Abstract
Background/Aims
Disease Activity Index for Psoriatic Arthritis (DAPSA) or the minimal disease activity (MDA) are considered for defining remission (REM) or low disease activity (LDA) in ...secukinumab-treated patients with psoriatic arthritis (PsA). Currently, limited secukinumab data are available on patients with PsA achieving sustained REM in clinical trials or real-world evidence using these stringent criteria. This abstract reports an exploratory analysis of achievement of sustained REM/LDA in patients with PsA treated with secukinumab and impact on structural outcomes, physical function and health-related quality of life (HRQoL) in the FUTURE 5 study (NCT02404350).
Methods
FUTURE 5 is a randomised, double-blind, placebo-controlled, 2-year phase 3 trial in patients with active PsA. Patients randomised to secukinumab 150 mg could be escalated to 300 mg from week 52 to 104, based on investigators’ judgement. Patients were categorised as either not achieving REM/LDA, achieving it once only, or sustained REM/LDA (defined as patients achieving REM/LDA between weeks 24-52 and maintaining the same response at least 2 of the next 6 visits visit every 8 weeks). Of patients who did not achieve REM/LDA or who achieved REM/LDA (VLDA, DAPSA REM, MDA, DAPSA LDA+REM) between weeks 24 and 52, the relationships between: absence of REM/LDA; REM/LDA; sustained REM/LDA; proportion of patients with non-radiographic progression (assessed using the van der Heijde mTSS); physical function (health assessment questionnaire disability index HAQ-DI); and short form-36 physical component score SF-36 PCS) were assessed.
Results
996 patients were randomised to 1 of 4 treatment groups: secukinumab 300 mg loading dose (LD; n = 222), secukinumab 150 mg LD (n = 220), secukinumab 150 mg no LD (NL; n = 222), and placebo (n = 332). The baseline clinical characteristics were comparable across treatment groups. Most patients achieved either sustained MDA or sustained DAPSA LDA+REM (Table). Patients achieving REM/LDA, whether at one visit or consistently, showed improved physical function and SF36-PCS at week 104. A high proportion of patients did not show radiographic progression at week 104 irrespective of achievement of REM/LDA category.
Conclusion
Most patients treated with secukinumab achieved a sustained LDA. Sustained LDA/REM was associated with improved HRQoL, physical function and inhibition of structural damage progression.
Disclosure
L.C. Coates: Consultancies; Abbvie, Amgen, Biogen, Boehringer Ingelheim, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, UCB. Grants/research support; Abbvie, Celgene, Lilly, Novartis, Pfizer. P.J. Mease: Consultancies; AbbVie, Amgen, BMS, Boehringer Ingelheim, Galapagos, Celgene, GlaxoSmithKline, Gilead, Janssen, Lilly, Novartis, Pfizer, SUN Pharma, UCB. Member of speakers’ bureau; AbbVie, Amgen, Janssen, Lilly, Novartis, Pfizer, UCB. Grants/research support; AbbVie, Amgen, BMS, Celgene, Galapagos, Gilead, Janssen, Lilly, Novartis, Pfizer, SUN, UCB. D.D. Gladman: Consultancies; Abbvie, Amgen, BMS, Celgene, Eli Lilly, Gilead, Galapagos, Janssen, Novartis, Pfizer, UCB. Grants/research support; Abbvie, Amgen, Celgene, Eli Lilly, Novartis, Pfizer, UCB. S. Navarra: Consultancies; Pfizer, Novartis, Astra-Zeneca, Janssen, Lilly, Astellas. Member of speakers’ bureau; Pfizer, Novartis, Astra-Zeneca, Janssen, Lilly, Astellas. W. Bao: Shareholder/stock ownership; Novartis. Other; Employee of Novartis. C. Gaillez: Shareholder/stock ownership; Novartis, BMS. Other; Employee of Novartis.
Aims
Sacubitril/valsartan has shown efficacy and tolerability in patients with heart failure (HF) and reduced ejection fraction (HFrEF) in the ambulatory setting (PARADIGM‐HF), and following ...stabilisation of acutely decompensated HF (ADHF) (PIONEER‐HF and TRANSITION). However, data are lacking for the initiation of sacubitril/valsartan in newly diagnosed (de novo) HFrEF. Here, we assess the tolerability of initiating sacubitril/valsartan following ADHF in TRANSITION subgroups of patients with a de novo vs. prior diagnosis of HFrEF.
Methods and results
TRANSITION randomised 1002 patients to pre‐ and post‐discharge initiation of sacubitril/valsartan (analysis set n = 991, following exclusions for mis‐randomisation). In this post‐hoc analysis, tolerability to sacubitril/valsartan proportion of patients achieving target dose (97/103 mg b.i.d.) at 10 weeks post‐randomisation, adverse events (AEs) and serious AEs (SAEs) were compared in de novo (n = 286) and prior HFrEF (n = 705) subgroups. More de novo than prior HFrEF patients achieved target dose at Week 10 (56% vs. 45%; relative risk ratio 1.30, 95% confidence interval 1.12–1.52, P < 0.001), and fewer had SAEs and permanent treatment discontinuations. Initiation of sacubitril/valsartan did not prevent the concomitant initiation and up‐titration of guideline‐directed HF therapies. De novo patients showed faster and greater decreases in N‐terminal pro‐B‐type natriuretic peptide and high‐sensitivity troponin‐T, and lower rates of HF and all‐cause rehospitalisation vs. prior HFrEF.
Conclusions
After ADHF, first‐line initiation of sacubitril/valsartan in de novo HFrEF, alongside the initiation of other guideline‐directed therapies, is feasible and is associated with a better risk–benefit profile than in patients with prior HFrEF. Early intervention with sacubitril/valsartan may be considered to delay disease progression in patients with de novo HFrEF.
Clinical Trial Registration: ClinicalTrials.gov, NCT02661217.
Approximately one-quarter of the global population have latent tuberculosis infection (LTBI), and tuberculosis (TB) is accountable for more than 1.5 million deaths annually. Methotrexate, ...cyclosporine, and tumor necrosis factor inhibitors may be associated with increased risk of TB and LTBI reactivation, although data are limited on the risks of TB with use of newer biologics.
To assess the association of secukinumab with reporting of active TB development, TB reactivation, and LTBI activation as an adverse event (AE) in patients with psoriasis, psoriatic arthritis, or ankylosing spondylitis.
This pooled cohort study pooled data from 28 clinical trials of secukinumab used in psoriasis (17 phase 3 or 3b and 2 phase 4 trials), psoriatic arthritis (5 phase 3 trials), and ankylosing spondylitis (4 phase 3 trials). A search of the Novartis Secukinumab Compound Pool Database was conducted for the 28 trials. All trial participants who had received at least 1 approved subcutaneous dose of secukinumab (150 mg or 300 mg) were included. Before randomization in these trials, patients underwent screening for TB. Patients with active TB were excluded, and patients with LTBI were treated according to local guidelines. Data were analyzed from the start of treatment in the individual studies through December 25, 2018.
Reporting of active TB or LTBI as an AE over a 5-year period using exposure-adjusted incidence rates (EAIR; incidence rates per 100 patient-years).
A total of 12 319 patients were included, of whom 8819 patients had psoriasis (71.6%; 5930 men 67.2%; mean SD age, of 44.9 13.5 years), 2523 had psoriatic arthritis (20.5%; 1323 women 52.4%; mean SD age, 48.8 12.1 years), and 977 had ankylosing spondylitis (7.3%; 658 men 67.3%; mean SD age, 42.3 11.9 years). In the total population, 684 patients (5.6%) had tested positive for LTBI at screening. Over 5 years, LTBI as an AE during secukinumab treatment was reported in 13 patients (0.1% of 12 319). Of these 13 patients, 6 had a prior positive LTBI test result, and 7 were newly diagnosed as having LTBI. Four of the 7 patients had psoriasis (EAIR, 0.03; 95% CI, 0.01-0.07), 1 had psoriatic arthritis (EAIR, 0.02; 95% CI, 0.00-0.11), and 2 had ankylosing spondylitis (EAIR, 0.08; 95% CI, 0.01-0.28). No cases of active TB were reported.
This study found that LTBI reported as an AE after secukinumab treatment was uncommon and appeared to support the use of secukinumab in chronic systemic inflammatory conditions.
Abstract
Background/Aims
The combined use of Power Doppler and B-mode ultrasound (PDUS) allows visualisation of morphological and pathophysiological changes of the synovium. ULTIMATE (NCT02662985) ...was the first large, randomised, double-blind, placebo-controlled PDUS phase IIIb study in psoriatic arthritis (PsA) to demonstrate that the validated Global OMERACT EULAR Synovitis Score (GLOESS), an ultrasound score at patient level, could detect the early and continuous decrease in synovitis in a multicentre setting using different ultrasound devices and examiners. Since the ultrasound assessment for GLOESS is time-consuming owing to the number of joints assessed, we investigated the ability of various reduced joint sets to predict GLOESS.
Methods
ULTIMATE was a 52-week study of secukinumab with a 12-week, double-blind, placebo-controlled period followed by a 12-week, open-label treatment period and 6-month open-label extension period. GLOESS for 24 paired joints was calculated, with a resultant potential score ranging from 0 to 144. Based on their composite PDUS scores, highly correlated joint clusters were identified with a Spearman’s rank correlation matrix and a Clustered Image Map. Representative joints were then selected from each group by various approaches (best correlation, model optimisation, etc.) yielding several joint combinations. For these reduced joint sets, GLOESS was predicted with linear models based on data from 60% of randomly selected patients from ULTIMATE. The remaining 40% of patient data were used for model validation and diagnostics.
Results
Five models were established with reduced pairs of joint sets (9-13 pairs) for PDUS-detected synovitis. The joints included in each linear model are summarised in the Table. All five reduced joint set models demonstrated scores very close to full 48 joint GLOESS (R2 ∼0.95); models 1-3 (based on 9 joint pairs) were less accurate at predicting GLOESS than models 4 and 5 (based on 13 and 12 joint pairs, respectively) for the secukinumab cohort in the open-label part (data to be shown in poster).
Conclusion
All models of reduced joint sets for PDUS-detected synovitis predicted GLOESS well. The next steps will be to document responsiveness and ability to discriminate between active and placebo treatment.
Disclosure
P.G. Conaghan: Consultancies; P.G.C. has received consultancy fees from AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Janssen, Merck, Novartis and Pfizer, Stryker and UCB. Member of speakers’ bureau; P.G.C. has received speakers bureau fees from AbbVie, Novartis and Pfizer. M. D'agostino: Consultancies; M.A.D'A. has received consultancy fees from AbbVie, BMS, Celgene, Eli Lilly, Janssen, Novartis, Roche, Sanofi, and UCB. Member of speakers’ bureau; M.A.D'A. has received speakers bureau fees from AbbVie, BMS, Celgene, Eli Lilly, Janssen, Novartis, Roche, Sanofi and UCB. M. Boers: Consultancies; M.B. has received consultancy fees from Novartis. E. Naredo: Honoraria; E.N. has received honoraria for clinical trials from AbbVie, BMS and Novartis. Member of speakers’ bureau; E.N. has received speakers bureau fees from AbbVie, BMS, Celgene GmbH, Janssen, Lilly, Novartis, Pfizer, Roche and UCB. Grants/research support; E.N. has received research grants from Eli Lilly. P. Mandl: Member of speakers’ bureau; P.M. has received speakers bureau fees from AbbVie, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Roche and UCB. Grants/research support; P.M. has received grant/research support from AbbVie, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Roche and UCB. P. Carron: Consultancies; P.C. has received consultancy fees from AbbVie, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Gilead, Merck Sharp Dohme, Novartis, Pfizer and UCB. Member of speakers’ bureau; P.C. has received speakers bureau fees from AbbVie, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Gilead, Merck Sharp Dohme, Novartis, Pfizer and UCB. Grants/research support; P.C. has received grant/research support from Merck Sharp Dohme, Pfizer and UCB. M. Backhaus: Consultancies; M.B. has received consultancy fees from BMS, Galapagos, Jonsson, MSD, Novartis, Pfizer, Roche and UCB. Member of speakers’ bureau; M.B. has received speakers bureau fees from BMS, Galapagos, Jonsson, MSD, Novartis, Pfizer, Roche and UCB. Grants/research support; M.B. has received grant/research support from BMS, Galapagos, Jonsson, MSD, Novartis, Pfizer, Roche and UCB. A. López-Rodríguez: Consultancies; A.L.R. has received consultancy fees from Eli Lilly, GSK, Janssen, Novartis, Roche and UCB. Member of speakers’ bureau; A.L.R. has received speakers bureau fees from Eli Lilly, GSK, Janssen, Novartis, Roche and UCB. P. Hanova: Consultancies; P.H. has received consultancy fees from Novartis. P. Goyanka: Other; P.G. is an employee of Novartis. B.G. Sahoo: Other; B.G.S. is an employee of Novartis. C. Gaillez: Shareholder/stock ownership; C.G. is a shareholder of Novartis and BMS. Other; C.G. is an employee of Novartis. W. Bao: Shareholder/stock ownership; W.B. is a shareholder of Novartis. Other; W.B. is an employee of Novartis.
Secukinumab showed consistent and sustained efficacy in clearing nail psoriasis in patients with psoriatic arthritis, with or without axial manifestations, irrespective of severity of nail ...involvement. Reduction of nail disease was also associated with response across all musculoskeletal and skin manifestations of psoriatic arthritis.
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