Baseline characteristics and effects of fingolimod on cognitive performance in patients with relapsing‐remitting multiple sclerosis

Abstract

Background and purpose: Studies reporting the baseline determinants of cognitive performance and treatment effect on cognition in patients with multiple sclerosis (MS) are limited. We investigated the baseline correlates of cognition and the long-term treatment effects of fingolimod 0.5 mg once daily on cognitive processing speed and attention in patients with relapsing-remitting MS. Methods:This post hoc analysis pooled data from the phase 3 FREEDOMS and FREEDOMS II trials (N = 1556). We assessed the correlation between baseline patient demographic and disease characteristics and baseline 3-second Paced Auditory Serial Addition Test (PASAT-3) scores (Spearman's rank test) and the changes from baseline in PASAT-3 (mixed model repeated measures model) in the fingolimod and placebo (up to 24 months) or placebo-fingolimod switched (from Month 24 up to 120 months) groups.Additionally, the predictive value of PASAT-3 score for future disease outcomes was assessed (Cox or logistic regression models).Results: Among the variables assessed, lower PASAT-3 score at baseline correlated with higher disease burden (total brain volume, T2 lesion volume, and Expanded Disability Status Scale score), longer disease duration and older age (p < 0.0001 for all). Fingolimod significantly improved PASAT-3 scores from baseline versus placebo at 6 (1.3; p = 0.0007), 12 (1.1; p = 0.0044) and 24 months (1.1; p = 0.0028), with a sustained effect (overall treatment effect p = 0.0012) up to 120 months. Improvements were seen regardless of baseline cognitive status (PASAT quartile). Baseline PASAT-3 score was predictive of both clinical and magnetic resonance imaging measures of disease activity at Month 24 (p < 0.001 for all). Conclusion:Early fingolimod treatment may offer long-term cognitive benefit in patients with relapsing-remitting MS.

Neurocognitive impairment in multiple sclerosis and its association with thiol‐disulfide homeostasis and ischemia‐modified albumin

“…Nevertheless, EDSS was associated with cognitive impairment in the patients with RRMS who were on fingolimod therapy. Similarly, a clear relationship has been reported between EDSS and PASAT-3 score in the phase 3 FREEDOMS and FREEDOMS II trials (Langdon et al, 2021).…”

“…Fingolimod treatment has been shown to improve cognitive performance, which may be due to the fact that it crosses the blood–brain barrier, encouraging myelin preservation, repair, and neurological function normalization (Groves et al, 2013). Phase 3 FREEDOMS and FREEDOMS II trials determined cognitive performance in patients with MS using the 3‐second Paced Auditory Serial Addition Test (PASAT‐3) and have suggested that early fingolimod therapy may provide long‐term cognitive improvement (Langdon et al, 2021). In a randomized controlled trial (the GOLDEN study), the benefits of fingolimod therapy on cognitive functions have been verified using Rao's Brief Repeatable Battery and Delis–Kaplan Executive Function System test (Comi et al, 2017).…”

“…Fingolimod (FTY720, Gilenya®) is an immunomodulatory oral medication used in the treatment of RRMS patients who cannot benefit from first‐line treatments or who have high disease activity from the beginning in many countries (Aydın Güngör et al, 2018). A recent phase 3 trial has reported evidence that early fingolimod therapy may provide long‐term beneficial cognitive effects (Langdon et al, 2021). The relationship between fingolimod treatment and oxidative stress has been evaluated in two recent studies, focusing on serum total oxidative stress (TOS), total antioxidant capacity (TAC) (Yevgi & Demir, 2021) or sulfhydryl groups, ceruloplasmin, and superoxide dismutase (SOD) activity (Adamczyk et al, 2018).…”

“…A recent phase 3 trial has reported evidence that early fingolimod therapy may provide long-term beneficial cognitive effects (Langdon et al, 2021). The relationship between fingolimod treatment and oxidative stress has been evaluated in two recent studies, focusing on serum total oxidative stress (TOS), total antioxidant capacity (TAC) (Yevgi & Demir, 2021) or sulfhydryl groups, ceruloplasmin, and superoxide dismutase (SOD) activity (Adamczyk et al, 2018).…”

Association between speech rate measures and cognitive function in people with relapsing and progressive multiple sclerosis

“…DMTs may affect cognition by reducing the progression of brain atrophy and relapse rates. 37 , 38 Emerging research described early treatment with fingolimod as providing a cognitive advantage in those with RMS by allowing adaptive neuroplastic changes and providing anti-inflammation effects 38 while Mattioli et al 37 reported that natalizumab-aided executive functioning and memory improvements through preservation of parahippocampal and frontal grey matter. However, there remains insufficient evidence of the efficacy of DMTs in the treatment of cognitive impairments in pwMS and no medication has been approved, specifically for these symptoms.…”