KeywordsSecukinumab, Cosentyx, Interleukin-17A, Monoclonal antibody, ERASURE, FIXTURE, JUNCTURE, FEATURE
Secukinumab is a first-in-class human monoclonal antibody against interleukin-17A.
Secukinumab has been demonstrated in clinical studies to be significantly more efficacious in the treatment of plaque psoriasis in comparison to etanercept and ustekinumab.
The most common side effects attributable to secukinumab are monilial infections.
Secukinumab is now US Food and Drug Administration–approved for the treatment of psoriatic arthritis and ankylosing spondylitis.
Secukinumab is a first-in-class human monoclonal antibody against interleukin-17A (IL-17A). The evolving literature on the role of immune cells and inflammatory mediators in the pathogenesis of psoriasis has advanced therapeutic efficacy tremendously in the last 20 years. Early clinical studies of T-cell–targeted therapies, such as those involving cyclosporine, indicated an integral role of T cells in the pathogenesis of psoriasis. Focus of research has recently been directed toward Th17 cells, a subset of T cells producing the cytokine IL-17A. On January 21, 2015, the US Food and Drug Administration (FDA) approved secukinumab for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.
Secukinumab is manufactured by Novartis Pharmaceuticals under the trade name of Cosentyx. Administered through subcutaneous injections, there are 3 different devices: secukinumab lyophilized powder in single-use vials reconstituted with sterile water for injection (reconstitution done by health care provider only), prefilled syringes (PFSs), and autoinjector/pens (Sensoready Pen). All forms administer a single dose of 150 mg of secukinumab and are to be stored in a refrigerator, between 2°C and 8°C (36°F and 46°F). The recommended dose and regimen are a 300-mg subcutaneous injection at weeks 0, 1, 2, 3, and 4 followed by maintenance dosing of 300 mg every 4 weeks thereafter ( Fig. 12.1 ). Dosing at 150 mg, secukinumab can be used in some patients. Injection sites should be alternated, and bruised, red, scaly, hard, or psoriatic skin should be avoided. Recommended sites include front of thighs, lower abdomen (except 2 inches around the navel), and upper outer arms.
Following a subcutaneous injection of secukinumab, 55%–77% reaches systemic circulation. Peak serum concentrations are reached in approximately 6 days after administration, and steady-state concentrations are reached by week 24 when following the every 4-week dosing regimen. At 1 and 2 weeks after a single 300-mg dose, secukinumab concentrations in interstitial fluid in lesional and nonlesional skin of plaque psoriasis patients ranged from 27% to 40% of serum concentrations. The mean half-life of secukinumab ranges from 22 to 31 days.
Mechanism of action
Secukinumab is a recombinant, high-affinity, fully human immunoglobulin 1/kappa monoclonal antibody that selectively binds to and neutralizes IL-17A. IL-17A is a naturally occurring proinflammatory cytokine that has been associated with several chronic inflammatory diseases and plays a key role in the pathogenesis of plaque psoriasis. Sources of IL-17A found in psoriatic skin include Th17 cells, mast cells, and neutrophils. IL-17A upregulates the expression of inflammatory-related genes in target cells, including endothelial cells, fibroblasts, and epithelial cells, including keratinocytes, and causes the release of cytokines, chemokines, antimicrobial peptides, and other mediators that help sustain inflammation in the skin.
Psoriatic lesions are thought to have higher expression of Th17 and IL-17A, which activate keratinocytes, leading to aberrant differentiation and proliferation and the production of keratinocyte-derived angiogenic and chemoattractant factors. Further recruitment of inflammatory cells and synergy of inflammatory cytokines set up a positive feedback loop for inflammation and keratinocyte-mediated psoriatic epidermal changes. These changes include acanthosis, hyperkeratosis, and parakeratosis. At therapeutic levels, secukinumab intercepts disease pathogenesis, leading to normalization of skin histology and achievement of clear to almost clear skin for most psoriatic patients.
Secukinumab has been proven to be a highly efficacious treatment in subjects with moderate-to-severe plaque psoriasis with the most pronounced effects seen with a 300-mg dose. Clinically meaningful and statistically significant improvement based on coprimary endpoints of Psoriasis Area Severity Index (PASI) -75 response and Investigator Global Assessment for clear to almost clear skin (IGA 0/1) at week 12 was produced by 4 phase III double-blind, randomized, placebo-controlled trials (ERASURE, FIXTURE, JUNCTURE, and FEATURE) that evaluated 2-dose regimens using either 300 mg or 150 mg of secukinumab compared with placebo ( Table 12.1 ).
|ERASURE (n = 738)||FIXTURE (n = 1306)|
|300 mg Secukinumab (%) (n = 245)||150 mg Secukinumab (%) (n = 244)||Placebo (%) (n = 246)||300 mg Secukinumab (%) (n = 323)||150 mg Secukinumab (%) (n = 327)||Etanercept (%) (n = 323)||Placebo (%) (n = 324)|
|IGA 0/1||65.3 a||51.2 a||2.4||62.5 a , b||51.1 a , b||27.2||2.8|
|PASI-75||81.6 a||71.6 a||4.5||77.1 a , b||67.0 a , b||44||4.9|
|PASI-90||59.2 a||39.1 a||1.2||54.2 a , b||41.9 a , b||20.7||1.5|
|PASI-100||28.6 a||12.8 a||0.8||24.1 b||14.4 b||4.3||0|
|300 mg Secukinumab (%) (n = 59)||150 mg Secukinumab (%) (n = 59)||Placebo (%) (n = 59)||300 mg Secukinumab (%) (n = 60)||150 mg Secukinumab (%) (n = 61)||Placebo (%) (n = 61)|
|IGA 0/1||69.0 a||52.5 a||0||73.3 a||53.3 a||0|
|PASI-75||75.9 a||69.5 a||0||86.7 a||71.7 a||3.3|
|PASI-90||60.3 a||45.8 a||0||55.0 a||40.0 a||0|
Enrolled subjects were 18 years of age or older with plaque psoriasis diagnosed at least 6 months before randomization who had a minimum body surface area (BSA) involvement of 10%, an IGA score 3 or greater, and a PASI score 12 or greater and who were candidates for phototherapy or systemic therapy. Exclusion criteria included forms of psoriasis other than chronic-plaque type, ongoing use of certain psoriasis treatments, active or ongoing inflammatory disease or chronic or recurrent infectious disease, evidence of tuberculosis (TB), history of human immunodeficiency virus infection, hepatitis B or C, underlying immunocompromising conditions, lymphoproliferative diseases, malignancy or history of malignancy within the past 5 years, significant medical problems, pregnant or nursing women, and women of child-bearing potential not using effective contraception during the study. Across all 4 studies, enrolled patients were characterized as 79% biologic-naïve, 45% nonbiologic failures, 8% biologic failures, 6% anti-tumor necrosis factor (TNF) failures, and 2% IL-12/23 inhibitor failures. However, median baseline PASI score, baseline IGA score range (moderate to severe), median baseline BSA (≥27), and median Dermatology Life Quality Index score of patients were generally consistent across all treatment groups.
ERASURE and FIXTURE
The ERASURE trial enrolled 738 patients, whom were randomized into the secukinumab 150 mg, secukinumab 300 mg, or placebo arm. Each group received their respective doses at weeks 0, 1, 2, 3, and 4 followed by a dose every 4 weeks until week 48. The FIXTURE trial evaluated 1308 patients, whom were randomized into similar arms to the ERASURE trial with similar dosing schedules, but with the addition of an etanercept arm. Patients randomized to etanercept received 50-mg doses twice per week for 12 weeks followed by 50 mg every week. In both trials, patients in the placebo group who were nonresponders at week 12 were crossed over to receive secukinumab in either the 150-mg or the 300-mg dose at weeks 12, 13,14, 15, and 16 followed by the same dose every 4 weeks. Each study consisted of a 12-week induction period (baseline to week 12) and a 40-week maintenance period (weeks 12–52).
In the ERASURE study, 81.6% and 71.6% of subjects, respectively, achieved a PASI-75 response, and 65.3% and 51.2%, respectively, achieved an IGA 0/1 response, at week 12. These values were significantly higher in comparison to placebo; 4.5% and 2.4% of the placebo group achieved a respective PASI-75 or IGA 0/1 response at week 12 ( P <.001 for each comparison of secukinumab vs placebo) (see Table 12.1 ).
In the FIXTURE study, 77.1% and 67.0% of subjects, respectively, achieved a PASI-75 response, and 65.3% and 51.2%, respectively, achieved an IGA 0/1 response, at week 12. These values were significantly higher in comparison to etanercept and to placebo; 44.0% and 27.2% of the etanercept group and 4.9% and 2.8% of the placebo group achieved a respective PASI-75 and IGA 0/1 response at week 12 ( P <.001 for each comparison of secukinumab vs etanercept and secukinumab vs placebo) (see Table 12.1 ).
In both trials, continued treatment through week 52 was associated with sustained high response rates (PASI-75 response in 81%–84% for 300 mg, and 72%–82% for 150 mg at week 52) in most patients ( Table 12.2 ).
|300 mg Secukinumab (%) (n = 245)||150 mg Secukinumab (%) (n = 244)||Placebo||300 mg Secukinumab (%) (n = 323)||150 mg Secukinumab (%) (n = 327)||Etanercept (%) (n = 323)||Placebo|
|IGA 0/1 from wk 12 to wk 52||74.4||59.2||NE||79.7||67.7||56.8||NE|
|PASI-75 from wk 12 to wk 52||80.5||72.4||NE||84.3||82.2||72.5||NE|
FEATURE and JUNCTURE
The FEATURE and JUNCTURE studies evaluated the safety, tolerability, and usability of administering secukinumab with a PFS or an autoinjector pen, respectively, and have also demonstrated the superior efficacy of secukinumab to placebo at week 12. The FEATURE and JUNCTURE studies enrolled 177 and 182 patients, respectively. Patients in each trial were randomized into the secukinumab 150 mg, secukinumab 300 mg, or placebo arm and received their respective doses at weeks 0, 1, 2, 3, and 4 followed by a dose every 4 weeks.
In FEATURE, treatment with secukinumab 300 and 150 mg via the PFS resulted in 75.9% and 69.5% of subjects, respectively, achieving a PASI-75 response, and 69.0% and 52.5%, respectively, achieving an IGA 0/1 response, at week 12. These values were significantly higher in comparison to placebo; 0% of the placebo group achieved a PASI-75 or IGA 0/1 response at week 12 ( P <.001 for each comparison of secukinumab vs placebo). Usability of PFS was demonstrated by most subjects successfully following the steps in the instructions for use for self-injection via the PFS and the absence of critical hazard incidents. In addition, acceptability of the PFS was evaluated at baseline and at week 12 by Self-Injection Assessment Questionnaire domains, which included feelings about injections, self -confidence, and satisfaction with self-injection. Scores for all 3 domains remained high from baseline to week 12 in all groups, indicating that self-injections with PFS was acceptable to subjects before the first injection and remained highly acceptable up to week 12.
In JUNCTURE, treatment with secukinumab 300 and 150 mg via the autoinjector pen resulted in 86.7% and 71.7% of subjects, respectively, achieving a PASI-75 response, and 73.3% and 53.3%, respectively, achieving an IGA 0/1 response, at week 12. These values were significantly higher in comparison to placebo; 3.3% and 0% of the placebo group achieved a PASI-75 or IGA 0/1 response at week 12, respectively ( P <.001 for each comparison of secukinumab vs placebo). Usability was evaluated in a similar fashion to the FEATURE trial and demonstrated high subject-reported injection tolerability, ease of use, absence of critical use-related hazards, and acceptability that was high at baseline and remained high up to week 12.
In all 4 studies, coprimary endpoints (PASI-75 response and IGA 0/1 response at week 12) and key secondary endpoints (ie, PASI-90 response at week 12) were met by both dosage arms of secukinumab with significantly higher proportions of patients compared with the placebo or etanercept (FIXTURE only) arm ( Fig. 12.2 ). Efficacy is dose dependent as evidenced by consistently better responses across all efficacy end points with the 300-mg versus the 150-mg regimen in each of the 4 trials. Onset of efficacy was observed early during the course of therapy; a 50% reduction in mean PASI from baseline was achieved by week 3 in the 300-mg group and by week 4 in the 150-mg group across all 4 trials. With regards to a maintenance regimen of secukinumab, recent evidence (SCULPTURE study) indicates that regular 4-week interval dosing is more efficacious than a re-treatment-as-needed regimen in maintaining long-term psoriasis control.