Safety of secukinumab in the treatment of psoriasis

ABSTRACT

Introduction: Secukinumab is a human monoclonal antibody that selectively targets and neutralizes interleukin (IL)-17A, a cytokine that is normally involved in mucocutaneous defense against extracellular organisms and is abnormally expressed in psoriasis. In 2015, secukinumab was the first IL-17A inhibitor approved for the treatment of moderate-to-severe psoriasis.

Areas covered: This review evaluates the safety profile of secukinumab for the treatment of moderate-to-severe psoriasis and its role in the clinical landscape. A literature search was performed for articles published through February 2016; additional data from a pooled safety analysis of 10 Phase II and III secukinumab studies were reviewed.

Expert opinion: Collectively, these studies show that secukinumab demonstrates a highly favorable safety profile, especially compared with commonly used psoriasis treatments such as methotrexate and TNF-α blockers. More specifically, secukinumab carries no increased risks for end-organ toxicities, serious infection, multiple sclerosis, reactivation of latent tuberculosis or hepatitis B, leukemia/lymphoma, and nonmelanoma skin cancer. Mucocutaneous candidiasis is a common side effect and occurs at a rate of 3.55/100 subject-years with secukinumab 300 mg, yet these infections usually do not interfere with maintenance of secukinumab therapy. The combination of proven efficacy and safety make secukinumab an excellent new treatment choice for individuals with moderate-to-severe psoriasis.

KEYWORDS:

• Interleukin-17A
• psoriasis
• safety
• secukinumab

1. Introduction

Psoriasis is a common, multisystem inflammatory disease that manifests predominantly in the skin [1,2]. Between 20% and 30% of patients with plaque psoriasis have moderate-to-severe forms that require systemic therapy [3]. The pathogenesis of psoriasis is not fully understood; however, critical T-cell subsets and effector cytokines that mediate chronic inflammation observed in psoriasis have been identified [2]. More specifically, mechanistic studies have demonstrated that therapeutic blockade of the cytokine interleukin (IL)-17A or its receptor can reverse the clinical, histologic, and molecular features of psoriasis [4–6]. These initial studies led to the development and approval of new psoriasis drugs that selectively targeted IL-17A, including secukinumab (Cosentyx®, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) and ixekizumab (Taltz®, Eli Lilly and Company, Indianapolis, IN, USA) [2].

Secukinumb is the focus of this safety review (Box 1). Its therapeutic efficacy was first demonstrated in a proof-of-concept study in patients with chronic plaque-type psoriasis [7]. Subsequently, secukinumab has been studied in patients with moderate-to-severe plaque psoriasis in a number of Phase II and Phase III clinical trials [8–14]. In 2015, secukinumab was approved for the treatment of adult patients with moderate-to-severe plaque psoriasis in the United States (US) who are candidates for systemic therapy or phototherapy and also in the European Union as a first-line systemic agent. Secukinumab is also approved in the US and Europe for the treatment of psoriatic arthritis and ankylosing spondylitis. Prior to discussing the safety profile of secukinumab, the normal functional role of IL-17A will be detailed, which informs the nature of potential side effects that may be observed with this drug.

Box 1. Drug summary

Drug name: Secukinumab

Phase: Approved in over 30 countries including the United States, European Union, and Japan

Indications: Patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Patients with active psoriatic arthritis. Patients with active ankylosing spondylitis

Mechanism of action: Human anti-IL-17A G1k monoclonal antibody that selectively targets and neutralizes IL-17A

Route of administration: Subcutaneous

Chemical structure: C6584H10134N1754O2042S44

Pivotal trials: Psoriasis: ERASURE, FIXTURE [10]. Psoriatic arthritis: FUTURE 1, FUTURE 2 [35,36]. Ankylosing spondylitis: MEASURE 1, MEASURE 2 [37]

2. Methods

A search of PubMed was performed with the search terms ‘secukinumab’ (or ‘AIN457’) and ‘psoriasis’ on 7 February 2016 from the start of records. Additional data were included from a pooled safety analysis of 10 Phase II and III studies of secukinumab in patients with moderate-to-severe plaque psoriasis that was subsequently published [15].

3. Mechanism of action

Secukinumab is a fully human anti-IL-17A G1k monoclonal antibody that selectively targets and neutralizes IL-17A [3,7]. IL-17A is a pro-inflammatory cytokine produced primarily by T-helper 17 (Th17) cells, and it is also produced by natural killer cells, mast cells, and neutrophils [3]. IL-17 circulates as a homodimer of 2 IL-17A chains or as a heterodimer of IL-17A and IL-17F [3]; both structures bind to the IL-17 cell surface receptor and initiate the NF-κB and cytosine–cytosine–adenosine–adenosine–thymidine enhancer binding protein transcription factor pathways, leading to inflammatory activity that has been linked to exacerbation of psoriasis [1,16]. By binding to circulating and tissue IL-17A, secukinumab inhibits its interaction with the IL-17A receptor, thereby inhibiting downstream release of pro-inflammatory cytokines and chemokines that contribute to the development of psoriasis [16,17].

Safety concerns related to IL-17A inhibition have been informed by genetic conditions in which the production or function of IL-17A is impaired, such as Job’s syndrome (hyper-Immunoglobulin E syndrome), chronic mucocutaneous candidiasis, and autoimmune polyendocrine syndrome [18]. Individuals with these diseases are susceptible to mucocutaneous candidiasis [18]; similarly, IL-17A knockout mice are prone to chronic cutaneous candidiasis [19]. Importantly, individuals with chronic mucocutaneous candidiasis do not tend to experience increased rates of systemic candidiasis. However, an association has been observed with esophageal carcinoma [20]. Thus, both human and mouse studies support the concept that IL-17A plays a key role in mucocutaneous defense, but not systemic immunity, against extracellular organisms such as Candida albicans.

4. Clinical applications and key efficacy data

4.1. Phase I and Phase II

A proof-of-concept study in patients with psoriasis demonstrated that a single dose of 3 mg/kg of secukinumab administered intravenously led to a 58% reduction in disease severity from Baseline (measured by the mean Psoriasis Area and Severity Index [PASI]) over a 12-week follow up, whereas patients receiving placebo experienced a PASI reduction of 4% (p = 0.0001) [7]. A similarly significant difference was noted in the investigator global assessment (IGA) score reduction at Week 4, and the differences in both PASI and IGA were maintained through Week 12 [7].

In a Phase II dose-ranging study, various subcutaneous doses of secukinumab administered at Weeks 0, 4, and 8 to patients with chronic plaque psoriasis led to significantly higher proportions of patients achieving a 75% reduction in PASI score (PASI 75 response rate) at Week 12 compared with placebo [8]. PASI 75 was achieved in 82% (150-mg dose group) and 57% (75-mg dose group) of secukinumab-treated patients compared with 9% of patients treated with placebo (p < 0.001 and p = 0.002, respectively) [8]. In another Phase II study, PASI 75 response rates for secukiumab 150 mg at Week 12 were significantly greater in all cases, except single dose [9].

4.2. Phase III

Results from two Phase III trials of secukinumab in patients with psoriasis, ERASURE and FIXTURE, showed that secukinumab 300 mg and secukinumab 150 mg were superior to placebo and etanercept [10]. At Week 12, the co-primary end points of PASI 75 and IGA modified 2011 0/1 were met in both studies. PASI 75 response rates in ERASURE and FIXTURE were 77.1–81.6% (secukinumab 300 mg) and 67.0–71.6% (secukinumab 150 mg), compared with 4.5–4.9% (placebo) and 44.0% (etanercept, analyzed in FIXTURE only; p < 0.001 for all comparisons vs. placebo and etanercept) [10]. Similarly, significantly more patients treated with secukinumab achieved an IGA modified 2011 response of 0 or 1 at Week 12 (62.5–65.3% and 51.1–51.2% for secukinumab 300 mg and secukinumab 150 mg, respectively) compared with placebo (2.4–2.8%) and etanercept (27.2%, FIXTURE only; p < 0.001 for all comparisons vs. placebo and etanercept) [10]. Further, PASI 90 and PASI 100 response rates at Week 12 were significantly greater with secukinumab 300 mg (54.2–59.2% and 24.1–28.6%, respectively) and secukinumab 150 mg (39.1–41.9% and 12.8–14.4%, respectively) compared with etanercept (20.7% and 4.3%, respectively; p < 0.001 for all comparisons) and placebo (1.2–1.5% and 0–0.8%; p < 0.001 for all evaluable comparisons). Efficacy increased beyond Week 12 and peak efficacy was observed around Week 16–20 and was maintained to 52 weeks. In the Phase III CLEAR trial, secukinumab 300 mg demonstrated superior efficacy compared with ustekinumab [13]. At Week 16, PASI 90 and PASI 100 responses were achevied by 79.0% and 44.3% of patients receiving secukinumab, respectively, and by 57.6% and 28.4% of patients receiving ustekinumab, respectively (p < 0.001 for both comparisons).

5. Safety evaluation

5.1. General overview of safety

In a pooled safety analysis of 10 studies (4 Phase II and 6 Phase III; Table 1) [8–12,14,21–23], secukinumab demonstrated a favorable safety profile in patients with moderate-to-severe plaque psoriasis over a total follow-up period of 52 weeks [15]. Exclusion criteria were similar across all 10 studies. Briefly, patients were excluded if they had a history or evidence of active or untreated tuberculosis; active systemic infections such as hepatitis; history or symptoms of malignancy; or history of congestive heart failure (NYHA class ≥ III). To determine eligibility for the trial, patients were tested for tuberculosis status using a blood test (QuantiFERON®-TB Gold In-Tube). Patients with evidence for latent tuberculosis may have been included in the trial after sufficient treatment had been initiated according to local regulations. Safety data were pooled at the individual patient level. Included patients received subcutaneous secukinumab (300, 150, 75, or 25 mg), intravenous secukinumab (3 or 10 mg/kg), subcutaneous etanercept (50 mg), or placebo (Table 1) [15]. This analysis included 3993 patients, of whom 3430 received secukinumab, 323 received etanercept, and 793 received placebo; all groups had similar duration of study treatment exposure over the first 12 weeks [15].

Table 1. Summary of Phase II and III studies included in the pooled analysis of secukinumab safety in moderate-to-severe plaque psoriasis.

Study	Duration (weeks)	Description	N	Treatment regimen
Phase III
ERASURE [10] A2302	52	Efficacy/Safety in target population Placebo-controlled	738	Interventions: secukinumab 300 mg (SC), secukinumab 150 mg (SC), placebo^a Regimen: Baseline, Weeks 1, 2, and 3, and then every 4 weeks from Week 4 to 48
FIXTURE [10] A2303	52	Efficacy/Safety in target population Placebo-controlled and active-controlled (etanercept)	1306	Interventions: secukinumab 300 mg (SC), secukinumab 150 mg (SC), etanercept 50 mg, placebo^a Regimen: Baseline, Weeks 1, 2, and 3, and then every 4 weeks from Week 4 to 48 (secukinumab and placebo); twice per week to Week 12, then every 4 weeks to Week 51 (etanercept)
FEATURE [18] A2308	12^b	Efficacy/Safety in target population Placebo-controlled	177	Interventions: secukinumab 300 mg (SC), secukinumab 150 mg (SC), placebo^a Regimen: Baseline, Weeks 1, 2 and 3, and then every 4 weeks from Week 4 to 48
JUNCTURE [12] A2309^b	12^b	Efficacy/safety in target population Placebo-controlled	182	Interventions: secukinumab 300 mg (SC), secukinumab 150 mg (SC), placebo^a Regimen: Baseline, Weeks 1, 2 and 3, and then every 4 weeks from Week 4 to 48
SCULPTURE [22] A2304	52	Maintenance of efficacy/safety in target population Maintenance regimen comparison	966	Interventions: secukinumab 300 mg (SC), secukinumab 150 mg (SC) Treatment regimen: Baseline, Weeks 1, 2, and 3, and then every 4 weeks to Week 12^c,d Maintenance regimen in PASI 75 responders at Week 12 Fixed interval: every 4 weeks to Week 48 Retreatment as needed: secukinumab retreatment at start of relapse^e
STATURE [14] A2307	40 (total exposure 52 weeks)^f	Efficacy/Safety of uptitration in partial responders from A2304 Dose regimen comparison	43	Interventions: Secukinumab 10 mg/kg (IV) and secukinumab 300 mg (SC) Regimen: Baseline, Week 2 (IV dosing only) and Week 4, then 300 mg SC every 4 weeks to Week 36
Phase II
A2211 [9]	32	Multidose regimen finding in target population	404	Interventions: secukinumab 150 mg (SC), placebo Regimen, 12-week treatment period Single: single treatment at Baseline Monthly: Baseline, Weeks 4, 8 Early: Baseline, Weeks 1, 2, 4 Maintenance regimen in PASI75 responders at Week 12 Fixed interval: Week 12, 24 Retreatment as needed: retreatment at start of relapse^g Maintenance regimen in partial or nonresponders Open label: every 4 weeks to Week 32
A2211E1 [21]	20 (total exposure 52 weeks)^h	Extension of A2211 study	276	Continued maintenance regimen Fixed interval: every 12 weeks Retreatment as needed: retreatment at start of relapse^g Open label: every 4 weeks
A2212 [23]	12	Multiple-loading dose regimen in target population	100	Interventions: secukinumab 3 mg/kg (IV), secukinumab 10 mg/kg (IV) Regimens: Day 1 only or Day 1, 15, 29 (secukinumab 10 mg/kg only)
A2220 [8]	12	Dose-ranging in target population	125	Interventions: Secukinumab 25 mg (SC), secukinumab 75 mg (SC), secukinumab 150 mg (SC) Regimens: Baseline only (secukinumab 25 mg only) or Baseline and Weeks 4, 8 (secukinumab 25 mg, secukinumab 75 mg, secukinumab 150 mg)

IV: Intravenous; PASI: Psoriasis Area and Severity Index; PASI 75: ≥75% improvement in baseline PASI score; SC: subcutaneous.

^aPASI 75 nonresponders on placebo were rerandomized 1:1 to secukinumab 150 or 300 mg and treated from Week 12 onward; ^b12 weeks of safety data available from 52-week study; ^cPartial responders could enter Study A2307; ^dPASI nonresponders discontinued study treatment; ^eStart of relapse was defined as a loss of ≥20% of the maximum PASI gained in the study, with a loss of PASI 75 response; ^fPatients in STATURE study were previously exposed to secukinumab for 12 weeks in SCULPTURE study and therefore total exposure was 52 weeks; ^gStart of relapse was defined as loss of one-third of maximum PASI improvement (compared with baseline) achieved at any visit after Week 12; ^hPatients in A2211E1 study were previously exposed for up to 36 weeks in A2211 study and therefore total exposure was 52 weeks.

During the initial 12 weeks of treatment, the overall incidences of adverse events (AEs) for secukinumab at doses of 300 mg and 150 mg (54.2% and 56.3%, respectively) were comparable to the incidence in patients treated with etanercept (57.6%), but numerically higher than the incidence in the placebo group (50.4%; Table 2). The most common AEs in secukinumab-treated patients over the first 12 weeks included nasopharyngitis, headache, and upper respiratory tract infection. Throughout the entire 52 weeks, exposure-adjusted incidence rates for total AEs in all secukinumab groups were comparable to those of etanercept, and there was no dose-dependency observed for secukinumab (Table 2). The most common AEs over the full 52 weeks included nasopharyngitis, headache, and upper respiratory tract infection (Table 2).

Table 2. Summary of AEs in the pooled psoriasis population. Data taken from [15].

	Secukinumab 300 mg^a	Secukinumab 150 mg^a	Secukinumab all doses^b	Etanercept^c	Placebo
Baseline to Week 12, n (%)
Number of patients	1173	1174	2877	323	793
Patients with any AE	636 (54.2)	661 (56.3)	1620 (56.3)	186 (57.6)	400 (50.4)
Death	0	0	0	0	0
Nonfatal serious AEs	23 (2.0)	22 (1.9)	62 (2.2)	3 (0.9)	13 (1.6)
AEs causing discontinuation	18 (1.5)	18 (1.5)	43 (1.5)	6 (1.9)	10 (1.3)
Most common AEs (≥2%) by preferred term in secukinumab any dose group
Nasopharyngitis	124 (10.6)	133 (11.3)	338 (11.8)	36 (11.1)	72 (9.1)
Headache	62 (5.3)	60 (5.1)	156 (5.4)	23 (7.1)	39 (4.9)
Upper respiratory tract infection	35 (3.0)	39 (3.3)	94 (3.3)	7 (2.2)	11 (1.4)
Pruritus	34 (2.9)	40 (3.4)	84 (2.9)	8 (2.5)	21 (2.6)
Diarrhea	36 (3.1)	25 (2.1)	68 (2.4)	11 (3.4)	11 (1.4)
Hypertension	18 (1.5)	33 (2.8)	62 (2.2)	5 (1.5)	13 (1.6)
Arthralgia	18 (1.5)	29 (2.5)	58 (2.0)	12 (3.7)	17 (2.1)
Serious AEs (≥0.2%) by system organ class in secukinumab any dose group
Injury, poisoning, and procedural complications	5 (0.43)	3 (0.26)	11 (0.38)	0	3 (0.4)
Cardiac disorders	2 (0.17)	4 (0.34)	10 (0.35)	0	0
Gastrointestinal disorders	2 (0.17)	4 (0.34)	8 (0.28)	0	0
Neoplasm benign, malignant, and unspecified	3 (0.26)	3 (0.26)	7 (0.24)	0	0
Infections and infestations	1 (0.09)	2 (0.17)	6 (0.21)	0	2 (0.3)
Baseline to Week 52, n (incidence rate per 100 subject-years)
Number of patients	1410	1395	3430	323	–
Patients with any AE	1091 (236.1)	1066 (239.9)	2637 (252.9)	253 (243.4)	–
Death	0	1^d,e	1^d,e	0	–
Nonfatal serious AEs	85 (7.4)	76 (6.8)	207 (7.8)	20 (7.0)	–
AEs causing discontinuation	46^e	43^e	118^e	12^e	–
Most common AEs (≥5/100 subject-years) by preferred term in secukinumab any dose group
Nasopharyngitis	281 (27.4)	267 (26.9)	687 (29.3)	86 (35.7)	–
Headache	115 (10.5)	111 (10.4)	280 (11.0)	40 (15.2)	–
Upper respiratory tract infection	91 (8.1)	92 (8.4)	228 (8.8)	18 (6.4)	–
Arthralgia	68 (6.0)	69 (6.2)	174 (6.6)	23 (8.2)	–
Hypertension	67 (5.8)	68 (6.2)	165 (6.2)	14 (4.9)	–
Diarrhea	79 (7.0)	63 (5.7)	163 (6.2)	22 (7.9)	–
Back pain	62 (5.4)	52 (4.7)	146 (5.5)	26 (9.4)	–
Pruritus	54 (4.7)	66 (6.0)	135 (5.1)	16 (5.7)	–
Cough	70 (6.1)	44 (3.9)	133 (5.0)	12 (4.2)	–
Serious AEs (≥0.5/100 subject-years) by system organ class in secukinumab any dose group
Infections and infestations	16 (1.36)	12 (1.05)	40 (1.47)	4 (1.37)	–
Cardiac disorders	7 (0.60)	13 (1.14)	25 (0.92)	3 (1.03)	–
Injury, poisoning, and procedural complications	15 (1.28)	3 (0.26)	23 (0.85)	3 (1.03)	–
Gastrointestinal disorders	7 (0.60)	9 (0.79)	21 (0.77)	0	–
Nervous system disorders	6 (0.51)	11 (0.97)	18 (0.66)	2 (0.68)	–
Neoplasm benign, malignant, and unspecified	5 (0.43)	6 (0.53)	17 (0.63)	0	–
Skin and subcutaneous tissue disorders	6 (0.51)	5 (0.44)	16 (0.59)	1 (0.34)	–
Musculoskeletal and connective tissue disorders	7 (0.60)	5 (0.44)	15 (0.55)	4 (1.37)	–

AE: Adverse event.

^aFor Weeks 1–12, includes patients from Phase III studies only who were randomized to the specified secukinumab dose at the study start; for Weeks 1–52, includes patients from Phase III studies only who were randomized to the specified secukinumab dose at the study start and patients on placebo who were rerandomized to secukinumab at Week 12; ^bFor Weeks 1–12, includes patients from Phase II and III studies who were randomized to any dose of secukinumab at the study start; for Weeks 1–52, includes patients from Phase II and III studies who were randomized to the specified secukinumab dose at the study start and patients on placebo who were rerandomized to secukinumab at Week 12; ^cEtanercept data are from 1 pivotal Phase III study, FIXTURE; ^dOne fatal case of major adverse cardiovascular event in SCULPTURE Phase III study; subject died due to cerebral hemorrhagic stroke (150 mg retreatment-as-needed maintenance regimen); ^eExposure-adjusted IR were not calculated for deaths and AEs causing discontinuation.

Reprinted from: Secukinumab longterm safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. van de Kerkhof PC, Griffiths CE, Reich K, et al. J Am Acad Dermatol. 2016;75(83–98):e4. Copyright 2016 Elsevier.

Serious AEs occurred very rarely across all treatment groups for both the 12-week and 52-week periods, with few AEs leading to discontinuation (Table 2). There was one death due to hemorrhagic stroke (which was an adjudicated major adverse cardiovascular event [MACE]). The event occurred on Day 319 in a patient receiving secukinumab 150 mg in a retreatment-as-needed maintenance regimen. Additionally, 2- and 3-year data have been reported from an extension study for secukinumab, with no new or unexpected safety concerns being observed [24].

5.2. AEs of interest

5.2.1. Infections

In the pooled population, the incidence of infections requiring antimicrobial treatment in the first 12 weeks was comparable among the secukinumab 300 mg, secukinumab 150 mg, and etanercept groups (11.1%, 9.0%, and 9.9%, respectively) and these rates were numerically higher than in the placebo group (7.4%) (Table 3) [15]. A similar trend was observed for the overall rate of infections during the first 12 weeks of treatment. Over 52 weeks in the pooled population, the exposure-adjusted incidence rates of infections were comparable among the secukinumab 300 mg (91.06/100 subject-years), secukinumab 150 mg (85.29/100 subject-years), and etanercept groups (93.68/100 subject-years). Serious infections were infrequent, and there were no clinically meaningful differences in the exposure-adjusted incidence rates across groups. No disseminated or central nervous system herpes simplex was reported and there was no reactivation of latent tuberculosis in any of the studies. This finding is in contrast to tumor necrosis factor alpha (TNF-α) inhibitors, which are associated with reactivation of latent tuberculosis [25].

Table 3. AEs of interest in the pooled psoriasis population. Data taken from [15].

	Secukinumab 300 mg^a	Secukinumab 150 mg^a	Secukinumab all doses^b	Etanercept^c	Placebo
Baseline to Week 12, n (%)
Number of patients	1173	1174	2877	323	793
Infections	302 (25.75)	316 (26.92)	774 (26.90)	83 (25.7)	163 (20.6)
Infections requiring antimicrobial treatment	130 (11.08)	106 (9.03)	285 (9.91)	32 (9.9)	59 (7.4)
Serious infections	1 (0.09)	2 (0.17)	6 (0.21)	0	2 (0.3)
Candida infection	13 (1.11)	4 (0.34)	19 (0.66)	1 (0.3)	2 (0.3)
Herpes viral infection	14 (1.19)	12 (1.02)	33 (1.15)	1 (0.3)	5 (0.6)
Reactivation of latent tuberculosis	0	0	0	0	0
Neutropenia AEs	8 (0.68)	7 (0.60)	16 (0.56)	2 (0.6)	0 (0.0)
Grade ≥ 2^d	19 (1.62)	23 (1.96)	47 (1.63)	11 (3.41)	3 (0.38)
Malignant or unspecified tumors	2 (0.17)	4 (0.34)	6 (0.21)	0	3 (0.4)
NMSC	1 (0.09)	2 (0.17)	3 (0.10)	0	3 (0.4)
Other malignant or unspecified tumors (excluding NMSC)	1 (0.09)	2 (0.17)	3 (0.10)	0	0
Adjudicated MACE	3 (0.26)	0	3 (0.10)	0	1 (0.1)
Inflammatory bowel disease	1 (0.09)	1 (0.09)	2 (0.07)	1 (0.3)	0
Crohn’s disease	0	1 (0.09)	1 (0.03)	0	0
Ulcerative colitis	1 (0.09)	0	1 (0.03)	1 (0.3)	0
Baseline to Week 52, n (incidence rate per 100 subject-years)
Number of patients	1410	1395	3430	323	–
Infections	704 (91.06)	653 (85.29)	1640 (91.36)	172 (93.68)	–
Serious infections	16 (1.36)	12 (1.05)	40 (1.47)	4 (1.37)	–
Candida infection	41 (3.55)	21 (1.85)	69 (2.56)	4 (1.37)	–
Herpes viral infection	38 (3.28)	33 (2.93)	81 (3.02)	11 (3.81)	–
Reactivation of latent tuberculosis	0	0	0	0	–
Neutropenia AE	16 (1.37)	15 (1.32)	34 (1.26)	5 (1.71)	–
Grade ≥ 2	44 (3.8)	46 (4.1)	103 (3.9)	20 (7.2)	–
Malignant or unspecified tumors	9 (0.77)	11 (0.97)	26 (0.96)	2 (0.68)	–
NMSC	5 (0.43)	7 (0.61)	13 (0.48)	0	–
Other malignant or unspecified tumors (excluding NMSC)	4 (0.34)	4 (0.35)	13 (0.48)	2 (0.68)	–
Adjudicated MACE^e	5 (0.42)	4 (0.35)	10 (0.37)	1 (0.34)	–
Inflammatory bowel disease^f	3 (0.26)	4 (0.35)	9 (0.33)	1 (0.34)	–
Crohn’s disease	0	2 (0.18)	3^g (0.11)	0	–
Ulcerative colitis	2 (0.17)	2 (0.18)	4^h (0.15)	1 (0.34)	–

AE: Adverse event; MACE: major adverse cardiovascular event; NMSC: nonmelanoma skin cancer.

^aFor Weeks 1–12, includes patients from Phase III studies only who were randomized to the specified secukinumab dose at the study start; for Weeks 1–52, includes patients from Phase III studies only who were randomized to the specified secukinumab dose at the study start and patients on placebo who were rerandomized to secukinumab at Week 12; ^bFor Weeks 1–12, includes patients from Phase II and III studies who were randomized to any dose of secukinumab at the study start; for Weeks 1–52, includes patients from Phase II and III studies who were randomized to the specified secukinumab dose at the study start and patients on placebo who were rerandomized to secukinumab at Week 12; ^cEtanercept data are from 1 pivotal Phase III study, FIXTURE; ^dNeutropenia defined based on laboratory results (Grade 2 = absolute neutrophil count <1.5–1.0 × 10⁹/L; ^eIncludes a case of myocardial infarction in a subject treated with an alternate secukinumab 150 mg regimen (dosing at Baseline and Weeks 1, 2, and 4, followed by 150 mg every 4 weeks) in a Phase II study; ^f‘Anal fistula’ and ‘sclerosing cholangitis,’ although not true inflammatory bowel disease, were also retrieved because of the broad search criteria applied; ^gtwo of the three cases of Crohn’s disease had a prior history of Crohn’s disease, and the third case was in a subject who had gastrointestinal symptoms at baseline suggestive of undiagnosed active Crohn’s disease, the event resolved with therapy and did not cause study treatment discontinuation; ^htwo of the four ulcerative colitis cases had a prior history of ulcerative colitis.

Reprinted from: Secukinumab longterm safety experience: a pooled analysis of 10 phase II and III clinical studies in patients with moderate to severe plaque psoriasis. van de Kerkhof PC, Griffiths CE, Reich K, et al. J Am Acad Dermatol. 2016;75(83–98):e4. Copyright 2016 Elsevier.

The overall frequency of Candida infections was low in secukinumab-treated patients and displayed dose-dependency, but was higher in both dose groups (300 and 150 mg) compared with either etanercept or placebo (Table 3). All Candida infections in patients treated with secukinumab were mucocutaneous, mild or moderate in severity, responded to standard oral or topical treatment, and did not lead to discontinuation of secukinumab [15].

5.2.2. Neutropenia

Over 52 weeks in the pooled population, 77% of newly occurring or worsening neutropenia cases were Grade 1 [15]. Overall, neutropenia Grade ≥2 was more frequently reported in the etanercept group than in either of the secukinumab groups (7.2/100 subject-years compared with 3.8–4.1/100 subject-years), and no dose effect was observed with secukinumab treatment (Table 3). The incidence of Grade 3 neutropenia in patients receiving secukinumab was 0.5% compared with 0.1% in patients receiving placebo [15]. Most cases were transient, lasting 1–2 visits, and decreased to a lower grade or normal at the subsequent visit with spontaneous resolution [15]. In these 10 clinical studies, no Grade 4 neutropenia was observed with secukinumab, while 1 patient (0.3%) receiving etanercept reported Grade 4 neutropenia, and there were no cases of febrile neutropenia with either treatment [15].

5.2.3. Injection-site reactions

Over 52 weeks in FIXTURE, the incidence of injection-site reactions was lower in the combined secukinumab group than in the etanercept group (7 patients [0.7%] vs. 36 patients [11.1%]) [10].

5.3. Comorbidities and special populations

5.3.1. Cancers

Results from a meta-analysis of epidemiologic studies in patients with psoriasis found that the standardized incidence ratio (SIR) of any cancer, excluding nonmelanoma skin cancer (NMSC), was 1.16 (95% confidence interval [CI] 1.07–1.25) [26]. Notably, patients with psoriasis have an increased risk of squamous cell carcinoma (SIR = 5.3; 95% CI 2.63–10.71) and basal cell carcinoma (SIR = 2.00; 95% CI 1.83–2.20), but not melanoma (SIR = 1.07; 95% CI 0.85–1.35) [26].

In the pooled safety analysis, the incidence of malignant or unspecified tumors over the first 12 weeks was comparable among the secukinumab 300 mg (0.17%), secukinumab 150 mg (0.34%), and placebo groups (0.4%), and no events were reported for patients treated with etanercept (Table 3) [15]. Over 52 weeks, the exposure-adjusted incidence rates of malignant or unspecified tumors were comparable among the secukinumab 300 mg (0.77/100 subject-years), secukinumab 150 mg (0.97/100 subject-years), and etanercept groups (0.68/100 subject-years; Table 3). These findings indicate that the incidence of malignant or unspecified tumors in patients receiving secukinumab is in line with expected rates for patients with psoriasis.

The majority of tumors were NMSC, primarily basal cell carcinoma; it is notable that most patients who developed basal cell carcinoma had a history of prior phototherapy [15]. The exposure-adjusted incidence rates of all NMSC were 0.43/100 subject-years (5 cases) in the secukinumab 300-mg group and 0.61/100 subject-years (7 cases) in the secukinumab 150-mg group; there were no cases of NMSC with etanercept (Table 3). No lymphoma was reported [15].

5.3.2. Adjudicated MACEs

According to a meta-analysis of nine observational studies, patients with severe psoriasis have an increased risk of MACEs; in particular, these patients had a 39% increased risk of cardiovascular death, a 70% increased risk of a myocardial infarction (MI), and a 56% increased risk of stroke compared with the general US population [27]. In an analysis of over 12,000 patients in the Psoriasis Longitudinal Assessment and Registry Study (PSOLAR), the cumulative overall rate of MACEs in patients with psoriasis was 0.36 per 100 patient-years [28].

During the first 12 weeks in secukinumab studies, adjudicated MACEs were reported in three patients receiving secukinumab 300 mg (0.26%), in no patients receiving etanercept, and in one patient treated with placebo (0.1%; Table 3) [15]. Over 52 weeks, exposure-adjusted incidence rates of adjudicated MACEs were comparable in patients receiving secukinumab 300 mg (0.42/100 subject-years), secukinumab 150 mg (0.35/100 subject-years), and etanercept (0.34/100 subject-years), despite the presence of higher baseline cardiovascular risk factors in the two secukinumab groups [15]. All patients with a MACE had prior or active cardiovascular disease or risk factors, such as hypertension, smoking, obesity, dyslipidemia, or diabetes [15].

5.3.3. Inflammatory bowel disease

Patients with psoriasis are approximately 2.5-times more likely to have comorbid Crohn’s disease and 1.6-times more likely to have comorbid ulcerative colitis compared with age- and sex-matched controls [29]. A randomized, double-blind, placebo-controlled Phase IIa study of 59 patients with moderate-to-severe Crohn’s disease treated with 2 × 10 mg/kg intravenous secukinumab (on days 1 and 22) did not meet its primary end point of reducing the mean Crohn’s Disease Activity Index by ≥50 points more than placebo at Week 6 (estimated <0.1% probability [95% credible interval −4.9–72.9]); the study was therefore terminated prematurely [30]. In the pooled analysis of patients with psoriasis, secukinumab treatment and the occurrence or exacerbation of inflammatory bowel disease (IBD) did not appear to be related [15]. The exposure-adjusted incidence rate of IBD was comparable between patients receiving any dose of secukinumab (0.33/100 subject-years) and those receiving etanercept (0.34/100 subject-years) over 52 weeks (Table 3). In particular, the exposure-adjusted incidence rates of Crohn’s disease and ulcerative colitis in patients receiving any dose of secukinumab were low over the same time period (0.11 and 0.15 per 100 subject-years, respectively). There was no clinically meaningful difference in the incidence of Crohn’s disease and ulcerative colitis across treatments after either 12 or 52 weeks of therapy.

5.3.4. Mental health disorders

Psoriasis is associated with various mental health disorders. A population-based cohort study reported the unadjusted incidence of clinical diagnoses of depression, anxiety, and suicidality in patients with psoriasis to be 25.9, 20.9, and 0.9 per 1000 subject-years, respectively [31]. In addition, patients with severe psoriasis had a 72% increased risk of developing depression compared with the general population [31].

In the pooled analysis of secukinumab studies, the exposure-adjusted incidence rates for psychiatric disorders classified by Medical Dictionary for Regulatory Activities System Organ Class were 4.17/100 subject-years, 6.15/100 subject-years, and 5.64/100 subject-years for patients receiving secukinumab 300 mg, secukinumab 150 mg, and etanercept, respectively, over 52 weeks of treatment [15]. When classified by the standardized Medical Dictionary for Regulatory Activities Query ‘depression and suicide/self-injury,’ the exposure-adjusted incidence rates were 1.20/100 subject-years, 1.85/100 subject-years, and 2.06/100 subject-years in the secukinumab 300 mg, secukinumab 150 mg, and etanercept treatment groups, respectively [15]. Additionally, significant alleviation of anxiety/depression in patients with moderate-to-severe psoriasis has been reported with secukinumab in comparison to etanercept and placebo [32].

5.4. Comparison of safety with other drugs

In addition to the pooled analysis comparisons of secukinumab with etanercept [15], patients treated with secukinumab 300 mg (n = 335) showed similar incidence rates of AEs compared to patients receiving ustekinumab (n = 336) in the Phase III CLEAR trial [13]. At Week 12, AEs were reported in 64.2% of patients in the secukinumab 300 mg group compared with 58.3% of patients receiving ustekinumab, and serious AEs were reported in 3.0% of patients in both groups [13]. The incidence of infections and infestations was similar between treatment groups (29.3% and 25.3% for secukinumab 300 mg and ustekinumab, respectively). Common AEs were similar to those of the pooled secukinumab analysis [15], with only headache and nasopharyngitis occurring in ≥ 5% of patients from both groups. No deaths were reported.

6. Expert opinion

Phase II and III clinical trials have demonstrated that secukinumab treatment provides high and sustained response rates for patients with moderate-to-severe psoriasis with a favorable safety profile. Patients with psoriasis receiving secukinumab should be monitored for mucocutaneous candidiasis, which occurs at a rate of 3.55/100 subject-years with secukinumab 300 mg [15]. These infections, however, tend to be mild-to-moderate in nature, easily treated, and generally do not interfere with maintenance of secukinumab therapy. While the incidence of AEs is numerically higher in secukinumab-treated patients than in placebo-treated patients, it is comparable to that of etanercept- and ustekinumab-treated patients. Additionally, the incidence of serious AEs was low in secukinumab-treated patients over a 52-week treatment period. Because of possible concerns for IBD in patients treated with IL-17A blockers, healthcare practitioners should question potential patients regarding past/current histories of signs and symptoms of IBD. More data are needed to determine whether IBD is a rare complication of therapeutic IL-17A blockade or whether it represents coincident occurrence of an underlying comorbidity of psoriasis.

Because of cost concerns, many practitioners are required to use methotrexate prior to insurance approval of biologic therapy for moderate-to-severe psoriasis. Yet, methotrexate has relatively poor efficacy (PASI 75 response of approximately 35% after 16 weeks) [33], is often complicated by nausea and fatigue, and requires laboratory monitoring for potentially serious hepatic and hematologic abnormalities [34]. Secukinumab carries none of the safety concerns observed with methotrexate. Although direct head-to-head comparisons have not been performed, secukinumab is arguably a much safer drug than methotrexate due to specific targeting of IL-17A, a cytokine centrally involved in psoriasis pathogenesis.

Similarly, it is not uncommon for practitioners to be required to undergo ‘step-through’ treatment with TNF-α blockers, again due to cost, prior to prescribing secukinumab. While TNF-α blockers revolutionized treatment of moderate-to-severe psoriasis over 12 years ago, newer biologic therapies that target the IL-23/Th17 pathway (i.e. ustekinumab, secukinumab, and ixekizumab) offer clear efficacy and safety advantages over older biologics. As described in detail here, secukinumab has been proven to have superior efficacy when compared head-to-head with etanercept. In these trials, safety profiles were deemed comparable with these two drugs; however, long-term experience with TNF-α blockers raised certain safety issues not yet observed with secukinumab, including serious infection, multiple sclerosis, reactivation of latent tuberculosis or hepatitis B, leukemia/lymphoma, and NMSC.

In summary, specific targeting of IL-17A, a cytokine critically involved in psoriatic inflammation, by secukinumab has led to increased efficacy (PASI 90 and PASI 100 responses at Week 16 of 79% and 44%, respectively) for individuals with moderate-to-severe psoriasis when compared with older treatments [13]. Because IL-17A plays little-to-no role in systemic immunity, unlike TNF-α, it is not surprising that secukinumab has also demonstrated little-to-no issue in terms of systemic infections. Thus, secukinumab represents a major advance in the treatment of psoriasis patients who require systemic therapy to control disease.

Declaration of interest

Medical Writing support was utilized in the preparation of the this paper by Scott Forbes, Oxford Pharmagenesis Inc and was funded by Novartis. A Blauvelt has serviced as a scientific advisor and clinical study investigator for Abbvie, Amgen, AstraZeneca, Boehringer Ingelheim, Celgene, Dermira, Genentech, GlaxoSmithKline, Janssen, Lilly, MedImmune, Merk, Novartis, Pfizer, Regeneron, Sansoz, Genzyme, Sanofi, Sun, UCB and Valeant and as a speaker for Lilly. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded by Novartis.