Long-term Safety of Secukinumab Over Five Years in Patients with Moderate-to-severe Plaque Psoriasis, Psoriatic Arthritis and Ankylosing Spondylitis: Update on Integrated Pooled Clinical Trial and Post-marketing Surveillance Data.

Secukinumab, a selective interleukin (IL)-17A inhibitor, is approved for use in adult and paediatric psoriasis, psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis. The aim of this study was to report the long-term safety of secukinumab in pooled data from 28 clinical trials and a post-marketing safety surveillance in psoriasis, psoriatic arthritis and ankylosing spondylitis patients. Analyses included 12,637 secukinumab-treated patients, corresponding to 15,063, 5,985 and 3,527 patient-years of exposure in psoriasis, psoriatic arthritis and ankylosing spondylitis patients, respectively. Incidences of serious adverse events were low, with no identifiable patterns across indications. Active tuberculosis or latent tuberculosis infections were rare. The incidence of opportunistic infections was < 0.2/100 patient-years, the incidence of malignancy was ≤ 1/100 patient-years, and the incidence of major adverse cardiovascular events was < 0.7/100 patient-years, with no apparent increases over time. Secukinumab demonstrated a favourable safety profile for up to 5 years of treatment across the 3 indications, and no new safety signals were identified.

Modified stoke ankylosing spondylitis spinal score as an outcome measure to assess the impact of treatment on structural progression in ankylosing spondylitis.

In ankylosing spondylitis (AS), structural damage that occurs as a result of syndesmophyte formation and ankylosis of the vertebral column is irreversible. Structural damage is currently assessed by conventional radiography and scoring systems that reliably assess radiographic structural damage are needed to capture the differential effects of drugs on structural damage progression. The validity of the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) as a primary outcome measure in evaluating the effect of AS treatments on radiographic progression rates was assessed in this review. The mSASSS has not been used, to date, as a primary outcome measure in a prospective randomized controlled clinical trial of biologic therapy in AS. This review of the medical literature confirmed that the mSASSS is the most validated and widely used method for assessing radiographic progression in AS, correlating with worsening measures of disease signs and symptoms, spinal mobility and physical function, with a 2-year interval being required to ensure sufficient sensitivity to change.

Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis.

BACKGROUND: Secukinumab is an anti-interleukin-17A monoclonal antibody that has been shown to control the symptoms of ankylosing spondylitis in a phase 2 trial. We conducted two phase 3 trials of secukinumab in patients with active ankylosing spondylitis. METHODS: In two double-blind trials, we randomly assigned patients to receive secukinumab or placebo. In MEASURE 1, a total of 371 patients received intravenous secukinumab (10 mg per kilogram of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. In MEASURE 2, a total of 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4. At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg. The primary end point was the proportion of patients with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16. RESULTS: In MEASURE 1, the ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for both comparisons with placebo); in MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P<0.001 for the 150-mg dose and P=0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period of MEASURE 1. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn's disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients. CONCLUSIONS: Secukinumab at a subcutaneous dose of 150 mg, with either subcutaneous or intravenous loading, provided significant reductions in the signs and symptoms of ankylosing spondylitis at week 16. Secukinumab at a subcutaneous dose of 75 mg resulted in significant improvement only with a higher intravenous loading dose. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT01358175 and NCT01649375.).

Secukinumab Inhibition of Interleukin-17A in Patients with Psoriatic Arthritis.

BACKGROUND: In a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis. We sought to evaluate the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in such patients. METHODS: In this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1:1:1 ratio to receive intravenous secukinumab (at a dose of 10 mg per kilogram) at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo. Patients in the placebo group were switched to subcutaneous secukinumab at a dose of 150 mg or 75 mg at week 16 or 24, depending on clinical response. The primary end point was the proportion of patients with an American College of Rheumatology 20 (ACR20) response at week 24, defined as a 20% improvement from baseline in the number of tender and swollen joints and at least three other important domains. RESULTS: ACR20 response rates at week 24 were significantly higher in the group receiving secukinumab at doses of 150 mg (50.0%) and 75 mg (50.5%) than in those receiving placebo (17.3%) (P<0.001 for both comparisons with placebo). Secondary end points, including the ACR50 response and joint structural damage, were significantly better in the secukinumab groups than in the placebo group. Improvements were sustained through 52 weeks. Infections, including candida, were more common in the secukinumab groups. Throughout the study (mean secukinumab exposure, 438.5 days; mean placebo exposure, 128.5 days), four patients in the secukinumab groups had a stroke (0.6 per 100 patient-years; 95% confidence interval [CI], 0.2 to 1.5), and two had a myocardial infarction (0.3 per 100 patient-years; 95% CI, 0.0 to 1.0), as compared with no patients in the placebo group. CONCLUSIONS: Secukinumab was more effective than placebo in patients with psoriatic arthritis, which validates interleukin-17A as a therapeutic target. Infections were more common in the secukinumab groups than in the placebo group. The study was neither large enough nor long enough to evaluate uncommon serious adverse events or the risks associated with long-term use. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT01392326.).

Effect of secukinumab on clinical and radiographic outcomes in ankylosing spondylitis: 2-year results from the randomised phase III MEASURE 1 study.

OBJECTIVE: To evaluate the effect of secukinumab, an interleukin-17A inhibitor, on clinical signs and symptoms and radiographic changes through 2 years in patients with ankylosing spondylitis (AS). METHODS: In the phase III MEASURE 1 study, patients were randomised to receive intravenous secukinumab 10 mg/kg (at baseline, week 2 and week 4) followed by subcutaneous secukinumab 150 mg (intravenous 150 mg; n=125) or 75 mg (intravenous 75 mg; n=124) every four weeks, or matched placebo (n=122). Placebo-treated patients were re-randomised to subcutaneous secukinumab 150 or 75 mg from week 16. Clinical efficacy assessments included Assessment of SpondyloArthritis international Society 20 (ASAS20) response rates through week 104. Radiographic changes at week 104 were assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). RESULTS: 97 (77.6%) and 103 (83.1%) patients in the intravenous 150 mg and intravenous 75 mg groups, respectively, completed week 104. In the full analysis set (intent-to-treat), ASAS20 response rates at week 104 were 73.7% and 68.0% in the intravenous 150 mg and intravenous 75 mg groups, respectively. Among patients with evaluable X-rays who were originally randomised to secukinumab (n=168), mean change in mSASSS from baseline to week 104 was 0.30±2.53. Serious adverse events were reported in 12.2% and 13.4% of patients in the 150 mg and 75 mg groups, respectively. CONCLUSIONS: Secukinumab improved AS signs and symptoms through 2 years of therapy, with no unexpected safety findings. Data from this study suggest a low mean progression of spinal radiographic changes, which will need to be confirmed in longer-term controlled studies. TRIAL REGISTRATION NUMBER: NCT01358175.

Secukinumab efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 Study.

BACKGROUND: There is significant unmet need in patients with ankylosing spondylitis (AS) who have inadequate response or intolerance to anti-tumour necrosis factor (TNF) treatment. Secukinumab, an anti-interleukin-17A monoclonal antibody, significantly improved signs and symptoms of AS in the MEASURE 2 study (NCT01649375). METHODS: Subjects with active AS (N=219) received secukinumab (150 or 75 mg) or placebo at baseline, weeks 1, 2, 3 and 4, and every 4 weeks thereafter. Randomisation was stratified by prior anti-TNF use: anti-TNF-naive or inadequate response/intolerance to one anti-TNF (anti-TNF-IR). The primary endpoint was Assessment of SpondyloArthritis International Society criteria (ASAS) 20 at week 16. RESULTS: At week 16, 68.2% of anti-TNF-naive subjects treated with secukinumab 150 mg achieved ASAS20 compared with 31.1% treated with placebo (p<0.001). In the anti-TNF-IR group, 50.0% of subjects treated with secukinumab 150 mg achieved an ASAS20 response compared with 24.1% treated with placebo (p<0.05). Numerically greater improvements were observed with secukinumab than with placebo for most secondary endpoints. Clinical responses were sustained through week 52. CONCLUSIONS: Secukinumab 150 mg provided sustained improvements in signs and symptoms of AS in anti-TNF-naive and anti-TNF-IR subjects through 52 weeks of therapy. TRIAL REGISTRATION NUMBER: NCT01649375.

Effect of Secukinumab Versus Adalimumab Biosimilar on Radiographic Progression in Patients With Radiographic Axial Spondyloarthritis: Results From a Head-to-Head Randomized Phase IIIb Study.

OBJECTIVE: Spinal radiographic progression is an important outcome in radiographic axial spondyloarthritis (SpA). The objective of the phase IIIb SURPASS study was to compare spinal radiographic progression in patients with radiographic axial SpA treated with secukinumab (interleukin-17A inhibitor) versus adalimumab biosimilar (Sandoz adalimumab [SDZ-ADL]; tumor necrosis factor inhibitor). METHODS: Biologic-naive patients with active radiographic axial SpA, at high risk of radiographic progression (high-sensitivity C-reactive protein [hsCRP] ≥5 mg/L and/or ≥1 syndesmophyte[s] on spinal radiographs), were randomized (1:1:1) to secukinumab (150/300 mg) or SDZ-ADL (40 mg). The proportion of patients with no radiographic progression (change from baseline [CFB] in modified Stoke Ankylosing Spondylitis Spinal Score [mSASSS] ≤0.5) on secukinumab versus SDZ-ADL at week 104 (primary endpoint), mean CFB-mSASSS, proportion of patients with ≥1 syndesmophyte(s) at baseline with no new syndesmophyte(s), and safety were evaluated. RESULTS: Overall, 859 patients (78.5% male, mSASSS 16.6, Bath Ankylosing Spondylitis Disease Activity Index 7.1, hsCRP 20.4 mg/L, and 73.0% with ≥1 syndesmophyte[s]) received secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or SDZ-ADL (n = 286). At week 104, the proportion of patients with no radiographic progression was 66.1%, 66.9%, and 65.6% (P = not significant, both secukinumab doses) and mean CFB-mSASSS was 0.54, 0.55, and 0.72 in secukinumab 150 mg, secukinumab 300 mg, and SDZ-ADL arms, respectively. Overall, 56.9%, 53.8%, and 53.3% of patients on secukinumab 150 mg, secukinumab 300 mg, and SDZ-ADL, respectively, with ≥1 syndesmophyte(s) at baseline did not develop new syndesmophyte(s) by week 104. There were no unexpected safety findings. CONCLUSION: Spinal radiographic progression over two years was low with no significant difference between secukinumab and SDZ-ADL arms. The safety of both treatments was consistent with previous reports.

Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study.

OBJECTIVE: To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA). METHODS: Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16. RESULTS: Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25-300 mg was 36.0-53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75-300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one). CONCLUSIONS: ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.

Two-year imaging outcomes from a phase 3 randomized trial of secukinumab in patients with non-radiographic axial spondyloarthritis.

BACKGROUND: Radiographic progression and course of inflammation over 2 years in patients with non-radiographic axial spondyloarthritis (nr-axSpA) from the phase 3, randomized, PREVENT study are reported here. METHODS: In the PREVENT study, adult patients fulfilling the Assessment of SpondyloArthritis International Society classification criteria for nr-axSpA with elevated CRP and/or MRI inflammation received secukinumab 150 mg or placebo. All patients received open-label secukinumab from week 52 onward. Sacroiliac (SI) joint and spinal radiographs were scored using the modified New York (mNY) grading (total sacroiliitis score; range, 0-8) and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS; range, 0-72), respectively. SI joint bone marrow edema (BME) was assessed using the Berlin Active Inflammatory Lesions Scoring (0-24) and spinal MRI using the Berlin modification of the AS spine MRI (ASspiMRI) scoring (0-69). RESULTS: Overall, 78.9% (438/555) of patients completed week 104 of the study. Over 2 years, minimal changes were observed in total radiographic SI joint scores (mean [SD] change, - 0.04 [0.49] and 0.04 [0.36]) and mSASSS scores (0.04 [0.47] and 0.07 [0.36]) in the secukinumab and placebo-secukinumab groups. Most of the patients showed no structural progression (increase ≤ smallest detectable change) in SI joint score (87.7% and 85.6%) and mSASSS score (97.5% and 97.1%) in the secukinumab and placebo-secukinumab groups. Only 3.3% (n = 7) and 2.9% (n = 3) of patients in the secukinumab and placebo-secukinumab groups, respectively, who were mNY-negative at baseline were scored as mNY-positive at week 104. Overall, 1.7% and 3.4% of patients with no syndesmophytes at baseline in the secukinumab and placebo-secukinumab group, respectively, developed ≥ 1 new syndesmophyte over 2 years. Reduction in SI joint BME observed at week 16 with secukinumab (mean [SD], - 1.23 [2.81] vs - 0.37 [1.90] with placebo) was sustained through week 104 (- 1.73 [3.49]). Spinal inflammation on MRI was low at baseline (mean score, 0.82 and 1.07 in the secukinumab and placebo groups, respectively) and remained low (mean score, 0.56 at week 104). CONCLUSION: Structural damage was low at baseline and most patients showed no radiographic progression in SI joints and spine over 2 years in the secukinumab and placebo-secukinumab groups. Secukinumab reduced SI joint inflammation, which was sustained over 2 years. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02696031.

Improvement of Signs and Symptoms of Nonradiographic Axial Spondyloarthritis in Patients Treated With Secukinumab: Primary Results of a Randomized, Placebo-Controlled Phase III Study.

OBJECTIVE: To report the primary (1-year) results from PREVENT, the first phase III study evaluating secukinumab in patients with active nonradiographic axial spondyloarthritis (SpA). METHODS: A total of 555 patients were randomized (1:1:1) to receive subcutaneous secukinumab 150 mg with a loading dose (loading dose [LD] group), secukinumab 150 mg without a loading dose (non-loading dose [NL] group), or placebo weekly and then every 4 weeks starting at week 4. The NL group received placebo at weeks 1, 2, and 3 to maintain blinding. Switch to open-label secukinumab or standard of care was permitted after week 20. The study had 2 independent analysis plans, per European Union and non-US (plan A; week 16) and US (plan B; week 52) regulatory requirements. The primary end point was 40% improvement in disease activity according to the Assessment of SpondyloArthritis international Society (ASAS40) criteria at week 16 (in the LD group) and at week 52 (in the NL group) in tumor necrosis factor inhibitor (TNFi)-naive patients. Safety analyses included all patients who received ≥1 dose of study treatment. RESULTS: Overall, 481 patients completed 52 weeks of treatment, including 84.3% (156 of 185) in the LD group, 89.7% (165 of 184) in the NL group, and 86.0% (160 of 186) in the placebo group. The proportion of patients who switched to open-label or standard of care between weeks 20 and 48 was 50.8% in the LD group, 47.3% in the NL group, and 64.0% in the placebo group. Both primary and all secondary end points were met at week 16. The proportion of TNFi-naive patients who met ASAS40 was significantly higher for LD at week 16 (41.5%) and NL at week 52 (39.8%) versus placebo (29.2% at week 16 and 19.9% at week 52; both P < 0.05). No new safety findings were reported. CONCLUSION: Our findings indicate that secukinumab 150 mg provides significant and sustained improvement in signs and symptoms of nonradiographic axial SpA through 52 weeks. Safety was consistent with previous reports.

Secukinumab in non-radiographic axial spondyloarthritis: subgroup analysis based on key baseline characteristics from a randomized phase III study, PREVENT.

BACKGROUND: To investigate the efficacy of secukinumab in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) grouped by disease activity as assessed by C-reactive protein (CRP) levels and/or magnetic resonance imaging (MRI) scores, human leukocyte antigen (HLA)-B27 status, and sex. METHODS: The phase III PREVENT study randomized (1:1:1) 555 patients to receive subcutaneous secukinumab 150 mg with (LD) or without (NL) loading dose or placebo weekly, followed by every 4 weeks starting at week 4. Here, we report the results of a post hoc analysis reporting the efficacy outcomes (pooled secukinumab) to 16 weeks by CRP, MRI, HLA-B27, and sex. RESULTS: Efficacy differences between the secukinumab and the placebo groups were highest in the CRP+, MRI+, HLA-B27+, and male subgroups, particularly for Ankylosing Spondylitis Disease Activity Score-CRP inactive disease and Assessment of SpondyloArthritis international Society (ASAS) partial remission outcomes. ASAS40 response rates in the CRP+/MRI+ subgroup was 52.3% (secukinumab) versus 21.8% (placebo; P < 0.0001) at week 16. ASAS40 response rates (secukinumab versus placebo) were 43.9% versus 32.6% in HLA-B27+, 32.7% versus 16.4% in HLA-B27- subgroups, 51.2% versus 30.8% in male, and 31.7% versus 25.3% in female patients, respectively. CONCLUSIONS: Secukinumab improved the signs and symptoms of nr-axSpA across patients grouped by CRP (+/-) and/or MRI (+/-) status, HLA-B27 (+/-) status, and sex. The highest treatment differences between secukinumab and placebo were observed in patients with both elevated CRP and evidence of sacroiliitis on MRI. Treatment difference was minimal between HLA-B27 (+) and (-) subgroups. Male patients had higher relative responses than female patients. TRIAL REGISTRATION: ClinicalTrials.gov , NCT02696031 . Registered on 02 March 2016.

Secukinumab 150/300 mg Provides Sustained Improvements in the Signs and Symptoms of Active Ankylosing Spondylitis: 3-Year Results from the Phase 3 MEASURE 3 Study.

OBJECTIVE: Secukinumab 150 mg has demonstrated significant improvement in signs and symptoms of ankylosing spondylitis (AS), with response rates sustained for up to 5 years. Here, we report end-of-study 3-year efficacy and safety results of secukinumab 150 and 300 mg from the MEASURE 3 study. METHODS: A total of 226 patients was randomized to intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous (s.c.) secukinumab 300/150 mg every 4 weeks or a matched placebo. At week 16, placebo patients were re-randomized to s.c. secukinumab 300/150 mg. Analysis at week 156 included patients initially randomized to secukinumab and those who switched from placebo to secukinumab at week 16 (any secukinumab 300/150 mg). Outcome measures at week 156 included Assessment of Spondyloarthritis International Society (ASAS) 20/40, Bath Ankylosing Spondylitis Disease Activity Index, ASAS partial remission (PR), ASAS 5/6, and Ankylosing Spondylitis Disease Activity Score-C-reactive protein inactive disease. RESULTS: The retention rates from weeks 16 to 156 were 80.5% and 80.9% in secukinumab 300 and 150 mg, respectively. ASAS 20/40 response rates at week 156 were 75.0%/56.5% and 68.2%/47.7% for secukinumab 300 and 150 mg, respectively. At week 156, response rates on more stringent clinical end points (eg, ASAS 40, ASAS-PR) were higher with the 300-mg dose, particularly in tumor necrosis factor (TNF)-inadequate responder (IR) patients. No new safety findings were observed. CONCLUSION: Secukinumab (300 and 150 mg) provided sustained improvements through 3 years in the signs and symptoms of active AS. Improvements with secukinumab 300 mg were numerically higher compared with the 150-mg dose for some higher hurdle end points and in TNF-IR patients. The safety profile of secukinumab was consistent with previous reports.

5-year efficacy and safety of secukinumab in patients with ankylosing spondylitis: end-of-study results from the phase 3 MEASURE 2 trial.

BACKGROUND: Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin 17A, has shown significant and sustained improvement in the signs and symptoms of ankylosing spondylitis over 3 years in the MEASURE 2 study. We report the 5-year (end-of-study) results of subcutaneous secukinumab 150 mg in the MEASURE 2 study. METHODS: MEASURE 2 was a phase 3, double-blind, randomised, placebo-controlled, study done in 13 countries and 53 centres. Patients with ankylosing spondylitis who were 18 years of age or older and fulfilled the modified New York criteria were randomly assigned to receive secukinumab (150 mg or 75 mg) or placebo subcutaneously at baseline and weeks 1, 2, and 3, and then every 4 weeks from week 4. At week 16, patients initially given placebo were randomly assigned again (placebo switchers) to receive secukinumab 150 mg or 75 mg. Efficacy results are reported for patients initially randomised to secukinumab 150 mg and those who switched from placebo to secukinumab 150 mg at week 16. An optional dose escalation from secukinumab 75 mg to 150 mg was initiated beginning week 140. We assessed efficacy endpoints at week 260 (5 years), including Assessment of Spondyloarthritis International Society (ASAS) 20 and ASAS 40, inactive disease according to ankylosing spondylitis disease activity score with C-reactive protein (ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI50, Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Functional Index, Short Form-36 Physical Component Summary, and ASAS partial remission. Analyses were stratified by anti-tumour necrosis factor (TNF) status (anti-TNF-naive and anti-TNF inadequate response). The safety analysis included all patients who received one dose or more of secukinumab. We report data as observed without accounting for missing data. The MEASURE 2 study was registered with ClinicalTrials.gov, NCT01649375. FINDINGS: 219 patients were randomly assigned during the trial and 150 (68%) completed 5 years of treatment, including 82 (77%) of 106 patients in the secukinumab 150 mg group and 68 (65%) of 105 in the secukinumab 75 mg group. Efficacy analysis in the secukinumab 150 mg group included 53 patients who completed the study and one additional patient who was assessed in the treatment period weeks 212-260, but did not complete the study. 134 (61%) of 219 patients were anti-TNF-naive and 85 (39%) were anti-TNF inadequate responders. ASAS responses at 5 years with secukinumab 150 mg were 36 (67%) of 54 patients (ASA20) and 27 (50%) patients (ASAS40). Sustained improvement was observed across other efficacy endpoints with secukinumab 150 mg at 5 years. At 5 years, the proportion of patients achieving efficacy endpoints of BASDAI 50 response was 53% (44/83); ASAS 5/6 response was 51% (42/83); ASDAS-CRP inactive disease was 21% (17/81); and ASAS partial remission was 25% (21/83). Exposure-adjusted incidence rates with any secukinumab dose for selected adverse events were 1·0 per 100 patient-years (95% CI 0·4-1·9) for Candida infections, 0·5 (0·1-1·2) for Crohn's disease, 0·4 (0·1-1·1) for ulcerative colitis, 0·6 (0·2-1·4) for major adverse cardiovascular events, 0·5 (0·1-1·2) for uveitis, and 0·6 (0·2-1·4) for malignant or unspecified tumours. INTERPRETATION: Secukinumab 150 mg provided sustained improvement in the signs, symptoms, and physical function in patients with ankylosing spondylitis after 5 years of treatment. The safety profile of secukinumab remained consistent with previous reports. FUNDING: Novartis Pharma.

Efficacy and Safety of Secukinumab 150 mg with and Without Loading Regimen in Ankylosing Spondylitis: 104-week Results from MEASURE 4 Study.

INTRODUCTION: To evaluate the efficacy and safety of secukinumab 150 mg, with or without a loading regimen, using a self-administered prefilled syringe in patients with ankylosing spondylitis (AS) over 104 weeks from the MEASURE 4 study. METHODS: Patients (N = 350) with active AS were randomized (1:1:1) to receive subcutaneous secukinumab 150 mg with loading dose (150 mg), without loading dose (150 mg no load), or placebo. All patients received secukinumab or placebo at baseline, weeks 1, 2, and 3 and every 4 weeks starting at week 4. The primary endpoint was the Assessment of SpondyloArthritis international Society criteria for 20% improvement (ASAS20) at week 16. RESULTS: A total of 96.9% of patients (339/350) completed 16 weeks and 82.6% (289/350) completed 104 weeks of treatment. The ASAS20 response rate at week 16 was 59.5% and 61.5% with 150 and 150 mg no load groups, respectively, versus placebo (47%; P = 0.057 and 0.054, respectively); the primary endpoint was not met. Increases in response rates achieved with secukinumab for ASAS20 at week 16 were sustained through week 104. The safety profile of secukinumab 150 mg, with or without a loading regimen, showed no new or unexpected safety signals. CONCLUSIONS: Secukinumab 150 mg, with or without loading regimen, provided rapid and sustained decreases in the signs and symptoms of patients with AS, but the differences were not statistically significant at week 16 due to higher than expected placebo responses. The responses and safety profile were consistent with previous phase 3 studies and sustained through 2 years. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02159053. FUNDING: Novartis Pharma AG, Basel, Switzerland.

Secukinumab in Active Rheumatoid Arthritis after Anti-TNFα Therapy: A Randomized, Double-Blind Placebo-Controlled Phase 3 Study.

INTRODUCTION: 'REASSURE' (NCT01377012), a phase 3 study, evaluated the efficacy and safety of secukinumab in patients with active rheumatoid arthritis (RA) who had an inadequate response to, or intolerance of, tumor necrosis factor inhibitors (TNF-inhibitors). METHODS: A total of 637 patients were randomized (1:1:1) to receive intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous secukinumab 150 mg or 75 mg every 4 weeks (starting from week 8) or placebo at the same dosing schedule. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) at week 24. Other predefined hierarchical endpoints included Health Assessment Questionnaire-Disability Index, van der Heijde modified total Sharp score (vdH-mTSS) at week 24, and major clinical response (MCR; continuous 6 month period of ACR70 response) at 1 year. RESULTS: The primary efficacy endpoint was met with both secukinumab dose groups: ACR20 response rate at week 24 was 35.2% for both secukinumab dose groups (P = 0.0009) vs 19.6% for placebo. The improvements in secondary endpoints were greater in the secukinumab dose groups vs placebo but did not meet statistical significance. The overall safety profile was similar across all treatment groups. CONCLUSION: Secukinumab demonstrated efficacy in reducing disease activity over placebo as measured by ACR20 in patients with active RA who had an inadequate response to TNF-inhibitors. Secukinumab demonstrated a safety profile similar to other biologics currently approved for RA. FUNDING: Novartis Pharma AG. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01377012.

Urinary biomarkers in lupus nephritis.

There has long been a need for biomarkers of disease activity in lupus nephritis (LN). Such markers ideally would be capable of detecting early sub-clinical disease and could be used to gauge response to therapy thus obviating the need for serial renal biopsies. Since urine can be readily obtained it lends itself as an obvious biological sample. Much of the focus has been on the measurement of urinary chemokines and cytokines in patients with LN. Elevations in urinary IL-6 and IL-10 had initially been reported to be associated with disease activity in LN but these markers have proven to be less reliable in larger studies. We and others have recently reported that MCP-1, a key chemokine involved in monocyte chemotaxis can be consistently found at high levels in the urine of patients with active LN. Moreover urinary MCP-1 levels decline with treatment of nephritis. In contrast urinary IL-8, a chemokine involved primarily in neutrophil chemotaxis is not a good predictor of disease activity in LN. Further longitudinal studies with larger numbers of patients are needed to determine the utility of urinary biomarkers such as MCP-1 which may act as surrogates of ongoing inflammation in LN.

Efficacy and Safety of Subcutaneous and Intravenous Loading Dose Regimens of Secukinumab in Patients with Active Rheumatoid Arthritis: Results from a Randomized Phase II Study.

OBJECTIVE: To evaluate the efficacy and safety of secukinumab, a fully human antiinterleukin-17A monoclonal antibody, administered with an intravenous (IV) or subcutaneous (SC) loading regimen versus placebo, in patients with active rheumatoid arthritis (RA). METHODS: In this phase II, double-blind, double-dummy, 52-week study (ClinicalTrials.gov NCT01359943), 221 patients with inadequate response to methotrexate were randomized (2:2:1) to secukinumab, IV loading 10 mg/kg at baseline, Weeks 2 and 4, then SC 150 mg every 4 weeks (n = 88); secukinumab SC loading 150 mg once weekly for 5 weeks, then every 4 weeks (n = 89); or a matching placebo (followed by secukinumab 150 mg every 4 weeks starting Week 16; n = 44). The primary endpoint was superior efficacy of pooled secukinumab versus placebo using American College of Rheumatology 20% response (ACR20) at Week 12. RESULTS: The primary efficacy endpoint was not met: ACR20 response at Week 12 was 49.2% for pooled secukinumab versus 40.9% for placebo (p = 0.3559). These variables improved significantly with pooled secukinumab versus placebo at Week 12 (all p < 0.05): the 28-joint Disease Activity Score (DAS28), patient's and physician's global assessment of disease activity, patient's assessment of RA pain, and high-sensitivity C-reactive protein levels. Results of continuous efficacy outcomes were similar between the IV and SC loading regimens. The most frequent adverse events were infections, with similar rates across secukinumab and placebo. CONCLUSION: Although the primary endpoint (ACR20) was not met, secukinumab demonstrated improved efficacy in reducing disease activity over placebo as measured by DAS28 and other secondary endpoints.

Effect of Secukinumab on Patient-Reported Outcomes in Patients With Active Ankylosing Spondylitis: A Phase III Randomized Trial (MEASURE 1).

OBJECTIVE: To evaluate the effect of secukinumab (interleukin-17A inhibitor) on patient-reported outcomes in patients with active ankylosing spondylitis (AS). METHODS: In this phase III study, 371 patients were randomized (1:1:1) to receive intravenous (IV) secukinumab 10 mg/kg at baseline and weeks 2 and 4 followed by subcutaneous (SC) secukinumab 150 mg every 4 weeks (IV→150 mg group), or SC secukinumab 75 mg every 4 weeks (IV→75 mg group), or placebo. Patient-reported outcomes included the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI criteria for 50% improvement (BASDAI 50), Short Form 36 (SF-36) physical component summary (PCS) score and mental component summary (MCS) score, Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire, Bath Ankylosing Spondylitis Functional Index (BASFI), EuroQol 5-domain (EQ-5D) questionnaire, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and Work Productivity and Activity Impairment-General Health questionnaire (WPAI-GH). RESULTS: At week 16, secukinumab IV→150 mg or IV→75 mg was associated with statistically and clinically significant improvements from baseline versus placebo in the BASDAI (-2.3 for both regimens versus -0.6; P < 0.0001 and P < 0.001, respectively), SF-36 PCS (5.6 for both regimens versus 1.0; P < 0.0001 and P < 0.001, respectively), and ASQoL (-3.6 for both regimens versus -1.0; P < 0.0001 and P < 0.001, respectively). Clinically significant improvements in the SF-36 MCS, BASFI, EQ-5D, and BASDAI 50 were observed with both secukinumab groups versus placebo at week 16; improvements were also observed in the FACIT-F and WPAI-GH. All improvements were sustained through week 52. CONCLUSION: Our findings indicate that secukinumab provides significant and sustained improvements in patient-reported disease activity and health-related quality of life, and reduces functional impairment, fatigue, and impact of disease on work productivity in patients with active AS.

Brief Report: Secukinumab Provides Significant and Sustained Inhibition of Joint Structural Damage in a Phase III Study of Active Psoriatic Arthritis.

OBJECTIVE: To assess whether secukinumab treatment in patients with active psoriatic arthritis (PsA) is associated with sustained inhibition of radiographic progression. METHODS: In this phase III, double-blind, placebo-controlled study, 606 patients with PsA were randomized to receive intravenous (IV) secukinumab at a dose of 10 mg/kg (weeks 0, 2, 4) followed by subcutaneous secukinumab at a dose of 150 mg or 75 mg (the IV→150 mg and IV→75 mg groups, respectively) or placebo. Patients were stratified according to prior anti-tumor necrosis factor (anti-TNF) exposure (71% were anti-TNF naive). At week 16, placebo-treated patients who had at least a 20% reduction in the tender and swollen joint counts (responders) continued to receive placebo until week 24; nonresponders were re-randomized to receive secukinumab at a dose of 150 mg or 75 mg. The modified total Sharp/van der Heijde score (SHS) was determined at baseline, week 16 or 24, and week 52. RESULTS: In the overall population, radiographic progression was inhibited through 52 weeks; efficacy was demonstrated for both erosion and joint space narrowing scores and in patients who switched from placebo to secukinumab at week 24. Subgroup analyses showed that secukinumab reduced radiographic progression at week 24, regardless of previous anti-TNF treatment. Among anti-TNF-naive patients, the mean changes from baseline to week 24 in the modified total SHS were 0.05 in the pooled secukinumab group and 0.57 in the placebo group; among patients with an inadequate response or intolerance to anti-TNF treatment, the mean changes were 0.16 and 0.58, respectively. Anti-TNF-naive patients showed negligible progression through week 52. Inhibition of structural damage was observed through week 52 irrespective of concomitant methotrexate use. A high proportion of patients receiving secukinumab showed no progression (change in SHS of ≤ 0.5) from baseline to week 24 (82.3% of the IV→150 mg group and 92.3% of the IV→75 mg group) and from week 24 to week 52 (85.7% of the IV→150 mg group and 85.8% of the IV→75 mg group). CONCLUSION: Secukinumab inhibited radiographic progression over 52 weeks of treatment in patients with active PsA.

Th1 cytokines in the pathogenesis of lupus nephritis: the role of IL-18.

Excessive T helper cell function is a hallmark of systemic lupus erythematosus and abnormalities of T helper cytokine profiles have been implicated in loss of immune tolerance, increased antigenic load, defective B cell suppression and a variety of clinical manifestations. Here, we emphasize the importance of T helper 1-type (i.e., IFN-gamma) with respect to T helper 2-type (i.e., IL-4) cytokines in promoting the pathogenesis of lupus nephritis focusing on the critical role of IL-18, a major T helper 1 differentiation factor. IL-18 is overexpressed in patients with lupus nephritis along with higher INF-gammaand lower IL-4 production as compared to non-nephritic lupus patients. We hypothesize a pathogenic model where both the onset and aggravation of nephritis are promoted by an imbalance of immune response towards a T helper 1 cytokine predominance due to IL-18 up-regulation. In contrast, a T helper 2-skewed cytokine profile may possibly prevent the development of renal disease. In this context, IL-18 represents a novel marker of lupus nephritis and its measurement may be helpful in the assessment of patients.