Dataset Information

Secukinumab Efficacy in Psoriatic Arthritis: Machine Learning and Meta-analysis of Four Phase 3 Trials.

ABSTRACT:

Background

Using a machine learning approach, the study investigated if specific baseline characteristics could predict which psoriatic arthritis (PsA) patients may gain additional benefit from a starting dose of secukinumab 300 mg over 150 mg. We also report results from individual patient efficacy meta-analysis (IPEM) in 2049 PsA patients from the FUTURE 2 to 5 studies to evaluate the efficacy of secukinumab 300 mg, 150 mg with and without loading regimen versus placebo at week 16 on achievement of several clinically relevant difficult-to-achieve (higher hurdle) endpoints.

Methods

Machine learning employed Bayesian elastic net to analyze baseline data of 2148 PsA patients investigating 275 predictors. For IPEM, results were presented as difference in response rates versus placebo at week 16.

Results

Machine learning showed secukinumab 300 mg has additional benefits in patients who are anti-tumor necrosis factor-naive, treated with 1 prior anti-tumor necrosis factor agent, not receiving methotrexate, with enthesitis at baseline, and with shorter PsA disease duration. For IPEM, at week 16, all secukinumab doses had greater treatment effect (%) versus placebo for higher hurdle endpoints in the overall population and in all subgroups; 300-mg dose had greater treatment effect than 150 mg for all endpoints in overall population and most subgroups.

Conclusions

Machine learning identified predictors for additional benefit of secukinumab 300 mg compared with 150 mg dose. Individual patient efficacy meta-analysis showed that secukinumab 300 mg provided greater improvements compared with 150 mg in higher hurdle efficacy endpoints in patients with active PsA in the overall population and most subgroups with various levels of baseline disease activity and psoriasis.

SUBMITTER: Gottlieb AB

PROVIDER: S-EPMC8389345 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BACKGROUND:Enthesitis is one of the psoriatic arthritis (PsA) domains. Patients with enthesitis are associated with worse outcomes than those without enthesitis. The effect of secukinumab on the resolution of enthesitis in patients with PsA was explored using pooled data from the FUTURE 2 and 3 studies. METHOD:Assessments of enthesitis through week 104 used the Leeds Enthesitis Index. These post hoc analyses included resolution of enthesitis count (EC = 0), median time to first resolution of enthesitis (Kaplan-Meϊer estimate), and shift analysis (as observed) of baseline EC (1, 2, or 3-6) to full resolution (FR), stable (similar or reduction of EC), or worse (EC > baseline). Efficacy outcomes (ACR, PASI, HAQ-DI, SF-36 PCS, and DAS28-CRP) were assessed in patients with or without baseline enthesitis. Results are reported for secukinumab 300 and 150 mg in the overall population and by prior TNFi treatment. RESULTS:A total of 65% (466/712) of patients had baseline enthesitis. In the overall population, FR was achieved as early as week 16 in 65% (300 mg) and 56% (150 mg) versus 44% (placebo) patients, with further improvements to 91% (300 mg) and 88% (150 mg) at week 104. The majority (89%) of patients without enthesitis at baseline maintained this status at week 104. Median days to resolution of EC were shorter with secukinumab 300 and 150 mg versus placebo (57 and 85 vs 167 days, respectively). In patients with EC of 1 or 2, shift analysis from baseline to week 24 showed that more patients achieved FR with secukinumab 300 mg and 150 mg versus placebo, whereas no difference between secukinumab and placebo was shown in the more severe patients with EC of 3-6. Increases in proportions of patients with FR were observed with secukinumab irrespective of the severity of EC from baseline to week 104. Improvements in efficacy outcomes were similar in patients with or without enthesitis treated with secukinumab 300 mg. CONCLUSION:Secukinumab provided early and sustained resolution of enthesitis in patients with PsA over 2 years. Secukinumab 300 mg provided higher resolution than 150 mg in patients with more severe baseline EC and showed similar overall efficacy in patients with or without enthesitis. TRIAL REGISTRATION:FUTURE 2: ClinicalTrials.gov, NCT01752634 (date of study registration: December 19, 2012), and EudraCT, 2012-004439-22 (date of study registration: December 12, 2012) FUTURE 3: ClinicalTrials.gov, NCT01989468 (date of study registration: November 21, 2013), and EudraCT, 2013-004002-25 (date of study registration: December 17, 2013).

Project description:BackgroundPsoriatic arthritis (PsA) is a chronic, heterogeneous, immune-mediated disease manifesting as a spectrum of possible inflammatory signs and symptoms. Clinicians need therapeutic choices that work across all active PsA disease domains, as well as practical information about efficacy of available treatments for individual domains in specific groups of patients. The objective of this study was to evaluate the effect of prior tumor necrosis factor inhibitor (TNFi) exposure on the efficacy of secukinumab across PsA core domains.MethodsData were pooled from 2049 participants with PsA in four phase 3 studies (FUTURE 2-5). Efficacy at week 16 was evaluated for each GRAPPA-OMERACT PsA core domain using nonresponder imputation for musculoskeletal disease activity and Psoriasis Area and Severity Index scores or as-observed data for other outcomes. For each measure, comparisons with placebo were made separately in the TNFi-naive and TNFi-inadequate responder/intolerant (TNF-IR) cohorts.ResultsTreatment with secukinumab improved PsA disease activity across all disease domains regardless of previous TNFi use, although TNFi-naive patients experienced numerically greater benefits in most outcomes. Among patients treated with secukinumab 300 mg, 41.5% and 24.4% of TNFi-naive patients (P < 0.05 vs placebo) and 18.6% and 9.0% of TNF-IR patients (nonsignificant vs placebo) experienced resolution in 66 swollen and 68 tender joint counts, respectively; additionally, 37.2% of TNFi-naive patients and 24.2% of TNF-IR patients achieved complete resolution of psoriasis at week 16 (all P < 0.05 vs placebo). Secukinumab effect sizes were generally larger in TNFi-naive vs TNF-IR patients for musculoskeletal and patient-reported domains.ConclusionsSecukinumab demonstrated efficacy vs placebo across GRAPPA-OMERACT PsA core domains. Higher responses among TNFi-naive vs TNF-IR patients suggest that secukinumab should be considered for first-line use in PsA.

Project description:IntroductionPsoriatic arthritis (PsA) is an immune-mediated chronic inflammatory arthropathy associated with impaired physical function and reduced quality of life. Biologic therapies that target tumor necrosis factor (anti-TNF) have significantly improved clinical outcomes. Partial, non- and transient responses remain common comprising significant unmet clinical need. New therapies with novel modes of action are urgently required.ObjectivesThe interleukin (IL)-17 pathway has recently been attributed a critical role in the pathogenesis of spondyloarthritides. Herein, we review data from clinical studies with secukinumab, a novel fully human IgG1κ anti-IL-17A monoclonal antibody (mAb), in patients with active PsA.ResultsAcross two pivotal phase 3 studies, secukinumab provided significant and sustained reductions in the signs and symptoms of PsA, inhibition of radiographic progression, and improved patient-reported outcomes and measures of quality of life. The primary efficacy endpoint, a ≥20% improvement from baseline according to the American College of Rheumatology 20 (ACR20) response at Week 24, was significantly higher in patients treated with secukinumab compared with placebo, with improvements sustained through at least 52 weeks. Clinical benefits were seen with secukinumab regardless of concomitant methotrexate treatment and in patients who were either anti-TNF-naïve or who were inadequate responders to anti-TNF therapy. Secukinumab was well-tolerated, with a safety profile consistent with that previously reported in psoriasis trials. The most common adverse events were nasopharyngitis, upper respiratory tract infections, and headache.ConclusionSecukinumab offers an effective new addition to the available treatment options for PsA. Regulatory submissions have been filed worldwide, with the first approvals recently obtained in Japan and Europe. Future studies are required to define the optimal timing and strategic use of this novel treatment modality.FundingNovartis Pharma.