Efficacy and safety of secukinumab in the treatment of moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled phase II dose-ranging study

Authors


  • Funding sources
    Novartis Pharma AG, Basel, Switzerland.

  • Conflicts of interest
    See Appendix.

Kim A. Papp.
E-mail: kapapp@probitymedical.com

Summary

Background  Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients, and although current biologic treatments are generally well tolerated, concerns exist with respect to long-term safety. Interleukin (IL)-17A is believed to be an important effector cytokine in the pathogenesis of psoriasis and is produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity.

Objectives  To assess the efficacy and safety of different doses of secukinumab, a fully human anti-IL-17A IgG1κ monoclonal antibody, in patients with moderate-to-severe plaque psoriasis.

Methods  Patients (n = 125) were randomized 1 : 1 : 1 : 1 : 1 to receive subcutaneous doses of placebo (n = 22) or secukinumab [1 × 25 mg (n = 29), 3 × 25 mg (n = 26), 3 × 75 mg (n = 21) or 3 × 150 mg (n = 27)] at weeks 0, 4 and 8. After the 12-week treatment period, patients entered a follow-up period of 24 weeks. The primary efficacy outcome was at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75); secondary outcomes included the Investigator’s Global Assessment (IGA) and PASI 90 and 50 response rates.

Results  After 12 weeks of treatment, secukinumab 3 × 150 mg and 3 × 75 mg resulted in significantly higher PASI 75 response rates vs. placebo (82% and 57% vs. 9%; P < 0·001 and P = 0·002, respectively). Higher PASI 75 response rates compared with placebo were maintained throughout the follow-up period with these dosages [week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively], with a gradual decline of PASI 75 response over time after the dosing period. IGA response rates were significantly higher in the 3 × 150 mg group vs. placebo at week 12 (48% vs. 9%; P = 0·005) and were consistently higher for the 3 × 150 mg and 3 × 75 mg groups vs. placebo at all time points from week 4 onward. The PASI 90 response rate was significantly higher in the 3 × 150 mg group vs. placebo (52% vs. 5%) at week 12 and remained higher during the follow-up period. Secukinumab was well tolerated. Two cases of neutropenia (≤ grade 2) were reported in the 3 × 150 mg cohort.

Conclusions  Treatment with subcutaneous secukinumab 3 × 75 mg and 3 × 150 mg met the primary outcome of PASI 75 response achievement after 12 weeks, demonstrating efficacy in moderate-to-severe psoriasis.

Plaque psoriasis is a chronic inflammatory skin disease characterized by variable clinical features. It affects 1–3% of the world’s population, causes significant morbidity, and diminishes quality of life through adverse effects on physical and emotional well-being.1

The immune system, in particular an aberrant T cell-mediated immune response, is crucial in the development of plaque psoriasis,2,3 which is characterized by extensive inflammation and altered keratinocyte differentiation.3 Various cytokines produced from keratinocytes – interleukin (IL)-23, IL-21, IL-22 and IL-17A and tumour necrosis factor-α– are highly upregulated in psoriatic skin.4 In psoriatic lesions, there is increased expression of IL-17A, which is thought to be an important effector cytokine in the pathogenesis of psoriasis.5 IL-17A is known to be produced by Th17 cells, a class of helper T cells that act outside the established Th1/Th2 paradigm for regulation of innate and adaptive immunity6,7 (Fig. S1; see Supporting information). In patients with psoriasis, IL-23 and IL-1β stimulate γδ T cells to produce large amounts of IL-17A in the skin, which leads to disease progression.8,9

Conventional systemic therapies for plaque psoriasis have not fully met the needs of patients,10 and current biologic treatments, although generally well tolerated, have a still-developing long-term safety profile.11 Proof-of-concept studies conducted in patients with plaque psoriasis, rheumatoid arthritis or noninfectious uveitis have provided evidence that secukinumab (Novartis Pharma AG, Basel, Switzerland), a recombinant, high-affinity, fully human monoclonal anti-IL-17A antibody of the IgG1κ class, may be safe and efficacious as a potential treatment for these disorders.12 Targeting of the Th17/IL-17A pathway for the treatment of psoriasis is being investigated with high interest. Recent phase II studies on other investigational monoclonal antibodies targeting IL-17A and its receptor have also suggested the validity of this approach.13,14

Here we report the efficacy and safety results of a phase II dose-ranging study that tested secukinumab (25–150 mg) administered subcutaneously to patients with moderate-to-severe plaque psoriasis. A separate regimen-finding phase II study of secukinumab was also conducted in a similar patient population.15 In the study, patients were randomized to subcutaneous placebo or one of three secukinumab 150 mg induction regimens: single (week 0), early (weeks 0, 1, 2, 4) and monthly (weeks 0, 4, 8); week 12 responders who achieved at least 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75) from active treatment arms were rerandomized to either a fixed-interval (secukinumab 150 mg at weeks 12 and 24) or a treatment-at-start-of-relapse maintenance regimen (secukinumab 150 mg at visits at which a start of relapse was observed).15

Methods

Study design and participants

This was a phase II, randomized, double-blind, placebo-controlled, parallel-group study conducted at 19 centres in six countries (Canada, Estonia, Iceland, Japan, Latvia and the U.S.A.). The study was approved by ethics committees for each centre and conducted in accordance with the ethical principles of the Declaration of Helsinki. Patients provided written consent to participate in the study. The study started in March 2010 (first patient first visit) and ended in February 2011 (last patient last visit). Adult patients were randomized in a 1 : 1 : 1 : 1 : 1 ratio to receive subcutaneous placebo or subcutaneous secukinumab 1 × 25 mg, 3 × 25 mg, 3 × 75 mg or 3 × 150 mg at weeks 0, 4 and 8. At the end of the 12-week treatment period, patients entered a follow-up period of 24 weeks (Fig. 1).

Figure 1.

 Study design. s.c., subcutaneous.

Key inclusion criteria were: (i) diagnosis of chronic plaque psoriasis with active disease for at least 6 months at the time of randomization; (ii) moderate-to-severe psoriasis as defined by a PASI score of at least 12, an Investigator’s Global Assessment (IGA) score of at least 3, and body surface area involvement of at least 10%; and (iii) nonresponse to topical treatment, phototherapy and/or other previous systemic therapy. Patients were excluded from the study if they had other forms of psoriasis (e.g. pustular, erythrodermic or guttate), drug-induced psoriasis or ongoing use of psoriasis treatments/medications (including alefacept, efalizumab, ustekinumab and other biologics, systemic therapies, photochemotherapy, phototherapy and topical treatments).

Randomization and masking

The randomization numbers were generated by an interactive voice response provider using a validated, automated system. Under supervision of Novartis Drug Supply Management, the randomized numbers were linked to different treatment arms, which were in turn linked to medication numbers. Patients, investigator staff, persons performing the assessments and data analysts were blinded to the identity of the treatment from the time of randomization until the primary outcome analysis. After the primary outcome analysis, the study sponsor team was unblinded; the patients, local monitors, investigator staff and persons performing the assessments remained blinded until final database lock. Patients were stratified with a target of approximately 30% of the patients in each of the following categories: bodyweight ≥ 90 kg and bodyweight < 90 kg.

Procedures

The primary outcome of this study was to assess the efficacy of three different subcutaneous doses of secukinumab, each administered monthly (25, 75 or 150 mg), and of a single subcutaneous dose of secukinumab 25 mg in patients with moderate-to-severe plaque psoriasis with respect to PASI 75 achievement after 12 weeks of treatment compared with placebo. The key secondary outcome was to evaluate treatment success as assessed by the static IGA 12 weeks after start of treatment. The other secondary outcomes were: efficacy of the three different doses administered monthly, and of the single dose on PASI 50 and PASI 90 achievement 12 weeks after start of treatment; time to relapse; the effect of secukinumab on PASI over time; and the safety and tolerability of secukinumab administered at different concentrations as assessed by vital signs, clinical laboratory variables, electrocardiogram (ECG) and frequency of adverse events (AEs) during the study. Subgroup analyses assessed PASI 75 response according to bodyweight stratum and according to prior exposure/nonexposure to biologic therapy.

Disease activity was assessed using PASI (a composite score ranging from 0 to 72)16 and static IGA. The IGA for overall psoriatic disease was done at each visit from week 0 to week 12 using the IGA scale (0 = clear; 1 = almost clear; 2 = mild disease; 3 = moderate disease; 4 = severe disease; 5 = very severe disease). IGA treatment response was defined as achievement of IGA 0 or 1 and improvement of at least 2 points on the IGA scale compared with baseline. IGA treatment response after 12 weeks of treatment (for overall psoriatic disease) was analysed by means of the number and percentage of patients, stratified Cochran–Mantel–Haenszel (CMH) test and logistic regression, as described for the primary efficacy analysis. A subgroup analysis of IGA treatment response (for overall psoriatic disease) was conducted in the same way as described for the primary efficacy analysis. In addition, IGA treatment response (for overall psoriatic disease) and the number and percentage of patients in each IGA category were summarized by treatment group and visit. IGA treatment response (for overall psoriatic disease) was analysed by means of logistic regression separately for each visit. The binary outcome was response (yes/no) at each visit. The model accounted for treatment group, region, bodyweight stratum and baseline IGA score. For pharmacokinetic assessments, blood samples were collected by venipuncture at the scheduled visits.

Safety assessments consisted of recording all AEs and serious AEs (SAEs) and noting their severity and relationship to the study drug. They included the regular monitoring of haematology, blood chemistry and urine; regular assessments of vital signs and bodyweight; and physical examination.

Laboratory evaluations

Patients were to avoid smoking during the hour preceding the blood draws. A central laboratory (Eurofins Medinet BV, Breda, the Netherlands) was used for analysis of all specimens collected and listed below. Haemoglobin, haematocrit, red blood cell count, white blood cell count with differential [neutrophils (including bands), lymphocytes, monocytes, eosinophils and basophils] and platelet count were measured at all scheduled study visits within the visit window. Serum chemistries, including urea, creatinine, total bilirubin, aspartate transaminase/serum glutamic oxaloacetic transaminase, alanine transaminase/serum glutamic pyruvate transaminase, gamma-glutamyl transpeptidase, alkaline phosphatase, sodium, potassium, bicarbonate, calcium, phosphorus, total protein, albumin and uric acid, were measured at all scheduled study visits within the visit window. Dipstick measurements for specific gravity, protein, glucose and blood were performed locally at scheduled visits.

Immunogenicity

Blood samples for immunogenicity (antisecukinumab antibodies) were taken prior to dosing at the scheduled time points. Antisecukinumab antibodies were assessed in serum by Biacore (surface plasmon resonance; GE Healthcare, Piscataway, NJ, U.S.A.). A disease-specific cut-off calculated from predose samples was used as a threshold to distinguish between samples screening positive and negative. In addition to samples above the cut-off, samples that showed an increase from predose to later visits of > 10 resonance units (RU; rationale is the acceptance of a 10-RU variance in the drug immobilization level stated in the method validation) in the screening assay, and samples with a technical problem in the screening assay were reanalysed in a confirmation assay.

Electrocardiograms

Standard 12-lead ECGs were performed on the machines provided for the study and were independently reviewed. Clinically relevant abnormalities noted after the baseline ECG (visit 2) had to be recorded as AEs.

Pregnancy assessments

Serum β-human chorionic gonadotropin (β-hCG) and urine pregnancy tests were performed. A positive urine pregnancy test required immediate interruption of study medication until serum β-hCG was performed and found to be negative. If it was positive, the patient had to be discontinued from the trial.

Statistical analysis

The sample size calculation was based on the primary outcome, achievement of PASI 75 after 12 weeks of treatment; the study was sufficiently powered to detect a difference of 40% between an active treatment group and the placebo group in the proportion of patients achieving a response. Assuming proportions of 50% responders in the active treatment groups and 10% in the placebo group, a sample size of 23 patients per group was required to reach a power of 80% (nQuery Advisor 6.01; Statistical Solutions Ltd, Cork, Ireland). Assuming a dropout rate of < 5%, and accounting for an analysis following the intent-to-treat principle, 24 patients per group were needed. With a balanced randomization scheme, the total sample size required was at least 120.

For IGA (secondary outcome), the study provided a power of at least 80% to detect a difference of 40% in rates of responders, assuming 50% for secukinumab vs. 10% in the placebo group (nQuery Advisor 6.01). The full analysis set consisted of all patients who were randomized. Following the intent-to-treat principle, patients were analysed according to the treatment and bodyweight stratum (i.e. ≥ 90 or < 90 kg) they were assigned to at randomization.

The primary outcome, achievement of PASI 75 after 12 weeks of treatment, was analysed by means of the stratified CMH test, with region and bodyweight (< 90 or ≥ 90 kg) as strata. The two-sided type I error was set to α = 5%. Because the analysis was exploratory, no adjustment for multiple testing was performed. If a patient’s total PASI score was missing at any visit after baseline (after assignment of follow-up PASI scores to visits of the treatment period as described above), regardless of the reason why it was missing (e.g. premature study discontinuation, missed visit, administrative issues), the missing score was imputed by carrying forward the last nonmissing post-baseline PASI score (last observation carried forward, LOCF). Data from scheduled and unscheduled visits were used for LOCF. If there was no post-baseline PASI score, missing values were not imputed and the patient was removed from the analysis of PASI. Missing post-baseline IGA data were imputed in the same way as the PASI score. Missing values at visit 2 and values measured at visit 2 after first injection of study drug were not imputed and thus resulted in missing baseline values. For the final analysis, efficacy data were analysed up to week 36. Data collected later than week 36 were only listed. Logistic regression of PASI 75 response at 12 weeks after the start of treatment was performed as a supportive analysis. The model accounted for treatment group, region, bodyweight stratum and baseline PASI. The key secondary outcome variables, IGA, PASI 50 and PASI 90 response in the treatment period, were analysed as described for PASI 75 response. An LOCF approach was used for imputing missing values.

The safety set included all patients who took at least one dose of study drug and had at least one post-baseline assessment. AEs were summarized by absolute and relative frequencies and by treatment group. This trial is registered at ClinicalTrials.gov, number NCT01071252; the full study protocol is available from the study sponsor.

Role of the funding source

The sponsor designed the study. The investigators collected the data, and the sponsor held and analysed them. All authors had full access to the data and approved their completeness and analysis. A medical writer employed by Novartis wrote the first draft of the manuscript, with inputs and critical revisions from all authors. All authors reviewed and provided feedback on the subsequent versions and agreed to submit the manuscript for publication. The corresponding author had final responsibility for the decision to submit for publication.

Results

The treatment groups were well balanced with respect to demographic features and baseline characteristics (Table 1). Approximately one-third of patients (28·8%, n = 36) included in the study were previously exposed to biologics.

Table 1. Baseline patient characteristics
VariableSecukinumabPlacebo (n = 22)
1 × 25 mg (n = 29)3 × 25 mg (n = 26)3 × 75 mg (n = 21)3 × 150 mg (n = 27)
  1. BSA, body surface area; IGA, Investigator’s Global Assessment; PASI, Psoriasis Area and Severity Index; UV, ultraviolet.

Age (years), mean ± SD46·1 ± 12·6546·3 ± 13·4345·8 ± 12·3645·4 ± 11·6445·9 ± 10·88
Sex, n (%)
 Male20 (69·0)22 (84·6)14 (66·7)21 (77·8)14 (63·6)
 Female9 (31·0)4 (15·4)7 (33·3)6 (22·2)8 (36·4)
Caucasian, n (%)24 (82·8)20 (76·9)15 (71·4)20 (74·1)17 (77·3)
Weight (kg)
 Mean ± SD99·1 ± 22·290·7 ± 20·686·9 ± 14·389·2 ± 26·389·2 ± 18·4
 Median86·390·788·081·892·5
 Min–max52–13555–13465–11457–15949–117
 < 90 kg, n (%)16 (55·2)13 (50·0)12 (57·1)16 (59·3)10 (45·5)
 ≥ 90 kg, n (%)13 (44·8)13 (50·0)9 (42·9)11 (40·7)12 (54·5)
Duration of psoriasis (years), mean ± SD19·8 ± 12·6617·7 ± 11·5317·1 ± 9·0116·2 ± 10·4121·4 ± 14·80
Psoriatic arthritis present, n (%)9 (31·0)3 (11·5)1 (4·8)5 (18·5)6 (27·3)
PASI score, mean ± SD21·6 ± 11·4720·5 ± 8·3619·7 ± 6·8821·3 ± 9·4121·7 ± 8·53
IGA for overall psoriatic disease, n (%)
 Clear00000
 Moderate disease19 (65·5)17 (65·4)12 (57·1)14 (51·9)14 (63·6)
 Severe disease8 (27·6)8 (30·8)9 (42·9)12 (44·4)7 (31·8)
 Very severe disease2 (6·9)1 (3·8)01 (3·7)1 (4·5)
BSA affected by plaque psoriasis, mean ± SD26·0 ± 19·2620·7 ± 16·1519·4 ± 12·0424·5 ± 15·5926·0 ± 18·84
Previous treatment, n (%)
 UV therapy21 (72·4)16 (61·5)13 (61·9)18 (66·7)16 (72·7)
 Systemic therapy22 (75·9)13 (50·0)11 (52·4)15 (55·6)16 (72·7)
 Biologic therapy10 (34·5)6 (23·1)4 (19·0)8 (29·6)8 (36·4)

A total of 168 patients were screened, and 125 were randomly assigned to receive subcutaneous injections of secukinumab or placebo (Fig. 2). Forty-three patients were excluded, for the following reasons: did not meet diagnostic/severity criteria, had unacceptable laboratory values, withdrew consent, had unacceptable test procedure results, made unacceptable use of excluded medications/therapies, had unacceptable past medical history/concomitant diagnosis, unknown, and ‘other’. A total of 78 patients (62·4%) completed the study. A total of 47 patients (37·6%) discontinued the study; most of these discontinuations were in the placebo group (due to lack of efficacy) and in the 1 × 25 mg group (due to withdrawal of consent). One patient each in the 3 × 25 mg and 3 × 150 mg groups discontinued the study because of AEs.

Figure 2.

 Disposition of patients and primary reason for premature discontinuation.

After 12 weeks of treatment, the secukinumab 3 × 150 mg and 3 × 75 mg groups met the primary outcome by achieving statistically significant differences in PASI 75 response rates compared with placebo [82% (n = 22) and 57% (n = 12) vs. 9% (n = 2); P < 0·001 and P = 0·002, respectively]. Similarly, logistic regression analysis of PASI 75 response rates showed significant superiority with 3 × 150 mg (P < 0·001) and 3 × 75 mg (P = 0·003) compared with placebo (Table S1; see Supporting information). Higher PASI 75 response rates compared with placebo were maintained throughout the follow-up period [week 36, 26% (n = 7) and 19% (n = 4) vs. 4% (n = 1), respectively], with a gradual decline of PASI 75 response over time after the dosing period (Fig. 3). Cumulative probability for PASI percentage change from baseline after 12 weeks of treatment was highest in the 3 × 150 mg dose cohort, followed by the 3 × 75 mg and 3 × 25 mg cohorts. Similar probabilities were reported for the 1 × 25 mg and placebo cohorts (Fig. 4).

Figure 3.

 Plaque psoriasis: 75% improvement from baseline in the Psoriasis Area and Severity Index score (PASI 75), by visit (full analysis set, last observation carried forward).

Figure 4.

 Plaque psoriasis: cumulative probabilities for Psoriasis Area and Severity Index (PASI) percentage change from baseline after 12 weeks of treatment (last observation carried forward).

The proportion of patients with IGA response for overall psoriatic disease after 12 weeks of treatment was higher in the 3 × 150 mg (48%, n = 13) and 3 × 75 mg (33%, n = 7) groups than in the placebo group (9%, n = 2) (Fig. 5). Only the difference between 3 × 150 mg and placebo was statistically significant (P = 0·005), as analysed by the CMH test. The IGA treatment response rates after 12 weeks of treatment for the lower secukinumab dose cohorts were comparable to or lower than those for the placebo group (12% for 3 × 25 mg and 0% for 1 × 25 mg). IGA response rates were higher for the 3 × 150 mg and 3 × 75 mg groups vs. placebo at all time points from week 4 onward (Table S2). The proportion of patients with IGA response for overall psoriatic disease increased during the treatment period for all treatment groups except the 1 × 25 mg group (Table S2). IGA response rates were higher with 3 × 150 mg and 3 × 75 mg than with placebo at all time points from week 4 onward and higher with 3 × 25 mg than with placebo at weeks 4, 12–20, 32 and 36. Maximum IGA response rates were seen at week 16 for 3 × 150 mg (52%) and 3 × 25 mg (19%), at week 20 for 3 × 75 mg (38%), and at week 24 for placebo (18%). Only one patient in the 1 × 25 mg group (3%) achieved the IGA treatment response, which was short-lived (observed at week 16 only).

Figure 5.

 Plaque psoriasis: Investigator’s Global Assessment (IGA) response achievement, by visit (full analysis set, last observation carried forward).

The PASI 90 response rates were consistently higher for the 3 × 150 mg and 3 × 75 mg groups than for the placebo group at weeks 8–36. However, the PASI 90 response rate vs. placebo after 12 weeks of treatment was statistically significant only in the 3 × 150 mg group [52% (n = 14) vs. 4% (n = 1); P < 0·001] (Fig. S2). For both PASI 90 and IGA responses, logistic regression analysis could not be performed, because no patient in the 1 × 25 mg group achieved these responses.

The PASI 50 response rate after 12 weeks of treatment was significantly higher in the 3 × 150 mg, 3 × 75 mg and 3 × 25 mg groups than in the placebo group [85% (n = 23), 81% (n = 17) and 58% (n = 15) vs. 18% (n = 4); P < 0·001, P < 0·001 and P = 0·01, respectively]. Logistic regression analysis of PASI 50 response rates showed superiority for the 3 × 150 mg (P < 0·001) and 3 × 75 mg (P < 0·001) regimens compared with placebo.

In the analysis of the effect of bodyweight on treatment response in all groups, patients weighing < 90 kg had better PASI 75 responses than the heavier patients after 12 weeks of treatment. At week 12 in the 3 × 150 mg group, the highest PASI 75 response rate was seen in patients weighing < 90 kg (94%, n = 15), whereas 64% (n = 7) of patients weighing ≥ 90 kg achieved this response.

IGA response rates after 12 weeks of treatment were numerically higher with 3 × 150 mg and 3 × 75 mg than with placebo in both weight groups (< 90 kg and ≥ 90 kg). Among patients treated with 3 × 150 mg, there was no discernible difference between the weight groups. However, for patients in the 3 × 75 mg group, better IGA response rates (50%) were seen among patients weighing < 90 kg than among those weighing ≥ 90 kg (11%). Notably, none of the patients treated with placebo or the lower secukinumab doses (3 × 25 mg or 1 × 25 mg) and weighing ≥ 90 kg achieved the IGA response for overall psoriatic disease after 12 weeks of treatment. Higher IGA treatment responses with 3 × 150 mg and 3 × 75 mg than with placebo were seen in both subgroups in the categories of previous exposure to biologics (yes/no) and previous systemic psoriasis therapy (yes/no). The number of evaluable patients was generally low, and no relevant differences were apparent between the subgroups.

A separate subgroup analysis showed that the frequency of PASI 75 response in patients in the higher-dose secukinumab cohorts who had no previous exposure to biologics [84% (n = 16) with 3 × 150 mg and 53% (n = 9) with 3 × 75 mg] was comparable to that in patients previously exposed to biologics [71% (n = 5) with 3 × 150 mg and 75% (n = 3) with 3 × 75 mg].

Dose-proportional increases in secukinumab concentrations were observed over the dose range from 3 × 25 to 3 × 150 mg. Trough concentrations increased from 4 weeks after the first dose (day 28 postdose) until 4 weeks after the third dose (day 84 post-first dose) in the three treatment groups with three administrations, which indicates that steady state was not reached after 12 weeks of treatment. The results from the first four time points (i.e. predose and 7, 14 and 28 days postdose) show the typical pharmacokinetic profile expected for secukinumab after subcutaneous administration. The elimination half-lives were 33·0 (SD 6·33), 33·6 (6·66) and 32·2 (6·48) days for the 3 × 25 mg, 3 × 75 mg, and 3 × 150 mg groups, respectively. In the 1 × 25 mg group, many values were below the limit of quantitation.

The overall incidence of AEs was higher in the 3 × 150 mg group (89%) than in the other secukinumab dose cohorts (73–76%), which were similar in AE incidence to the placebo group (73%) (Table 2). The higher incidence of AEs in the 3 × 150 mg group was due to pharyngitis, fatigue and peripheral oedema, as well as injury, poisoning and nonprocedural complications (e.g. muscle strain, insect bites, bone fissure and tooth fracture). Of the AEs, 41·6% (n = 52) were mild, 26·4% (n = 33) were moderate and 9·6% (n = 12) were severe in intensity. The most frequently reported AEs (≥ 5%) across all cohorts were worsening of psoriasis (16·8%, n = 21), nasopharyngitis (12·0%, n = 15) and upper respiratory tract infection (6·4%, n = 8).

Table 2. Summary of adverse events (AEs)
Preferred termaSecukinumab, n (%)Placebo, n (%) (n = 22)
1 × 25 mg (n = 29)3 × 25 mg (n = 26)3 × 75 mg (n = 21)3 × 150 mg (n = 27)
  1. SAE, serious adverse event. aPreferred terms are presented in descending order of frequency in the total column.

Patients with any AE(s)22 (75·9)19 (73·1)16 (76·2)24 (88·9)16 (72·7)
Death00001 (4·5)
SAEs02 (7·7)1 (4·8)02 (9·1)
AEs leading to discontinuation01 (3·8)01 (3·7)0
AEs and infections ≥ 5% in any treatment group
 Psoriasis (worsening)8 (27·6)4 (15·4)4 (19·0)3 (11·1)2 (9·1)
 Nasopharyngitis1 (3·4)4 (15·4)4 (19·0)4 (14·8)2 (9·1)
 Pharyngitis01 (3·8)02 (7·4)0
 Upper respiratory tract infection3 (10·3)2 (7·7)1 (4·8)2 (7·4)0
 Headache1 (3·4)2 (7·7)1 (4·8)1 (3·7)0
 Pruritus1 (3·4)001 (3·7)3 (13·6)
 Respiratory tract infection, viral1 (3·4)1 (3·8)1 (4·8)02 (9·1)
 Back pain01 (3·8)2 (9·5)1 (3·7)0
 Fatigue0003 (11·1)1 (4·5)
 Hypertension1 (3·4)1 (3·8)02 (7·4)0
 Muscle strain1 (3·4)002 (7·4)0
 Myalgia2 (6·9)0001 (4·5)
 Oedema, peripheral0002 (7·4)1 (4·5)
Other AEs of interest
 Atrial fibrillation01 (3·8)001 (4·5)
 Acute myocardial infarction00001 (4·5)
 Arrhythmia1 (3·4)0000
 Cardiac failure, congestive01 (3·8)000
 Cardiomyopathy01 (3·8)000
 Myocardial infarction00001 (4·5)
 Wolff–Parkinson–White syndrome001 (4·8)00

AEs that led to permanent discontinuation of study drug occurred in one patient in the 3 × 25 mg group (exacerbation of psoriatic arthropathy) and one patient in the 3 × 150 mg group (abnormal liver function test results).

The incidence of newly occurring liver function test abnormalities was low overall, and such events were transient, with the exception of one in a patient who had abnormal values at baseline and exited the study 9 days after the first dose because of abnormal transaminase levels. Two cases of transient (single time point) decreases in absolute neutrophils (1·3 and 1·5 × 109 L−1) were reported in two patients in the 3 × 150 mg cohort.

The rate of infections across the cohorts was 40·8% (n = 51; Table 2). This was partly attributable to nasopharyngitis (15–19% for 3 × 25–3 × 150 mg vs. 3% for 1 × 25 mg and 9% for placebo). One infection in a patient in the 3 × 25 mg group (viral gastroenteritis) was reported as an SAE. No opportunistic infections, malignancies, hypersensitivity reactions, injection site reactions or autoimmune reactions were observed. No antibodies against secukinumab could be detected, and all of the samples collected from patients for immunogenicity assessment were negative.

There were five patients (4%) with SAEs: two patients each in the 3 × 25 mg (8%) and placebo (9%) groups, and one patient (5%) in the 3 × 75 mg group. The SAEs in the placebo group were one case of acute myocardial infarction (fatal) and one case of myocardial infarction (4% for each). One patient in the 3 × 25 mg group had a transient ischaemic attack, atrial fibrillation, cardiomyopathy and viral gastroenteritis and another patient in the 3 × 25 mg group experienced exacerbation of psoriatic arthropathy (4% for each event). One patient (5%) in the 3 × 75 mg group had Wolff–Parkinson–White syndrome, which already existed at the time of study entry. None of the SAEs were suspected to be related to the study drug.

Discussion

The current study was one of two dose-/regimen-finding trials to determine the optimal dose with respect to efficacy and safety of subcutaneous secukinumab in the treatment of moderate-to-severe plaque psoriasis. In our study, fixed regimens of subcutaneous secukinumab 3 × 75 mg and 3 × 150 mg every 4 weeks demonstrated efficacy in moderate-to-severe plaque psoriasis after 12 weeks of treatment. In contrast, secukinumab at 1 × 25 mg and 3 × 25 mg did not proffer substantial benefit when compared with placebo. Only the 3 × 150 mg group achieved significant PASI 90 and IGA response rates, indicating that doses of secukinumab > 75 mg led to improved efficacy. As expected, the analysis of bodyweight and treatment response showed that patients weighing < 90 kg had higher PASI 75 response rates across all dose groups, indicating that higher doses of secukinumab may be required for some patients with greater bodyweight. In this study, secukinumab was well tolerated, with an overall good safety profile, suggesting that targeted blockade of IL-17A does not result in specific target organ or immune system toxicities over the short term. These findings must be corroborated by larger, longer-term studies.

While the present study was aimed at defining optimal dose ranges, a separate regimen-finding study assessed fixed doses of 150 mg secukinumab administered at different intervals [single (week 0), early (weeks 0, 1, 2, 4) and monthly (weeks 0, 4, 8)], and week 12 PASI 75 responders from active treatment arms were rerandomized to either a fixed-interval (secukinumab 150 mg at weeks 12 and 24) or a treatment-at-start-of-relapse maintenance regimen (secukinumab 150 mg at visits at which a start of relapse was observed).15 At week 12, the early and monthly induction regimens resulted in higher PASI 75 response rates vs. placebo (54% and 42% vs. 1·5%; P < 0·001 for both). Fifteen weeks after last study drug administration, < 10% of patients in the fixed-interval and start-of-relapse groups experienced a start of relapse. The results from this regimen-finding study15 and our own dose-ranging study, together with supportive information from other trials, have been used as the basis for the design of the secukinumab phase III programme.

Limitations of the present study are its small size and short duration. It should be noted that the high rate of discontinuations in the placebo arm (11 of 22 patients) was largely attributable to lack of treatment effect (6 of 11 discontinuations). This was not totally unexpected, as patients on placebo did not have the option to switch to active treatment during the 24-week follow-up period. Phase III studies in large cohorts are ongoing and will define the long-term efficacy and safety of secukinumab.

In conclusion, secukinumab 3 × 75 mg and 3 × 150 mg administered subcutaneously met the primary outcome of PASI 75 response achievement after 12 weeks of treatment, demonstrating efficacy in the treatment of moderate-to-severe plaque psoriasis. The efficacy and safety of secukinumab observed in this trial support the initiation of confirmatory phase III studies.

Acknowledgments

We thank the patients who participated in this study. We also thank Raghuraj Puthige, PhD, Novartis Healthcare Pvt Ltd, for support in the writing of this manuscript. BioScience Communications provided editorial assistance, supported by Novartis Pharma AG. Simone McKernan and Claudia Seper provided operational excellence during the conduct of the study; Achim Guettner provided additional biostatistical advice (all Novartis Pharma AG).

Appendix

K.A.P. has received honoraria for lecturing at industry-sponsored meetings and has received industry funding for presentations and consultation at national and international meetings; he has also received research grants from and been a paid consultant to Novartis and other pharmaceutical companies; has served as a scientific officer for pharmaceutical and biotechnology corporations; and is a participant on clinical, scientific and corporate advisory boards. R.G.L. has been a member of scientific advisory boards and served as a clinical investigator for Abbott, Amgen, Celgene, Centocor/Johnson & Johnson, Eli Lilly, Fujisawa, Novartis and Pfizer, and has served as a speaker for Abbott, Amgen, Centocor/Johnson & Johnson, Fujisawa and Novartis. B.S. has consulted for Novartis and several other pharmaceutical companies; he has been a member of an advisory board for Novartis and several other pharmaceutical companies. S.H., H.J.T., C.P. and H.B.R. are full-time employees of and own stock in Novartis. M.A., D.R.B. and P.K. declare no conflicts of interest.

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