Tracy Stites

Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis

BACKGROUND Fingolimod (FTY720), a sphingosine-1-phosphate-receptor modulator that prevents lymphocyte egress from lymph nodes, showed clinical efficacy and improvement on imaging in a phase 2 study involving patients with multiple sclerosis. METHODS In this 12-month, double-blind, double-dummy study, we randomly assigned 1292 patients with relapsing-remitting multiple sclerosis who had a recent history of at least one relapse to receive either oral fingolimod at a daily dose of either 1.25 or 0.5 mg or intramuscular interferon beta-1a (an established therapy for multiple sclerosis) at a weekly dose of 30 microg. The primary end point was the annualized relapse rate. Key secondary end points were the number of new or enlarged lesions on T(2)-weighted magnetic resonance imaging (MRI) scans at 12 months and progression of disability that was sustained for at least 3 months. RESULTS A total of 1153 patients (89%) completed the study. The annualized relapse rate was significantly lower in both groups receiving fingolimod--0.20 (95% confidence interval [CI], 0.16 to 0.26) in the 1.25-mg group and 0.16 (95% CI, 0.12 to 0.21) in the 0.5-mg group--than in the interferon group (0.33; 95% CI, 0.26 to 0.42; P<0.001 for both comparisons). MRI findings supported the primary results. No significant differences were seen among the study groups with respect to progression of disability. Two fatal infections occurred in the group that received the 1.25-mg dose of fingolimod: disseminated primary varicella zoster and herpes simplex encephalitis. Other adverse events among patients receiving fingolimod were nonfatal herpesvirus infections, bradycardia and atrioventricular block, hypertension, macular edema, skin cancer, and elevated liver-enzyme levels. CONCLUSIONS This trial showed the superior efficacy of oral fingolimod with respect to relapse rates and MRI outcomes in patients with multiple sclerosis, as compared with intramuscular interferon beta-1a. Longer studies are needed to assess the safety and efficacy of treatment beyond 1 year. (ClinicalTrials.gov number, NCT00340834.)

Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial

BACKGROUND Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients. METHODS We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients-those aged 18-55 years with relapsing-remitting multiple sclerosis-to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134. FINDINGS Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34-0·48) in patients given placebo and 0·21 (0·17-0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40-0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was -0·86 (SD 1·22) for fingolimod 0·5 mg versus -1·28 (1·50) for placebo (treatment difference -0·41, 95% CI -0·62 to -0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61-1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs 0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]). INTERPRETATION Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis. FUNDING Novartis Pharma AG.

Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study

BACKGROUND In a 12-month phase 3 study in patients with relapsing-remitting multiple sclerosis (RRMS), TRANSFORMS, fingolimod showed greater efficacy on relapse rates and MRI outcomes compared with interferon beta-1a. We had two aims in our extension: to compare year 2 with year 1 in the switched patients to assess the effect of a change from interferon beta-1a to fingolimod, and to compare over 24 months the treatment groups as originally randomised to assess the effect of delaying the start of treatment with fingolimod. METHODS Patients randomly assigned to receive 0.5 mg or 1.25 mg daily oral fingolimod in the core study continued with the same treatment in our extension; patients who originally received 30 μg weekly intramuscular interferon beta-1a were randomly reassigned (1:1) to receive either 0.5 mg or 1.25 mg fingolimod. The initial randomisation and dose of fingolimod assigned for the extension remained masked to the patients and investigators. As in the core study, re-randomisation was done centrally in blocks of six and stratified according to site. Our efficacy endpoints were annualised relapse rate (ARR), disability progression, and MRI outcomes. Our within-group analyses were based on the intention-to-treat and safety populations that entered our extension study. Our between-group analyses were based on the intention-to-treat and safety populations from the core study. This study is registered with ClinicalTrials.gov, number NCT00340834. FINDINGS 1027 patients entered our extension and received the study drug, and 882 completed 24 months of treatment. Patients receiving continuous fingolimod showed persistent benefits in ARR (0.5 mg fingolimod [n=356], 0.12 [95% CI 0.08-0.17] in months 0-12 vs 0.11 [0.08-0.16] in months 13-24; 1.25 mg fingolimod [n=330], 0.15 [0.10-0.21] vs 0.11 [0.08-0.16]; however, in patients who initially received interferon beta-1a, ARR was lower after switching to fingolimod compared with the previous 12 months (interferon beta-1a to 0.5 mg fingolimod [n=167], 0.31 [95% CI 0.22-0.43] in months 0-12 vs 0.22 [0.15-0.31], in months 13-24 p=0.049; interferon beta-1a to 1.25 mg fingolimod [n=174], 0.29 [0.20-0.40] vs 0.18 [0.12-0.27], p=0.024). After switching to fingolimod, numbers of new or newly enlarging T2 and gadolinium (Gd)-enhancing T1 lesions were significantly reduced compared with the previous 12 months of interferon beta-1a therapy (p<0.0001 for T2 lesions at both doses; p=0.002 for T1 at 0.5 mg; p=0.011 for T1 at 1.25 mg), and the pattern of adverse events shifted towards that typical for fingolimod. Over 24 months, in continuous fingolimod groups compared with the group that switched from interferon beta-1a to fingolimod, we recorded lower ARRs (0.18 [95% CI 0.14-0.22] for 0.5 mg; 0.20 [0.16-0.25] for 1.25 mg; 0.33 [0.27-0.39] for the switch group; p<0.0001 for both comparisons), fewer new or newly enlarged T2 lesions (p=0.035 for 0.5 mg, p=0.068 for 1.25 mg), and fewer patients with Gd-enhancing T1 lesions (p=0.001 for 0.5 mg fingolimod vs switch group; p=0.002 for 1.25 mg fingolimod vs switch group). There was no benefit on disability progression. INTERPRETATION Switching from interferon beta-1a to fingolimod led to enhanced efficacy with no unexpected safety concerns. Compared with patients switched from interferon beta-1a to fingolimod, continuous treatment with fingolimod for 2 years provides a sustained treatment effect with improved clinical and MRI outcomes. FUNDING Novartis Pharma AG.

Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis

Objective: We assessed CSF levels of the light chain subunit of neurofilaments (NfL) at baseline and after fingolimod therapy or placebo in patients with relapsing-remitting multiple sclerosis (RRMS). Changes in NfL levels were also correlated with relapse and MRI outcomes. Methods: CSF samples were available, at baseline and 12 months after treatment initiation, from a subset of 36 patients with RRMS (fingolimod 0.5 mg: n = 9; fingolimod 1.25 mg: n = 15; placebo: n = 12) participating in the 2-year, phase 3 Fingolimod (FTY720) Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study. NfL levels were determined in a blinded fashion using a commercial ELISA kit. Results: Median NfL levels did not differ between treatment groups at baseline (0.5 mg: 644 pg/mL; 1.25 mg: 659 pg/mL; pooled 0.5/1.25 mg: 652 pg/mL, placebo: 886 pg/mL; p value [fingolimod vs placebo] = 0.619, 0.495, and 0.481, respectively). Following 12 months of treatment, median changes from baseline in NfL levels were lower than zero in the fingolimod groups (0.5 mg: −346 pg/mL, p = 0.039; 1.25 mg: −313 pg/mL, p = 0.035) and pooled 0.5/1.25 mg fingolimod group (−326 pg/mL, 83.3% with reduction, p = 0.002) but not in the placebo group (−214 pg/mL, 66.7% with reduction, p = 0.388). Reductions in NfL levels at month 12 correlated with an improvement in relapse and MRI outcomes. Conclusions: Our results suggest a beneficial effect of fingolimod on this marker of axonal injury and support the utility of NfL as a quantitative biomarker in multiple sclerosis.

Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study

Objective The 12-month (M), phase 3, double-blind, randomised TRANSFORMS study demonstrated significant benefits of fingolimod 0.5 or 1.25 mg over interferon β-1a (IFNβ-1a) in patients with relapsing–remitting multiple sclerosis. We report the results of long-term (up to 4.5 years) extension of TRANSFORMS. Methods Patients randomised to fingolimod (0.5/1.25 mg) in the core phase continued the same dose (continuous-fingolimod) in the extension, whereas those on IFNβ-1a were re-randomised (1:1) to fingolimod (IFN-switch; IFN: 0.5/1.25 mg). Outcomes included annualised relapse rate (ARR), confirmed disability progression and MRI measures. Results are presented here for the continuous-fingolimod 0.5 mg and pooled IFN-switch groups. Results Of the 1027 patients who entered the extension, 772 (75.2%) completed the study. From baseline to the end of the study (EOS), ARR in patients on continuous-fingolimod 0.5 mg was significantly lower than in the IFN-switch group (M0–EOS: 0.17 vs 0.27). After switching to fingolimod (M0–12 vs M13–EOS), patients initially treated with IFN had a 50% reduction in ARR (0.40 vs 0.20), reduced MRI activity and a lower rate of brain volume loss. In a post hoc analysis, the proportion of IFN-switch patients with no evidence of disease activity increased by approximately 50% in the first year after switching to fingolimod treatment (44.3% to 66.0%). The safety profile was consistent with that observed in the core phase. Conclusions These results support a continued effect of long-term fingolimod therapy in maintaining a low rate of disease activity and sustained improved efficacy after switching from IFNβ-1a to fingolimod. Clinical trial registration No NCT00340834.

Oxcarbazepine adjunctive therapy in infants and young children with partial seizures

Objective: To evaluate the efficacy, safety, and pharmacokinetics of oxcarbazepine as adjunctive therapy in infants and young children (1 month to <4 years). Methods: Children 1 month to <4 years of age with inadequately controlled partial seizures taking up to two concomitant antiepileptic drugs (AEDs) were enrolled in this rater-blind, randomized, parallel-group study. Patients received either high-dose (60 mg/kg/day) or low-dose (10 mg/kg/day) oxcarbazepine as oral suspension. The primary efficacy variable was the absolute change in electrographic partial seizures with a behavioral correlate (type 1 seizure) frequency per 24 hours during the last 72 hours of continuous video-EEG monitoring in the treatment phase compared with baseline seizure frequency. Results: Of 191 patients screened, 128 were randomized: 64 to both oxcarbazepine dose groups. The median absolute change in type 1 seizure frequency per 24 hours was more effective for the high-dose group (−2.00) compared with the low-dose group (−1.37; p = 0.043). The median percentage reduction in type 1 seizure frequency per 24 hours was also greater in the high-dose group (83.33%) than in the low-dose group (46.18%; p = 0.047). The most frequent adverse events (≥10%) were somnolence and pyrexia, and most were mild in severity. Conclusions: In this study, high-dose oxcarbazepine was significantly more effective than low-dose oxcarbazepine in controlling partial seizures in infants and very young children.