Early initiation of fingolimod reduces the rate of severe relapses over the long term: Post hoc analysis from the FREEDOMS, FREEDOMS II, and TRANSFORMS studies.

BACKGROUND: Relapse frequency is often correlated with the prognosis of multiple sclerosis (MS). In patients with relapsing-remitting MS (RRMS), relapses vary in severity and may affect activities of daily living, require steroid intervention, or hospitalization. Incomplete recovery from relapses results in increasing disability. In pivotal phase III studies of fingolimod (FREEDOMS, FREEDOMS II, and TRANSFORMS), the frequency of overall and severe relapses was significantly reduced in patients with RRMS treated with fingolimod compared with placebo or intramuscular interferon ß-1a (IFN ß-1a). The objective of this study was to report the effect of early initiation of fingolimod on relapse severity in patients with RRMS. METHODS: This is a post hoc descriptive analysis of data from the pooled placebo-controlled FREEDOMS/FREEDOMS II studies and from the active-comparator TRANSFORMS study. Patients were analyzed under 2 groups: patients initially randomized to receive fingolimod 0.5 mg during the core phase and continued fingolimod 0.5 mg in the extension phase (immediate fingolimod group), and patients initially randomized to placebo or IFN ß-1a during the core phase and switched to fingolimod during the extension phase (delayed fingolimod group). Annualized relapse rate (ARR) was estimated for severe relapses (defined as Expanded Disability Status Scale increase of >1 point, or >2-point change in 1 or 2 Functional Systems, respectively, or >1-point change in >4 Functional Systems). ARR was also estimated for relapses that affected activities of daily living, required steroid use, or hospitalization. RESULTS: In the pooled FREEDOMS/FREEDOMS II extensions, the immediate fingolimod group showed sustained reductions in the proportion (core: 15.8% and extension: 9.3%) and in ARR over 4 years (0.032 and 0.015) for severe relapses, in relapses requiring steroids (0.149 and 0.123), hospitalization (0.049 and 0.039) and relapses affecting activities of daily living (0.155 and 0.112). In the TRANSFORMS extension, similar reductions were observed in the immedaite group for the proportion of severe relapses (core: 11.8% and extension: 9.8%). ARR remained low over 2 years for severe relapses (0.024 and 0.018), relapses affecting activities of daily living (0.112 and 0.109), relapses requiring steroids (0.156 and 0.161) and hospitalization (0.027 and 0.033). Results in the FREEDOMS/FREEDOMS II and TRANSFORMS extensions for the delayed group were similar. In the TRANSFORMS extension, the proportion of severe relapses were 18.0% (core) and 11.1% (extension); there were significant reductions in ARR for severe relapses (core: 0.079 and extension: 0.029), relapses requiring steroids (0.366 and 0.232), hospitalization (0.092 and 0.055), and relapses affecting activities of daily living (0.285 and 0.144) (all p < 0.0001). Complete recovery was reported for the majority of relapses during the core and extension phases in both the immediate and delayed fingolimod groups (Pooled FREEDOMS/FREEDOMS II: immediate group 59.7%-65.5% and delayed group 64.9%-67.7%; TRANSFORMS: 72.1%-80.0% and 65.4%-70.8%). CONCLUSIONS: In patients with RRMS, the frequency of severe relapses and relapse severity remained low in the immedaite fingolimod group over a period of 4 years. Reductions in the proportion of severe relapses post switch from IFN ß-1a or placebo to fingolimod underscore the clinical benefit and the relevance of an early initiation of fingolimod.

Efficacy and safety outcomes in vitamin D supplement users in the fingolimod phase 3 trials.

BACKGROUND: Low serum levels of 25-hydroxyvitamin D have been associated with worse outcomes in multiple sclerosis (MS) patients treated with interferon-beta. Association of vitamin D nutrition on the outcomes of other MS therapies has been studied less. OBJECTIVE: Whether patients in the phase 3 fingolimod trials using vitamin D supplements have better clinical, MRI and safety outcomes than non-users. MATERIALS AND METHODS: Pooled data from phase 3 FREEDOMS trials was analyzed post hoc. Vitamin D use was defined as 'non-users' (n = 562), 'casual users' (n = 157) and 'daily users' (usage 100% time in the study, n = 110). RESULTS: Expanded Disability Status Scale change from baseline to month 24, and annual relapse rate and proportion of patients with relapses were similar across the vitamin D user groups. Proportion of patients free of new/enlarging T2 lesions significantly favored vitamin D 'daily users' versus 'non-users'. Mean number of lesions were lower and proportion of patients free of gadolinium-enhanced T1-lesions were higher in the 'daily users'. At month 12, percent brain volume change was significantly lower in the 'daily users' versus 'non-users' and remained low at month 24 (non-significant). Incidence of depression was lower for vitamin D 'daily users' (non-significant). CONCLUSIONS: We observed improved MRI outcomes on percent brain volume change and proportion of patients free of new/enlarging T2 lesions, and a trend of less depression in the 'daily users' of vitamin D supplement in patients in the FREEDOMS trials.

Effect of fingolimod on diffuse brain tissue damage in relapsing-remitting multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) affects all areas of the brain resulting in both focal and diffuse damage. In Phase 3 clinical trials, fingolimod showed significant reductions in both focal lesions and rate of brain volume loss (BVL) in patients with relapsing-remitting MS. OBJECTIVE: To investigate if the effects of fingolimod 0.5mg on BVL are mediated exclusively through its effects on focal damage or if fingolimod also acts independently in reducing diffuse damage. METHODS: This was a pooled post-hoc analysis of patients from two Phase 3 studies (FREEDOMS [N=1272] and FREEDOMS II [N=1083]), with no evidence of focal disease activity as defined by absence of gadolinium-enhancing lesions at baseline and new active lesions and clinical relapses at follow-up. The percent brain volume change (PBVC), as a measure of diffuse tissue damage, was assessed at Month (M) 12 and M24 by using the Structural Image Evaluation using Normalization of Atrophy (SIENA) method. A regression analysis was performed in the pooled intent-to-treat (ITT) population to quantify the treatment effect of fingolimod on BVL vs. placebo (PBO) in the overall population (unadjusted model), and whether this effect is sustained after adjusting for new active lesions and on-study relapses (adjusted model). RESULTS: Of 1088 patients, 638 (PBO, n=127; fingolimod, n=511) at M12 and 450 patients (PBO, n=68; fingolimod, n=382) at M24 showed no focal activity. Fingolimod significantly reduced PBVC by 65.5% over 12M (fingolimod vs. PBO: -0.16 vs. -0.45; p=0.001) and by 48.2% over 24M (-0.42 vs. -0.81; p=0.004). An absolute difference in PBVC of -0.27% (p<0.001) in favor of fingolimod vs. PBO over 24M was still evident in the pooled ITT population, after adjusting for active lesions and on-study relapses. The regression model suggests that 54% (-0.27%/-0.51%) of effects of fingolimod on PBVC are independent of its effects on visible focal damage. CONCLUSIONS: The effect of fingolimod on diffuse damage is partly independent of its treatment effect on focal damage, suggesting that both inflammatory and neurodegenerative components of MS are affected.

The relationship between the rate of brain volume loss during first 24 months and disability progression over 24 and 48 months in relapsing MS.

Clinical evidence in patients with relapsing-remitting multiple sclerosis suggests an association between MRI outcome measures and disability progression (DP). Post hoc analysis to investigate the association and potential predictive value of brain volume loss (BVL) with long-term DP in FREEDOMS. Patients were categorized into quartiles by SIENA-calculated percent brain volume change from baseline to month (M) 24. Patient characteristics at baseline were determined for each quartile, as were the proportions of patients at M24 and M48 reaching Expanded Disability Status Scale (EDSS) scores of ≥4.0 or ≥6.0 or DP confirmed at 3 months (CDP3) or 6 months (CDP6), and change in EDSS and Multiple Sclerosis Functional Composite. MS disease activity and severity as well as brain volume at baseline were predictive of subsequent BVL over 24 months. The quartiles of patients with greater BVL at 24 months were at highest risk (odds ratio, p value) for reaching EDSS ≥4 (2.8, p = 0.001) or ≥6 (5.73, p = 0.0005) and experienced more DP at M24 (CDP3 2.13, p = 0.002; CDP6 2.17, p = 0.003) and M48 (CDP3 1.98, p = 0.006; CDP6 1.87, p = 0.018) compared to the quartile of patients with the least amount of BVL. These findings confirm the clinical relevance of early brain volume changes for long-term DP.

Investigation of immune and CNS-mediated effects of fingolimod in the focal delayed-type hypersensitivity multiple sclerosis model.

We examined the effect of fingolimod (0.1 and 0.3 mg/kg/day orally) on blood-brain barrier (BBB) function, demyelination and leukocyte recruitment at different stages of the focal delayed-type hypersensitivity (DTH) multiple sclerosis model in Lewis rats using immunohistochemistry and gadolinium (Gd)-enhancing magnetic resonance imaging (MRI). During DTH lesion formation, fingolimod reduced BBB breakdown (52%; p = 0.05), and lymphocyte (53%; p = 0.016) and macrophage/activated microglia (49%; p = 0.002) recruitment to the DTH lesion compared with vehicle-treated controls. Following DTH lesion establishment, fingolimod reduced the area of BBB breakdown (75%; p = 0.04), lymphocyte recruitment to the DTH lesion (41%; p = 0.01) and activated microglia outside of the lesion core (p = 0.01), but did not reduce recruitment of macrophages/activated microglia within the DTH lesion. During the chronic disease phase, when the BBB was resealed, fingolimod reduced the area of demyelination by 43% (p = 0.019) compared with vehicle-treated controls, while not affecting lymphocyte recruitment within the lesion. Fingolimod had different beneficial effects during different stages of DTH, reducing BBB breakdown and lesion development/brain tissue damage whilst reducing lymphocyte recruitment when BBB breakdown was apparent, but reducing demyelination independent of lymphocyte infiltration behind an intact BBB. These results suggest a direct CNS effect of fingolimod in this model.

Ascomycete derivative to MS therapeutic: S1P receptor modulator FTY720.

Fingolimod (FTY720) represents the first in a new class of immune-modulators whose target is sphingosine-1-phosphate (S1P) receptors. It was first identified by researchers at Kyoto University and Yoshitomi Pharmaceutical as a chemical derivative of the ascomycete metabolite ISP-1 (myriocin). Unlike its natural product parent, FTY720 does not interfere with sphingolipid biosynthesis. Instead, its best characterized mechanism of action upon in vivo phosphorylation, leading to the active principle FTY720-P, is the rapid and reversible inhibition of lymphocyte egress from peripheral lymph nodes. As a consequence of S1P1 receptor internalization, tissue-damaging T-cells can not recirculate and infiltrate sites of inflammation such as the central nervous system (CNS). Furthermore, FTY720-P modulation of S1P receptor signaling also enhances endothelial barrier function. Due to its mode of action, FTY720 effectively prevents transplant rejection and is active in various autoimmune disease models. The most striking efficacy is in the multiple sclerosis (MS) model of experimental autoimmune encephalomyelitis, which has now been confirmed in the clinic. FTY720 demonstrated promising results in Phase II trials and recently entered Phase III in patients with relapsing MS. Emerging evidence suggests that its efficacy in the CNS extends beyond immunomodulation to encompass other aspects of MS pathophysiology, including an influence on the blood-brain-barrier and glial repair mechanisms that could ultimately contribute to restoration of nerve function. FTY720 may represent a potent new therapeutic modality in MS, combined with the benefit of oral administration.