Research

JAMA Dermatology | Original Investigation

Association of Secukinumab Treatment With Tuberculosis Reactivation in Patients With Psoriasis, Psoriatic Arthritis, or Ankylosing Spondylitis Boni E. Elewski, MD; John W. Baddley, MD, MSPH; Atul A. Deodhar, MD; Marina Magrey, MD; Phoebe A. Rich, MD; Enrique R. Soriano, MD, MSc; Jennifer Soung, MD; Weibin Bao, MSc; Dorothy Keininger, MSCB; Kwaku Marfo, PharmD, MPH; Manmath Patekar, MD; Abhishek Sharma, MD; Abhijit Shete, MD; Mark Gabriel Lebwohl, MD

IMPORTANCE Approximately one-quarter of the global population have latent tuberculosis infection (LTBI), and tuberculosis (TB) is accountable for more than 1.5 million deaths annually. Methotrexate, cyclosporine, and tumor necrosis factor inhibitors may be associated with increased risk of TB and LTBI reactivation, although data are limited on the risks of TB with use of newer biologics. OBJECTIVE To assess the association of secukinumab with reporting of active TB

development, TB reactivation, and LTBI activation as an adverse event (AE) in patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. DESIGN, SETTING, AND PARTICIPANTS This qualitative study pooled data from 28 clinical trials of secukinumab used in psoriasis (17 phase 3 or 3b and 2 phase 4 trials), psoriatic arthritis (5 phase 3 trials), and ankylosing spondylitis (4 phase 3 trials). A search of the Novartis Secukinumab Compound Pool Database was conducted for the 28 trials. All trial participants who had received at least 1 approved subcutaneous dose of secukinumab (150 mg or 300 mg) were included. Before randomization in these trials, patients underwent screening for TB. Patients with active TB were excluded, and patients with LTBI were treated according to local guidelines. Data were analyzed from the start of treatment in the individual studies through December 25, 2018. MAIN OUTCOMES AND MEASURES Reporting of active TB or LTBI as an AE over a 5-year period using exposure-adjusted incidence rates (EAIR; incidence rates per 100 patient-years). RESULTS A total of 12 319 patients were included, of whom 8819 patients had psoriasis (71.6%; 5930 men [67.2%]; mean [SD] age, of 44.9 [13.5] years), 2523 had psoriatic arthritis (20.5%; 1323 women [52.4%]; mean [SD] age, 48.8 [12.1] years), and 977 had ankylosing spondylitis (7.3%; 658 men [67.3%]; mean [SD] age, 42.3 [11.9] years). In the total population, 684 patients (5.6%) had tested positive for LTBI at screening. Over 5 years, LTBI as an AE during secukinumab treatment was reported in 13 patients (0.1% of 12 319). Of these 13 patients, 6 had a prior positive LTBI test result, and 7 were newly diagnosed as having LTBI. Four of the 7 patients had psoriasis (EAIR, 0.03; 95% CI, 0.01-0.07), 1 had psoriatic arthritis (EAIR, 0.02; 95% CI, 0.00-0.11), and 2 had ankylosing spondylitis (EAIR, 0.08; 95% CI, 0.01-0.28). No cases of active TB were reported. CONCLUSIONS AND RELEVANCE This study found that LTBI reported as an AE after secukinumab treatment was uncommon and appeared to support the use of secukinumab in chronic systemic inflammatory conditions.

Author Affiliations: Author affiliations are listed at the end of this article.

JAMA Dermatol. doi:10.1001/jamadermatol.2020.3257 Published online September 30, 2020.

Corresponding Author: Boni E. Elewski, MD, University of Alabama at Birmingham, Department of Dermatology, Eye Foundation Hospital, 1720 University Blvd, Room 414, Birmingham, AL 35294 ([email protected]).

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Research Original Investigation

Secukinumab and Tuberculosis Reactivation in Patients With Psoriasis, Psoriatic Arthritis, or Ankylosing Spondylitis

T

uberculosis (TB) caused by Mycobacterium tuberculosis is the leading cause of death from an infectious agent.1 In 2017, there were an estimated 10 million new cases of TB infection worldwide, and more than 1.5 million deaths annually were attributed to this infection.1 Only a small proportion of those with M tuberculosis will develop active TB and show signs and symptoms of infection. Most people with M tuberculosis will have latent TB infection (LTBI) and show no clinical signs or symptoms of disease. Most cases of active TB are associated with the development of LTBI.2 The global burden of LTBI is estimated to be 23%, amounting to approximately 1.7 billion people.3 Therefore, a window of opportunity to detect and treat LTBI in at-risk populations is needed to reduce the global burden of active TB. Psoriasis, psoriatic arthritis, and ankylosing spondylitis are chronic immunological conditions that require long-term immunomodulatory therapies, which are associated with increased risk of infection. Methotrexate sodium, cyclosporine, and tumor necrosis factor (TNF) inhibitors have been associated with increased risk of TB and LTBI activation.4,5 Because of this increased risk, guidelines have been developed for the management of TB infection in patients who are starting antiTNF therapy.6-10 Clinical treatment with biologics targeting other pathways, such as interleukin (IL)-12/23 or IL-17, appears to have a lower risk of active TB and/or LTBI activation11-13; however, data on their long-term use are limited. This qualitative study assesses the association of secukinumab, a monoclonal antibody that directly inhibits IL-17A, with reporting of active TB development, TB reactivation, and LTBI activation as an adverse event (AE) in patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis. This ad hoc analysis includes 5-year data from 28 phase 3 and 4 clinical trials of secukinumab across the 3 indications.

Methods Each clinical trial sought and received institutional review board approval. Additional institutional review board approval was not necessary for the present study because it analyzed already acquired data. We followed the Standards for Reporting Qualitative Research (SRQR) reporting guideline.

Analysis Design The data set was pooled from 28 clinical trials of secukinumab in psoriasis (5 phase 3, 12 phase 3b, and 2 phase 4 trials), psoriatic arthritis (5 phase 3 trials), and ankylosing spondylitis (4 phase 3 trials) with up to 5-year follow-up data. A search of the Novartis Secukinumab Compound Pool Database was conducted for the 28 trials. The following preferred terms were used to retrieve cases: tuberculosis, latent tuberculosis, tuberculin test positive, pulmonary tuberculosis, mycobacterium test positive, joint tuberculosis, and mycobacterium tuberculosis complex test positive. All trial participants who had received at least 1 approved subcutaneous dose of secukinumab, 150 mg or 300 mg, were included. This study population included patients who did not respond to placebo and were randomized again to E2

Key Points Question What is the association of secukinumab with active tuberculosis (TB) development, TB reactivation, and latent tuberculosis infection (LTBI) activation? Findings In this qualitative study of 12 319 patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis, spontaneous reporting of new LTBI while undergoing secukinumab treatment was rare. No active cases of TB or LTBI reactivation were reported. Meaning The findings of this study provide a broader understanding of the safety of secukinumab and appear to support its long-term use in chronic systemic inflammatory conditions.

secukinumab at the end of the placebo-controlled blinded period (12-24 weeks).

Patients Table 1 lists details of the clinical trials selected for this analysis.14-39 Eligible patients 18 years or older with moderateto-severe plaque psoriasis or active psoriatic arthritis or ankylosing spondylitis were enrolled in the trials according to prespecified inclusion criteria. A history of TB or LTBI was not an exclusion criterion for enrollment in the trials. Prior to enrollment, all patients underwent screening for TB according to local guidelines. As per the study protocols, repeated screening for TB or LTBI was not required after randomization. Patients were tested for TB using 1 of 3 methods outlined in the individual clinical study protocol: QuantiFERON-TB Gold In-Tube test (Qiagen), T-SPOT TB test (Oxford Immunotec International), both of which are interferon (IFN)-γ release assays, or purified protein derivative (PPD) test and tuberculin skin test (TST). For all psoriatic arthritis and ankylosing spondylitis clinical trials, either a QuantiFERON or a PPD test could be used at screening. For 17 of the 19 psoriasis clinical trials, the QuantiFERON was used for TB testing at screening. The 2 exceptions were the CARIMA trial (Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated with Secukinumab),27 which used a combination of both the QuantiFERON and PPD tests, and the AJP01 trial (Open-Label Study of Subcutaneous Secukinumab to Evaluate Efficacy and Safety in Patients With Plaque Psoriasis Who Had Inadequate Response to Cyclosporine A),26 which used the T-SPOT TB test (Table 1). In addition to laboratory analysis, all patients underwent chest imaging at screening (or ≤12 weeks prior to screening) in all trials, with the exception of the PRIME study (Study of Secukinumab Compared to Fumaderm in Adults With Moderate to Severe Psoriasis),30 which did not require chest imaging before study initiation. Repeat chest imaging was not mandated by the clinical study protocol after screening. If a patient had a positive screening test result for TB, an evaluation for active TB was completed according to local guidelines. Any patient with a diagnosis of active TB at screening was excluded from study enrollment. Patients with LTBI at screening (defined as a positive QuantiFERON, PPD, or TSPOT test result with no clinical signs or symptoms of active

JAMA Dermatology Published online September 30, 2020 (Reprinted)

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jamadermatology.com

Secukinumab and Tuberculosis Reactivation in Patients With Psoriasis, Psoriatic Arthritis, or Ankylosing Spondylitis

Original Investigation Research

Table 1. Overview of Clinical Studies Included in Pooled Analysis Study (ClinicalTrials.gov identifier) ERASURE14 (NCT01365455)

Patients per trial, No. 702

Study phase 3

FIXTURE14 (NCT01358578)

936

SCULPTURE15 (NCT01406938)

Comparator Placebo

Indication Moderate to severe psoriasis

3

Etanercept, placebo

Moderate to severe psoriasis

966

3

NA

Moderate to severe psoriasis

FEATURE16 (NCT01555125) JUNCTURE17 (NCT01636687) GESTURE18 (NCT01806597) TRANSFIGURE19 (NCT01807520) CLEAR20 (NCT02074982)

174 177 199 190 335

3 3 3b 3b 3b

Moderate to severe psoriasis Moderate to severe psoriasis Palmoplantar psoriasis Nail psoriasis Moderate to severe psoriasis

ALLURE21 (NCT02748863) PROSE22 (NCT02752776) 2PRECISE23 (NCT02008890)

211 1660 214

3b 4 3b

Placebo Placebo Placebo Placebo Ustekinumab, placebo Placebo NA Placebo

OPTIMISE24 (NCT02409667) SCALP25 (NCT00267135)

1647 97

3b 3b

NA Placebo

Inadequate response to cyclosporine A26 (NCT02547714) CARIMA27 (NCT02559622) PSORITUS28 (NCT02362789) GAIN (NCT02474069)29 PRIME30 (NCT02474082) IPSI-PSO31 (NCT02595970) FUTURE 132 (NCT01392326) FUTURE 233 (NCT01752634) FUTURE 334 (NCT01989468) MEASURE 435 (NCT02294227) FUTURE 536 (NCT02404350) MEASURE 137 (NCT01358175) MEASURE 238 (NCT01649375) MEASURE 339 (NCT02008916) MEASURE 435 (NCT02159053)

34

4

NA

Moderate to severe psoriasis Moderate to severe psoriasis Palmoplantar pustular psoriasis Moderate to severe psoriasis Moderate to severe scalp psoriasis Moderate to severe psoriasis

150 130 772 105 120 475 344 406 334 964 263 145 223 346

3b 3b 3b 3b 3b 3 3 3 3 3 3 3 3 3

Placebo Placebo NA Fumaric acid esters NA Placebo Placebo Placebo Placebo NA Placebo Placebo Placebo Placebo

Moderate to severe psoriasis Moderate to severe psoriasis Moderate to severe psoriasis Moderate to severe psoriasis Moderate to severe psoriasis Psoriatic arthritis Psoriatic arthritis Psoriatic arthritis Psoriatic arthritis Psoriatic arthritis Anklyosing spondylitis Anklyosing spondylitis Anklyosing spondylitis Anklyosing spondylitis

Abbreviations: 2PRECISE, Palmoplantar Pustular Psoriasis Efficacy and Safety With Secukinumab; ALLURE, Study of Secukinumab With 2 mL Pre-Filled Syringes; CARIMA, Evaluation of Cardiovascular Risk Markers in Psoriasis Patients Treated With Secukinumab; CLEAR, A 52-Week, Multicenter, Randomized, Double-blind Study of Subcutaneous Secukinumab to Demonstrate Efficacy as Assessed by Psoriasis Area and Severity Index at 16 Weeks of Treatment Compared to Ustekinumab and to Assess Long-term Safety, Tolerability and Efficacy in Subjects With Moderate to Severe Plaque Psoriasis; ERASURE, Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis; FEATURE, First Study of Secukinumab in Pre-Filled Syringes in Subjects With Chronic Plaque-Type Psoriasis: Response at 12 Weeks; FIXTURE, Full Year Investigative Examination of Secukinumab vs Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis; FUTURE 1-3 and 5, 1: Efficacy at 24 Weeks and Long Term Safety, Tolerability and Efficacy Up to 2 Years of Secukinumab (AIN457) in Patients With Active Psoriatic Arthritis (PsA), 2: Efficacy at 24 Weeks With Long Term Safety, Tolerability and Efficacy up to 5 Years of Secukinumab in Patients of Active Psoriatic Arthritis, 3: 24-Week Efficacy and 3-Year Safety and Efficacy of Secukinumab in Active Psoriatic Arthritis, and 5: Study to Demonstrate the Efficacy (Including Inhibition of Structural Damage), Safety and Tolerability Up to 2 Years of Secukinumab in Active Psoriatic Arthritis; GAIN, A Randomized, Double-Blind, Multicenter Study to Assess the Efficacy and Safety of 16 Weeks Secukinumab Dosage Interval Shortening (2-weekly 300 mg s.c.) in Comparison to Continued Standard Treatment (4-weekly 300 mg s.c.) in Patients With Moderate-Severe Plaque Type Psoriasis Who Achieved Less Than Clear or Almost Clear Skin (Psoriasis Area Severity Index [PASI] Response ⱖ75 to PASI