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COSENTYX® (secukinumab), the first and only fully
human interleukin 17A (IL-17A) antagonist, is indicated for the treatment of adult
patients with active AS, PsA, and moderate to severe plaque PsO. COSENTYX was
initially approved for the treatment of moderate to severe plaque PsO in adult
patients who are candidates for systemic therapy or phototherapy in January
2015. In January of 2016, the FDA approved expanded indications for COSENTYX
for the treatment of active PsA and AS in adult patients.

 

Mechanism of
Action

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IL-17A is a naturally occurring cytokine that is
involved in normal inflammatory and immune responses. Elevated levels of IL-17A
are found in psoriatic plaques, and increased quantities of IL-17A–producing
lymphocytes and innate immune cells and increased levels of IL-17A have also
been found in the blood of patients with PsA and AS. As shown in Figure 1, COSENTYX
is a monoclonal antibody that selectively binds to the IL-17A cytokine and
inhibits its interaction with the IL-17 receptor.

 The COSENTYX mechanism of action. COSENTYX selectively binds to IL-17A, thus
inhibiting the

interaction between IL-17A and its receptor. The clinical significance of the COSENTYX
mechanism of action is unknown.

“When treating patients with PsO, PsA, and AS, it’s important
that COSENTYX has a distinct mechanism because…” – Dr Mease

COSENTYX
for Patients With Active AS

 

AS is an inflammatory condition that affects
roughly 0.5% of Americans. Patients with AS experience sacroiliitis, spinal
inflammation, and enthesitis (Figure 2). A definitive diagnosis of AS requires
the presence of x-ray evidence of sacroiliitis, along with other clinical
criteria. AS typically appears first in young adulthood, with an average age of
disease onset estimated to be ~25 years of age. However, patients on average
experience a delay of nearly 9 years between disease onset and diagnosis,
placing the average age at diagnosis in the mid-30s. 

“We often see patients with AS who have been previously
misdiagnosed or were living with undiagnosed symptoms for some time…”

“Some common reasons for delays in AS diagnosis include…” –
Dr Schwartzman

 

Overview of the MEASURE
Clinical Trial Program

MEASURE 1 and MEASURE 2, two multicenter,
randomized, double-blind, placebo-controlled studies, evaluated the safety and
efficacy of COSENTYX in 590 adult patients aged 18 years and older with active
AS. MEASURE 1 was a phase 3 study of the efficacy and safety of intravenous (IV)
loading and subcutaneous (SC) maintenance dosing of COSENTYX versus placebo in
patients with active AS. MEASURE 2 was a phase 3 study of the efficacy and
safety of COSENTYX versus placebo in patients with AS that utilized SC loading
and maintenance dosing. COSENTYX is approved for administration by SC injection
for patients with AS. Therefore, we will focus on results from the MEASURE 2
study.

 

A schematic of the study design for MEASURE 2 is
presented in Figure 3. MEASURE 2 evaluated 219 adult patients with active AS,
defined as a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score
?4 despite the therapeutic use of nonsteroidal anti-inflammatory drugs (NSAIDs),
corticosteroids, or disease modifying antirheumatic drugs (DMARDs). The study
population included patients who were anti-tumor necrosis factor-? (TNF?) naive
(two-thirds of patients) and anti-TNF? experienced (one-third of patients).
Patients received an initial loading dose of COSENTYX 150 mg SC once weekly for
5 weeks, and continued with injections every 4 weeks thereafter. At week 16,
patients initially receiving placebo were assigned to an active drug arm and began
receiving COSENTYX on a monthly maintenance dosing regimen. The primary end
point was Assessment of SpondyloArthritis iternational NR5 Society
(ASAS) 20 response at week 16.

Efficacy of
COSENTYX in Patients With AS—Results From MEASURE 2

In MEASURE 2, patients treated with COSENTYX 150
mg demonstrated significantly greater improvements compared with placebo in ASAS20
(61% vs 28%, P<0.001) and ASAS40 (36% vs 11%, P<0.001) responses at week 16, and responses were seen in some patients as early as week 3. Responses were similar in patients regardless of concomitant therapies, such as methotrexate or sulfasalazine.   After week 16, patients knew they were taking the active treatment but remained blind to the dose. From 1 to 2 years, patients continued to receive the same active dose and were assessed every 8 weeks.  As with other studies with uncontrolled extensions, this phase of the study has limitations. For example, there was no placebo for comparison, and patients remaining in the extension phase may be those with better results. At 2 years, 83% (60 of 72) of patients remained in the study. An exploratory analysis of efficacy shows that the proportion of patients who achieved ASAS20 remained consistent through 2 years (Figure 4). Data are presented using multiple imputation analysis from baseline through week 104; each piece of missing data was replaced with multiple values representing an overall distribution of the plausible data and reflecting the uncertainty of the missing data. With this method, multiple data sets are created, analyzed separately, and combined for the final result. Patients reported better health-related quality of life with COSENTYX vs placebo at week 16 as assessed by Ankylosing Spondylitis Quality of Life (ASQoL) (Figure 5). The ASQoL is a self-administered questionnaire designed to assess the disease-specific quality of life (QOL) of patients with AS. The ASQoL contains 18 items assessing mobility or energy, self-care, and mood or emotion. Scores range from 0 to 18, with lower scores indicating better quality of life. Safety of COSENTYX in Patients With AS—Safety Across MEASURE 1 and MEASURE 2 COSENTYX was studied in 2 placebo-controlled AS trials with 590 patients (394 patients on COSENTYX and 196 patients on placebo). During the 16-week placebo-controlled period, the adverse events that occurred at a proportion of at least 2% and at a higher proportion in the COSENTYX groups than the placebo groups were nasopharyngitis, nausea, and upper respiratory tract infection, and there was an increased proportion of patients with infections in the COSENTYX groups (31%) compared with the placebo group (18%). Of the 571 patients exposed to COSENTYX, there were 8 cases of inflammatory bowel disease (IBD) during the entire treatment period: 5 cases of Crohn's disease (0.7 per 100 patient-years) and 3 cases of ulcerative colitis (0.4 per 100 patient-years). PsO and PsA Are Common Inflammatory Conditions PsO and PsA affect a significant proportion of adults in the United States (Figure 6). The National Psoriasis Foundation estimates that PsO affects as many as 7.5 million Americans and most often emerges during young adulthood. Roughly 1 in 10 patients with PsO also have a diagnosis of PsA, and up to 30% of patients with PsO may develop PsA. In most patients, PsA symptoms begin to appear between the ages of 30 and 50 years. A clinical study, Prevalence of Psoriatic Arthritis in Adults with Psoriasis: An Estimate From Dermatology Practice (PREPARE), was conducted to estimate the prevalence of PsA in patients with psoriasis presenting to dermatologists' offices and evaluated by rheumatologists. In the overall population, among the 949 patients evaluated, 285 (30%) received a clinical diagnosis of PsA by the study rheumatologist using medical history, physical examination, and laboratory test findings. These findings suggest that in addition to those patients with PsO who have been diagnosed with PsA, additional patients may already have PsA, and that careful examination of patients with PsO using PsA screening tools may shorten the delay in diagnosis of PsA. NR11  "Dermatologists can use various diagnostics and questionnaires to assess joint symptoms. One example is the PEST questionnaire (PASQ, ToPAS) …" "Patients with plaque PsO are not usually aware of their risk of developing PsA, so it is important that clinicians…– Dr Armstrong   COSENTYX for Patients With Moderate to Severe PsO Overview of the Pivotal Trials in Patients With PsO Four multicenter, randomized, double-blind, placebo-controlled trials enrolled 2403 patients 18 years of age and older with plaque PsO who had a minimum body surface area (BSA) involvement of 10%, and Psoriasis Area and Severity Index (PASI) score ?12, Investigator's Global Assessment modified 2011 (IGA mod 2011) score ?3, and who were candidates for phototherapy or systemic therapy.   The 4 trials shared a similar study design: patients received SC treatment at weeks 0, 1, 2, 3, and 4, followed by dosing every 4 weeks. Patients randomized to receive placebo who were nonresponders (those who did not achieve PASI 75 at week 12) were crossed over to receive COSENTYX (either 300 mg or 150 mg) at weeks 12, 13, 14, 15, and 16, followed by the same dose every 4 weeks. Coprimary end points were the proportion of patients who achieved a PASI 75 response and treatment success (clear or almost clear) on the IGA mod 2011 at week 12.   ERASURE and FIXTURE were the largest trials, examining the efficacy and safety of COSENTYX administered by a healthcare provider (Figure 7). FEATURE and JUNCTURE assessed safety, tolerability, efficacy, and usability of COSENTYX self-administration via prefilled syringe and autoinjector, respectively.  Efficacy of COSENTYX in Patients With PsO—Results From ERASURE and FIXTURE In the ERASURE study, 82% of patients treated with COSENTYX 300 mg achieved PASI 75 at week 12; of those, 7 out of 10 achieved PASI 90. In the COSENTYX 150-mg arm, 71% achieved PASI 75, and 4% of patients on placebo achieved PASI 75 at week 12 (P<0.001 for both doses vs placebo). The majority of patients achieved clear or almost clear skin: an IGA mod 2011 of 0 or 1 was achieved by 65% of patients receiving COSENTYX 300 mg and by 51% of patients receiving COSENTYX 150 mg vs 2% with placebo (P<0.001 for both doses vs placebo).   In the FIXTURE study, PASI 75 was achieved by 76% and 67% of patients in the 300-mg and 150-mg COSENTYX arms, respectively, vs 5% in the placebo arm. Clear or almost clear skin was achieved by 62% and 51% of patients in the 300-mg and 150-mg COSENTYX arms, respectively, vs 3% in the placebo arm (P<0.001 for all comparisons vs placebo).   In the COSENTYX 300-mg treatment arm, 81% and 84% of patients in ERASURE and FIXTURE, respectively, who achieved PASI 75 at week 12 sustained their response at week 52. In the COSENTYX 150-mg treatment arm, 72% and 82% of patients in ERASURE and FIXTURE, respectively, who achieved PASI 75 at week 12 sustained their response at week 52. Actual patient photos taken by investigators during clinical trials representative of average responses to COSENTYX are shown in Figure 8. Results From the ERASURE/FIXTURE Extension Study The ERASURE/FIXTURE extension study was a multicenter, randomized, double-blind, uncontrolled, withdrawal extension study of COSENTYX up to 2 yearsNW16  in patients who had completed 52 weeks in ERASURE and FIXTURE. Patients treated with COSENTYX 300 mg or 150 mg during the maintenance period in ERASURE or FIXTURE who maintained PASI 75 at week 52 were eligible to be rerandomized (N=995; COSENTYX 300 mg, n=363; COSENTYX 150 mg, n=297) to continue the same doses of COSENTYX or placebo once monthly up to week 104. Over 80% of patients treated with COSENTYX 300 mg in the ERASURE and FIXTURE studies who achieved PASI 75 at week 12 sustained their response at week 52 (81% of patients in ERASURE, and 84% in FIXTURE). In the COSENTYX 150-mg treatment arm, 72% and 82% of patients who achieved PASI 75 at week 12 sustained their response at week 52 in ERASURE and FIXTURE, respectively. Maintenance of PASI 75 at week 104 was evaluated for these patients using multiple imputation analysis.   Of the 363 patients entering the extension study who were randomized to continue on 300 mg from weeks 52 to 104, 88% maintained PASI 75 response at week 104. Baseline (week 52) PASI 90 response rates were 83%, and 71% of patients in the 300-mg arm maintained a PASI 90 response at week 104 (Figure 9). Of patients treated continuously with COSENTYX 300 mg, 87% reached week 104 without relapse. In the 150-mg arm (n=297), 76% of patients maintained a PASI 75 response at week 104. Baseline PASI 90 response rates were 64%, and 45% maintained a PASI 90 response at week 104. Safety of COSENTYX in Patients With PsO—Pooled Safety From Pivotal Trials The 4 placebo-controlled pivotal trials evaluated the safety of COSENTYX in comparison with placebo up to 12 weeks after treatment initiation. In total, 2077 subjects were evaluated, including 691 exposed to COSENTYX 300 mg, 692 to COSENTYX 150 mg, and 694 who received placebo. Adverse reactions that occurred at a rate of ?1% and at a higher rate in the COSENTYX groups than the placebo group during the 12-week placebo-controlled period of the trials were nasopharyngitis, diarrhea, upper respiratory tract infection, rhinitis, oral herpes, pharyngitis, urticaria, and rhinorrhea. Infections were reported in 28.7% of patients treated with COSENTYX compared with 18.9% of patients treated with placebo. Serious infections occurred in 0.14% of patients treated with COSENTYX and in 0.3% of patients treated with placebo. Candida infections, herpes viral infections, staphylococcal skin infections, and infections requiring treatment increased as serum concentration of COSENTYX increased. Neutropenia was observed in clinical trials; however, most cases of COSENTYX-associated neutropenia were transient and reversible, and no serious infections were associated with cases of neutropenia. Cases of IBD, in some cases serious, were observed in clinical trials with COSENTYX. In the plaque PsO  program, with 3430 patients exposed to COSENTYX over the entire treatment period for up to 52 weeks (2725 patient-years), there were 3 cases of exacerbation of Crohn's disease (0.11 per 100 patient-years), 2 cases of exacerbation of ulcerative colitis (0.08 per 100 patient-years), and 2 cases of new-onset ulcerative colitis (0.08 per 100 patient-years). There were no cases in placebo patients (n=793; 176 patient-years) during the 12-week placebo-controlled period. One case of exacerbation of Crohn's disease was reported from long-term noncontrolled portions of ongoing clinical trials in PsO. COSENTYX for Patients With Active PsA PsA is an inflammatory disease characterized by skin and joint inflammation (Figure 10). Patients with PsA may experience mild or severe skin lesions as well as mild or severe joint inflammation, including dactylitis, and enthesitis. "Patients who test positive for genetic markers associated with PsO or PsA are at an increased risk of developing these diseases…" "Some examination techniques that rheumatologists may use to assess skin symptoms in their patients include…" "Opportunities for dermatologists and rheumatologists to work together may lead to improved care for patients with PsO and PsA…" – Dr Mease   Overview of the FUTURE Clinical Trial Program Two multicenter, randomized, double-blind, placebo-controlled studies, FUTURE 1 and FUTURE 2, evaluated the safety and efficacy of COSENTYX in 1003 adult patients aged 18 years and older with active PsA. FUTURE 1 was a phase 3 study of the efficacy and safety of IV loading and SC maintenance dosing of COSENTYX versus placebo in patients with active PsA. FUTURE 2 was also a phase 3 study of the efficacy and safety of COSENTYX versus placebo in patients with PsA; however, FUTURE 2 utilized SC loading and maintenance dosing. COSENTYX is approved for administration by SC injection for patients with PsA. Therefore we will focus on results from the FUTURE 2 study.   A schematic of the study design for MEASURE 2 is presented in Figure 11. FUTURE 2 evaluated 397 adult patients with active PsA (?3 swollen and ?3 tender joints) despite the use of NSAIDs, corticosteroids, or DMARDs. The study population included a mix of patients who were anti-TNF? naive (two-thirds of patients) and anti-TNF? experienced (one-third of patients). Patients received an initial loading dose of COSENTYX 150 mg or 300 mg SC once weekly for 5 weeks, and continued with injections every 4 weeks thereafter. Nonresponder patients receiving placebo, defined as showing <20% reduction in tender or swollen joint counts, were rerandomized to receive COSENTYX (either 150 mg or 300 mg every 4 weeks) starting at week 16. Responders in the placebo group continued on placebo to week 24, and were then assigned to active drug arms and continued receiving SC injections every 4 weeks. The primary end point was American College of Rheumatology (ACR) 20 score at week 24. Efficacy of COSENTYX in Patients With PsA—Results From FUTURE 2 In FUTURE 2, patients treated with COSENTYX 300 mg and 150 mg demonstrated significantly greater improvements compared with placebo in ACR20 (57% and 60%, respectively, vs 18%; P<0.0001 for both comparisons vs placebo), ACR50 (35% and 37%, respectively, vs 6%; P<0.0001 for both comparisons vs placebo), and ACR70 (15% and 17%, respectively, vs 2%; P=0.0054 and P=0.0021, respectively, vs placebo) responses at week 16. Early improvements were seen in some patients starting at week 3. Responses were similar in patients regardless of concomitant methotrexate treatment, and regardless of prior anti-TNF? exposure. PASI 75 and PASI 90 responses were assessed in patients with ?3% of their BSA affected by PsO at baseline. In those patients with coexisting plaque PsO receiving COSENTYX (n=99), the skin lesions of PsO improved with treatment relative to placebo, as measured by the PASI.   After week 24, patients knew they were taking the active treatment but remained blind to the dose until after 1 year; at 1 year, the open-label period began. Patients who benefited from study treatment, based on the investigator's clinical assessment, continued in the 1-year, long-term posttreatment period on the same dose. At 2 years, 76% (76 of 100) of patients on 150 mg and 86% (86 of 100) of patients on 300 mg remained in the study.   In an uncontrolled exploratory analysis using multiple imputation analysis from baseline through week 104, the proportion of patients who achieved ACR20 remained consistent through 2 years (Figure 12). Patients treated with COSENTYX 150 mg and 300 mg achieved complete responses in enthesitis and dactylitis. At baseline, enthesitis or dactylitis was present in up to 66% and 46% of patients, respectively. Of those patients, the proportions with no observed enthesitis or dactylitis at week 24 are presented in Figure 13 using nonresponder imputation analysis; missing data points were imputed as nonresponses, regardless of the reason for missing data (eg, premature study discontinuation, missed visit, administrative issues). Safety of COSENTYX in Patients With PsA—Safety Across FUTURE 1 and FUTURE 2 COSENTYX was studied in 2 placebo-controlled PsA trials with 1003 patients (703 patients on COSENTYX and 300 patients on placebo). During the 16-week placebo-controlled period, adverse events that occurred at a proportion of ?2% and at a higher proportion in the COSENTYX groups than the placebo groups were nasopharyngitis, upper respiratory tract infection, headache, nausea, and hypercholesterolemia, and there was an increased proportion of patients with infections in the COSENTYX groups (29%) compared with the placebo group (26%).   There were cases of Crohn's disease and ulcerative colitis, which occurred as either exacerbations or as the development of new disease. Three cases of IBD were reported, 2 in patients who were given COSENTYX and 1 in a patient who received placebo. "Based on the available data for COSENTYX in a mixed population of patients with PsA who were anti-TNF?-naive and anti-TNF? non-responders, I consider using COSENTYX…" – Dr Schwartzman Adult patients with active AS treated with COSENTYX show improvement in ASAS scores and increased mobility compared with placebo. Adult patients with moderate to severe plaque PsO treated with COSENTYX experience significantly clearer skin at week 12 and enduring efficacy. Adult patients with active PsA treated with COSENTYX show significant improvements in joint and skin symptoms compared with placebo.   The safety profile of COSENTYX is consistent across all 3 indications with the most common adverse reactions occurring in >1% of patients being nasopharyngitis, diarrhea, and upper respiratory tract
infection. Less than 1% of patients treated with COSENTYX developed antibodies
to secukinumab in up to 52 weeks of treatment—approximately 0.5% of patients
had antibodies that were classified as neutralizing, but neutralizing
antibodies were not associated with loss of efficacy.

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