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Papers by Todd Fox

Research paper thumbnail of 182 Secukinumab provides sustained improvement in function, quality of life and fatigue over two years in patients who achieved disease activity index for psoriatic arthritis remission

Rheumatology, 2018

Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure... more Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure disease activity states in psoriatic arthritis (PsA) and can be used to assess treatment targets such as remission or low-disease activity (LDA). Secukinumab has shown sustained improvements in PsA disease activity as assessed by Disease Activity Score 28-joint count (DAS28)-C-reactive protein (CRP), physical function and patient-reported outcomes (PROs) over 104 weeks in the FUTURE 2 study. This post-hoc exploratory analysis assessed the relationship between DAPSA states and function, health-related quality of life (QoL) and PROs, and the individual DAPSA components in the different states in secukinumab-treated patients. Methods: DAPSA was derived as the sum of five variables: tender joint and swollen joint counts (TJC68 and SJC66), patient global assessment and pain assessed on a 10-cm visual analogue scale, and C-reactive protein levels (mg/dL) with validated cutoffs to indicate remission (4), LDA (>4 and 14), moderate-disease activity (MODA; >14 and 28) and high-disease activity (HDA; >28). MeanAESD of each DAPSA core component was analysed at Weeks 16, 24, 52 and 104 using observed data. The relationship between HAQ-DI, SF-36 PCS and MCS, PsAQoL, DLQI, FACIT-Fatigue and DAPSA states was assessed in the pooled treatment arms at each time-point using a mixed-effect model for repeated measures (MMRM) analyses. Results: Baseline characteristics were similar across treatment groups. DAPSA scores at baseline (meanAESD) were 42.0AE17.4, 46.8AE24.3 and 44.9AE25.3 in the secukinumab 300 mg, 150 mg and placebo groups, respectively. Mean scores of each component by DAPSA state at week 16 are shown in the table; these were sustained through week 104. Significant differences were observed among secukinumab-treated patients between remission vs. HDA and LDA vs. HDA states for PRO scores through Week 104. Conclusion: In patients treated with secukinumab 300 mg or 150 mg who achieved DAPSA remission, mean scores for the five individual components were all <1, in contrast with other disease states, and were sustained through week 104. DAPSA remission was associated with significantly greater improvement in physical function, health-related QoL and fatigue, indicating that it is an important target to be achieved and sustained in PsA patients. Disclosures: I. McInnes has received consultancies from Abbvie, BMS, Celgene, Janssen, Novartis, UCB, Lilly, AstraZeneca and grants/ research support from Janssen, Celgene, Roche, Pfizer and BMS.

Research paper thumbnail of 184 Secukinumab provides sustained remission and low disease activity related to disease activity index for psoriatic arthritis: two year results from the FUTURE 2 study

Rheumatology, Apr 1, 2018

Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure... more Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure disease activity states, focusing on peripheral joint involvement in psoriatic arthritis (PsA), and can be used to assess targets such as remission or low-disease activity (LDA). This post-hoc exploratory analysis assessed DAPSA states through to week 104 in FUTURE 2. Methods: In total, 397 active PsA patients were randomised to subcutaneous (s.c.) secukinumab or placebo at baseline and weeks 1, 2, 3 and 4, and every 4 weeks (q4w) thereafter. Placebo patients were re-randomised to secukinumab 300 or 150 mg s.c. q4w from Week 16 or 24, depending on week 16 clinical response. DAPSA was derived as the sum of five variables: tender joint and swollen joint counts (TJC68 and SJC66); patient global assessment and pain assessed on a 10-cm visual analogue scale; and C-reactive protein levels (mg/dL) with validated cutoffs to indicate remission (4), LDA (>4 and 14), moderate-disease activity (MDA; >14 and 28) and high-disease activity (HDA; >28). DAPSA was assessed in the overall population and in patients stratified by prior tumour necrosis factor inhibitor (TNFi) use (TNFi-naive vs. inadequate response/intolerance to these agents [TNFi-IR]) and time since first PsA diagnosis (2 vs. >2 years) using observed data. Only data for secukinumab 300 and 150 mg (approved doses) are reported. Results: Baseline demographics and clinical characteristics were similar across treatment groups and have been previously reported. DAPSA score at baseline (mean [SD]) was 42.0 (17.4), 46.8 (24.3) and 44.9 (25.3) in the secukinumab 300 mg, 150 mg, and placebo groups, respectively. In the overall population, at Week 16, remission was achieved in 14/97 (14.4%) with secukinumab 300 mg and 10/100 (10%) with secukinumab 150 mg vs. placebo 4/87 (4.6%); LDA in 27/ 97 (27.8%) and 34/100 (34%) vs. 12/87 (13.8%), respectively. Remission or LDA were sustained through Week 104 with secukinumab 300 and 150 mg (55/84 [65.5%; remissionþLDA] and 41/77 [53.2%; remissionþLDA], respectively). At Week 16, a higher proportion of TNFi-naive patients treated with secukinumab achieved and sustained DAPSA remission than TNFi-IR patients and a higher proportion of patients with early diagnosis (2 years) achieved DAPSA remission vs. patients diagnosed later (>2 years). Conclusion: In the overall population, a higher proportion of patients treated with secukinumab at week 16 achieved DAPSA remission than those treated with placebo, with remission and LDA being sustained through to Week 104. The proportion of patients treated with secukinumab achieving remission was greater in TNFi-naive and in early PsA patients (time since diagnosis 2 years) vs. TNFi-IR patients and patients with established PsA (>2 years).

Research paper thumbnail of SAT0315 STRUCTURAL Damage Progression Over 4 Years of Secukinumab Treatment in Ankylosing Spondylitis: Post-Hoc Analysis of MEASURE-1 Trial Using a Longitudinal Bayesian Mixture Model

Saturday, 15 June 2019, 2019

Research paper thumbnail of Secukinumab sustains early patient-reported outcome benefits through 1 year: Results from 2 phase III randomized placebo-controlled clinical trials comparing secukinumab with etanercept

Journal of the American Academy of Dermatology, 2017

Research paper thumbnail of FRI0511 Secukinumab demonstrates consistent safety over long-term exposure in patients with psoriatic arthritis and moderate-to-severe plaque psoriasis: updated pooled safety analyses

Poster Presentations, 2017

Research paper thumbnail of Inhibition of IL-17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections

Clinical & Translational Immunology, 2017

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-1... more Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), has been shown to have significant efficacy in the treatment of moderate to severe psoriasis, psoriatic arthritis and ankylosing spondylitis. Blocking critical mediators of immunity may carry a risk of increased opportunistic infections. Here we present clinical and in vitro findings examining the effect of secukinumab on Mycobacterium tuberculosis infection. We reassessed the effect of secukinumab on the incidence of acute tuberculosis (TB) and reactivation of latent TB infection (LTBI) in pooled safety data from five randomized, double-blind, placebo-controlled, phase 3 clinical trials in subjects with moderate to severe plaque psoriasis. No cases of TB were observed after 1 year. Importantly, in subjects with a history of pulmonary TB (but negative for interferon-γ release and receiving no anti-TB medication) or positive for latent TB (screened by interferon-γ release assay and receiving anti-TB medication), no cases of active TB were reported. Moreover, an in vitro study examined the effect of the antitumor necrosis factor-α (TNFα) antibody adalimumab and secukinumab on dormant M. tuberculosis H37Rv in a novel human three-dimensional microgranuloma model. Auramine-O, Nile red staining and rifampicin resistance of M. tuberculosis were measured. In vitro, anti-TNFα treatment showed increased staining for Auramine-O, decreased Nile red staining and decreased rifampicin resistance, indicative of mycobacterial reactivation. In contrast, secukinumab treatment was comparable to control indicating a lack of effect on M. tuberculosis dormancy. To date, clinical and preclinical investigations with secukinumab found no evidence of increased M. tuberculosis infections.

Research paper thumbnail of THU0325 Secukinumab demonstrates a consistent safety profile with up to 5 years treatment in patients with psoriatic arthritis and moderate to severe plaque psoriasis: updated pooled safety analyses

THURSDAY, 14 JUNE 2018:, 2018

Background: Pooled safety data from secukinumab (SEC) studies in psoriasis and psoriatic arthriti... more Background: Pooled safety data from secukinumab (SEC) studies in psoriasis and psoriatic arthritis (PsA) have been reported previously. 1 Objectives: To report updated longer-term safety data with up to 5 years of SEC treatment from psoriasis and PsA studies. Methods: The moderate to severe plaque psoriasis and active PsA data pool consisted of 15 and 3 Phase III studies, respectively. Different SEC doses in the studies included intravenous (up to 10 mg/kg) or subcutaneous (s.c.; 75-300 mg) loading, followed by s.c. maintenance dosing (300, 150 or 75 mg). Placebo patients were re-randomised to SEC at 12-24 weeks depending on study design. Adverse events (AEs) were reported as exposure adjusted incident rates (EAIR) per 100 patient-years and analyses included all patients who received !1 dose of SEC. Results: A total of 5181 and 1380 patients from psoriasis and PsA studies representing an exposure of 10416.9 and 3866.9 patient years, respectively, were included in this study. The most frequently reported AE was viral upper respiratory tract infection (table 1). EAIRs for serious infections, Candida infections, inflammatory bowel disease (IBD) and major adverse cardiac events (MACE) were low and similar in both psoriasis and PsA indications (table 1). No cases of tuberculosis were reported.

Research paper thumbnail of 185 Secukinumab demonstrates consistent safety over long-term exposure in patients with psoriatic arthritis and moderate-to-severe plaque psoriasis: updated pooled safety analyses

Rheumatology, 2018

Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure... more Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure disease activity states, focusing on peripheral joint involvement in psoriatic arthritis (PsA), and can be used to assess targets such as remission or low-disease activity (LDA). This post-hoc exploratory analysis assessed DAPSA states through to week 104 in FUTURE 2. Methods: In total, 397 active PsA patients were randomised to subcutaneous (s.c.) secukinumab or placebo at baseline and weeks 1, 2, 3 and 4, and every 4 weeks (q4w) thereafter. Placebo patients were re-randomised to secukinumab 300 or 150 mg s.c. q4w from Week 16 or 24, depending on week 16 clinical response. DAPSA was derived as the sum of five variables: tender joint and swollen joint counts (TJC68 and SJC66); patient global assessment and pain assessed on a 10-cm visual analogue scale; and C-reactive protein levels (mg/dL) with validated cutoffs to indicate remission (4), LDA (>4 and 14), moderate-disease activity (MDA; >14 and 28) and high-disease activity (HDA; >28). DAPSA was assessed in the overall population and in patients stratified by prior tumour necrosis factor inhibitor (TNFi) use (TNFi-naive vs. inadequate response/intolerance to these agents [TNFi-IR]) and time since first PsA diagnosis (2 vs. >2 years) using observed data. Only data for secukinumab 300 and 150 mg (approved doses) are reported. Results: Baseline demographics and clinical characteristics were similar across treatment groups and have been previously reported. DAPSA score at baseline (mean [SD]) was 42.0 (17.4), 46.8 (24.3) and 44.9 (25.3) in the secukinumab 300 mg, 150 mg, and placebo groups, respectively. In the overall population, at Week 16, remission was achieved in 14/97 (14.4%) with secukinumab 300 mg and 10/100 (10%) with secukinumab 150 mg vs. placebo 4/87 (4.6%); LDA in 27/ 97 (27.8%) and 34/100 (34%) vs. 12/87 (13.8%), respectively. Remission or LDA were sustained through Week 104 with secukinumab 300 and 150 mg (55/84 [65.5%; remissionþLDA] and 41/77 [53.2%; remissionþLDA], respectively). At Week 16, a higher proportion of TNFi-naive patients treated with secukinumab achieved and sustained DAPSA remission than TNFi-IR patients and a higher proportion of patients with early diagnosis (2 years) achieved DAPSA remission vs. patients diagnosed later (>2 years). Conclusion: In the overall population, a higher proportion of patients treated with secukinumab at week 16 achieved DAPSA remission than those treated with placebo, with remission and LDA being sustained through to Week 104. The proportion of patients treated with secukinumab achieving remission was greater in TNFi-naive and in early PsA patients (time since diagnosis 2 years) vs. TNFi-IR patients and patients with established PsA (>2 years).

Research paper thumbnail of The risk of depression, suicidal ideation and suicide attempt in patients with psoriasis, psoriatic arthritis or ankylosing spondylitis

Journal of the European Academy of Dermatology and Venereology, 2017

Background: Sparse information is available concerning mental health issues in psoriasis, psoriat... more Background: Sparse information is available concerning mental health issues in psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS) patients. Objective: To estimate risk of depression, suicidal ideation, and suicide attempt in patients with psoriasis, PsA, and AS, respectively, compared with the general population. Methods: This population-based cohort study analyzed 36,214 psoriasis patients, 5,138 PsA patients, and 1,878 AS patients who were frequency-matched with a general population cohort. Annual incidence rate of depression, suicidal ideation, and suicide attempt was calculated separately for psoriasis, PsA and AS.

Research paper thumbnail of TNF-α antagonists differentially induce TGF-β1-dependent resuscitation of dormant-like Mycobacterium tuberculosis

PLOS Pathogens, 2020

TNF-α-as well as non-TNF-α-targeting biologics are prescribed to treat a variety of immune-mediat... more TNF-α-as well as non-TNF-α-targeting biologics are prescribed to treat a variety of immune-mediated inflammatory disorders. The well-documented risk of tuberculosis progression associated with anti-TNF-α treatment highlighted the central role of TNF-α for the maintenance of protective immunity, although the rate of tuberculosis detected among patients varies with the nature of the drug. Using a human, in-vitro granuloma model, we reproduce the increased reactivation rate of tuberculosis following exposure to Adalimumab compared to Etanercept, two TNF-α-neutralizing biologics. We show that Adalimumab, because of its bivalence, specifically induces TGF-β1-dependent Mycobacterium tuberculosis (Mtb) resuscitation which can be prevented by concomitant TGF-β1 neutralization. Moreover, our data suggest an additional role of lymphotoxin-α-neutralized by Etanercept but not Adalimumab-in the control of latent tuberculosis infection. Furthermore, we show that, while Secukinumab, an anti-IL-17A antibody, does not revert Mtb dormancy, the anti-IL-12-p40 antibody Ustekinumab and the recombinant IL-1RA Anakinra promote Mtb resuscitation, in line with the importance of these pathways in tuberculosis immunity.

Research paper thumbnail of Prevalence of silent gastrointestinal complications in maintenance renal transplant population

Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia, 2010

This study aims to determine the prevalence of silent GI complications within a stable renal tran... more This study aims to determine the prevalence of silent GI complications within a stable renal transplant population and to investigate whether the conversion to enteric-coated myco-phenolate sodium (EC-MPS, Myfortic) would improve symptom scores. This was a single-center, open-label, non-randomized, prospective study. Patients without any history of GI com-plaints were evaluated by means of the gastrointestinal symptom rating scale (GSRS), with subse-quent switch to EC-MPS in a group of patients. Silent complications were defined as patients who voiced no GI complaints at clinic visits despite a score of > or = 2 on GSRS scale. A total of 236 stable patients participated in the trial. The prevalence of baseline scores > or = 2 was relatively high with abdominal pain 29.66%, reflux 37.28%, indigestion 50%, constipation 58.47% and diarrhea 33.4%. Of 236 patients, 80 were converted to EC-MPS. There was statistically significant improvement on all scales in the subgroup of patients...

Research paper thumbnail of Secukinumab's effect on structural damage progression in psoriatic arthritis: longitudinal mixture modelling of FUTURE-1 and FUTURE-5

Clinical and Experimental Rheumatology

Objective Peripheral and axial manifestations of psoriatic arthritis (PsA) can lead to irreversib... more Objective Peripheral and axial manifestations of psoriatic arthritis (PsA) can lead to irreversible structural damage and chronic disability. Our objective was to explore predictors of radiographic progression and to increase our understanding of treatment effects in subgroups of patients with different rates of structural damage progression. Methods We analysed data from two large Phase-3 trials of secukinumab in PsA patients, FUTURE-1 (NCT01392326, n=606) and FUTURE-5 (NCT02404350, n=996), where different posologies ranging from 75 mg to 300 mg were used. We applied a longitudinal Bayesian mixture model with random effects to account for the variability in the repeated radiographic assessments. "Fast progressors" were defined post hoc as patients with a 50% model-estimated probability to progress at least 0.5 mTSS/year faster than an average patient. Results Higher baseline inflammation and higher body weight were identified as significant predictors of radiographic progression (multivariate model). Model-estimated structural damage progression in an average patient treated with secukinumab 150 mg subcutaneous (s.c.) was slower (0.04 mTSS/year; 95% CI-0.28, 0.34) compared to a patient treated with placebo (0.94 mTSS/year; 95% CI 0.45, 1.45). According to the model, the subgroup of "fast progressors" (hsCRP ≥26 mg/L, body weigth ≥94 kg, inadequate response to prior anti-TNF-alpha, structural damage ≥42 mTSS) treated with secukinumab 150 mg s.c. progressed at 0.56 mTSS/year (95% CI 0.02, 1.09) and 1.46 mTSS/year (95% CI 0.81, 2.11) when treated with placebo. Conclusions Greater systemic inflammation and higher body weight at baseline were identified as significant predictors of progression. Even patients with fast radiographic progression could experience a beneficial effect with secukinumab that holds promise to prevent further mobility loss.

Research paper thumbnail of Secukinumab Efficacy on Enthesitis in Patients With Ankylosing Spondylitis: Pooled Analysis of Four Pivotal Phase III Studies

The Journal of Rheumatology, 2021

ObjectiveTo assess the efficacy of secukinumab on axial and peripheral enthesitis in patients wit... more ObjectiveTo assess the efficacy of secukinumab on axial and peripheral enthesitis in patients with ankylosing spondylitis (AS) using pooled data from randomized controlled phase III studies.MethodsIn this posthoc analysis, data were pooled from patients originally randomized to secukinumab 150 mg, 300 mg, or placebo (PBO) from phase III MEASURE 1–4 studies (ClinicalTrials.gov: NCT01358175, NCT01649375, NCT02008916, and NCT02159053). Maastricht AS Enthesitis Score (MASES) was used for assessments of enthesitis through Week 52. Efficacy outcomes were mean change in MASES score and complete resolution (MASES = 0) of enthesitis in patients with baseline MASES > 0.ResultsA total of 693 (71.5%) patients had enthesitis at baseline in secukinumab 300 mg, 150 mg, and PBO groups (58 [76.3%], 355 [70.4%], and 280 [72%], respectively) out of 969 patients pooled in this analysis. At Week 16, mean changes from baseline for overall MASES and enthesitis at axial MASES sites, respectively, were a...

Research paper thumbnail of THU0397 SYMPTOMS of Peripheral Arthritis Are Significantly Improved in Patients with Ankylosing Spondylitis Treated with Secukinumab

Annals of the Rheumatic Diseases, 2020

Background:Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial skeleton as... more Background:Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial skeleton associated with pain, stiffness, and disability.1Up to 66% of patients (pts) with AS may also have peripheral involvement, including swollen and tender joints (STJs),2,3which are associated with worse overall disease activity.4A previous analysis showed that secukinumab, a selective inhibitor of interleukin 17A, led to significant improvements in efficacy outcomes vs placebo, regardless of peripheral joint involvement.3However, the effect of secukinumab on symptoms of peripheral arthritis in pts with AS was not assessed.Objectives:The objective of this analysis was to assess changes in peripheral symptoms in pts with AS treated with secukinumab vs placebo.Methods:Data from pts with active AS and peripheral symptoms who were enrolled in MEASURE 1 (NCT01358175), 2 (NCT01649375), 3 (NCT02008916), and 4 (NCT02159053) were pooled in this post hoc, hypothesis-generating analysis. No adjustments ...

Research paper thumbnail of Methods for Imputing Missing Efficacy Data in Clinical Trials of Biologic Psoriasis Therapies: Implications for Interpretations of Trial Results

Journal of drugs in dermatology : JDD, 2017

BACKGROUND: An issue in long-term clinical trials of biologics in psoriasis is how to handle miss... more BACKGROUND: An issue in long-term clinical trials of biologics in psoriasis is how to handle missing efficacy data. This methodological challenge may not be understood by clinicians, yet can have a significant effect on the interpretation of clinical trials. OBJECTIVE Evaluate the effects of different data imputation methods on apparent secukinumab response rates. METHODS: Post hoc analyses were conducted on efficacy data from 2 phase III, multicenter, randomized, double-blind trials (FIXTURE and ERASURE) of secukinumab in moderate to severe plaque psoriasis. Per study protocols, missing data were imputed using strict non-response imputation (NRI), a highly conservative method that assumes non-response for all missing data. Alternative imputation methods (observed data, last observation carried forward [LOCF], modified NRI, and multiple imputation [MI]) were applied in this analysis and the resultant response rates compared. RESULTS: Response rates obtained with each imputation meth...

Research paper thumbnail of FRI0380 SECUKINUMAB Provides Sustained Improvement of Enthesitis in Patients with Ankylosing Spondylitis: Pooled Analysis of Four Pivotal Phase 3 Studies

Spondyloarthritis – treatment, 2019

Background: Evaluation of long-term efficacy and safety for treatments for ankylosing spondylitis... more Background: Evaluation of long-term efficacy and safety for treatments for ankylosing spondylitis (AS) is important. Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin-17A, has shown significant and sustained improvement in the signs and symptoms of AS through 3 years in the MEASURE 2 study (NCT01649375). 1 Objectives: We report the 5-year end-of-study results of subcutaneous (s. c.) secukinumab 150 mg in the MEASURE 2 study. Methods: AS patients (pts; N = 219) were randomised to receive s.c. secukinumab 150 mg, 75 mg or placebo at baseline, Weeks (Wks) 1, 2 and 3 and every 4 wks from Wk 4. At Wk 16, placebo-treated pts were re-randomised to receive secukinumab 150/75 mg. Efficacy results are reported for pts initially randomised to secukinumab 150 mg and those who switched from placebo to secukinumab 150 mg at Wk 16 (N = 106). An optional dose escalation from secukinumab 75 mg to 150 mg was initiated beginning Wk 140. Outcome measures at Wk 260 included ASAS20/40, BASDAI50, BASMI, BASFI, SF-36 PCS and ASAS partial remission. Analyses stratified by anti-TNF status (anti-TNF-naïve and anti-TNF inadequate response [IR]) were performed. Safety analysis included all pts who received !1 dose of secukinumab. Results are reported as observed. Results: The retention rate to Wk 260 was 77% (82/106) for secukinumab 150 mg. Sustained efficacy was observed with secukinumab 150 mg across all endpoints through 5 years (Table). Improvements were maintained regardless of prior exposure to anti-TNF therapy with greater responses in anti-TNF-naïve pts. A total of 49 pts on secukinumab 75 mg (46.7%) escalated dose to 150 mg after Wk 140; efficacy responses improved in pts whose dose was escalated. Over the entire study period, the mean exposure (±SD) to secukinumab was 1459.1 ± 597.8 days. Exposure-adjusted incidence rates (per 100 pt-years) with any secukinumab dose for selected adverse events were: Candida infections (1.0), Crohn's disease (0.5), major adverse cardiovascular events (0.7), uveitis (0.5), and malignant/unspecified tumours (0.5). Conclusion: Secukinumab 150 mg provided sustained improvement in the signs, symptoms, and physical function in pts with AS through 5 years of treatment. The safety profile of secukinumab remained consistent with previous reports. 1-3

Research paper thumbnail of Secukinumab provides rapid and sustained pain relief in psoriatic arthritis over 2 years: results from the FUTURE 2 study

Arthritis Research & Therapy, 2018

Background: Pain is one of the most important domains affecting health-related quality of life (H... more Background: Pain is one of the most important domains affecting health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). Secukinumab has demonstrated rapid and sustained improvements in signs and symptoms, including HRQoL, among patients with active PsA. This analysis evaluates the effect of secukinumab on patient-reported pain in PsA through 104 weeks of treatment. Methods: Pain was assessed through week 104 using clinically relevant measures, including change from baseline in a pain visual analog scale (VAS) and Short Form-36 (SF-36) bodily domain scores; proportion of patients reporting improvements equal to or better than minimum clinically meaningful differences in the pain VAS and SF-36 bodily pain domain scores; and proportion of patients with no, moderate, or extreme pain/discomfort measured by the EuroQoL 5-Dimension 3-Level Questionnaire (EQ-5D-3 L) pain item scores. Correlations of pain measures were analyzed using Pearson's correlation coefficient. Pre-specified analyses of TNF-naïve patients and patients who stopped TNF-inhibitors (TNFis) due to inadequate responses or safety/tolerability (TNF-IR patients) were performed using "as-observed data." Results: Mean improvements from baseline in pain VAS scores were greater with secukinumab versus placebo by week 3 (− 16.9; P < 0.0001 with secukinumab 300 mg and − 12.6; P < 0.05 with secukinumab 150 mg) and sustained through week 104. SF-36 bodily pain domain scores were significantly greater with 300 mg secukinumab and secukinumab 150 mg versus placebo by week 4 (16.2 and 16.3, respectively; P < 0.0001 for both), and these changes were maintained through week 104. With both secukinumab 300 mg and secukinumab 150 mg, improvements equal to or better than the minimum clinically meaningful differences in pain VAS and SF-36 bodily pain were significant versus placebo at week 3 and week 4, respectively. At week 4, 15%, 9%, and 5% of patients receiving secukinumab 300 mg, secukinumab 150 mg, and placebo, respectively, reported "no pain/discomfort" measured by EQ-5D-3 L; these proportions increased to week 104 with both secukinumab doses. Similarly, improvements in pain measures were significant in both TNF-naïve and TNF-IR patients. Conclusion: Secukinumab provided rapid and sustained pain relief in PsA over 2 years of treatment. Improvements in pain were reported regardless of prior exposure to TNFis.

Research paper thumbnail of Incidence rates of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis treated with secukinumab: a retrospective analysis of pooled data from 21 clinical trials

Annals of the Rheumatic Diseases, 2019

ObjectivesHere, we present the reported incidence rates of inflammatory bowel disease (IBD) in pa... more ObjectivesHere, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a pooled analysis of 21 clinical trials.MethodsData from all patients who had received at least one dose of secukinumab were included. Safety analyses were conducted to evaluate cumulative IBD rates as well as per-year rates, by indication. Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) events were analysed using exposure-adjusted incidence rates (patient incidence rates per 100 patient-years (PY)).ResultsA total of 7355 patients with a cumulative exposure of 16 226.9 PY were included in the pooled analysis. Among 5181 patients with PsO, there were 14 cases of UC, 5 cases of CD and 1 case of IBDU, with exposure adjusted incidence rates (EAIRs) of 0.13, 0.05 and 0.01, respectively. Of these 20 cases, 14 were new-onset. In 1380 patients wi...

Research paper thumbnail of Secukinumab maintains reductions in PASI through second year of treatment: A randomized extension of the ERASURE and FIXTURE studies in plaque psoriasis

Journal of the American Academy of Dermatology, 2016

Introduction: We report the effect of secukinumab, with and without concomitant methotrexate (MTX... more Introduction: We report the effect of secukinumab, with and without concomitant methotrexate (MTX), on radiographic progression in psoriatic arthritis (PsA) patients in an exploratory subgroup analysis of the randomized, double-blind, placebo (PBO)-controlled study (FUTURE 1; NCT01392326). Methods: 606 patients with active PsA were randomized to secukinumab or PBO. Patients on secukinumab received 10 mg/kg intravenous (i.v.) loading dose at baseline (BL), Weeks (Wks) 2 and 4, followed by subcutaneous (sc) secukinumab 150 (IVe150 mg) or 75 mg (IVe75 mg) every 4 wks (q4wk) from Wk 8. PBO was given on the same schedule. At Wk 16, PBO patients with ˂20% reduction in tender or swollen joint count (nonresponders) were rerandomized to secukinumab 75 or 150 mg sc q4wk; responders received secukinumab 75 or 150 mg sc q4wk from Wk 24. van der Heijde modified total Sharp score (mTSS) and erosion and joint space narrowing (JSN) scores were determined at BL, Wks 16/24 (depending upon response) and Wk 52. Analysis of radiographic progression at Wk 24 used linear extrapolation for patients with X-ray assessments at Wk 16. Wk 52 analyses used evaluable data. Results: In the overall study population, secukinumab significantly inhibited radiographic progression from BL to Wk 24 vs PBO. There was lower mean change in mTSS score from BL to Wk 24 in patients on secukinumab compared to those on PBO, irrespective of concomitant MTX use. Inhibition of radiographic progression with secukinumab was sustained from Wk 24 to Wk 52. Improvements in mean change in erosion and JSN scores were also observed with secukinumab throughout the study. Conclusions: Secukinumab provided significant and sustained inhibition of radiographic disease in patients with PsA. Within the limitations of suboptimal statistical power, the exploratory analysis does not suggest a clinically meaningful difference in radiographic progression between the secukinumab with MTX and secukinumab without MTX subgroups.

Research paper thumbnail of THU0359 Secukinumab demonstrates consistent safety over long-term exposure (up to 3 years) in patients with active ankylosing spondylitis: pooled analysis of three phase 3 trials

Poster Presentations, 2017

to the application of the EMA recommendation (interaction p value=0.140). In the 59 pts not treat... more to the application of the EMA recommendation (interaction p value=0.140). In the 59 pts not treated in accordance with the EMA recommendation, the treatment effect in the subgroups of pts without (vs with) concomitant FM was 38% vs 40% respectively, p=0.891. In the 449 pts treated in accordance with the EMA recommendation, the treatment effect in the subgroups of pts without (vs with) concomitant FM was 56% vs 46%, p=0.042). Conclusions: This study suggests that 1/ French rheumatologists are applying the EMA recommendation in daily practice 2/ these recommendations result in a better outcome in terms of short term symptomatic treatment effect. In this study, concomitant FM was not more frequently observed in patients without (vs with) objective sign of structural damage or inflammation and the impact of a concomitant FM was not more pronounced (or even lower) in pts without (vs with) objective sign of structural damage or inflammation. References: [1] Perrot S, et al. Development and validation of the Fibromyalgia Rapid Screening Tool (FiRST). Pain.2010;150:250-6. Acknowledgements: This study was conducted thanks to an unrestricted grant from MSD.

Research paper thumbnail of 182 Secukinumab provides sustained improvement in function, quality of life and fatigue over two years in patients who achieved disease activity index for psoriatic arthritis remission

Rheumatology, 2018

Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure... more Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure disease activity states in psoriatic arthritis (PsA) and can be used to assess treatment targets such as remission or low-disease activity (LDA). Secukinumab has shown sustained improvements in PsA disease activity as assessed by Disease Activity Score 28-joint count (DAS28)-C-reactive protein (CRP), physical function and patient-reported outcomes (PROs) over 104 weeks in the FUTURE 2 study. This post-hoc exploratory analysis assessed the relationship between DAPSA states and function, health-related quality of life (QoL) and PROs, and the individual DAPSA components in the different states in secukinumab-treated patients. Methods: DAPSA was derived as the sum of five variables: tender joint and swollen joint counts (TJC68 and SJC66), patient global assessment and pain assessed on a 10-cm visual analogue scale, and C-reactive protein levels (mg/dL) with validated cutoffs to indicate remission (4), LDA (>4 and 14), moderate-disease activity (MODA; >14 and 28) and high-disease activity (HDA; >28). MeanAESD of each DAPSA core component was analysed at Weeks 16, 24, 52 and 104 using observed data. The relationship between HAQ-DI, SF-36 PCS and MCS, PsAQoL, DLQI, FACIT-Fatigue and DAPSA states was assessed in the pooled treatment arms at each time-point using a mixed-effect model for repeated measures (MMRM) analyses. Results: Baseline characteristics were similar across treatment groups. DAPSA scores at baseline (meanAESD) were 42.0AE17.4, 46.8AE24.3 and 44.9AE25.3 in the secukinumab 300 mg, 150 mg and placebo groups, respectively. Mean scores of each component by DAPSA state at week 16 are shown in the table; these were sustained through week 104. Significant differences were observed among secukinumab-treated patients between remission vs. HDA and LDA vs. HDA states for PRO scores through Week 104. Conclusion: In patients treated with secukinumab 300 mg or 150 mg who achieved DAPSA remission, mean scores for the five individual components were all <1, in contrast with other disease states, and were sustained through week 104. DAPSA remission was associated with significantly greater improvement in physical function, health-related QoL and fatigue, indicating that it is an important target to be achieved and sustained in PsA patients. Disclosures: I. McInnes has received consultancies from Abbvie, BMS, Celgene, Janssen, Novartis, UCB, Lilly, AstraZeneca and grants/ research support from Janssen, Celgene, Roche, Pfizer and BMS.

Research paper thumbnail of 184 Secukinumab provides sustained remission and low disease activity related to disease activity index for psoriatic arthritis: two year results from the FUTURE 2 study

Rheumatology, Apr 1, 2018

Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure... more Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure disease activity states, focusing on peripheral joint involvement in psoriatic arthritis (PsA), and can be used to assess targets such as remission or low-disease activity (LDA). This post-hoc exploratory analysis assessed DAPSA states through to week 104 in FUTURE 2. Methods: In total, 397 active PsA patients were randomised to subcutaneous (s.c.) secukinumab or placebo at baseline and weeks 1, 2, 3 and 4, and every 4 weeks (q4w) thereafter. Placebo patients were re-randomised to secukinumab 300 or 150 mg s.c. q4w from Week 16 or 24, depending on week 16 clinical response. DAPSA was derived as the sum of five variables: tender joint and swollen joint counts (TJC68 and SJC66); patient global assessment and pain assessed on a 10-cm visual analogue scale; and C-reactive protein levels (mg/dL) with validated cutoffs to indicate remission (4), LDA (>4 and 14), moderate-disease activity (MDA; >14 and 28) and high-disease activity (HDA; >28). DAPSA was assessed in the overall population and in patients stratified by prior tumour necrosis factor inhibitor (TNFi) use (TNFi-naive vs. inadequate response/intolerance to these agents [TNFi-IR]) and time since first PsA diagnosis (2 vs. >2 years) using observed data. Only data for secukinumab 300 and 150 mg (approved doses) are reported. Results: Baseline demographics and clinical characteristics were similar across treatment groups and have been previously reported. DAPSA score at baseline (mean [SD]) was 42.0 (17.4), 46.8 (24.3) and 44.9 (25.3) in the secukinumab 300 mg, 150 mg, and placebo groups, respectively. In the overall population, at Week 16, remission was achieved in 14/97 (14.4%) with secukinumab 300 mg and 10/100 (10%) with secukinumab 150 mg vs. placebo 4/87 (4.6%); LDA in 27/ 97 (27.8%) and 34/100 (34%) vs. 12/87 (13.8%), respectively. Remission or LDA were sustained through Week 104 with secukinumab 300 and 150 mg (55/84 [65.5%; remissionþLDA] and 41/77 [53.2%; remissionþLDA], respectively). At Week 16, a higher proportion of TNFi-naive patients treated with secukinumab achieved and sustained DAPSA remission than TNFi-IR patients and a higher proportion of patients with early diagnosis (2 years) achieved DAPSA remission vs. patients diagnosed later (>2 years). Conclusion: In the overall population, a higher proportion of patients treated with secukinumab at week 16 achieved DAPSA remission than those treated with placebo, with remission and LDA being sustained through to Week 104. The proportion of patients treated with secukinumab achieving remission was greater in TNFi-naive and in early PsA patients (time since diagnosis 2 years) vs. TNFi-IR patients and patients with established PsA (>2 years).

Research paper thumbnail of SAT0315 STRUCTURAL Damage Progression Over 4 Years of Secukinumab Treatment in Ankylosing Spondylitis: Post-Hoc Analysis of MEASURE-1 Trial Using a Longitudinal Bayesian Mixture Model

Saturday, 15 June 2019, 2019

Research paper thumbnail of Secukinumab sustains early patient-reported outcome benefits through 1 year: Results from 2 phase III randomized placebo-controlled clinical trials comparing secukinumab with etanercept

Journal of the American Academy of Dermatology, 2017

Research paper thumbnail of FRI0511 Secukinumab demonstrates consistent safety over long-term exposure in patients with psoriatic arthritis and moderate-to-severe plaque psoriasis: updated pooled safety analyses

Poster Presentations, 2017

Research paper thumbnail of Inhibition of IL-17A by secukinumab shows no evidence of increased Mycobacterium tuberculosis infections

Clinical & Translational Immunology, 2017

Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-1... more Secukinumab, a fully human monoclonal antibody that selectively neutralizes interleukin-17A (IL-17A), has been shown to have significant efficacy in the treatment of moderate to severe psoriasis, psoriatic arthritis and ankylosing spondylitis. Blocking critical mediators of immunity may carry a risk of increased opportunistic infections. Here we present clinical and in vitro findings examining the effect of secukinumab on Mycobacterium tuberculosis infection. We reassessed the effect of secukinumab on the incidence of acute tuberculosis (TB) and reactivation of latent TB infection (LTBI) in pooled safety data from five randomized, double-blind, placebo-controlled, phase 3 clinical trials in subjects with moderate to severe plaque psoriasis. No cases of TB were observed after 1 year. Importantly, in subjects with a history of pulmonary TB (but negative for interferon-γ release and receiving no anti-TB medication) or positive for latent TB (screened by interferon-γ release assay and receiving anti-TB medication), no cases of active TB were reported. Moreover, an in vitro study examined the effect of the antitumor necrosis factor-α (TNFα) antibody adalimumab and secukinumab on dormant M. tuberculosis H37Rv in a novel human three-dimensional microgranuloma model. Auramine-O, Nile red staining and rifampicin resistance of M. tuberculosis were measured. In vitro, anti-TNFα treatment showed increased staining for Auramine-O, decreased Nile red staining and decreased rifampicin resistance, indicative of mycobacterial reactivation. In contrast, secukinumab treatment was comparable to control indicating a lack of effect on M. tuberculosis dormancy. To date, clinical and preclinical investigations with secukinumab found no evidence of increased M. tuberculosis infections.

Research paper thumbnail of THU0325 Secukinumab demonstrates a consistent safety profile with up to 5 years treatment in patients with psoriatic arthritis and moderate to severe plaque psoriasis: updated pooled safety analyses

THURSDAY, 14 JUNE 2018:, 2018

Background: Pooled safety data from secukinumab (SEC) studies in psoriasis and psoriatic arthriti... more Background: Pooled safety data from secukinumab (SEC) studies in psoriasis and psoriatic arthritis (PsA) have been reported previously. 1 Objectives: To report updated longer-term safety data with up to 5 years of SEC treatment from psoriasis and PsA studies. Methods: The moderate to severe plaque psoriasis and active PsA data pool consisted of 15 and 3 Phase III studies, respectively. Different SEC doses in the studies included intravenous (up to 10 mg/kg) or subcutaneous (s.c.; 75-300 mg) loading, followed by s.c. maintenance dosing (300, 150 or 75 mg). Placebo patients were re-randomised to SEC at 12-24 weeks depending on study design. Adverse events (AEs) were reported as exposure adjusted incident rates (EAIR) per 100 patient-years and analyses included all patients who received !1 dose of SEC. Results: A total of 5181 and 1380 patients from psoriasis and PsA studies representing an exposure of 10416.9 and 3866.9 patient years, respectively, were included in this study. The most frequently reported AE was viral upper respiratory tract infection (table 1). EAIRs for serious infections, Candida infections, inflammatory bowel disease (IBD) and major adverse cardiac events (MACE) were low and similar in both psoriasis and PsA indications (table 1). No cases of tuberculosis were reported.

Research paper thumbnail of 185 Secukinumab demonstrates consistent safety over long-term exposure in patients with psoriatic arthritis and moderate-to-severe plaque psoriasis: updated pooled safety analyses

Rheumatology, 2018

Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure... more Background: Disease Activity Index for Psoriatic Arthritis (DAPSA) is a validated tool to measure disease activity states, focusing on peripheral joint involvement in psoriatic arthritis (PsA), and can be used to assess targets such as remission or low-disease activity (LDA). This post-hoc exploratory analysis assessed DAPSA states through to week 104 in FUTURE 2. Methods: In total, 397 active PsA patients were randomised to subcutaneous (s.c.) secukinumab or placebo at baseline and weeks 1, 2, 3 and 4, and every 4 weeks (q4w) thereafter. Placebo patients were re-randomised to secukinumab 300 or 150 mg s.c. q4w from Week 16 or 24, depending on week 16 clinical response. DAPSA was derived as the sum of five variables: tender joint and swollen joint counts (TJC68 and SJC66); patient global assessment and pain assessed on a 10-cm visual analogue scale; and C-reactive protein levels (mg/dL) with validated cutoffs to indicate remission (4), LDA (>4 and 14), moderate-disease activity (MDA; >14 and 28) and high-disease activity (HDA; >28). DAPSA was assessed in the overall population and in patients stratified by prior tumour necrosis factor inhibitor (TNFi) use (TNFi-naive vs. inadequate response/intolerance to these agents [TNFi-IR]) and time since first PsA diagnosis (2 vs. >2 years) using observed data. Only data for secukinumab 300 and 150 mg (approved doses) are reported. Results: Baseline demographics and clinical characteristics were similar across treatment groups and have been previously reported. DAPSA score at baseline (mean [SD]) was 42.0 (17.4), 46.8 (24.3) and 44.9 (25.3) in the secukinumab 300 mg, 150 mg, and placebo groups, respectively. In the overall population, at Week 16, remission was achieved in 14/97 (14.4%) with secukinumab 300 mg and 10/100 (10%) with secukinumab 150 mg vs. placebo 4/87 (4.6%); LDA in 27/ 97 (27.8%) and 34/100 (34%) vs. 12/87 (13.8%), respectively. Remission or LDA were sustained through Week 104 with secukinumab 300 and 150 mg (55/84 [65.5%; remissionþLDA] and 41/77 [53.2%; remissionþLDA], respectively). At Week 16, a higher proportion of TNFi-naive patients treated with secukinumab achieved and sustained DAPSA remission than TNFi-IR patients and a higher proportion of patients with early diagnosis (2 years) achieved DAPSA remission vs. patients diagnosed later (>2 years). Conclusion: In the overall population, a higher proportion of patients treated with secukinumab at week 16 achieved DAPSA remission than those treated with placebo, with remission and LDA being sustained through to Week 104. The proportion of patients treated with secukinumab achieving remission was greater in TNFi-naive and in early PsA patients (time since diagnosis 2 years) vs. TNFi-IR patients and patients with established PsA (>2 years).

Research paper thumbnail of The risk of depression, suicidal ideation and suicide attempt in patients with psoriasis, psoriatic arthritis or ankylosing spondylitis

Journal of the European Academy of Dermatology and Venereology, 2017

Background: Sparse information is available concerning mental health issues in psoriasis, psoriat... more Background: Sparse information is available concerning mental health issues in psoriasis, psoriatic arthritis (PsA), and ankylosing spondylitis (AS) patients. Objective: To estimate risk of depression, suicidal ideation, and suicide attempt in patients with psoriasis, PsA, and AS, respectively, compared with the general population. Methods: This population-based cohort study analyzed 36,214 psoriasis patients, 5,138 PsA patients, and 1,878 AS patients who were frequency-matched with a general population cohort. Annual incidence rate of depression, suicidal ideation, and suicide attempt was calculated separately for psoriasis, PsA and AS.

Research paper thumbnail of TNF-α antagonists differentially induce TGF-β1-dependent resuscitation of dormant-like Mycobacterium tuberculosis

PLOS Pathogens, 2020

TNF-α-as well as non-TNF-α-targeting biologics are prescribed to treat a variety of immune-mediat... more TNF-α-as well as non-TNF-α-targeting biologics are prescribed to treat a variety of immune-mediated inflammatory disorders. The well-documented risk of tuberculosis progression associated with anti-TNF-α treatment highlighted the central role of TNF-α for the maintenance of protective immunity, although the rate of tuberculosis detected among patients varies with the nature of the drug. Using a human, in-vitro granuloma model, we reproduce the increased reactivation rate of tuberculosis following exposure to Adalimumab compared to Etanercept, two TNF-α-neutralizing biologics. We show that Adalimumab, because of its bivalence, specifically induces TGF-β1-dependent Mycobacterium tuberculosis (Mtb) resuscitation which can be prevented by concomitant TGF-β1 neutralization. Moreover, our data suggest an additional role of lymphotoxin-α-neutralized by Etanercept but not Adalimumab-in the control of latent tuberculosis infection. Furthermore, we show that, while Secukinumab, an anti-IL-17A antibody, does not revert Mtb dormancy, the anti-IL-12-p40 antibody Ustekinumab and the recombinant IL-1RA Anakinra promote Mtb resuscitation, in line with the importance of these pathways in tuberculosis immunity.

Research paper thumbnail of Prevalence of silent gastrointestinal complications in maintenance renal transplant population

Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia, 2010

This study aims to determine the prevalence of silent GI complications within a stable renal tran... more This study aims to determine the prevalence of silent GI complications within a stable renal transplant population and to investigate whether the conversion to enteric-coated myco-phenolate sodium (EC-MPS, Myfortic) would improve symptom scores. This was a single-center, open-label, non-randomized, prospective study. Patients without any history of GI com-plaints were evaluated by means of the gastrointestinal symptom rating scale (GSRS), with subse-quent switch to EC-MPS in a group of patients. Silent complications were defined as patients who voiced no GI complaints at clinic visits despite a score of > or = 2 on GSRS scale. A total of 236 stable patients participated in the trial. The prevalence of baseline scores > or = 2 was relatively high with abdominal pain 29.66%, reflux 37.28%, indigestion 50%, constipation 58.47% and diarrhea 33.4%. Of 236 patients, 80 were converted to EC-MPS. There was statistically significant improvement on all scales in the subgroup of patients...

Research paper thumbnail of Secukinumab's effect on structural damage progression in psoriatic arthritis: longitudinal mixture modelling of FUTURE-1 and FUTURE-5

Clinical and Experimental Rheumatology

Objective Peripheral and axial manifestations of psoriatic arthritis (PsA) can lead to irreversib... more Objective Peripheral and axial manifestations of psoriatic arthritis (PsA) can lead to irreversible structural damage and chronic disability. Our objective was to explore predictors of radiographic progression and to increase our understanding of treatment effects in subgroups of patients with different rates of structural damage progression. Methods We analysed data from two large Phase-3 trials of secukinumab in PsA patients, FUTURE-1 (NCT01392326, n=606) and FUTURE-5 (NCT02404350, n=996), where different posologies ranging from 75 mg to 300 mg were used. We applied a longitudinal Bayesian mixture model with random effects to account for the variability in the repeated radiographic assessments. "Fast progressors" were defined post hoc as patients with a 50% model-estimated probability to progress at least 0.5 mTSS/year faster than an average patient. Results Higher baseline inflammation and higher body weight were identified as significant predictors of radiographic progression (multivariate model). Model-estimated structural damage progression in an average patient treated with secukinumab 150 mg subcutaneous (s.c.) was slower (0.04 mTSS/year; 95% CI-0.28, 0.34) compared to a patient treated with placebo (0.94 mTSS/year; 95% CI 0.45, 1.45). According to the model, the subgroup of "fast progressors" (hsCRP ≥26 mg/L, body weigth ≥94 kg, inadequate response to prior anti-TNF-alpha, structural damage ≥42 mTSS) treated with secukinumab 150 mg s.c. progressed at 0.56 mTSS/year (95% CI 0.02, 1.09) and 1.46 mTSS/year (95% CI 0.81, 2.11) when treated with placebo. Conclusions Greater systemic inflammation and higher body weight at baseline were identified as significant predictors of progression. Even patients with fast radiographic progression could experience a beneficial effect with secukinumab that holds promise to prevent further mobility loss.

Research paper thumbnail of Secukinumab Efficacy on Enthesitis in Patients With Ankylosing Spondylitis: Pooled Analysis of Four Pivotal Phase III Studies

The Journal of Rheumatology, 2021

ObjectiveTo assess the efficacy of secukinumab on axial and peripheral enthesitis in patients wit... more ObjectiveTo assess the efficacy of secukinumab on axial and peripheral enthesitis in patients with ankylosing spondylitis (AS) using pooled data from randomized controlled phase III studies.MethodsIn this posthoc analysis, data were pooled from patients originally randomized to secukinumab 150 mg, 300 mg, or placebo (PBO) from phase III MEASURE 1–4 studies (ClinicalTrials.gov: NCT01358175, NCT01649375, NCT02008916, and NCT02159053). Maastricht AS Enthesitis Score (MASES) was used for assessments of enthesitis through Week 52. Efficacy outcomes were mean change in MASES score and complete resolution (MASES = 0) of enthesitis in patients with baseline MASES > 0.ResultsA total of 693 (71.5%) patients had enthesitis at baseline in secukinumab 300 mg, 150 mg, and PBO groups (58 [76.3%], 355 [70.4%], and 280 [72%], respectively) out of 969 patients pooled in this analysis. At Week 16, mean changes from baseline for overall MASES and enthesitis at axial MASES sites, respectively, were a...

Research paper thumbnail of THU0397 SYMPTOMS of Peripheral Arthritis Are Significantly Improved in Patients with Ankylosing Spondylitis Treated with Secukinumab

Annals of the Rheumatic Diseases, 2020

Background:Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial skeleton as... more Background:Ankylosing spondylitis (AS) is a chronic inflammatory disease of the axial skeleton associated with pain, stiffness, and disability.1Up to 66% of patients (pts) with AS may also have peripheral involvement, including swollen and tender joints (STJs),2,3which are associated with worse overall disease activity.4A previous analysis showed that secukinumab, a selective inhibitor of interleukin 17A, led to significant improvements in efficacy outcomes vs placebo, regardless of peripheral joint involvement.3However, the effect of secukinumab on symptoms of peripheral arthritis in pts with AS was not assessed.Objectives:The objective of this analysis was to assess changes in peripheral symptoms in pts with AS treated with secukinumab vs placebo.Methods:Data from pts with active AS and peripheral symptoms who were enrolled in MEASURE 1 (NCT01358175), 2 (NCT01649375), 3 (NCT02008916), and 4 (NCT02159053) were pooled in this post hoc, hypothesis-generating analysis. No adjustments ...

Research paper thumbnail of Methods for Imputing Missing Efficacy Data in Clinical Trials of Biologic Psoriasis Therapies: Implications for Interpretations of Trial Results

Journal of drugs in dermatology : JDD, 2017

BACKGROUND: An issue in long-term clinical trials of biologics in psoriasis is how to handle miss... more BACKGROUND: An issue in long-term clinical trials of biologics in psoriasis is how to handle missing efficacy data. This methodological challenge may not be understood by clinicians, yet can have a significant effect on the interpretation of clinical trials. OBJECTIVE Evaluate the effects of different data imputation methods on apparent secukinumab response rates. METHODS: Post hoc analyses were conducted on efficacy data from 2 phase III, multicenter, randomized, double-blind trials (FIXTURE and ERASURE) of secukinumab in moderate to severe plaque psoriasis. Per study protocols, missing data were imputed using strict non-response imputation (NRI), a highly conservative method that assumes non-response for all missing data. Alternative imputation methods (observed data, last observation carried forward [LOCF], modified NRI, and multiple imputation [MI]) were applied in this analysis and the resultant response rates compared. RESULTS: Response rates obtained with each imputation meth...

Research paper thumbnail of FRI0380 SECUKINUMAB Provides Sustained Improvement of Enthesitis in Patients with Ankylosing Spondylitis: Pooled Analysis of Four Pivotal Phase 3 Studies

Spondyloarthritis – treatment, 2019

Background: Evaluation of long-term efficacy and safety for treatments for ankylosing spondylitis... more Background: Evaluation of long-term efficacy and safety for treatments for ankylosing spondylitis (AS) is important. Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin-17A, has shown significant and sustained improvement in the signs and symptoms of AS through 3 years in the MEASURE 2 study (NCT01649375). 1 Objectives: We report the 5-year end-of-study results of subcutaneous (s. c.) secukinumab 150 mg in the MEASURE 2 study. Methods: AS patients (pts; N = 219) were randomised to receive s.c. secukinumab 150 mg, 75 mg or placebo at baseline, Weeks (Wks) 1, 2 and 3 and every 4 wks from Wk 4. At Wk 16, placebo-treated pts were re-randomised to receive secukinumab 150/75 mg. Efficacy results are reported for pts initially randomised to secukinumab 150 mg and those who switched from placebo to secukinumab 150 mg at Wk 16 (N = 106). An optional dose escalation from secukinumab 75 mg to 150 mg was initiated beginning Wk 140. Outcome measures at Wk 260 included ASAS20/40, BASDAI50, BASMI, BASFI, SF-36 PCS and ASAS partial remission. Analyses stratified by anti-TNF status (anti-TNF-naïve and anti-TNF inadequate response [IR]) were performed. Safety analysis included all pts who received !1 dose of secukinumab. Results are reported as observed. Results: The retention rate to Wk 260 was 77% (82/106) for secukinumab 150 mg. Sustained efficacy was observed with secukinumab 150 mg across all endpoints through 5 years (Table). Improvements were maintained regardless of prior exposure to anti-TNF therapy with greater responses in anti-TNF-naïve pts. A total of 49 pts on secukinumab 75 mg (46.7%) escalated dose to 150 mg after Wk 140; efficacy responses improved in pts whose dose was escalated. Over the entire study period, the mean exposure (±SD) to secukinumab was 1459.1 ± 597.8 days. Exposure-adjusted incidence rates (per 100 pt-years) with any secukinumab dose for selected adverse events were: Candida infections (1.0), Crohn's disease (0.5), major adverse cardiovascular events (0.7), uveitis (0.5), and malignant/unspecified tumours (0.5). Conclusion: Secukinumab 150 mg provided sustained improvement in the signs, symptoms, and physical function in pts with AS through 5 years of treatment. The safety profile of secukinumab remained consistent with previous reports. 1-3

Research paper thumbnail of Secukinumab provides rapid and sustained pain relief in psoriatic arthritis over 2 years: results from the FUTURE 2 study

Arthritis Research & Therapy, 2018

Background: Pain is one of the most important domains affecting health-related quality of life (H... more Background: Pain is one of the most important domains affecting health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). Secukinumab has demonstrated rapid and sustained improvements in signs and symptoms, including HRQoL, among patients with active PsA. This analysis evaluates the effect of secukinumab on patient-reported pain in PsA through 104 weeks of treatment. Methods: Pain was assessed through week 104 using clinically relevant measures, including change from baseline in a pain visual analog scale (VAS) and Short Form-36 (SF-36) bodily domain scores; proportion of patients reporting improvements equal to or better than minimum clinically meaningful differences in the pain VAS and SF-36 bodily pain domain scores; and proportion of patients with no, moderate, or extreme pain/discomfort measured by the EuroQoL 5-Dimension 3-Level Questionnaire (EQ-5D-3 L) pain item scores. Correlations of pain measures were analyzed using Pearson's correlation coefficient. Pre-specified analyses of TNF-naïve patients and patients who stopped TNF-inhibitors (TNFis) due to inadequate responses or safety/tolerability (TNF-IR patients) were performed using "as-observed data." Results: Mean improvements from baseline in pain VAS scores were greater with secukinumab versus placebo by week 3 (− 16.9; P < 0.0001 with secukinumab 300 mg and − 12.6; P < 0.05 with secukinumab 150 mg) and sustained through week 104. SF-36 bodily pain domain scores were significantly greater with 300 mg secukinumab and secukinumab 150 mg versus placebo by week 4 (16.2 and 16.3, respectively; P < 0.0001 for both), and these changes were maintained through week 104. With both secukinumab 300 mg and secukinumab 150 mg, improvements equal to or better than the minimum clinically meaningful differences in pain VAS and SF-36 bodily pain were significant versus placebo at week 3 and week 4, respectively. At week 4, 15%, 9%, and 5% of patients receiving secukinumab 300 mg, secukinumab 150 mg, and placebo, respectively, reported "no pain/discomfort" measured by EQ-5D-3 L; these proportions increased to week 104 with both secukinumab doses. Similarly, improvements in pain measures were significant in both TNF-naïve and TNF-IR patients. Conclusion: Secukinumab provided rapid and sustained pain relief in PsA over 2 years of treatment. Improvements in pain were reported regardless of prior exposure to TNFis.

Research paper thumbnail of Incidence rates of inflammatory bowel disease in patients with psoriasis, psoriatic arthritis and ankylosing spondylitis treated with secukinumab: a retrospective analysis of pooled data from 21 clinical trials

Annals of the Rheumatic Diseases, 2019

ObjectivesHere, we present the reported incidence rates of inflammatory bowel disease (IBD) in pa... more ObjectivesHere, we present the reported incidence rates of inflammatory bowel disease (IBD) in patients receiving treatment with secukinumab for psoriasis (PsO), psoriatic arthritis (PsA) or ankylosing spondylitis (AS), in a pooled analysis of 21 clinical trials.MethodsData from all patients who had received at least one dose of secukinumab were included. Safety analyses were conducted to evaluate cumulative IBD rates as well as per-year rates, by indication. Crohn’s disease (CD), ulcerative colitis (UC) and IBD unclassified (IBDU) events were analysed using exposure-adjusted incidence rates (patient incidence rates per 100 patient-years (PY)).ResultsA total of 7355 patients with a cumulative exposure of 16 226.9 PY were included in the pooled analysis. Among 5181 patients with PsO, there were 14 cases of UC, 5 cases of CD and 1 case of IBDU, with exposure adjusted incidence rates (EAIRs) of 0.13, 0.05 and 0.01, respectively. Of these 20 cases, 14 were new-onset. In 1380 patients wi...

Research paper thumbnail of Secukinumab maintains reductions in PASI through second year of treatment: A randomized extension of the ERASURE and FIXTURE studies in plaque psoriasis

Journal of the American Academy of Dermatology, 2016

Introduction: We report the effect of secukinumab, with and without concomitant methotrexate (MTX... more Introduction: We report the effect of secukinumab, with and without concomitant methotrexate (MTX), on radiographic progression in psoriatic arthritis (PsA) patients in an exploratory subgroup analysis of the randomized, double-blind, placebo (PBO)-controlled study (FUTURE 1; NCT01392326). Methods: 606 patients with active PsA were randomized to secukinumab or PBO. Patients on secukinumab received 10 mg/kg intravenous (i.v.) loading dose at baseline (BL), Weeks (Wks) 2 and 4, followed by subcutaneous (sc) secukinumab 150 (IVe150 mg) or 75 mg (IVe75 mg) every 4 wks (q4wk) from Wk 8. PBO was given on the same schedule. At Wk 16, PBO patients with ˂20% reduction in tender or swollen joint count (nonresponders) were rerandomized to secukinumab 75 or 150 mg sc q4wk; responders received secukinumab 75 or 150 mg sc q4wk from Wk 24. van der Heijde modified total Sharp score (mTSS) and erosion and joint space narrowing (JSN) scores were determined at BL, Wks 16/24 (depending upon response) and Wk 52. Analysis of radiographic progression at Wk 24 used linear extrapolation for patients with X-ray assessments at Wk 16. Wk 52 analyses used evaluable data. Results: In the overall study population, secukinumab significantly inhibited radiographic progression from BL to Wk 24 vs PBO. There was lower mean change in mTSS score from BL to Wk 24 in patients on secukinumab compared to those on PBO, irrespective of concomitant MTX use. Inhibition of radiographic progression with secukinumab was sustained from Wk 24 to Wk 52. Improvements in mean change in erosion and JSN scores were also observed with secukinumab throughout the study. Conclusions: Secukinumab provided significant and sustained inhibition of radiographic disease in patients with PsA. Within the limitations of suboptimal statistical power, the exploratory analysis does not suggest a clinically meaningful difference in radiographic progression between the secukinumab with MTX and secukinumab without MTX subgroups.

Research paper thumbnail of THU0359 Secukinumab demonstrates consistent safety over long-term exposure (up to 3 years) in patients with active ankylosing spondylitis: pooled analysis of three phase 3 trials

Poster Presentations, 2017

to the application of the EMA recommendation (interaction p value=0.140). In the 59 pts not treat... more to the application of the EMA recommendation (interaction p value=0.140). In the 59 pts not treated in accordance with the EMA recommendation, the treatment effect in the subgroups of pts without (vs with) concomitant FM was 38% vs 40% respectively, p=0.891. In the 449 pts treated in accordance with the EMA recommendation, the treatment effect in the subgroups of pts without (vs with) concomitant FM was 56% vs 46%, p=0.042). Conclusions: This study suggests that 1/ French rheumatologists are applying the EMA recommendation in daily practice 2/ these recommendations result in a better outcome in terms of short term symptomatic treatment effect. In this study, concomitant FM was not more frequently observed in patients without (vs with) objective sign of structural damage or inflammation and the impact of a concomitant FM was not more pronounced (or even lower) in pts without (vs with) objective sign of structural damage or inflammation. References: [1] Perrot S, et al. Development and validation of the Fibromyalgia Rapid Screening Tool (FiRST). Pain.2010;150:250-6. Acknowledgements: This study was conducted thanks to an unrestricted grant from MSD.