Onboarding of siponimod in secondary progressive multiple sclerosis patients in Australia: Novel, real-world evidence from the MSGo digital support programme
Ontology highlight
ABSTRACT:
SUBMITTER:
PROVIDER: S-EPMC10787529 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundTherapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing-remitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape.MethodsWe conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18 months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions.ResultsUnder siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12 months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12 months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12 months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy.ConclusionTreatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE.
| S-EPMC9639325 | biostudies-literature
Project description:BackgroundIn multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.ObjectiveTo distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.MethodsThree estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.ResultsPrincipal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.ConclusionBy controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.
| S-EPMC8414818 | biostudies-literature
Project description:BACKGROUNDSiponimod (BAF312) is a selective sphingosine-1-phosphate receptor 1 and 5 (S1PR1, S1PR5) modulator recently approved for active secondary progressive multiple sclerosis (SPMS). The immunomodulatory effects of siponimod in SPMS have not been previously described.METHODSWe conducted a multicentered, randomized, double-blind, placebo-controlled AMS04 mechanistic study with 36 SPMS participants enrolled in the EXPAND trial. Gene expression profiles were analyzed using RNA derived from whole blood with Affymetrix Human Gene ST 2.1 microarray technology. We performed flow cytometry-based assays to analyze the immune cell composition and microarray gene expression analysis on peripheral blood from siponimod-treated participants with SPMS relative to baseline and placebo during the first-year randomization phase.RESULTSMicroarray analysis showed that immune-associated genes involved in T and B cell activation and receptor signaling were largely decreased by siponimod, which is consistent with the reduction in CD4+ T cells, CD8+ T cells, and B cells. Flow cytometric analysis showed that within the remaining lymphocyte subsets there was a reduction in the frequencies of CD4+ and CD8+ naive T cells and central memory cells, while T effector memory cells, antiinflammatory Th2, and T regulatory cells (Tregs) were enriched. Transitional regulatory B cells (CD24hiCD38hi) and B1 cell subsets (CD43+CD27+) were enriched, shifting the balance in favor of regulatory B cells over memory B cells. The proregulatory shift driven by siponimod treatment included a higher proliferative potential of Tregs compared with non-Tregs, and upregulated expression of PD-1 on Tregs. Additionally, a positive correlation was found between Tregs and regulatory B cells in siponimod-treated participants.CONCLUSIONThe shift toward an antiinflammatory and suppressive homeostatic immune system may contribute to the clinical efficacy of siponimod in SPMS.TRIAL REGISTRATIONNCT02330965.
| S-EPMC7098784 | biostudies-literature
Project description:BackgroundCirculating immune cells play a pathogenic role in multiple sclerosis (MS). However, the role of specific lymphocyte subpopulations is not unveiled yet, especially in progressive stages. We aimed to investigate lymphocyte changes during siponimod treatment in active secondary progressive MS (aSPMS) and their associations with clinical outcomes.MethodsWe enrolled 46 aSPMS patients starting on siponimod treatment with at least 6 months of follow-up and two visits within the scheduled timeframes and 14 sex- and age-matched healthy controls (HCs). Clinical and laboratory data were collected retrospectively at baseline, 3rd, 6th, 12th, and 24th month for MS patients, and at baseline for HCs.ResultsAt baseline SPMS patients presented with increased naïve regulatory T lymphocytes (p = 0.02) vs. HCs. Over time, SPMS patients showed decreased T CD4+ (coeff. range = -24/-17, 95% CI range = -31.60 to -10.40), B lymphocyte (coeff. range = -3.77/-2.54, 95% CI range = -6.02 to -0.35), memory regulatory B cells (coeff. range = -0.78/-0.57, 95% CI range = -1.24 to -0.17) and CD4/CD8 ratio (coeff. range = -4.44/-0.67, 95% CI range = -1.61 to -0.17) from month 3 thereafter vs. baseline, and reduced CD3+CD20+ lymphocytes from month 12 thereafter (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03). Patients not experiencing disability progression while on siponimod treatment showed B lymphocyte reduction from month 3 (coeff. range = -4.23/-2.32, 95% CI range = -7.53 to -0.15) and CD3+CD20+ lymphocyte reduction from month 12 (coeff. range = -0.32/-0.24, 95% CI range = -0.59 to -0.03) vs. patients experiencing progression.ConclusionsPatients treated with siponimod showed a T and B lymphocyte reduction, especially CD4+, CD3+CD20+ and naïve regulatory T cells and memory regulatory B cells. Disability progression while on siponimod treatment was associated with a less pronounced effect on B and CD3+CD20+ lymphocytes.
| S-EPMC11233419 | biostudies-literature
Project description:Siponimod selectively enriched regulatory T and B lymphocytes in active secondary progressive multiple sclerosis patients: 20 SPMS baseline including 3 repeats, 19 treated with 5 placebo and 14 siponimod treated.
2020-04-07 | GSE141381 | GEO
Project description:BackgroundSiponimod is an effective treatment for patients with secondary progressive multiple sclerosis (SPMS), with active disease evidenced by relapses or imaging features characteristic of multiple sclerosis inflammatory activity, however there is a need to evaluate its economic value and sustainability compared to other disease modifying-therapies (DMTs).ObjectiveTo estimate the siponimod cost-effectiveness profile and its relative budget impact compared with other DMTs, by using the Italian National Healthcare System perspective.MethodsWe performed: 1) a cost-effectiveness analysis (CEA) vs interferon beta-1b using an analytical Markov model and a life time-horizon, and 2) a budget impact analysis by using 3-years time-horizon. The results were reported as incremental cost-effectiveness ratio (ICER) and net-monetary benefit (NMB) for CEA, using a willingness to pay threshold of €40,000 per QALY gained, and as difference in the overall budget (Euro) between the scenario with and without siponimod for budget impact.ResultsIn the base case scenario siponimod resulted cost-effective compared with interferon beta-1b 28,891€ per QALY. Overall, the market access of siponimod was associated to an increased budget of about 3€ millions (+0.9%) in the next 3 years simulated.ConclusionCompared to interferon beta-1b, siponimod seems to be cost-effective in SPMS patients and sustainable, with less than 1% overall budget increased in the next 3 years. Future studies need to confirm our results in the real word setting and in other countries.
| S-EPMC8903273 | biostudies-literature
Project description:BackgroundSiponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS.MethodsPost hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND.Endpoints3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline-month 24; number of new/enlarging (N/E) T2 lesions over all visits.ResultsData from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p < 0.01); there was no significant effect on T25FW. Siponimod increased likelihood of 6-month confirmed SDMT improvement vs placebo (by 62%; p = 0.007) and reduced risk of 6-month confirmed SDMT worsening (by 27%; p = 0.060). Siponimod was associated with less increase in T2LV (1316.3 vs 13.3 mm3; p < 0.0001), and fewer T1 Gd + and N/E T2 lesions than placebo (85% and 80% reductions, respectively; p < 0.0001).ConclusionsIn aSPMS, siponimod reduced risk of disability progression and was associated with benefits on cognition and MRI outcomes vs placebo.Trial registrationClinicalTrials.gov number: NCT01665144.
| S-EPMC9363350 | biostudies-literature
Project description: Not available
| S-EPMC8592914 | biostudies-literature
Project description:BackgroundSiponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study.ObjectiveThe aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years.MethodsIn the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group).ResultsContinuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66-0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65-0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term.ConclusionThe sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation.Trial registration numberNCT01665144.
| S-EPMC9315196 | biostudies-literature
Project description:Secondary progressive multiple sclerosis (SPMS) is characterized by progressive accumulation of disability without intermittent recovery. Treatment of these patients is challenging due to limited understanding of pathogenesis and fewer therapeutic options. This article summarizes difficulties in defining and conducting trials in SPMS, review major clinical trials on therapies approved and unapproved in SPMS and lastly, therapies in pipeline for use in SPMS.
| S-EPMC6472227 | biostudies-literature