2 and 3).

To determine response to treatment, the clinician group suggested achievement of a 50% reduction in abscesses and sinuses with no new lesions after initiation of therapy with secukinumab. The clinician group further suggested patient-reported outcomes, such as pain, odour, and drainage management, as alternative outcome measures.

Drug Program Input

Input was obtained from the drug programs that participate in the Reimbursement Review process. The following items were identified as key factors that could potentially impact the implementation of a CDA-AMC recommendation for secukinumab:

• relevant comparators

• consideration for initiation of therapy

• consideration for continuation or renewal of therapy

• consideration for prescribing of therapy

• generalizability

• care provision issues

• system and economic issues.

The clinical experts consulted by CDA-AMC provided advice on the potential implementation issues raised by the drug programs (Table 5).

Clinical Evidence

Systematic Review

Description of Studies

Two phase III, randomized, double-blind, placebo-controlled, parallel-group trials, SUNSHINE (N = 541) and SUNRISE (N = 543), assessed whether 2 SC secukinumab dose regimens improved HiSCR50 response from baseline compared with placebo after 16 weeks of treatment in adult patients (≥ 18 years) with moderate to severe HS. The outcomes measured in the trials and selected for a Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment were response to treatment and disease severity (HiSCR50 and AN count), disease worsening (patients experiencing flares), symptoms (NRS30 skin pain), HRQoL (DLQI and EQ-5D health state assessment), and notable harms (infections and infestations; candida infections; malignant or unspecified tumours; neoplasms benign, malignant, or unspecified, including cysts and polyps; squamous cell carcinoma of an HS-affected area; and inflammatory bowel disease). Baseline characteristics were generally similar between groups and across trials. Across trials, the mean age of patients ranged from 35.5 years (SD = 10.75) in the placebo group in the SUNSHINE trial to 37.3 years (standard deviation [SD] = 11.48) in the secukinumab group in the SUNRISE trial. At baseline, most patients were categorized with Hurley stage 2 disease severity, ranging from 51.1% of patients (92 of 180) in the secukinumab group in the SUNRISE trial to 67.2% of patients (121 of 180) in the placebo group in the SUNSHINE trial, across trials. At baseline, patients with Hurley stage 3 disease severity ranged from 28.3% of patients (51 of 180) in the placebo group in the SUNSHINE trial to 45.6% (82 of 180 patients) in the secukinumab group in the SUNRISE trial, across trials. The proportions of patients with 1 to 11 anatomic regions with at least 1 fistula, inflammatory nodule, or abscess were generally well balanced between groups and across trials. The mean baseline AN count across trials ranged from 12.8 (SD = 8.15) in the placebo group in the SUNSHINE trial to 13.9 (SD = 9.93) in the secukinumab group in the SUNRISE trial.

Note that 2 different dose regimens were assessed in both trials; however, only the maintenance dose of 300 mg of secukinumab administered every 2 weeks is included in the Health Canada indication. Therefore, only the results of the dose regimen of every 2 weeks are summarized in this report.

Efficacy Results

Response to Treatment and Disease Severity

Hidradenitis Suppurativa Clinical Response

Both the SUNSHINE and SUNRISE studies met the primary end point, achievement of HiSCR50 response at week 16, for the secukinumab 300 mg every 2 weeks dose regimen. In the SUNSHINE trial, the marginal risk difference in HiSCR50 response at week 16 between secukinumab and placebo was █████ (96% confidence interval [CI], ████ ██ █████) (odds ratio [OR] = 1.75; 96% CI, ████ ██ ████; P value = 0.0070), in favour of secukinumab. In the SUNRISE trial, the marginal risk difference in HiSCR50 response at week 16 between secukinumab and placebo was █████ (96% CI, ████ ██ █████) (OR = 1.64; 96% CI, ████ ██ ████; P value = 0.0149), also in favour of secukinumab. The sensitivity analysis, supplementary analysis, and tipping point analysis results for HiSCR50 response at week 16 were generally consistent with and supportive of the primary analysis results for the secukinumab 300 mg every 2 weeks dose regimen in both studies. The results of the subgroup analysis by the key subgroups (concomitant antibiotic use, body weight stratum, previous use of systemic biologics, Hurley stage, and baseline AN count) are generally consistent with the primary analysis, with the exception of the results experienced by patients with Hurley stage 1 in the SUNRISE trial.

The proportion of patients achieving an HiSCR50 response observed at week 52 was an exploratory end point in both studies. In the SUNSHINE trial, █████ (██ of 117 patients; 95% CI, █████ ██ █████) in the secukinumab group and █████ (██ of 58 patients; 95% CI, █████ ██ █████) in the placebo-to-secukinumab group achieved HiSCR50 response at week 52. In the SUNRISE trial, █████ (██ of 137 patients; 95% CI, █████ ██ █████) in the secukinumab group and █████ (██ of 64 patients; 95% CI, █████ ██ █████) in the placebo-to-secukinumab group achieved HiSCR50 response at week 52.

Abscesses and Inflammatory Nodules Count

Both the SUNSHINE and SUNRISE studies met the secondary end point, percentage change from baseline in AN count at week 16, for the secukinumab 300 mg every 2 weeks dose regimen; this secondary end point was tested in a hierarchical manner to control for type I error rate. In the SUNSHINE trial, the least squares (LS) mean difference in percentage change from baseline in AN count at week 16 between secukinumab and placebo was −23.05 (96% CI, ██████ ██ ██████; P < 0.0001), in favour of secukinumab. In the SUNRISE trial, the LS mean difference in percentage change from baseline in AN count at week 16 between secukinumab and placebo was −16.33 (96% CI, ██████ ██ █████; P = 0.0051), also in favour of secukinumab. The sensitivity analysis and tipping point analysis results for AN count at week 16 were generally consistent with and supportive of the primary analysis results for the secukinumab 300 mg every 2 weeks dose regimen in both studies.

The percentage change from baseline in AN count observed at week 52 was an exploratory end point in both studies. In the SUNSHINE trial, the mean percentage change from baseline in AN count at week 52 was █████ (95% CI, █████ ██ █████) in the secukinumab group and █████ (95% CI, █████ ██ █████) in the placebo-to-secukinumab group. In the SUNRISE trial, the mean percentage change from baseline in AN count at week 52 was █████ (95% CI, █████ ██ █████) in the secukinumab group and █████ (95% CI, ████ ██ █████) in the placebo-to-secukinumab group.

Remission

Disease remission was not measured in the SUNSHINE and SUNRISE trials.

Disease Worsening

Flare

Only the SUNSHINE study met the secondary end point, experience of any flares at week 16, for the secukinumab 300 mg every 2 weeks dose regimen; this secondary end point was tested in a hierarchical manner to control for type I error. In the SUNSHINE trial, the marginal risk difference in flares at week 16 between secukinumab and placebo was ██████ (96% CI, ██████ ██ █████) (OR = 0.42; 96% CI, ████ ██ ████; P value = 0.0010), in favour of secukinumab. In the SUNRISE trial, the marginal risk difference in flares at week 16 between secukinumab and placebo was █████ (96% CI, ██████ ██ ████) (OR = 0.68; 96% CI, ████ ██ ████; P value = 0.0732). The sensitivity analysis and tipping point analysis results of flares at week 16 were generally consistent with and supportive of the primary analysis results for secukinumab 300 mg every 2 weeks dose regimen in both studies.

The proportion of patients experiencing any flares observed at week 52 was an exploratory end point in both studies. In the SUNSHINE trial, █████ (██ of 138 patients; 95% CI, █████ ██ █████) in the secukinumab group and █████ (██ of 65 patients; 95% CI, █████ ██ █████) in the placebo-to-secukinumab group experienced any flares at week 52. In the SUNRISE trial, █████ (██ of 151 patients; 95% CI, █████ ██ █████) in the secukinumab group and █████ (██ of 67 patients; 95% CI, █████ ██ █████) in the placebo-to-secukinumab group experienced any flares at week 52.

Symptoms

Skin Pain

The secondary end point, achievement of NRS30 (reduction in skin pain at its worst) at week 16, for the secukinumab 300 mg every 2 weeks dose regimen was met based on pooled data from the SUNSHINE and SUNRISE studies in patients with a baseline numerical rating scale (NRS) score of 3 or more; this secondary end point was tested in a hierarchical manner to control for type I error. The marginal risk difference in NRS30 at week 16 between secukinumab and placebo was █████ (96% CI, ████ ██ █████) (OR = ████; 96% CI, ████ ██ ████; P value = 0.0003), in favour of secukinumab. The tipping point analysis results of NRS30 at week 16 were supportive of the primary analysis results for secukinumab 300 mg every 2 weeks dose regimen in both studies.

The proportion of patients achieving NRS30 observed at week 52 was an exploratory end point based on pooled data from both trials in patients with baseline NRS of 3 or more. Based on the pooled data, █████ (███ of ███ patients) (95% CI, █████ ██ █████) in the secukinumab group and █████ (██ of ██ patients) (95% CI, █████ ██ █████) in the placebo-to-secukinumab group achieved NRS30 at week 52.

Health-Related Quality of Life

Dermatology Life Quality Index

The proportion of patients achieving DLQI response observed at week 16 was an exploratory end point in both studies. In the SUNSHINE trial, the risk difference in DLQI response at week 16 between secukinumab and placebo was ██████ (95% CI, █████ ██ ██████) (OR = ████; 95% CI, ████ ██ ████; P value = ██████). In the SUNRISE trial, the risk difference in DLQI response at week 16 between secukinumab and placebo was █████ (95% CI, ██████ ██ ██████) (OR = ████; 95% CI, ████ ██ ████; P value = ██████).

The proportion of patients with a DLQI response observed at week 52 was an exploratory end point in both studies. In the SUNSHINE trial, 51.0% (49 of 96 patients; 95% CI, █████ ██ █████) in the secukinumab group and 50.0% (25 of 50 patients; 95% CI, █████ ██ █████) in the placebo-to-secukinumab group achieved DLQI response at week 52. In the SUNRISE trial, 55.2% (64 of 116 patients; 95% CI, █████ ██ █████) in the secukinumab group and 47.5% of patients (29 of 61; 95% CI, █████ ██ █████) in the placebo-to-secukinumab group achieved DLQI response at week 52.

The change from baseline in DLQI total score observed at week 16 was an exploratory end point in both studies. In the SUNSHINE trial, the mean difference in absolute change from baseline in DLQI total score at week 16 between secukinumab and placebo was ████ (95% CI, ████ ██ ████). In the SUNRISE trial, the mean difference in absolute change from baseline in DLQI total score at week 16 between secukinumab and placebo was ████ (95% CI, ████ ██ ████).

The change from baseline in DLQI total score observed at week 52 was an exploratory end point in both studies. In the SUNSHINE trial, the mean absolute change from baseline in DLQI total score at week 52 was ████ (95% CI, ████ ██ ████) in the secukinumab group and ████ (95% CI, ████ ██ ████) in the placebo-to-secukinumab group. In the SUNRISE trial, the mean absolute change from baseline in DLQI total score at week 52 was ████ (95% CI, ████ ██ ████) in the secukinumab group and ████ (95% CI, ████ ██ ████) in the placebo-to-secukinumab group.

EQ-5D Health State Assessment (Visual Analogue Scale)

The change from baseline in the EQ-5D health state assessment visual analogue scale (EQ VAS) observed at week 16 was an exploratory end point in both studies. In the SUNSHINE trial, the mean difference in absolute change from baseline in the EQ VAS score at week 16 between secukinumab and placebo was ███ (95% CI, ████ ██ ███). In the SUNRISE trial, the mean difference in absolute change from baseline in the EQ VAS score at week 16 between secukinumab and placebo was ███ (95% CI, ███ ██ ████).

The change from baseline in the EQ VAS score observed at week 52 was an exploratory end point in both studies. In the SUNSHINE trial, the mean absolute change from baseline in the EQ VAS score at week 52 was ███ (95% CI, ███ ██ ████) in the secukinumab group and ███ (95% CI, ███ ██ ████) in the placebo-to-secukinumab group. In the SUNRISE trial, the mean absolute change from baseline in the EQ VAS score at week 52 was ████ (95% CI, ███ ██ ████) in the secukinumab group and ███ (95% CI, ████ ██ ███) in the placebo-to-secukinumab group.

Harms Results

Adverse Events

In treatment period 1, the proportion of patients with any AE was generally similar between groups and across trials, ranging from 62.8% of patients (113 of 180) in the secukinumab group in the SUNRISE trial to 67.4% of patients (122 of 181) in the secukinumab group in the SUNSHINE trial.

The most common AEs (frequency ≥ 5% in any group) reported in the SUNSHINE trial were nasopharyngitis (11.0% [20 of 181 patients] in the secukinumab group compared with 7.2% [13 of 180 patients] in the placebo group), headache (9.4% [17 patients] compared with 7.8% [14 patients], respectively), hidradenitis (6.1% [11 patients] compared with 13.3% [24 patients], respectively), and diarrhea (2.8% [5 patients] compared with 5.0% [9 patients], respectively).

The most common AEs (frequency ≥ 5% in any group) reported in the SUNRISE trial were headache (11.7% [21 of 180 patients] in secukinumab group compared with 8.2% [15 of 183 patients] in placebo group), nasopharyngitis (7.2% [13 patients] compared with 8.7% [16 patients], respectively), hidradenitis (5.6% [10 patients] compared with 7.7% [14 patients], respectively), upper respiratory tract infection (5.0% [9 patients] compared with 3.8% [7 patients], respectively), and diarrhea (4.4% [8 patients] compared with 7.1% [13 patients], respectively).

In the entire study period, the proportion of patients with any AE continued to be generally similar across trials, ranging from 80.1% (209 of 261 patients) in the any-secukinumab group in the SUNRISE trial to 85.1% (154 of 181 patients) in the secukinumab group in the SUNSHINE trial. The most common AEs (frequency ≥ 10% in any group) reported in both trials were headache, nasopharyngitis, and hidradenitis.

Serious Adverse Events

In treatment period 1, the proportion of patients with any serious adverse event (SAE) was generally similar between groups and across trials, ranging from 1.7% (3 of 181 patients) in the secukinumab group to 3.3% (6 of 180 patients) in the placebo group in the SUNSHINE trial. The most common SAE (frequency ≥ 1% in any group in both trials) reported was hidradenitis in 0.6% (1 of 181 patients) in the secukinumab group and 1.1% (2 of 180 patients) in the placebo group in the SUNSHINE trial, and 0.6% (1 of 180 patients) in the secukinumab group and no patients in the placebo group in the SUNRISE trial.

In the entire study period, the proportion of patients with any SAE was generally similar across trials, ranging from 6.8% (18 of 266 patients) in the any-secukinumab group in the SUNSHINE trial to 10.6% (19 of 180 patients) in the secukinumab group in the SUNRISE trial. In both trials, the most common SAE (frequency ≥ 1% in any group) reported was hidradenitis, reported in 1.7% (3 of 181 patients) in the secukinumab group and 1.5% (4 of 266 patients) in the any-secukinumab group in the SUNSHINE trial, and 2.2% (4 of 180 patients) in the secukinumab group and 1.9% (5 of 261 patients) in the any-secukinumab group in the SUNRISE trial. In the SUNRISE trial, 2 SAEs, acute kidney injury and pyrexia, were reported in 1.1% (2 of 180 patients) in the secukinumab group and 0.8% (2 of 261 patients) in the any-secukinumab group.

Withdrawals Due to Adverse Events

In treatment period 1, the proportion of patients who stopped treatment due to any AE was generally similar between groups and across trials, ranging from 0.6% (1 of 180 patients) in the placebo group to 2.8% (5 of 181 patients) in the secukinumab group in the SUNSHINE trial. No AE that led to treatment discontinuation was reported in 1% or more of patients in any group in either the SUNSHINE or SUNRISE trial.

In the entire study period, the proportion of patients who stopped treatment due to any AE was generally similar across trials, ranging from 3.4% (9 of 261 patients) in the any-secukinumab group in the SUNRISE trial to 5.5% (10 of 181 patients) in the secukinumab group in the SUNSHINE trial. Similar to treatment period 1, no AE that led to treatment discontinuation was reported in 1% or more of patients in any group in either trial.

Mortality

In treatment period 1 and the entire study period, no deaths were reported in either trial.

Notable Harms

In general, AEs of special interest (notable harms) were similar between the secukinumab and placebo groups and across trials in treatment period 1. For infections and infestations (system organ class [SOC]), the risk difference was ████ (95% CI, █████ ██ ████) in the SUNSHINE trial and █████ (95% CI, █████ ██ ████) in the SUNRISE trial. For candida infections (high-level term [HLT]), the risk difference was █████ (95% CI, █████ ██ ████) in the SUNSHINE trial and ████ (95% CI, █████ ██ ████) in the SUNRISE trial. For malignant and unspecified tumour (Standardised MedDRA [Medical Dictionary for Regulatory Activities] Query [SMQ]), the risk difference was █████ (95% CI, █████ ██ ████) in the SUNSHINE trial and █████ (95% CI, █████ ██ ████) in the SUNRISE trial. For neoplasms benign, malignant, and unspecified (including cysts and polyps), the risk difference was █████ (95% CI, █████ ██ ████) in the SUNSHINE trial and █████ (95% CI, █████ ██ ████) in the SUNRISE trial. In treatment period 1, no patients were reported with squamous cell carcinoma of an HS-affected area or inflammatory bowel disease.

In the entire study period, patients with any notable harms continued to be generally similar across trials. Patients reported with infections and infestations (SOC) ranged from 51.7% (93 of 180 patients) in the secukinumab group in the SUNRISE trial to 58.6% of patients (106 of 181) in the secukinumab group in the SUNSHINE trial. Patients reported with candida infections (HLT) ranged from 5.4% of patients (14 of 261) in the any-secukinumab group to 6.7% (12 of 180 patients) in the secukinumab group in the SUNRISE trial. The proportion of patients reported with a malignant or unspecified tumour (SMQ) or neoplasm (benign, malignant, or unspecified, including cysts and polyps) was less than 5% of patients in each group for both trials. Similar to treatment period 1, no patients were reported with squamous cell carcinoma of an HS-affected area or inflammatory bowel disease in the entire study period.

Critical Appraisal

The SUNSHINE and SUNRISE trials were randomized, double-blind, and placebo-controlled. Randomization was stratified by region, concomitant antibiotic use, and body weight. The proportions of patients with the relevant medical history and disease characteristics (effect modifiers) at baseline were generally well balanced between the secukinumab and placebo groups in both trials. There were slightly more patients with Hurley stage 3 disease in the secukinumab group versus placebo. The experts indicated that Hurley stage 3 disease is more severe and difficult to treat and, as such, potential bias against secukinumab may have been introduced in analyses that were unadjusted for this characteristic; however, the magnitude is unclear and could be small. Of note, there was no active or placebo comparator group for the assessments made at week 52 and, as such, the ability to draw definitive conclusions about the 52-week results is limited due to the potential for confounding.

A statistical testing strategy was implemented in both trials to control for type I error rate at the level of the individual studies and at the level of the pooled dataset of both studies. Exploratory end point analyses, including DLQI, EQ-5D health state assessment, and efficacy outcomes at week 52 were not adjusted for multiple comparisons and are therefore at an increased risk of false-positive results. Subgroup analyses were not adjusted for multiple testing; moreover, the ability to draw definitive conclusions about the results is limited because of the relatively small sample size of most subgroups.

There is evidence in the literature to support the measurement properties of HiSCR^20,21 as a measure of response to treatment and the clinical importance of HiSCR50 in patients with HS.^20,22 There is also evidence in the literature to support the validity of the patient-reported outcomes, NRS30,²³ DLQI,²⁴ and EQ-5D health state assessment,²⁵ as a measure of skin pain and HRQoL in patients with HS. Furthermore, there is evidence to support the clinical importance of NRS30 skin pain (albeit only a 30% threshold was suggested and not in patients with HS)^26-28 and DLQI response (estimated minimal important difference [MID] of 5 points in patients with HS)²² as defined in the trials. Note that an MID in the EQ-5D health state assessment has not been estimated in patients with HS.

According to the experts, the inclusion and exclusion criteria used in the trials were considered standard in HS. Although some potential candidates for treatment (identified by the experts) were excluded from the trials, the experts indicated the results would likely be applicable in those patients (e.g., patients with fewer than 5 inflammatory lesions). The experts agreed that the criteria for the use of rescue therapy and the options for rescue therapy used in the trials generally reflected clinical practice. According to the feedback from the experts, aside from minocycline, which is used less commonly in practice in Canada, the concomitant use of antibiotics in the antibiotic strata and nonopioid analgesics in the trials was consistent with clinical practice and aligned with the guidelines.^19,29 Although topical antibiotic therapy was prohibited in the trials, the experts anticipated that patients would continue topical antibiotic therapy while on treatment with secukinumab if they had previously experienced a partial response to the topical antibiotic therapy.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For the pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform the expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group.^30,31

For RCTs: Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

For single arms of trials (not presented in the summary of findings table): Although GRADE guidance is not available for noncomparative studies, the CDA-AMC review team assessed the noncomparative (52 weeks) outcomes for study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias to present these important considerations. Because the lack of a comparator arm does not allow for a conclusion to be drawn on the effect of the intervention versus any comparator, the certainty of evidence for single-arm trials started at very low certainty with no opportunity for rating up.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The reference points for the certainty of evidence assessment for HiSCR50 response, AN count, flares, NRS30 skin pain, DLQI response, and EQ-5D health state assessment was set according to the presence or absence of an important effect based on thresholds informed by the clinical experts consulted for this review. The reference point for the certainty of evidence assessment for DLQI total score was set according to the presence or absence of an important effect based on the threshold identified in the literature. The reference points for the certainty of evidence assessment for notable harms was set according to the presence or absence of an important effect based on thresholds informed by the clinical experts.

For the GRADE assessments, findings from the SUNSHINE and SUNRISE studies were considered together and summarized narratively per outcome because these studies were similar in population, interventions, design, and outcome measures.

The selection of outcomes for GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with clinical experts, and the input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• Response to treatment and disease severity: HiSCR50 and AN count

• Disease worsening: Flares

• Symptoms: NRS30 skin pain

• HRQoL: DLQI and EQ-5D health state assessment

• Notable harms: Infections and infestations; candida infections; malignant or unspecified tumours; neoplasms (benign, malignant, or unspecified, including cysts and polyps); squamous cell carcinoma of an HS-affected area; and inflammatory bowel disease.

Results of GRADE Assessments

Secukinumab Versus Placebo

Table 3 presents the GRADE summary of findings for secukinumab 300 mg every 2 weeks versus placebo as well as secukinumab 300 mg every 4 weeks versus placebo. Note that the data presented in the table on GRADE summary of findings are based on data provided by the sponsor following the submission update dated April 24, 2024 (details in Appendix 2).

Table 3: Summary of Findings for Secukinumab Versus Placebo for Patients With Hidradenitis Suppurativa

AN = abscesses and inflammatory nodules; CDA-AMC = Canada’s Drug Agency; CI = confidence interval; DLQI = Dermatology Life Quality Index; HiSCR = Hidradenitis Suppurativa Clinical Response; HRQoL = health-related quality of life; HS = hidradenitis suppurativa; LS = least squares; NA = not applicable; NMQ = SMQ, narrow; NRS = numeric rating scale; NRS30 = at least a 30% reduction and at least a 2-unit reduction from baseline in skin pain at its worst as measured by a numerical rating scale; OR = odds ratio; PT = preferred term; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; RCT = randomized controlled trial; RR = risk ratio; SMQ = Standardised MedDRA Query; SOC = system organ class.

Notes: Data presented in this table are based on data provided by the sponsor following the April 24, 2024, submission update (details in Appendix 2).

Study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

Applicable to all outcomes of importance in this table: Although some potential candidates for treatment with secukinumab were excluded from the SUNNY trials, in consultation with the 2 clinical experts consulted by CDA-AMC for the purpose of this review, it was concluded that the results are likely generalizable to those patients and, as such, the review team did not rate down for indirectness.

Applicable to the primary and secondary end points in the SUNNY trials: The analysis of the secondary end point (flares at week 16) on the secukinumab q.2.w. dosing group failed to meet statistical significance in the statistical hierarchy in the SUNRISE trial. The analysis of the primary end point, HiSCR50 response at week 16, on the secukinumab q.4.w. dosing group failed to meet statistical significance in the statistical hierarchy in the SUNSHINE trial and, as such, all subsequent tests of the secondary end points were considered not statistically significant. These can be considered as supportive evidence only.

Applicable to the patient-reported outcomes (NRS30 skin pain and HRQoL measures) — analysis of these outcomes was not adjusted for multiplicity and as such, results are considered supportive evidence. Although the outcome measures were subjective, in consideration of the low rates of discontinuation and the double-blind trial design, did not rate down for risk of bias.

Applicable to outcomes for which the analysis did not adjust for Hurley stage (DLQI total score and EQ-5D health state assessment [VAS score]) — in consideration of the small baseline imbalance in Hurley stage 3 (effect modifier identified by the clinical experts) between groups, did not rate down for risk of bias.

^aRated down 1 level for serious imprecision; data from both trials show secukinumab may provide benefit or little-to-no benefit, based on a conservative threshold of 100 more per 1,000 patients (50 to 100 per 1,000 was suggested by clinical experts).

^bRated down 1 level for serious inconsistency; although the 99% CIs are largely overlapping, there is large variability in the point estimates where SUNSHINE suggests little-to-no important difference while SUNRISE suggests a clinically important benefit. Rated down 1 level for serious imprecision; data from both trials show secukinumab may provide benefit or little-to-no benefit based on a conservative threshold of 100 more per 1,000 patients (50 to 100 per 1,000 was suggested by clinical experts). Although the boundaries of the 99% CIs least favourable to the intervention include the possibility of harm, it was concluded that it did not considerably cross the null (i.e., not a substantial harm); therefore, imprecision was rated down by 1 level only.

^cRated down 1 level for serious imprecision; data from both trials show secukinumab may provide benefit or little-to-no benefit based on a conservative threshold of 10% difference (5% to 10% difference was suggested by clinical experts).

^dRated down 1 level for serious inconsistency; although the 96% CIs are largely overlapping, there is large variability in the point estimates; where SUNSHINE suggest a clinically important benefit while SUNRISE suggest little-to-no difference. Rated down 1 level for serious imprecision. Data from both trials show secukinumab may provide benefit or little-to-no benefit, based on a conservative threshold of 100 less per 1,000 patients (50 to 100 per 1,000 was suggested by clinical experts).

^eDid not rate down for inconsistency; although there is some variability in the point estimates, the 99% CIs are largely overlapping and the following concerns in imprecision that led to the rating down of the level of certainty in the evidence was felt to sufficiently reflect the level of certainty in the evidence. Rated down 2 levels for very serious imprecision; based on a conservative threshold of 100 less per 1,000 patients (50 to 100 per 1,000 was suggested by clinical experts), data from the trials show secukinumab may provide benefit or little-to-no benefit and includes the possibility of harm. The boundary of the 99% CI least favourable to the intervention includes the possibility of harm and it was concluded that it did considerably cross the null (i.e., a substantial harm); therefore, imprecision was rated down by 2 levels.

^fRated down 1 level for serious imprecision. Data from the pooled results show secukinumab may provide benefit or little-to-no benefit, based on a conservative threshold of 100 more per 1,000 patients (50 to 100 per 1,000 was suggested by clinical experts).

^gRated down 1 level for serious imprecision; data from the trials show secukinumab may provide benefit or little-to-no benefit based on a conservative threshold of 50 more per 1,000 patients (as suggested by clinical experts).

^hData from the trials show secukinumab may provide benefit based on a conservative threshold of 50 more per 1,000 patients (as suggested by clinical experts).

ⁱA treatment difference of at least 5 points is considered clinically meaningful (based on literature findings and aligned with clinical expert input); data from both trials show secukinumab may provide a trivial (or no) effect.

^jRated down 1 level for serious inconsistency. Minimal overlap of the 95% CIs was considered. Rated down 1 level for serious imprecision. Based on a conservative threshold of 5 points (as suggested by clinical experts), data from both trials show secukinumab may provide benefit or little-to-no benefit.

^kRated down 1 level for serious imprecision. Based on a conservative threshold of 5 points (as suggested by clinical experts), data from both trials show secukinumab may provide benefit or little-to-no-benefit.

^lIn the absence of a threshold for clinical importance, the null was used. Rated down 2 levels for very serious imprecision. Based on the null, data from both trials show secukinumab may provide benefit and harm.

^mIn the absence of a threshold for clinical importance, the null was used. Rated down 2 levels for very serious imprecision. There are very few events; ratio of the upper to the lower bound of the 95% CIs associated with the relative risk from both trials are greater than 3.0; therefore, the number of events is likely far from meeting the optimal information size.³²

ⁿIn the absence of a threshold for clinical importance, the null was used. Rated down 1 level for serious indirectness. Follow-up was not sufficiently long to observe events. Rated down 2 levels for very serious imprecision. Few or no events were observed because of insufficient follow-up.

^oIn the absence of a threshold for clinical importance, the null was used. Rated down 1 level for serious indirectness. Follow-up was not sufficiently long to observe events. Rated down 2 levels for very serious imprecision. Few or no events were observed because of insufficient follow-up. The ratio of the upper to the lower bound of the 95% CI associated with the relative risk from the trial is greater than 3.0; therefore, the number of events is likely far from meeting the optimal information size.³²

Sources: SUNSHINE Clinical Study Report,³³ SUNRISE Clinical Study Report,³⁴ and sponsor response to requests on June 19, 2023, July 5, 2023, and May 22, 2024, from CDA-AMC for additional information regarding the secukinumab review.^35-37

Long-Term Extension Study

The extension study, NCT04179175, assessing the effects of noninterrupted versus interrupted and long-term treatment of 2 dose regimes of secukinumab in patients with HS was ongoing and no results were available at the time of this report.³⁸

Indirect Comparisons

Description of Studies

The sponsor submitted a network meta-analysis (NMA) that assessed the short-term efficacy (12 to 16 weeks) of secukinumab versus adalimumab for the treatment of adults with moderate to severe HS. The base-case Bayesian NMA was informed by 4 RCTs and limited to patients who were biologic-naive (N = 1,462).

Efficacy Results

For secukinumab 300 mg every 2 weeks versus adalimumab 40 mg weekly, the results of the NMA were inconclusive, showing 95% CrIs that were wide and included the null for HiSCR50, skin pain NRS30 response, the proportion of patients with flares or who achieved a DLQI score of 0 or 1. The change from baseline in AN count and DLQI total score and the multinomial model that examined HiSCR25, HiSCR50, and HiSCR75 response thresholds (i.e., a decrease of 25%, 50%, or 75%, respectively, in the AN count with no increase in the number of abscesses or draining fistulae compared with baseline) also showed a 95% CrI that included the null. The sensitivity analyses that included biologic-naive and biologic-experienced patients showed similar findings.

Harms Results

No safety end points were analyzed in the NMA.

Critical Appraisal

No major issues were identified by CDA-AMC on the methods used to conduct the systematic review or the statistical methods used in the NMA. The evidence networks were sparse, and the analyses were limited to short-term efficacy outcomes at the end of the induction period. There was heterogeneity present for some patient characteristics (e.g., the distribution of males, smokers, and Hurley stage), as well as study characteristics (treatment duration, definition of NRS30 response, and imputation methods for missing study data). Most effect estimates lacked precision, showing 95% CrIs that included the null. Thus, it is unclear whether secukinumab is superior, inferior, or had comparable efficacy to adalimumab 40 mg once daily. The comparative safety is unknown, as there were no safety end points analyzed in the NMA.

Studies Addressing Gaps in the Evidence From the Systematic Review

No additional studies were submitted by the sponsor for this review.

Conclusion

Collectively, the evidence from the SUNSHINE study (N = 541) and the SUNRISE study (N = 543) (referred to as the SUNNY trials) demonstrated that 16 weeks of treatment with secukinumab 300 mg every 2 weeks (biweekly maintenance dosing) likely results in a clinically meaningful improvement in HS (measured by HiSCR50 response, AN lesion count, and NRS30 skin pain response), and may result in a clinically meaningful decrease in the proportion of patients experiencing flares when compared with placebo in patients aged 18 years and older with moderate to severe HS. Uncertainty in the evidence is primarily because, in all cases, the CIs included the potential that the difference compared with placebo is small and unimportant. Findings for secukinumab 300 mg every 4 weeks (monthly maintenance dosing) were similar, but the certainty of evidence was lower for HiSCR50 response because there was some inconsistency across trials in the magnitude of the effect and statistical significance was not reached in the SUNSHINE trial. Impacts on exploratory HRQoL end points for both dosing regimens were difficult to interpret, as the findings differed based on how the change in DLQI and EQ-5D scores were analyzed. Overall, no serious risk of bias concern and no serious concern about the generalizability of results to the population of interest was identified in the appraisal of the placebo-controlled phase of the trials. The results from the sponsor-conducted NMA were inconclusive for the assessment of short-term efficacy (12 to 16 weeks) of secukinumab (both dose regimens) versus adalimumab, showing 95% CrIs that were wide and included the null for all outcomes tested (HiSCR50, AN count, skin pain, flares, HRQoL). Overall, no new concerns with the harms of secukinumab were identified based on the harms data observed with follow-up at 16 and 52 weeks across the SUNNY trials. In the absence of a comparator group for the 52-week follow-up time point, it is not possible to draw definitive conclusions about the harms (and efficacy) of secukinumab versus any comparator, including placebo.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of secukinumab 150 mg/1 mL and 300 mg/2 mL solution by SC injection in the treatment of HS in adult patients with moderate to severe HS.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical experts input. The following has been summarized and validated by the CDA-AMC review team.

HS is a chronic, debilitating skin condition characterized by abscesses that lead to tissue destruction and scarring on the skin, particularly in the skin folds, such as the axillae, groin, and perineum.^2,3 HS is thought to involve a combination of factors, including immune and endocrine dysregulation, genetics, and bacterial infection.^4-10 Key symptoms of HS are pain, itch, malodorous discharge, burning sensations, and local warmth.^2,11 The pain caused by HS impacts physical functioning and activities of daily living,³⁹ and HS flares impact work and productivity.^40-43 Additionally, HS has a negative impact on emotional and social functioning,^40,44 sexual health,⁴⁵ and the quality of life of patients living in Canada.⁴⁴ HS is associated with comorbidities such as metabolic syndrome, diabetes mellitus, inflammatory bowel disease,^46-48 and anxiety and depression.⁴⁹

Smoking is a risk factor for the development of HS; approximately 90% of patients with HS are smokers,⁵⁰ and smoking is associated with more severe HS presentations compared with nonsmokers.⁸ A meta-analysis investigating the association between current smoking status and HS found there was a 4.2 times higher risk of developing HS in active smokers.⁵¹

The onset of HS typically occurs after puberty, mostly occurring in the second or third decade of life.¹² A survey of patients with HS, including 30% of patients living in Canada, reported an average age of diagnosis of 32 years.⁵² The estimated prevalence of HS in North America and Europe is approximately 1% of the population.^13-17 A study of patients with HS living in Canada suggested that approximately 44% of patients have stage 2 disease and 12% of patients have stage 3 disease.¹⁸

Diagnosis is based on a visual examination of patients and the reporting of symptoms by patients.^53,54 The Dessau criteria are used to diagnose HS by characterizing recurrent, painful, or suppurating nodules that are present on 2 or more occasions within 6 months.⁵⁵ In general, the diagnosis of HS is based on 3 diagnostic criteria: lesion morphology (e.g., nodules, abscesses, or fistulas), distribution of lesions (e.g., axillary, inframammary, or perineal), and chronicity and recurrence (e.g., whether more than 2 lesions are present during a time period of 6 months or more).⁵⁶ Imaging may also be used to confirm the diagnosis and staging of HS; skin ultrasonography and MRI scans can detect specific features of HS.^57-59

The severity of HS is evaluated using the Hurley staging system, which is based on the extent of inflammatory lesions, skin tunnels, and scarring.^60-62 Disease severity is classified into 3 groups: Hurley stage 1 (mild disease typically presenting as inflammatory nodules or abscess formation without sinus tracts and scarring), Hurley stage 2 (moderate disease typically presenting as recurrent abscesses and nodules with sinus tract formation or scarring either as single or multiple widely separated lesions), and Hurley stage 3 (severe and refractory disease typically presenting as diffuse or near-diffuse involvement with multiple interconnected sinus tracts, scarring, and abscesses across an entire area).

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical experts input. The following has been summarized and validated by the CDA-AMC review team.

The clinical experts consulted by CDA-AMC for the purpose of this review identified the following as goals of therapy in HS: reduce active inflammatory lesion count, achieve pain relief (i.e., discontinue opioids, if possible), prevent progression (i.e., absence of disease occurrence in new body areas), reduce need for surgery and improve surgical outcomes (i.e., reduce visits to primary care provider and emergency department), improve quality of life, and improve productivity, if applicable.

The experts indicated that systemic antibiotics are the first-line systemic therapies in the treatment of HS; a 3-month trial is typically required to assess efficacy. The experts indicated that tetracyclines are the most commonly utilized antibiotic class, with prescriptions for doxycycline and tetracycline exceeding those for minocycline. The experts further indicated that clindamycin combined with rifampin and IV ertapenem are used much less frequently than tetracyclines. In general, the North American clinical management guidelines for HS¹⁹ (published in 2019) indicated that systemic antibiotics are used as adjunctive therapy in advanced disease due to lower response rates and increased recurrence. Specific to moderate to severe disease, the guidelines¹⁹ reference treatment with moxifloxacin, metronidazole, and rifampin in combination as second- or third-line therapy. The guidelines¹⁹ note that the duration and frequency of antibiotic use should balance treatment benefit with the risk of antibiotic resistance.

The experts indicated that patients with moderate to severe HS that has not responded to systemic antibiotic therapy would be eligible for adalimumab, the only biologic therapy currently approved by Health Canada for use in HS. This is aligned with the guidelines,¹⁹ which advise on treatment with adalimumab in patients with moderate to severe disease. Note that some adalimumab biosimilars are listed for the indication under review in most jurisdictions in Canada. Other biologics that are not approved for use in HS but are discussed in the guidelines¹⁹ for moderate to severe HS include infliximab, anakinra, and ustekinumab.

The experts further indicated that topical therapy may be continued as adjunct therapy in a patient with moderate to severe HS who has experienced a partial response to the topical therapy before starting systemic therapy. More specifically, the North American clinical management guidelines for HS¹⁹ reference treatment with topical clindamycin and resorcinol; however, they are associated with risk of bacterial resistance and contact dermatitis, respectively.

Additionally, lifestyle modifications and alternative treatments, antibacterial washes, wound care, laser treatment, surgical intervention, immunosuppressants, hormonal therapy, and retinoids in the management of HS; steroid therapy in the management of HS flares; and analgesics in the management of pain due to HS are discussed in the guidelines.^19,29 Of note, the experts indicated that systemic immunosuppressants (i.e., methotrexate, azathioprine, and cyclosporine) and retinoids (i.e., isotretinoin, acitretin, and alitretinoin) are no longer routinely used in practice for HS due to their poor efficacy, and systemic steroids are not suitable for long-term management of HS due to their potential side effects.

Drug Under Review

Key characteristics of secukinumab are summarized in Table 4 with the other treatments available for moderate to severe HS.

Secukinumab is indicated for the treatment of adult patients with moderate to severe HS (acne inversa) who have responded inadequately to conventional systemic HS therapy. The reimbursement request is as per the Health Canada indication. The recommended dose is 300 mg of secukinumab by SC injection with initial dosing at weeks 0, 1, 2, 3, and 4, followed by monthly maintenance dosing (every 4 weeks). Based on clinical response, the maintenance dose can be increased to 300 mg every 2 weeks. Each 300 mg dose is given as 1 SC injection of 300 mg or as 2 SC injections of 150 mg.¹

Secukinumab is a human immunoglobulin G1 kappa monoclonal antibody that selectively binds to IL-17A, a naturally occurring cytokine involved in inflammatory and immune responses. IL-17A is upregulated in HS lesions compared with skin lesions in patients with psoriasis and healthy controls. Secukinumab targets IL-17A, inhibiting the interaction it has with IL-17 receptors, thus inhibiting the release of cytokines and chemokines, which promote inflammation.¹

Note that secukinumab has been previously reviewed by CDA-AMC for psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis.

Table 4: Key Characteristics of Secukinumab and Adalimumab

HS = hidradenitis suppurativa; IgG1 = immunoglobulin G1; IL = interleukin; NYHA = New York Heart Association; TNF = tumour necrosis factor.

^aHealth Canada–approved indication.

Sources: Product monographs for secukinumab and adalimumab.^1,63

Patient Group and Clinician Group Perspectives

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website publicly accessible here.

Patient Group Input

This section was prepared by the CDA-AMC review team based on the input provided by patient groups.

The Canadian Skin Patient Alliance, HS Heroes, and Hidradenitis and Me Support Group collaboratively provided input for this review. Patient input was gathered from the survey results from the 2020 National Report of Patients’ Experiences Living With Hidradenitis Suppurativa and a patient survey hosted by the patient groups from March 28 to May 23, 2023. The 2020 survey gathered responses from 537 individuals with HS, of which 73 (14%) were from Canada, 267 (50%) were from the US, and 67 (12%) were from the UK. The greatest proportion of participants living in Canada were from Ontario (41%), followed by Alberta (18%). In total, the 2023 survey received 15 responses; all respondents were from Canada, with the majority being from Ontario (47%), followed by Alberta (27%). Four patients who responded to the 2023 survey mentioned using secukinumab previously; 1 of these patients mentioned stopping it during treatment because of ineffectiveness.

More than 80% of respondents from the 2020 survey reported that HS negatively impacted their work performance (81%), social interactions, and intimacy with their partner. Patients reported being worried about the odour, staining of clothes, and the unpredictable onset of very painful disease flares. Intimacy and family life were affected by living with HS, as reported by 87% and 68% of survey respondents, respectively. Nearly 70% of respondents reported feelings of depression because of a variety of stressors related to HS. Per the 2020 national report, nearly all patients reported experiencing some degree of moderate pain daily (5.3 on a scale of 10). Only 11% of all respondents considered their pain well controlled, while 46% reported poorly controlled pain. Moreover, 51% of patients reported self-managing with difficulty the process of accessing prescriptions. Respondents from the 2023 survey identified the severe impact of HS on their day-to-day life, including drainage, severe pain, lesions that make it challenging to walk, and challenges to find clothes. The costs of wound care and treatments were reported to be high, as was the high anxiety and irritation from living with HS. All patients reported their HS lesions to be chronic, with the majority of patients constantly having active HS lesions.

Misdiagnosis and delayed diagnosis of HS have been identified as an issue for patients in Canada with HS, often translating into worse symptoms and more advanced disease by the time patients reached the point of being offered a treatment plan. According to a 2020 CPSA report, people living in Canada who responded to a survey reported a median of 7 years from symptom onset to HS diagnosis, and the average age of diagnosis was 30 years. The survey respondents reported facing many unmet needs, and 1 respondent described the condition as “so painful, so disgusting, and so life-altering.”

In the 2020 survey, respondents reported trying an average of 15 different medications, surgical procedures, home treatments, or lifestyle modifications to help manage symptoms, with only a few finding any significant improvement. Fifty-three percent of respondents in Canada reported receiving at least 1 corticosteroid injection, while 18% reported receiving injections more than 10 times. Additionally, 74% reported having at least 1 boil or cyst incised or drained, and 19% reported undergoing this procedure more than 10 times. Moreover, 82% of survey participants reported getting a long course of antibiotics, with 11% reporting improvement in symptoms. Other treatments reported by the respondents were carbon dioxide lasers (26% effective), radiotherapy (33%), incision and drainage (23%), and surgical therapies other than incision and drainage (39%). Only 27% of respondents mentioned using biologics, with 38% reporting symptomatic improvement. Overall, only 13% of respondents reported being satisfied with the current treatments. In addition, less than 35% of respondents reported using available treatments; based on this information, the patient groups suggested that access to and affordability of treatments for HS are challenges that patients face. Back pain, headache, intestinal problems, and fatigue were some of the side effects reported by the respondents regarding currently available treatments.

The main treatment goals described by the 2020 survey participants were to control HS symptoms (90%), cure HS completely (71%), and be able to enjoy personal relationships (69%). Moreover, according to the input from the patient groups, patients expressed that they would derive emotional, physical, and daily life benefits with effective therapy. While describing the experience with the current drug under review, 2 of the 4 patients indicated secukinumab was effective in reducing their HS lesions and pain and decreasing the need for wound care, whereas 1 patient reported having complete resolution of lesions and remission of HS. All patients taking secukinumab reported concerns with the cost of treatment and an inability to afford it.

Clinician Input

Input From the Clinical Experts Consulted by CDA-AMC

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of HS.

Unmet Needs

The experts indicated that not all patients respond to currently available treatment options, including adalimumab; the experts estimated that 40% to 60% of patients would have a partial response to adalimumab and 20% of patients would have a good response to adalimumab. The experts also indicated that HS becomes refractory to systemic therapies, including adalimumab; up-dosing of adalimumab is commonly used to maintain response in clinical practice.

Place in Therapy

The experts suggested it would be reasonable to recommend at least 1 adequate trial of systemic antibiotic therapy before initiating treatment with secukinumab, given the relative cost of antibiotics versus biologics.

The experts anticipated secukinumab being an alternative treatment option to adalimumab as a second-line systemic drug used after the failure of systemic antibiotics. The experts anticipated secukinumab being offered to patients with HS that has not responded to, developed AEs to, or have contraindications to adalimumab. The experts indicated that secukinumab can be offered as the patient’s first biologic therapy. As such, the experts concluded that it may cause a slight shift in the current treatment paradigm.

The experts expected that secukinumab will be used in combination with topical therapies, antiandrogen therapies, intralesional corticosteroids, and deroofing surgery. The experts also expected that patients treated with secukinumab may also receive treatment with systemic antibiotic therapy for flares.

Patient Population

According to the experts, the patient population best suited for treatment with secukinumab are patients with moderate to severe HS that has not responded to systemic antibiotic therapy or antibiotic therapy and adalimumab and who are eligible for adalimumab (i.e., as an alternative to adalimumab).

According to the experts, the patient population least suitable for treatment with secukinumab are patients with mild HS (which would extend beyond the Health Canada indication), no prior experience with systemic therapy, and relative contraindication(s) to IL-17 inhibitors, such as active inflammatory bowel disease, active infection, malignancy, and severe candidiasis.

The experts indicated that HS is a clinical diagnosis made by dermatologists (i.e., diagnostic tests are not required) and misdiagnosis is common before the patient presents to a dermatologist.

Assessing the Response to Treatment

The experts identified the following as outcomes used in clinical practice to assess response to treatment: lesion count (abscess, nodule, and fistula), pain scale, number of sites involved, extent of disease, and patient-reported outcomes such as DLQI, activities of daily living, and HRQoL. The experts indicated that outcomes are typically assessed every 3 to 6 months.

The experts also noted the importance of the number of sites involved, as a reduction in lesion count with new sites of involvement would likely be interpreted as treatment failure by the patient.

Discontinuing Treatment

When deciding to discontinue treatment with secukinumab, the experts indicated they would consider the following: disease progression, less than 50% improvement after 6 months of treatment, and severe AEs related to secukinumab, such as severe inflammatory bowel disease.

Prescribing Considerations

The experts suggested community or home treatment, under the direction of a dermatologist, would be an appropriate setting for treatment with secukinumab.

Clinician Group Input

This section was prepared by the CDA-AMC review team based on the input provided by 1 clinician group.

Clinician group input on the review of secukinumab was received from a Canadian Hidradenitis Suppurativa Foundation group. Two clinicians provided input for this review.

The clinician group mentioned that the management of the disease is currently based on staging. The group also mentioned that adalimumab is the only approved biologic option in Canada. They also added that there are no additional Health Canada–approved options for patients with HS that has not responded to adalimumab. The clinician group pointed out that some off-label alternative biologics, such as infliximab, ustekinumab, IL-17 inhibitors, and IL-1 inhibitors are offered to patients, depending on the availability of extended benefits coverage or compassionate programs. The clinician group further added that current management options are not effective in inducing remission in patients with HS.

While describing treatment gaps or unmet needs, the clinician group noted that current management options are not fully able to control the disease. They also mentioned that for patients with severe disease, higher doses are sometimes required to maintain efficacy despite the initiation of adalimumab, whereas some patients also lose benefits. The clinician group described the role of secukinumab in addressing a different mechanism of action in the pathogenesis of HS, thus providing the clinicians with an alternative treatment option. More specifically, the clinician group suggested that secukinumab may be an alternative treatment option for patients who have not experienced efficacy with the current standard of care (i.e., secukinumab should be offered as a biologic alternative to patients with HS that has not responded to treatment with systemic antibiotics after 12 weeks).

While describing patients who would be best suited for treatment with the drug under review, the clinician group mentioned those with moderate to severe HS (Hurley stage 2 and 3). While mentioning the outcomes that would indicate a response, the clinician group referred to the currently available RCT evidence, suggesting the achievement of a 50% reduction in abscesses and sinuses with no new lesions after initiation of therapy with secukinumab. The group also suggested alternative measures, particularly in the forms of PATIENT-REPORTED outcomes such as pain, odour, and drainage management. The group also suggested that the decision to initiate secukinumab in the management of HS should be decided by a dermatologist.

Drug Program Input

The drug programs provide input on each drug being reviewed through our Reimbursement Review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and the corresponding responses from the clinical experts consulted by CDA-AMC are summarized in Table 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

CDA-AMC = Canada’s Drug Agency; CDEC = Canadian Drug Expert Committee; HS = hidradenitis suppurativa; IL = interleukin; NA = not applicable; NOC = Notice of Compliance; OTC = over the counter.

Clinical Evidence

The objective of this Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of secukinumab 150 mg/1 mL and 300 mg/2 mL solution by SC injection in the treatment of adult patients with moderate to severe HS. The focus will be placed on comparing secukinumab with relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of secukinumab is presented in 2 sections, with our critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies that were selected according to the sponsor’s systematic review protocol. Our assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes indirect evidence from the sponsor. No long-term extension studies and no additional studies were submitted by the sponsor.

Included Studies

Clinical evidence from the following is included in the CDA-AMC review and appraised in this document:

• 2 pivotal studies identified in systematic review

• 1 ITC.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the CDA-AMC review team.

Description of Studies

Characteristics of the included studies are summarized in Table 6.

Table 6: Details of Studies Included in the Systematic Review

AN = abscesses and inflammatory nodules; CRP = C-reactive protein; DLQI = Dermatology Life Quality Index; ESR = erythrocyte sedimentation rate; FPFV = first patient first visit; HiSCR = Hidradenitis Suppurativa Clinical Response; HS = hidradenitis suppurativa; HS-PGA = Hidradenitis Suppurativa Physician’s Global Assessment; IL = interleukin; mHSS = modified Hidradenitis Suppurativa Score; NRS = numerical rating scale; OTC = over the counter; PGI-S = Patient Global Impression–Severity; PGIC = Patient Global Impression of Change; q.2.w. = every 2 weeks; q.4.w. = every 4 weeks; RCT = randomized controlled trial; SC = subcutaneous; VAS = visual analogue scale; WPAI-SHP = Work Productivity and Activity Impairment–Specific Health Problem.

Sources: SUNSHINE Clinical Study Report,³³ SUNRISE Clinical Study Report,³⁴ SUNSHINE Clinical Study Report Week 52,⁶⁵ and SUNRISE Clinical Study Report Week 52.⁶⁶ Details included in the table are from the sponsor’s summary of clinical evidence.⁶⁷

The SUNSHINE (N = 541) and SUNRISE (N = 543) trials were identically designed multicentre, randomized, double-blind, placebo-controlled, parallel-group studies assessing the short- and long-term efficacy, safety, pharmacokinetics, and tolerability of 2 SC secukinumab dose regimens in adult patients (≥ 18 years) with moderate to severe HS. The SUNSHINE trial was conducted at 111 sites, including 4 sites in Canada, and the SUNRISE trial was conducted at 108 sites, including 3 sites in Canada; all patients in Canada were enrolled from Ontario and Quebec. The primary objective of both studies was to demonstrate the efficacy of 2 secukinumab dose regimens compared with placebo with respect to HiSCR after 16 weeks of treatment.

The screening period (to assess patient eligibility and to wash out and/or taper any prohibited medications) was up to 4 weeks from baseline, followed by the 16-week placebo-controlled treatment period 1 and 36-week treatment period 2 (Figure 1). Patients who discontinued from the study, or who completed the study but did not enter the extension study (NCT04179175), were required to complete an 8-week posttreatment follow-up. For patients rolling over to the extension study, week 52 was the end-of-study visit. For patients continuing to the posttreatment follow-up, week 60 was the end-of-study visit.

At baseline, patients were randomized through interactive response technology in a 1:1:0.5:0.5 ratio to receive secukinumab 300 mg every 2 weeks, secukinumab 300 mg every 4 weeks (with placebo between doses to be indistinguishable from the every 2 weeks dosing regimen), placebo to secukinumab 300 mg every 2 weeks, or placebo to secukinumab 300 mg every 4 weeks, respectively. Randomization was stratified by region, concomitant antibiotic use (yes or no), and body weight (< 90 kg or ≥ 90 kg). Note that up to 40% of patients were permitted to enter the study on treatment with a stable dose of antibiotics.

The data cut-off date was September 23, 2021, in the SUNRISE trial and October 1, 2021, in the SUNSHINE trial for the primary efficacy analysis at week 16. The database lock date was August 9, 2022, in the SUNRISE trial and August 17, 2022, in the SUNSHINE trial.

Note that 2 different dose regimens were assessed in both trials; however, only the maintenance dose of 300 mg of secukinumab administered every 2 weeks is included in the Health Canada indication. Therefore, only the results of the dose regimen of every 2 weeks are summarized in this report.

Figure 1: Study Design of SUNSHINE and SUNRISE Trials

AIN457 = secukinumab; BSL = baseline; EOT1 = end of treatment 1; EOT2 = end of treatment 2; F8 = end of follow-up visit at week 60; Q2W = every 2 weeks; Q4W = every 4 weeks; s.c = subcutaneous.

Notes: Treatment allocation for the patients in the placebo arm switching to the secukinumab arms at week 16 was performed at the randomization visit in a 1:1 ratio and did not account for potential discontinuations during treatment period 1.

The only patients who entered follow-up were those who discontinued treatment prematurely during treatment period 1 or 2 or who did not enrol in the extension study.

Sources: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.³⁴

Populations

Inclusion and Exclusion Criteria

The eligibility criteria were the same across both trials (Table 6). Briefly, adult patients (≥ 18 years) with moderate to severe HS who had a diagnosis of HS at least 1 year before baseline were included. Moderate to severe HS was defined as a total of at least 5 inflammatory lesions (abscesses and/or inflammatory nodules) affecting at least 2 distinct anatomic areas. Patients were required to agree to daily use of topical over-the-counter (OTC) antiseptics on areas affected by HS lesions while on study treatment. Patients were excluded if they had a total fistula count of 20 or more at baseline, or other active skin disease or condition that may interfere with the assessment of HS. Patients were excluded if they had prior exposure to secukinumab or to any other drug targeting the IL-17 receptor. Additionally, patients with a history of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system treated or untreated within the past 5 years were excluded from the trials.

Interventions

Study Drugs

The interventions administered were the same in both studies. Secukinumab 300 mg and placebo solutions for SC injection were supplied in a 2 mL prefilled syringe. The study treatments were identical in appearance, packaging, labelling, and administration schedule. At baseline, patients were instructed by site staff on how to self-inject using the prefilled syringe. All doses of the study treatment were self-administered (injected in a nonaffected area of the skin) by the patient or a trained caregiver either at the study site or at home at predefined visits.

In treatment period 1 (defined as baseline to before week 16 dosing), all patients received a single SC injection of the blinded study drug once a week (induction) at baseline and weeks 1, 2, 3, and 4. Thereafter, the frequency of the study drug injections was every 2 weeks for all patients to maintain the treatment blind: secukinumab every 2 weeks (secukinumab 300 mg every 2 weeks group), secukinumab alternating with placebo every 2 weeks (secukinumab 300 mg every 4 weeks group), or placebo (placebo-to-secukinumab groups) (Figure 1). Patients who completed treatment period 1 entered treatment period 2.

In treatment period 2 (defined as post week 16 dosing through week 52), all patients received secukinumab. At week 16, all patients previously assigned to the placebo group received a reinduction consisting of a single SC injection of the blinded study drug once a week at weeks 16, 17, 18, 19, and 20. Note that patients who were randomized to receive secukinumab in treatment period 1 received placebo at weeks 17, 18 (only in the secukinumab every 4 weeks group), and 19 to maintain the blind. Thereafter, all patients received study drug injections every 2 weeks: secukinumab every 2 weeks (secukinumab 300 mg every 2 weeks group and placebo to secukinumab 300 mg every 2 weeks group) or secukinumab alternating with placebo every 2 weeks (secukinumab 300 mg every 4 weeks group and placebo to secukinumab 300 mg every 4 weeks group) until week 50 (Figure 1).

Dose adjustments and/or interruptions of the study drug were not permitted; however, a dose could be temporarily interrupted if, in the opinion of the investigator, a patient experienced a significant safety risk. Study treatment could be restarted at the next scheduled visit after the safety risk had been resolved.

Rescue Therapies

During treatment period 1 (specifically at weeks 4, 8, and 12), if a patient experienced an increase in AN count (e.g., total AN count ≥ 150% of the weighted average of the AN count at screening and baseline) with a minimum increase of 3 lesions, then an oral antibiotic (minocycline or doxycycline up to 100 mg twice daily) could be provided as rescue medication; the dosing regimen must have remained stable until week 16. Note that there was no requirement regarding the duration of increased AN count in the criteria for use of oral antibiotic rescue medication.³⁶

At any time, if a patient experienced an acutely painful single lesion that required an immediate intervention, then the investigator could perform an unplanned surgery or intervention for the lesion such as excision, drainage, or intralesion steroid administration. Note that other HS-related surgeries could not be performed until after week 16. Evaluations at study visits occurred before any interventions were performed.

Concomitant Therapies

Patients were instructed to use daily topical OTC antiseptics on areas affected by HS lesions. Additionally, use of wound care dressings on HS wounds was permitted.

For patients in the antibiotic strata, treatment with tetracycline up to 500 mg twice daily, minocycline up to 100 mg twice daily, or doxycycline up to 100 mg twice daily on a stable dose was permitted, defined as a dose regimen that had not changed in the previous 28 days before baseline and was anticipated to remain stable for at least 16 weeks of treatment. Systemic antibiotics for the treatment of acute systemic infectious disease both related and unrelated to HS were permitted as required.

Patients on a stable dose of a nonopioid analgesic could continue the analgesic, provided the dose was stable in the 14 days before baseline and was anticipated to remain stable for at least 16 weeks of treatment. Note that “as needed” was not considered a stable dose of a nonopioid analgesic. If a patient presented with HS-related uncontrolled pain during the study, ibuprofen and acetaminophen were permitted. If the HS-related pain was uncontrolled with ibuprofen or acetaminophen at the maximal dose as per the local label during the study, patients could be prescribed tramadol at a dose of up to 100 mg oral every 4 hours, not to exceed 400 mg in 24 hours.

Prohibited Treatments

The following concomitant medications for the treatment of HS were prohibited: topical antibiotic therapies, systemic antibiotics (nonantibiotic strata), systemic corticosteroids, and surgeries other than those permitted as rescue therapy. Additionally, systemic biologic and nonbiologic immunomodulating treatments, opioid analgesics, live vaccines, and any other investigational treatment were prohibited. Note that patients could have received these prohibited therapies before beginning study treatment if they had completed the prespecified washout period (Table 37 in Appendix 1).

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 7, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review according to the clinical experts consulted by CDA-AMC and input from patient groups, clinician groups, and public drug plans. Using the same considerations, the CDA-AMC review team selected end points that were considered to be most relevant to inform our expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select harms outcomes considered important for informing our expert committee deliberations were also assessed using GRADE.

The following were considerations that went into the selection of the efficacy outcomes summarized in this report and assessed using GRADE:

• According to the input from the patient groups, the main treatment goals described by patients were to control HS symptoms, cure HS completely, and be able to enjoy personal relationships.

• The clinical experts consulted by CDA-AMC for this review identified the following as outcomes used in clinical practice to assess response to treatment: lesion count (abscess, nodule, and fistula), pain scale, number of sites involved, extent of disease, and patient-reported outcomes such as DLQI, activities of daily living, and HRQoL.

• The clinician group identified the following outcomes that are used to determine response to treatment: HiSCR50 and patient-reported outcomes such as pain, odour, and drainage management.

• The experts identified remission, defined as free (clearance) of active inflammatory lesions (i.e., abscess or nodules) while on treatment over a 6-month period, as an important outcome in making clinical decisions in practice. Note that remission was not measured in the SUNSHINE and SUNRISE trials.

• All notable harms of interest identified by the experts and input from patient and clinician groups and public drug plans are summarized in this report; however, only the notable harms included in Table 7 were assessed using GRADE. As advised by the experts, infections and infestations, malignant or unspecified tumours, and squamous cell carcinoma of an HS-affected area were included because secukinumab is an immune modulatory drug. Candidiasis was included because IL-17 inhibitors, such as secukinumab, are associated with a risk of candidiasis.⁶⁸ Inflammatory bowel disease was included because it is identified in the warnings and precautions of the product monograph for secukinumab.¹

• The experts indicated that long-term assessment (e.g., 2 years) would be meaningful considering HS is a life-long disease.

The following were considerations that went into the exclusion of efficacy outcomes in the report:

• There is evidence in the literature to support the clinical importance of HiSCR50 response in patients with HS;^20,22 moreover, the experts agreed on the clinical importance of this threshold. Additionally, the experts considered other HiSCR thresholds to be important but not essential in making clinical decisions (e.g., achieving HiSCR25 can be used to identify patients with HS that responds early to treatment). As such, results for HiSCR25, HiSCR50, HiSCR75, HiSCR90, and HiSCR100, based on observed data, are included in Appendix 1, which also inform the pharmacoeconomic model submitted to CDA-AMC.

• The experts indicated that the modified Hidradenitis Suppurativa Score (mHSS) is not commonly used in clinical practice to assess patients with HS in Canada.

• When considering the outcome measures, mHSS, HS Physician’s Global Assessment, Patient Global Impression–Severity, and Patient Global Impression of Change, the experts suggested disease severity would be adequately measured by the included outcome measures (HiSCR50, AN count, and pain), which align with the outcomes described previously and are used in clinical practice to assess response to treatment.

• The experts identified disease recurrence, defined as the return of active inflammatory lesions (i.e., abscess or nodules) or, more specifically, a patient presenting with multiple inflammatory abscesses and nodules after being free of inflammatory lesions in the preceding 6 months, as an important outcome in making clinical decisions in practice. However, the experts suggested that disease recurrence could be adequately captured in HiSCR (e.g., loss of HiSCR50, HiSCR75, or HiSCR90 response).

Table 7: Outcomes Summarized From the SUNSHINE and SUNRISE Trials

AN = abscesses and inflammatory nodules; CDA-AMC = Canada’s Drug Agency; DLQI = Dermatology Life Quality Index; GRADE = Grading of Recommendations Assessment, Development and Evaluation; HiSCR = Hidradenitis Suppurativa Clinical Response; HS = hidradenitis suppurativa; NRS30 = at least a 30% reduction and at least a 2-unit reduction from baseline in skin pain at its worst as measured by a numerical rating scale; VAS = visual analogue scale.

^aHiSCR50 was defined as at least a 50% decrease in AN count compared with baseline with no increase in the number of abscesses and/or in the number of draining fistulas from baseline in the SUNSHINE and SUNRISE trials.

^bStatistical testing for these end points was adjusted for multiple comparisons (i.e., hierarchal testing).

^cThe clinical experts consulted by CDA-AMC for this review identified remission, defined as free (clearance) of active inflammatory lesions (i.e., abscess or nodules) while on treatment over a 6-month period, as an important outcome in making clinical decisions in practice. Note that remission was not measured in the SUNSHINE and SUNRISE trials.

^dFlare was defined as at least a 25% increase in AN count with a minimum increase of 2 AN relative to baseline in the SUNSHINE and SUNRISE trials.

^eNRS30 (skin pain) was defined as at least a 30% reduction and at least 2-unit reduction from baseline in the patient's global assessment of skin pain on the NRS for pain at its worst averaged over the last 7 days in the SUNSHINE and SUNRISE trials.

^fDLQI response was defined as a decrease of ≥ 5 points on DLQI total score from baseline in the SUNSHINE and SUNRISE trials.

^gAll notable harms of interest identified by the clinical experts consulted by CDA-AMC and input from patient and clinician groups and public drug plans are summarized in this report; however, only the notable harms included in this table were assessed using GRADE. As advised by the clinical experts, infections and infestations, malignant or unspecified tumours, and squamous cell carcinoma of an HS-affected area were included because secukinumab is an immune modulatory drug. Candidiasis was included because IL-17 inhibitors, such as secukinumab, are associated with a risk of candidiasis.⁶⁸ Inflammatory bowel disease was included because it is identified in the warnings and precautions of the product monograph for secukinumab.¹

Sources: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.³⁴ Details included in the table are from the sponsor’s summary of clinical evidence.⁶⁷

Efficacy Outcomes

HS Clinical Response and Individual Lesion Count Assessment

In both the SUNSHINE and SUNRISE trials, achievement of HiSCR50 response at week 16 was the primary end point, and HiSCR50 response at week 52 was an exploratory end point. In both trials, percentage change from baseline in AN count at week 16 and week 52 were secondary and exploratory end points, respectively. Response to treatment (HiSCR50 achievement) was defined as at least a 50% reduction in AN count with no increase in the number of abscesses and/or in the number of draining fistulas from baseline to week 16, where increase was defined as at least 1 abscess or 1 draining fistula more than the baseline value. Additionally, HiSCR25, HiSCR50, HiSCR75, HiSCR90, and HiSCR100, which describe a decrease of at least 25%, 50%, 75%, 90%, 100% in AN count with no increase in the number of abscesses and/or in the number of draining fistulae compared with baseline, at week 16 and week 52 based on observed data were exploratory end points in both trials. The HiSCR was derived from the individual lesion counts of abscesses, nodules, and fistulae at scheduled visits. Any existing and newly observed lesions were counted by area by the physician at screening, in treatment period 1 (at baseline, week 2, week 4, and every 4 weeks thereafter to week 16), in treatment period 2 (at week 18, week 20, every 4 weeks thereafter to week 52), and at posttreatment follow-up (at week 60).

The HiSCR is used to measure response to treatment based on lesion counts. Areas affected by HS, including right and left axillary, right and left gluteal, right and left inguinal–femoral, perineal, pubic, sternal, and right and left submammary, were assessed by the physician for the presence of inflammatory nodules, abscesses, draining fistulae, total fistulae, and other lesions (Table 8).

Table 8: Definitions of HS Lesions

HS = hidradenitis suppurativa.

Sources: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.³⁴ Details included in the table are from the sponsor’s summary of clinical evidence.⁶⁷

Flares

In both trials, experience of flares at week 16 and week 52 were secondary and exploratory end points, respectively. A flare was defined as at least a 25% increase in AN count with a minimum increase of 2 AN relative to baseline. The occurrence of a flare was calculated from the lesion count assessment.

Skin Pain

In both trials, achievement of NRS30 at week 16 and week 52 were secondary and exploratory end points, respectively. Achievement of NRS30 was defined as at least a 30% reduction and at least 2-unit reduction from baseline in the patient's global assessment of skin pain at its worst on the NRS. Patients completed a daily diary of their skin pain at screening and in treatment period 1 (from baseline through week 16). Patients also completed skin pain assessments on a weekly basis in treatment period 2 (from week 16 through week 52) and at the posttreatment follow-up (at week 60).

The NRS is a patient-reported, segmented numeric version of the VAS that is used to measure the intensity of skin pain at its worst as well as the average intensity of skin pain due to HS in the last 24 hours. The range of the NRS includes whole numbers from 0 (no skin pain) to 10 (skin pain as bad as you can imagine).

Dermatology Life Quality Index

In both trials, achievement of DLQI response at week 16 and week 52 as well as change from baseline in DLQI total score at week 16 and week 52 were exploratory end points. Response according to DLQI was defined as a decrease of 5 points or more on the DLQI total score from baseline. The DLQI was completed in treatment period 1 (at baseline and weeks 2, 4, 12, and 16) and treatment period 2 (at weeks 28 and 52).

The DLQI is a 10-item, self-administered, general dermatology disability index used to assess HRQoL in adults with skin diseases (e.g., eczema, psoriasis, and acne). The questionnaire consists of 6 domains, including symptoms and feelings, daily activities, leisure, work and school, personal relationships, and treatment. The recall period is the last week. Each item is scored on a 4-point scale from 0 (not relevant or not at all) to 3 (very much). The total score is the sum of the scores of each item, ranging from 0 (no effect at all on patient’s life) to 30 (extremely large effect on patient’s life), with a higher score indicating greater impairment in HRQoL.

EQ-5D Health State Assessment

In both trials, change from baseline in EQ-5D health state assessment at week 16 and week 52 were exploratory end points. The EQ-5D was completed in treatment period 1 (at baseline and weeks 2, 4, 12, and 16) and treatment period 2 (at weeks 28 and 52).

The EQ-5D-3L is a self-administered, generic instrument consisting of the EQ-5D descriptive system and the EQ VAS that is used to assess patient health status. The descriptive system consists of the following 5 dimensions: mobility, self-care, usual activities, pain and discomfort, severe problems, and anxiety and depression. Each dimension has 3 response levels: no problem, moderate problem, and severe problems. The VAS is used to assess the patient’s self-rated health on a vertical 20 cm VAS where the end points are labelled 0 (worst imaginable health state) and 100 (best possible health state). The recall period is the day of the assessment.

Harms Outcomes

In both the SUNSHINE and SUNRISE trials, AEs were assessed at screening and throughout the study.

Notable harms for secukinumab included hypersensitivity, injection site reaction, infections and infestations, candidiasis, malignant or unspecified tumours, squamous cell carcinoma of an HS-affected area, inflammatory bowel disease, and suicidal ideation or behaviour or suicide attempt.

Table 9: Summary of Outcome Measures and Their Measurement Properties

AN = abscesses and inflammatory nodules; CI = confidence interval; DLQI = Dermatology Life Quality Index; EQ VAS = EQ-5D visual analogue scale; HiSCR = Hidradenitis Suppurativa Clinical Response; HRQoL = health-related quality of life; HS = hidradenitis suppurativa; HS-PGA = Hidradenitis Suppurativa Physician’s Global Assessment; HSS = Hidradenitis Suppurativa Score; ICC = intraclass correlation coefficient; mHSS = modified Hidradenitis Suppurativa Score; MID = minimal important difference; NRS30 = at least a 30% reduction and at least a 2-unit reduction from baseline in skin pain at its worst as measured by a numerical rating scale; OR = odds ratio; PGI-S = Patient Global Impression–Severity; PGIC = Patient Global Impression of Change; PRO = patient-reported outcome; RCT = randomized controlled trial; VAS = visual analogue scale; Work Productivity and Activity Impairment–Specific Health Problem.

Statistical Analysis

Analysis of clinical end points in the SUNSHINE and SUNRISE trials is summarized in Table 10.

Sample Size and Power Calculation

The sample size for both trials was driven by the primary end point, HiSCR50 achievement at week 16. Both studies were independently powered to address the primary end point and secondary end points of AN count and flares. The initial plan was to randomize 471 patients in a 1:1:0.5:0.5 ratio to the study drug. To account for the impact of COVID-19, a protocol amendment was made to increase the number of randomized patients by 15% to 541 patients to ensure that power was maintained throughout the trial.

For the testing of the primary end point, a response rate of 30% for placebo was assumed, based on the PIONEER I and II trials comparing adalimumab with placebo.⁷⁰ The initial sample size of 471 patients was sufficient to achieve 93% power for demonstration of a 20% difference of secukinumab 300 mg every 2 weeks over placebo, assuming a secukinumab response rate of 50%, based on the primary end point.

Expected responses for the primary and secondary end points were based on the results from the PIONEER I and II trials:⁷⁰

• A difference of at least 18% in favour of secukinumab versus placebo was assumed for the mean percentage change from baseline in AN count. The approximate sample size for analysis of this end point was based on a simple t test. The initial sample size of 471 patients was expected to achieve 92% power in testing secukinumab 300 mg every 2 weeks versus placebo, assuming an SD of 46%.

• A placebo rate of 35% was assumed for flares. The initial sample size of 471 patients was expected to achieve 98% power in demonstrating a 20% difference of secukinumab 300 mg every 2 weeks over placebo, assuming a rate of 15% for secukinumab 300 mg every 2 weeks.

• A placebo rate of 23% was assumed for NRS30. Assuming that 80% of patients would qualify for the NRS30 analysis, a total sample size of 942 patients across both studies was expected to achieve 85% power to demonstrate a difference of 13% of secukinumab 300 mg every 2 weeks group over placebo, assuming a rate of 36% for secukinumab 300 mg every 2 weeks.

Primary End Point

The primary analysis method for HiSCR50 response at week 16 was logistic regression with treatment group, Hurley stage, baseline AN count, geographical region, use of antibiotics, and baseline body weight as explanatory variables. ORs were computed for comparisons of secukinumab dose regimens versus placebo based on the logistic regression model fit.

Secondary End Points

Both studies included the following secondary end points:

• percentage change from baseline in AN count at week 16

• proportion of patients who experience at least 1 HS flare over 16 weeks; a flare was defined as at least a 25% increase in AN count, with a minimum increase of 2 AN relative to baseline

• proportion of patients achieving NRS30 at week 16 in patients with baseline NRS ≥ 3; NRS30 was defined as at least 30% reduction and at least 2-unit reduction from baseline in the patient’s global assessment of skin pain.

The analysis method for percentage change from baseline in AN count at week 16 was an analysis of covariance (ANCOVA) model with treatment group, Hurley stage, baseline AN count, geographical region, use of antibiotics, and baseline body weight as explanatory variables.

The analysis method for flares over 16 weeks and NRS30 at week 16 was logistic regression with treatment group, Hurley stage, geographical region, use of antibiotics, baseline body weight, baseline value of the variable being assessed, and study (NRS30 only) as explanatory variables. ORs were computed for the comparisons of the secukinumab dose regimens versus placebo based on the logistic regression model fit.

Exploratory End Points

For exploratory end point analyses at week 16, the corresponding P values for pairwise comparisons were not adjusted for multiple comparisons and no formal confirmatory hypothesis testing was planned.

• The analysis method for DLQI response at week 16 was logistic regression based on observed data, with treatment group, Hurley stage, geographical region, use of antibiotics, baseline body weight, and baseline DLQI score as explanatory variables. ORs were computed for the comparisons of the secukinumab dose regimens versus placebo based on the logistic regression model fit.

• The analyses of the DLQI total score and EQ-5D health state assessment were descriptive and based on observed data only.

• The analyses of HiSCR25, HiSCR50, HiSCR75, HiSCR90, and HiSCR100 were descriptive and based on observed data only.

Exploratory end point analyses at week 52 were descriptive and used only observed data. A Kaplan-Meier analysis based on observed values for the cumulative incidence of the flare-free period up to week 52 was presented for each treatment group; patients without any flares were censored at the last known visit.

Testing Strategy

There was initially an equal alpha split for the testing of each dose versus placebo, but this was later amended to allocate four-fifths of the alpha to the biweekly maintenance dosing following results of another study (CAIN457A2324), suggesting it may be reasonable to believe there would be a better treatment effect with biweekly maintenance dosing compared with monthly maintenance dosing.

The primary and secondary end points (percentage change from baseline in AN count at week 16 and proportion of patients experiencing any flares at week 16) were tested in each study separately. The secondary end point, NRS30 at week 16, was tested using the pooled data from both studies. To control for type I error at the level of the individual studies and at the level of the pooled dataset of both studies, a 5% 2-sided type I error rate was used and split, and the following testing strategy was implemented (Figure 6 in Appendix 1).

The primary end point in both dose regimens was first tested, with 4% alpha allocated to test secukinumab every 2 weeks against placebo, and 1% to test secukinumab every 4 weeks against placebo. For each dose regimen, if the primary hypothesis was rejected, then the allocated alpha was passed to the first secondary end point (percentage change from baseline in AN count at week 16) in the testing strategy for the same dose regimen and, subsequently, to the next secondary end point (flares over 16 weeks). If statistical significance was achieved for the primary end point and the 2 secondary end points for a secukinumab dose regimen, then the respective allocated alpha was passed on to test the end points of the other secukinumab dose regimen if they did not already achieve statistical significance at the initial allocated alpha.

Statistical testing for the secondary end point, NRS30 at week 16, was dependent on the statistical significance having been achieved in both studies for the primary end point on the same secukinumab dose regimen. Additionally, the allocated alpha for this secondary end point could be passed from 1 dose regimen for which statistical significance was achieved to the other dose regimen. The secondary end point, NRS30 was based on pooled data from the SUNNY trials; the initial significance level for the skin pain hypothesis was set to alpha squared minus alpha (1-sided alpha is 0.025) and could be increased, dependent on which hypotheses were rejected; the subtraction of alpha squared was to account for the maximum possible type I error for HiSCR50 response and percentage change in AN count and flares in both studies.

Note that, based on an interim futility and efficacy analysis that was performed for the SUNNY trials when 40% of patients in both studies had completed week 16, a Haybittle-Peto–type adjustment of the 1-sided levels of significance was applied in the analysis of the primary and secondary end points. However, the adjustment was deemed to be very small (0.00001) by the investigator and they concluded that it did not have any impact on the results; thus, the original significance levels are referenced in the results. Therefore, the primary and secondary end points (AN count and flares) were tested in a hierarchical order with 1-sided significance level of 0.02 for the biweekly maintenance dosing and 0.005 for the monthly maintenance dosing.

Data Imputation Methods

Missing data for the primary and secondary end points were addressed using multiple imputation. To account for different postrandomization events, missing data were multiply imputed using a reference-based approach or based on a missing at random assumption, depending on the intercurrent event or unrelated to an intercurrent event. Note that for the intake of any prohibited medications, such events were ignored and all observed values were considered. Any observations after a patient had permanently discontinued study treatment for reasons other than AEs or lack of efficacy were discarded. For 2 intercurrent events, intake of rescue medication and permanent discontinuation of study treatment because of AEs or lack of efficacy, a patient was either considered a nonresponder, or a score of 0 (no change) would be imputed in the analysis of the percentage change from baseline in AN count at week 16. In the analysis of NRS30, a patient was also considered a nonresponder in the intercurrent event of prohibited medication intake.

Imputations were performed on the continuous variables from which the imputed binary outcomes were then constructed. More specifically, for the primary end point analysis, the number of abscesses, inflammatory nodules, and draining fistulae were imputed, from which the response variable was then constructed. Since these lesion count variables were used to derive HiSCR, AN count, and flares, 1 set of multiple imputations of the lesion count variables was generated for consistency between the analyses of these end points. For the analysis of NRS30, the values of the patient’s global assessment of skin pain were imputed, from which the imputed binary outcome was then constructed.

Sensitivity and Supplementary Analyses

A tipping point analysis was implemented for both the primary and secondary end points to assess the robustness of the multiple imputation approach.

A sensitivity analysis using a weighted average of the screening and baseline visits (compared with the value at baseline that was used in the primary analysis) was performed for the primary end point and the 2 secondary end points (AN count and flares). For inflammatory nodules, abscesses, and draining fistulae, a weighted average based on screening visit 1 (with a weight of 1/6), screening visit 2 (with a weight of 2/6), and randomization visit (with a weight of 3/6) was taken. Note that this weighted average was used during the study to identify the need for rescue medication.

A supplementary analysis was implemented for only the primary end point and all attributes of this end point remained the same as defined for the primary end point; however, the intercurrent events were considered differently, per protocol.

Subgroup Analysis

The primary and secondary end points of both trials were evaluated using the following subgroup variables:

• concomitant antibiotics use

• body weight stratum (< 90 kg, ≥ 90 kg)

• geographical region

• age

• gender

• race

• previous use of systemic biologics

• C-reactive protein levels (< 5, 5 to 10, ≥ 10)

• erythrocyte sedimentation rate levels (< 20, ≥ 20)

• Hurley stage (1, 2, 3)

• baseline AN count (≤ 10, > 10)

• baseline disease duration (< 2 years, 2 to 5 years, 5 to 10 years, ≥ 10 years).

To assess for any potential difference in treatment effect between subgroups, logistic regression models were used to test for an interaction between treatment and the subgroups. A separate model was used to assess each subgroup with treatment group weight, baseline AN count, and the interaction between treatment and the assessed subgroup as covariates. For the primary end point, the P values of the interaction terms did not support any assumption of a difference in the treatment effect between the subgroups. Note that the subgroup analyses were not adjusted for multiple testing.

Of the subgroups listed previously, the clinical experts consulted by CDA-AMC for this review identified concomitant antibiotic use, body weight stratum, previous use of systemic biologics, Hurley stage, and baseline AN count as patient demographic or disease characteristics that would be expected to influence the efficacy of treatment (i.e., effect modifiers).

Table 10: Statistical Analysis of the Efficacy End Points in the SUNSHINE and SUNRISE Trials

AN = abscesses and inflammatory nodules; ANCOVA = analysis of covariance; DLQI = Dermatology Life Quality Index; HiSCR50 = Hidradenitis Suppurativa Clinical Response 50, i.e., a decrease of 50% or greater in the AN count with no increase in the number of abscesses or draining fistulae compared with baseline; NRS = numerical rating scale; VAS = visual analogue scale.

Sources: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.³⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁶⁷

Analysis Populations

The analysis sets used in both trials are summarized in Table 11. The definitions of each analysis population were the same across both trials. Additionally, the full analysis set was the same as the randomized set. The analysis of efficacy end points was based on the full analysis set.

For all analyses in treatment period 1, placebo to secukinumab 300 mg every 2 weeks group and placebo to secukinumab 300 mg every 4 weeks group were pooled together (placebo group). The any-secukinumab group included the patients who received secukinumab at initial randomization and the patients who switched from placebo to secukinumab.

Table 11: Analysis Populations of the SUNSHINE and SUNRISE Trials

Notes: Patients who were misrandomized were excluded and patients who had experienced a serious violation of good clinical practice at their site were excluded. Patients who are misrandomized are those who did not advance past screening but had been randomized by the investigator before eligibility was finally assessed; however, they were not treated.

Treatment received is defined as the randomized or assigned treatment if the patient took at least 1 dose of that treatment, or the first treatment received if the randomized or assigned treatment was never received (patient received the wrong treatment during the entire study).

Sources: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.³⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁶⁷

Results

Although 2 different dosing schedules were assessed in the SUNSHINE and SUNRISE trials, only the maintenance dose of 300 mg of secukinumab administered every 2 weeks is included in the Health Canada indication. Therefore, only the results of the dosing schedule of every 2 weeks were summarized in this report.

Patient Disposition

A summary of patient disposition during treatment period 1 in both trials is presented in Table 12. Patient disposition was generally similar between groups and across trials. A total of 676 and 687 patients were screened for eligibility in the SUNSHINE and SUNRISE trials, respectively. The most common reason for screen failure was due to screen failure (15.5% [105 patients] in the SUNSHINE trial and 13.5% [93 patients] in the SUNRISE trial). In the SUNSHINE trial, 181 patients were randomized to the secukinumab group and 180 patients to the placebo group. In the SUNRISE trial, 180 patients were randomized to the secukinumab group and 183 patients to the placebo group.

In the SUNSHINE trial, 7.2% (13 patients) in the secukinumab group and 4.4% (8 patients) in the placebo group discontinued from the study. In the SUNRISE trial, 5.6% (10 patients) and 8.7% (16 patients) randomized to secukinumab and placebo, respectively, discontinued from the study. Of the patients who were randomized to secukinumab and placebo, the most common reason for study discontinuation was patient decision (3.3% [6 patients] and 2.8% [5 patients], respectively, in the SUNSHINE trial, and 3.3% [6 patients] and 3.8% [7 patients], respectively, in the SUNRISE trial).

After completing treatment period 1, patients initially randomized to the placebo group were switched to a secukinumab regimen, while patients initially randomized to secukinumab continued to receive their regimen. A summary of patient disposition during the entire study period in both trials is presented in Table 13. In the SUNSHINE trial, ██ of ███ randomized patients (█████) in the secukinumab group discontinued from the study. In the SUNRISE trial, ██ of ███ randomized patients (█████) in the secukinumab group discontinued from the study. Similar to treatment period 1, the most common reason for study discontinuation was patient decision in the secukinumab group (██|█████| patients in the SUNSHINE trial and ██|████| patients in the SUNRISE trial).

Table 12: Summary of Patient Disposition From the SUNSHINE and SUNRISE Trials in Treatment Period 1

q.2.w. = every 2 weeks.

Note: In the SUNSHINE trial, 3 patients were excluded from the randomized set per the statistical analysis plan: 1 patient was misrandomized in interactive response technology, 1 patient experienced a serious violation of good clinical practice, and 1 patient experienced a serious breach. In the SUNRISE trial, 1 patient was misrandomized in the interactive response technology and excluded from the randomized set, per the analysis plan.

Sources: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.³⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁶⁷

Table 13: Summary of Patient Disposition From the SUNSHINE and SUNRISE Trials in Entire Study Period

q.2.w. = every 2 weeks.

Notes: The entire study period included treatment period 1, treatment period 2, and the follow-up period.

In the SUNSHINE trial, 3 patients were excluded from the randomized set per the statistical analysis plan: 1 patient was misrandomized in interactive response technology, 1 patient experienced a serious violation of good clinical practice, and 1 patient experienced a serious breach. In the SUNRISE trial, 1 patient was misrandomized in the interactive response technology and excluded from the randomized set, per the analysis plan.

Patients in the placebo group who discontinued in treatment period 1 and did not receive secukinumab are not included in this table. The safety analysis set included only patients who received the active treatment (secukinumab).

Sources: SUNSHINE^65,66Clinical Study Report Week 52 and SUNRISE Clinical Study Report Week 52. Details included in the table are from the sponsor’s summary of clinical evidence.⁶⁷

Protocol Deviations

A summary of the protocol deviations that occurred during treatment period 1 in both trials is presented in Table 14. The number of patients with at least 1 protocol deviation was similar between groups and across trials, with approximately one-third of patients reporting at least 1 protocol deviation. Most protocol deviations were related to treatment deviation; in the SUNSHINE trial, this was reported in ██ of 181 (██████) patients in the secukinumab group and ██ of 180 (█████) patients in the placebo group, and in the SUNRISE trial, treatment deviation was reported in ██ of 180 (█████) patients in the secukinumab group and ██ of 183 (█████) patients in the placebo group. Note that the “treatment deviation” category was related mainly to drug administration at home versus at the site.

Table 14: Summary of Protocol Deviations From the SUNSHINE and SUNRISE Trials in Treatment Period 1 (Randomized Set)

q.2.w. = every 2 weeks.

Note: A patient with multiple protocol deviations in the same category was counted only once in that category. Patients could have protocol deviations in more than 1 protocol deviation category.

^aThe “treatment deviation” category was related mainly to drug administration at home vs. at the site.

^bThe “other” category covers protocol deviations that do not fall into any of the previous categories (selection criteria not met, patient withdrawal as per protocol, treatment deviation, or prohibited concomitant medication) but that impact the completeness, accuracy, and/or reliability of the study data or the patient’s rights, safety, or well-being. For example, a procedure was performed after the patient withdrew consent, the study site was not compliant with good clinical practice, or primary end point assessment was missed.

Sources: Source: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.³⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁶⁷

A summary of the protocol deviations that occurred during the entire study period in both trials is presented in Table 15. A similar proportion of patients in the secukinumab group across trials reported at least 1 protocol deviation (███ of 181 |█████| patients in the SUNSHINE trial and ███ of 180 |█████| patients in the SUNRISE trial). Similar to treatment period 1, most protocol deviations in the secukinumab group were related to treatment deviation (██ of 181 |█████| patients in the SUNSHINE trial and ██ of 180 |█████| patients in the SUNRISE trial).

Table 15: Summary of Protocol Deviations From the SUNSHINE and SUNRISE Trials in Entire Study Period (Randomized Set)

q.2.w. = every 2 weeks.

Notes: The entire study period comprised treatment period 1, treatment period 2, and the follow-up period.

A patient with multiple occurrences of a protocol deviation in the same category was counted only once in that category. Patients could have protocol deviations in more than 1 protocol deviation category.

^aThe “other” category covers protocol deviations that do not fall into the previous categories (selection criteria not met, patient withdrawal as per protocol, treatment deviation, or prohibited concomitant medication) but that impact the completeness, accuracy, and/or reliability of the study data or the patient’s rights, safety, or well-being (e.g., a procedure was performed after the patient withdrew consent, the study site was not compliant with good clinical practice, or the assessment of the primary end point was missed).

Sources: SUNSHINE Clinical Study Report Week 52⁶⁵ and SUNRISE Clinical Study Report Week 52.⁶⁶ Details included in the table are from the sponsor’s summary of clinical evidence.⁶⁷

Baseline Characteristics

A summary of baseline characteristics from both the SUNSHINE and SUNRISE trials in treatment period 1 is presented in Table 16. Baseline characteristics were generally similar between groups and across trials. Across trials, the mean age of patients ranged from 35.5 years (SD = 10.75) in the placebo group in the SUNSHINE trial to 37.3 years (SD = 11.48) in the secukinumab group in the SUNRISE trial. Across trials, the proportion of patients who were male ranged from 42.6% (78 of 183 patients) in the placebo group to 45.6% (82 of 180 patients) in the secukinumab group in the SUNRISE trial, and patients who were female ranged from 54.4% (98 of 180 patients) in the secukinumab group to 57.4% (105 to 183 patients) in the placebo group in the SUNRISE trial. The majority of patients across trials were white, ranging from 73.9% (133 of 180 patients) in the secukinumab group in the SUNRISE trial to 80.1% (145 of 181 patients) in the SUNSHINE trial. Across trials, the mean body mass index ranged from 31.42 kg/m² (SD = 7.382) in the placebo group in the SUNRISE trial to 32.64 kg/m² (SD = 7.904) in the secukinumab group in the SUNSHINE trial.

In terms of smoking status, more than half of the patients were current smokers; across trials, the proportion of patients who were current smokers ranged from 52.5% (95 of 181 patients) in the secukinumab group in the SUNSHINE trial to 57.9% (106 of 183 patients) in the placebo group in the SUNRISE trial. Across trials, the proportion of patients with obesity ranged from ████ (██ of 180 patients) in the placebo group in the SUNSHINE trial to █████ (██ of 180 patients) in the secukinumab group in the SUNRISE trial. Across trials, the proportion of patients with diabetes mellitus ranged from ████ (||| of 180 patients) in the secukinumab group to ████ (||| of 183 patients) in the placebo group in the SUNRISE trial. One patient in each group in the SUNRISE trial was reported to have hyperandrogenism; no patients in the SUNSHINE trial were reported to have hyperandrogenism.

In the SUNSHINE trial, the mean time since HS symptom onset across trials ranged from ████ years (SD = ████) in the placebo group to ████ years (SD = ████) in the secukinumab group. At baseline, most patients were categorized with Hurley stage 2 disease severity, ranging from 51.1% (92 of 180 patients) in the secukinumab group in the SUNRISE trial to 67.2% (121 of 180 patients) in the placebo group in the SUNSHINE trial. At baseline, patients with Hurley stage 3 disease severity ranged from 28.3% (51 of 180 patients) in the placebo group in the SUNSHINE trial to 45.6% (82 of 180 patients) in secukinumab group in the SUNRISE trial. The proportions of patients with 1 to 11 anatomic regions with at least 1 total fistula, inflammatory nodule, or abscess were generally well balanced between groups and across trials.

Across trials, the mean baseline AN count ranged from 12.8 (SD = 8.15) in the placebo group in the SUNSHINE trial to 13.9 (SD = 9.93) in the secukinumab group in the SUNRISE trial. The mean baseline NRS score ranged from 5.0 (SD = 2.61) in the placebo group in the SUNSHINE trial to 5.4 (SD = 2.42) in the secukinumab group in the SUNRISE trial. The mean baseline DLQI total score ranged from ████ (SD = ████) in the placebo group in the SUNSHINE trial to ████ (SD = ████) in the secukinumab group in the SUNRISE trial.

In the SUNSHINE trial, 13.8% (25 of 181 patients) in the secukinumab group and 10.6% (19 of 180 patients) in the placebo group enrolled in the antibiotic strata. Similarly, in the SUNRISE trial, 9.4% (17 of 180 patients) in the secukinumab group and 10.4% (19 of 183 patients) in the placebo group enrolled in the antibiotic strata.

The baseline characteristics outlined in Table 16 are limited to those that are most relevant to this review or that were felt by the review team to affect the outcomes or interpretation of the study results.

A summary of the baseline characteristics from both the SUNSHINE and SUNRISE trials in the entire study period is presented in Table 17. The baseline characteristics in the secukinumab group were generally similar between trials and generally similar to the baseline characteristics in treatment period 1.

Table 16: Summary of Baseline Characteristics From the SUNSHINE and SUNRISE Trials in Treatment Period 1 (Randomized Analysis Set)

AN = abscesses and inflammatory nodules; BMI = body mass index; DLQI = Dermatology Life Quality Index; HS = hidradenitis suppurativa; m = number of patients with nonmissing DLQI total score at the baseline; mHSS = modified Hidradenitis Suppurativa Score; NA = not applicable; NR = not reported; NRS = numerical rating scale; q.2.w. = every 2 weeks; SD = standard deviation.

^aRace – multiple means multiple entries were selected in the electronic case report form.

^bAnatomic regions were defined as the following: intermammary area; submammary or inframammary area, left; submammary or inframammary area, right; buttock, left; buttock, right; inguinocrural fold, left; inguinocrural fold, right; perianal; perineal; axilla, left; axilla, right; neck; abdomen; chest; back; pubic region; genital region; upper extremity, left; upper extremity, right; lower extremity, left; lower extremity, right.

^cBased on the full analysis set.

^dPerineum included the genital, perianal, perineal, and pubic anatomic regions. Lesions included total fistula, inflammatory nodule, or abscess.

Sources: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.^34-36 Details included in the table are from the sponsor’s summary of clinical evidence.⁶⁷

Table 17: Summary of Baseline Characteristics From the SUNSHINE and SUNRISE Trials in Entire Study Period (Randomized Analysis Set)

AN = abscesses and inflammatory nodules; BMI = body mass index; DLQI = Dermatology Life Quality Index; HS = hidradenitis suppurativa; NRS = numerical rating scale; q.2.w. = every 2 weeks; SD = standard deviation.

Note: The entire study period included treatment period 1, treatment period 2, and the follow-up period.

^aRace – multiple means multiple entries were selected in the electronic case report form.

Sources: SUNSHINE Clinical Study Report Week 52⁶⁵ and SUNRISE Clinical Study Report Week 52.⁶⁶ Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁶⁷

A summary of prior HS therapies in the SUNSHINE and SUNRISE trials is presented in Table 18. The proportion of patients with reported prior exposure to any HS medications was generally similar between groups and across trials. Overall, █████ (███ of 180 patients) in the placebo group in the SUNSHINE trial to █████ (███ of 180 patients) in the secukinumab group in the SUNRISE trial reported prior exposure to any HS medications. In both trials, the majority (approximately █████) of patients in each group reported prior systemic antibiotics use, with the most common reason (approximately █████) for discontinuation of systemic antibiotics being lack of efficacy; these proportions were generally similar between groups and across trials. In particular, ||████ (██ of 181 patients) in the secukinumab group and █████ (██ of 180 patients) in the placebo group reported prior exposure to adalimumab and the reason for discontinuation in the SUNSHINE trial. Similarly, █████ (██ of 180 patients) in the secukinumab group and █████ (██ of 183 patients) in the placebo group reported exposure to adalimumab and the reason for discontinuation in the SUNRISE trial. In both trials, the majority (| █████ of patients with prior adalimumab use) in each group discontinued because of lack of efficacy; the proportion of patients who discontinued adalimumab because of lack of efficacy was generally similar between groups and across trials.

Table 18: Summary of Prior HS Therapies From the SUNSHINE and SUNRISE Trials (Safety Set)

CDA-AMC = Canada’s Drug Agency; HS = hidradenitis suppurativa; q.2.w. = every 2 weeks.

Note: A patient with multiple types of therapy is counted only once in the total row. A patient can have multiple medications discontinued for different reasons within a type of therapy.

^aBased on the randomized analysis set. In the SUNSHINE trial, 41 patients in the secukinumab group and 44 patients in the placebo group reported prior adalimumab discontinuation; 41 patients in the secukinumab group and 43 patients in the placebo group had nonmissing reason of discontinuation. In the SUNRISE trial, 35 patients in the secukinumab group and 46 patients in the placebo group reported prior adalimumab discontinuation; 34 patients in the secukinumab group and 44 patients in the placebo group had nonmissing reason of discontinuation.

^bBased on the full analysis set. The N was the number of patients with prior use of adalimumab for HS.

^cIf treatment discontinuation was not due to lack of efficacy or lack of tolerability, then the other category was selected in the case report form.

Sources: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.^34,36 Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁶⁷

Exposure to Study Treatments

A summary of patient exposure to treatment in the SUNSHINE and SUNRISE trials during treatment period 1 is presented in Table 19. Exposure to treatment was generally similar between groups and across trials. At week 16, the proportion of patients with exposure to the study treatment ranged from █████ (███ of 181 patients) in the secukinumab group to █████ (███ of 180 patients) in the placebo group in the SUNSHINE trial, across trials. Note that not all patients had undergone 16 weeks of treatment at the time of data cut-off. The mean duration of treatment ranged from █████ (SD = █████) days in the placebo group in the SUNSHINE trial to █████ (SD = █████) days in the placebo group in the SUNRISE trial. In the secukinumab group, the mean total number of secukinumab injections was ███ (SD = ████) in the SUNSHINE trial and ███ (SD = ████) in the SUNRISE trial. The cumulative exposure to secukinumab was ████ patient-years in the SUNSHINE trial and ████ patient-years in the SUNRISE trial.

Table 19: Summary of Patient Exposure From the SUNSHINE and SUNRISE Trials in Treatment Period 1 (Safety Set)

q.2.w. = every 2 weeks; SD = standard deviation.

^aFor those patients who came earlier than day 112 for the week 16 visit, the treatment period was shorter than 16 weeks, and therefore these patients were not included in the “≥ 16 weeks” row but were counted in that category for the entire study period if they continued treatment after day 112.

^bDuration of exposure to study treatment is defined as min (end date of treatment period 1, last dose date plus 84 days) minus start date of study treatment plus 1.

^cPatient time in patient-years was calculated as a sum of individual patient durations in days divided by 365.25.

Sources: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.³⁴ Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁶⁷

A summary of patient exposure to treatment in the SUNSHINE and SUNRISE trials during the entire study period and at the time of database lock is presented in Table 20. At week 52, █████ (███ of 181 patients) in the secukinumab group in the SUNSHINE trial and █████ (███ of 180 patients) in the secukinumab group in the SUNRISE trial had exposure to the study drug. In the secukinumab group, the mean duration of exposure to treatment was █████ days (SD = █████) the SUNSHINE trial and █████ days (SD = █████) in the SUNRISE trial. In the secukinumab group, the mean total number of secukinumab injections was ████ (SD = ████) in the SUNSHINE trial and ████ (SD = ████) in the SUNRISE trial. The cumulative exposure to secukinumab in the secukinumab group was █████ patient-years in the SUNSHINE trial and █████ patient-years in the SUNRISE trial.

Table 20: Summary of Patient Exposure From the SUNSHINE and SUNRISE Trials in Entire Study Period (Safety Set)

q.2.w. = every 2 weeks; SD = standard deviation.

Notes: The entire study period included treatment period 1, treatment period 2, and the follow-up period.

The database lock was August 17, 2022, in the SUNSHINE trial and August 9, 2022, in the SUNRISE trial.

^aDuration of exposure to study treatment is defined as end date of treatment period 1 last dose date plus 84 days minus the start date of study treatment plus 1.

^bFor placebo-to-secukinumab switchers, exposure after the first intake of secukinumab is counted in the any-secukinumab groups accordingly.

^cPatient time in patient-years was calculated as the sum of individual patient durations in days divided by 365.25.

Sources: SUNSHINE Clinical Study Report Week 52⁶⁵ and SUNRISE Clinical Study Report Week 52.⁶⁶ Details included in the table are from the sponsor’s Summary of Clinical Evidence.⁶⁷

Concomitant Therapy

A summary of concomitant therapy from the SUNSHINE and SUNRISE trials in treatment period 1 is presented in Table 21. In treatment period 1, the use of any concomitant therapy was similar between groups and across trials, with the majority of patients (approximately █████) in each group using concomitant therapies. In the SUNSHINE trial, ibuprofen was used by █████ (██ of 181 patients) in the secukinumab group and █████ (██ of 180 patients) in the placebo group, and paracetamol was used by █████ (██ of 181 patients) in the secukinumab group and █████ (██ of 180 patients) in the placebo group. Similarly, in the SUNRISE trial, ibuprofen was used by █████ (██ of 180 patients) in the secukinumab group and █████ (██ of 183 patients) in the placebo group, and paracetamol was used by █████ (██ of 180 patients) in the secukinumab group and █████ (██ of 183 patients) in the placebo group. Tramadol, ibuprofen with paracetamol, doxycycline, minocycline, tetracycline, spironolactone, ethinyl estradiol, and cyproterone acetate were used by less than ███ of patients in each group and were generally similar between groups and across trials.

In the SUNSHINE trial, a total of ████ (██ of 181 patients) in the secukinumab group and █████ (██ of 180 patients) in the placebo group underwent a concomitant medical procedure and/or significant nondrug therapy (Table 21). In the SUNRISE trial, a total of █████ (██ of 180 patients) in the secukinumab group and █████ (██ of 183 patients) in the placebo group underwent a concomitant medical procedure and/or significant nondrug therapy. Note that no specific concomitant medical procedure and/or significant nondrug therapy was reported in more than ██ of patients in each group, across trials.

A summary of concomitant therapy from the SUNSHINE and SUNRISE trials in the entire study period is presented in Table 22. In the entire study period, the use of any concomitant therapy continued to be similar across trials, with the majority of patients (approximately ███ ██████) in each group using concomitant therapies. In both trials in the entire study period, the proportion of patients in the secukinumab group using any of the permitted concomitant therapies or any of the concomitant therapies anticipated to be used (according to the clinical experts consulted by CDA-AMC for this review), were generally similar to the proportions in treatment period 1, with a slightly higher proportion of patients using ibuprofen or paracetamol in the SUNSHINE trial (approximately one-half of patients in the secukinumab group).

In both trials, approximately one-third of patients in each group underwent a concomitant medical procedure and/or significant nondrug therapy (Table 22). Note that no concomitant medical procedure and/or significant nondrug therapy was reported in more than ██ of patients in each group, across trials.

Table 21: Summary of Concomitant Therapy From the SUNSHINE and SUNRISE Trials in Treatment Period 1 (Safety Set)

NR = not reported; q.2.w. = every 2 weeks.

Note: A patient with multiple occurrences within an ATC class is counted only once in the total row.

Sources: SUNSHINE Clinical Study Report³³ and SUNRISE Clinical Study Report.³⁴

Table 22: Summary of Concomitant Therapy From the SUNSHINE and SUNRISE Trials in Entire Study Period (Safety Set)

NR = not reported; q.2.w. = every 2 weeks.

Note: A patient with multiple occurrences within an ATC class is counted only once in the total row.

Sources: SUNSHINE Clinical Study Report Week 52⁶⁵ and SUNRISE Clinical Study Report Week 52.⁶⁶

Rescue Therapy

A summary of rescue therapy used in the SUNSHINE and SUNRISE trials is presented in Table 23 and Table 24. In both studies, relatively few patients required any rescue medication or any rescue therapy procedure during either treatment period 1 or the entire study period.

Table 23: Summary of Rescue Therapy From the SUNSHINE and SUNRISE Trials (Safety Set)