Safety and efficacy of evobrutinib in relapsing multiple sclerosis (evolutionRMS1 and evolutionRMS2): two multicentre, randomised, double-blind, active-controlled, phase 3 trials.

BACKGROUND: Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis. METHODS: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated). FINDINGS: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy's law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment. INTERPRETATION: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis. FUNDING: Merck.

Serum tau protein elevation in migraine: a cross-sectional case-control study.

BACKGROUND: Migraine is a disorder associated with neuropeptide release, pain and inflammation. Tau protein has recently been linked to inflammatory diseases and can be influenced by neuropeptides such as CGRP, a key neurotransmitter in migraine. Here, we report serum concentrations of total-tau protein in migraine patients and healthy controls. METHODS: In this cross-sectional study, interictal blood samples from n = 92 patients with episodic migraine (EM), n = 93 patients with chronic migraine (CM), and n = 42 healthy matched controls (HC) were studied. We assessed serum total-tau protein (t-tau) and for comparison neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP), and ubiquitin carboxy-terminal hydrolase L (UCH-L1) concentrations using the Neurology 4-plex kit, on a single molecule array HD-X Analyzer (Quanterix Corp Lexington, MA). Matched serum/cerebrospinal fluid (CSF) samples were used for post-hoc evaluations of a central nervous system (CNS) source of relevant findings. We applied non-parametric tests to compare groups and assess correlations. RESULTS: Serum t-tau concentrations were elevated in EM [0.320 (0.204 to 0.466) pg/mL] and CM [0.304 (0.158 to 0.406) pg/mL] patients compared to HC [0.200 (0.114 to 0.288) pg/mL] (p = 0.002 vs. EM; p = 0.025 vs. CM). EM with aura [0.291 (0.184 to 0.486 pg/mL); p = 0.013] and EM without aura [0.332 (0.234 to 0.449) pg/mL; p = 0.008] patients had higher t-tau levels than HC but did not differ between each other. Subgroup analysis of CM with/without preventive treatment revealed elevated t-tau levels compared to HC only in the non-prevention group [0.322 (0.181 to 0.463) pg/mL; p = 0.009]. T-tau was elevated in serum (p = 0.028) but not in cerebrospinal fluid (p = 0.760). In contrast to t-tau, all proteins associated with cell damage (NfL, GFAP, and UCH-L1), did not differ between groups. DISCUSSION: Migraine is associated with t-tau elevation in serum but not in the CSF. Our clinical study identifies t-tau as a new target for migraine research.

Two-year efficacy and safety of erenumab in participants with episodic migraine and 2-4 prior preventive treatment failures: results from the LIBERTY study.

OBJECTIVE: To evaluate individual and group long-term efficacy and safety of erenumab in individuals with episodic migraine (EM) for whom 2-4 prior preventatives had failed. METHODS: Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could continue into an open-label extension phase (OLEP) receiving erenumab 140 mg monthly for up to 3 years. Main outcomes assessed at week 112 were: ≥50%, ≥75% and 100% reduction in monthly migraine days (MMD) as group responder rate and individual responder rates, MMD change from baseline, safety and tolerability. RESULTS: Overall 240/246 (97.6%) entered the OLEP (118 continuing erenumab, 122 switching from placebo). In total 181/240 (75.4%) reached 112 weeks, 24.6% discontinued, mainly due to lack of efficacy (44.0%), participant decision (37.0%) and adverse events (AEs; 12.0%). The ≥50% responder rate was 57.2% (99/173) at 112 weeks. Of ≥50% responders at the end of the DBTP, 36/52 (69.2%) remained responders at ≥50% and 22/52 (42.3%) at >80% of visits. Of the non-responders at the end of the DBTP, 60/185 (32.4%) converted to ≥50% responders in at least half the visits and 24/185 (13.0%) converted to ≥50% responders in >80% of visits. Change from baseline at 112 weeks in mean (SD) MMD was -4.2 (5.0) days. Common AEs (≥10%) were nasopharyngitis, influenza and back pain. CONCLUSIONS: Efficacy was sustained over 112 weeks in individuals with difficult-to-treat EM for whom 2-4 prior migraine preventives had failed. Erenumab treatment was safe and well tolerated, in-line with previous studies. TRIAL REGISTRATION NUMBER: NCT03096834.

Reduction in migraine pain intensity in patients treated with erenumab: A post hoc analysis of two pivotal randomized studies.

BACKGROUND: Erenumab (erenumab-aooe in the US) effectively reduces monthly migraine days in episodic and chronic migraine. This traditional outcome does not capture the intensity of headache pain on days with migraine. METHODS: This post hoc analysis of two pivotal randomized, placebo-controlled studies in patients with episodic migraine and chronic migraine examined the effect of erenumab 70 and 140 mg on migraine pain. Cumulative monthly migraine pain intensity is the sum of the peak pain intensity scores (0 = no migraine to 3 = migraine day with severe pain) on migraine days. Change from baseline in cumulative monthly migraine pain and average monthly pain intensity was assessed over months 4 to 6 for episodic migraine and month 3 for chronic migraine; change in average monthly pain intensity was assessed among monthly migraine days responders/non-responders. RESULTS: Efficacy analysis included 946 patients for the episodic migraine study and 656 patients for the chronic migraine study. Cumulative monthly migraine pain decreased significantly with erenumab versus placebo (p < 0.001, for episodic migraine and chronic migraine). In addition, monthly average migraine pain intensity decreased significantly with erenumab versus placebo for episodic migraine (p < 0.01); decreases were non-significant for chronic migraine. In comparison with placebo-treated patients, a greater proportion of erenumab-treated patients were pain intensity responders regardless of threshold used. Episodic migraine and chronic migraine patients with a ≥50% reduction in monthly migraine days (responders) had a greater reduction in monthly average pain intensity than non-responders. CONCLUSIONS: Erenumab reduced cumulative monthly migraine pain in episodic migraine and chronic migraine patients and significantly reduced monthly average migraine pain in episodic migraine, demonstrating treatment benefit beyond reduction in migraine frequency.Clinical Trial Registration: ClinicalTrials.gov, NCT02456740; ClinicalTrials.gov, NCT02066415.

Randomised, controlled trial of erenumab for the prevention of episodic migraine in patients from Asia, the Middle East, and Latin America: The EMPOwER study.

OBJECTIVE: EMPOwER, a double-blind, randomised, phase 3 study, evaluated the efficacy and safety of erenumab in adults with episodic migraine from Asia, the Middle East, and Latin America. METHODS: Randomised patients (N = 900) received monthly subcutaneous injections of placebo, erenumab 70 mg, or 140 mg (3:3:2) for 3 months. Primary endpoint was change from baseline in monthly migraine days at Month 3. Other endpoints included achievement of ≥50%, ≥75%, and 100% reduction in monthly migraine days, change in monthly acute migraine-specific medication treatment days, patient-reported outcomes, and safety assessment. RESULTS: At baseline, mean (standard deviation) age was 37.5 (9.9) years, 81.9% were women, and monthly migraine days was 8.2 (2.8). At Month 3, change from baseline in monthly migraine days (primary endpoint) was -3.1, -4.2, and -4.8 days for placebo, erenumab 70 mg, and erenumab 140 mg, respectively, with a statistically significant difference for erenumab versus placebo (P = 0.002 [70 mg], P < 0.001 [140 mg]). Both erenumab doses were also significantly superior to placebo on all secondary endpoints, including the proportion of patients achieving ≥50% reduction from baseline in monthly migraine days, change from baseline in monthly acute migraine-specific medication treatment days and change from baseline in the Headache Impact Test-6™ scores. The safety profile of erenumab was comparable with placebo; no new safety signals were observed. CONCLUSIONS: This study of erenumab in patients with episodic migraine from Asia, the Middle East, and Latin America met all primary and secondary endpoints. A consistent numerical benefit was observed with erenumab 140 mg versus erenumab 70 mg across all efficacy endpoints. These findings extend evidence of erenumab's efficacy and safety to patients under-represented in previous trials.ClinicalTrials.gov identifier: NCT03333109.

Long-Term Efficacy and Safety of Erenumab: Results From 64 Weeks of the LIBERTY Study.

OBJECTIVE: To report the efficacy and safety of erenumab among episodic migraine (EM) patients who were unsuccessful on 2-4 preventive treatments observed at week 64 of Open-Label Extension Phase (OLEP) of the LIBERTY study (ClinicalTrials.gov NCT03096834). METHODS: The OLEP evaluating monthly erenumab 140 mg for 3 years, enrolled 240 patients who completed the double-blind treatment phase (DBTP) of 12 weeks during which they received placebo or erenumab 140 mg subcutaneous injections every 4 weeks as monotherapy. Efficacy outcomes were evaluated through the initial 52 weeks of OLEP (from DBTP baseline to total 64 weeks) in the overall population, patients receiving erenumab in DBTP, and patients from DBTP placebo arm who switched to erenumab in OLEP. Endpoints included reduction of ≥50% in monthly migraine days (MMD) from DBTP baseline and change in MMD from DBTP baseline, Headache Impact Test, and Migraine Physical Function Impact Diary (Physical Impairment and Everyday Activities) scores. RESULTS: Altogether, the week 52 visit of the OLEP was completed by 204/240 (85.0%) patients. Among patients continuing erenumab, the 50% responder rate increase from 29.9% at weeks 9%-12% to 44.3% at week 61-64. The 50% responder rate in patients who initiated erenumab in the OLEP remained higher in the OLEP (50.0% at week 61-64) than during DBTP (14.2% at weeks 9-12) compared to patients in continuous erenumab arm. In the OLEP, the 50% responder rate for the overall population increased from weeks 13-16 until weeks 37-40 and then remained stable through weeks 61-64. Patients treated with erenumab in DBTP showed sustained effects on all efficacy outcomes; those initiating erenumab in the OLEP demonstrated continued improvement from week 13 onward. Adverse events (AEs) were reported, considering both treatment groups, by ∼80.8% (serious AEs [SAEs] by 6.7%); 76.3% (5.9%) in the continuing erenumab arm; and 85.2% (7.4%) in those starting erenumab in OLEP. No deaths were reported. CONCLUSIONS: In patients with EM who were unsuccessful on 2-4 prior preventive treatments, the LIBERTY study demonstrated sustained efficacy on erenumab monotherapy treatment through 64 weeks in both treatment arms. Safety of erenumab was consistent with that observed in previous clinical trials. CLASSIFICATION OF EVIDENCE: The current study provides Class IV evidence on data from patients with episodic migraine, that erenumab is safe and provides sustained efficacy at 52 weeks. CLINICALTRIALSGOV IDENTIFIER: NCT03096834.

Efficacy and Safety of 2 Fingolimod Doses vs Glatiramer Acetate for the Treatment of Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial.

IMPORTANCE: Doses of fingolimod lower than 0.5 mg per day were not investigated during the fingolimod clinical development program. Whether lower doses of fingolimod might retain efficacy with fewer safety risks remains unknown. OBJECTIVE: To evaluate the efficacy and safety of fingolimod, 0.5 mg, and fingolimod, 0.25 mg, compared with glatiramer acetate and to assess whether these doses of fingolimod show superior efficacy to glatiramer acetate in adult patients with relapsing-remitting multiple sclerosis. INTERVENTIONS: Fingolimod, 0.5 mg, or fingolimod, 0.25 mg, orally once per day or glatiramer acetate, 20 mg, subcutaneously once per day. DESIGN, SETTING, AND PARTICIPANTS: The Multiple Sclerosis Study Evaluating Safety and Efficacy of Two Doses of Fingolimod Versus Copaxone (ASSESS) was a phase 3b multicenter randomized rater-blinded and dose-blinded 12-month clinical trial conducted between August 9, 2012, and April 30, 2018 (including the time required to recruit participants). A total of 1461 patients aged 18 to 65 years with relapsing-remitting multiple sclerosis were screened, and 1064 participants were randomized. These participants had at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years and an Expanded Disability Status Scale score of 0 to 6 at screening. Data were analyzed between September and November 2018. MAIN OUTCOMES AND MEASURES: The superiority of the fingolimod doses was tested hierarchically, with fingolimod, 0.5 mg, vs glatiramer acetate, 20 mg, tested first, followed by fingolimod, 0.25 mg, vs glatiramer acetate, 20 mg. The primary end point was the reduction in annualized relapse rate (ARR). Magnetic resonance imaging parameters, safety, and tolerability were also assessed. RESULTS: Of 1461 adult patients screened, 1064 participants (72.8%) were randomized (mean [SD] age, 39.6 [11.0] years; 792 women [74.4%]) to 3 treatment groups: 352 participants received fingolimod, 0.5 mg, 370 participants received fingolimod, 0.25 mg, and 342 participants received glatiramer acetate, 20 mg. In total, 859 participants (80.7%) completed the study. Treatment with fingolimod, 0.5 mg, was superior to treatment with glatiramer acetate, 20 mg, in reducing ARR (40.7% relative reduction); the relative reduction with fingolimod, 0.25 mg, was 14.6%, which was not statistically significant (for fingolimod, 0.5 mg, ARR, 0.15; 95% CI, 0.11-0.21; for fingolimod, 0.25 mg, ARR, 0.22; 95% CI, 0.17-0.29; for glatiramer acetate, 20 mg, ARR, 0.26; 95% CI, 0.20-0.34). Treatment with both fingolimod doses (0.5 mg and 0.25 mg) significantly reduced new or newly enlarging T2 and gadolinium-enhancing T1 lesions compared with treatment with glatiramer acetate. Adverse events were reported in similar proportions across treatment groups (312 participants [90.4%] in the fingolimod, 0.5 mg, group, 323 participants [88.3%] in the fingolimod, 0.25 mg, group, and 283 participants [87.3%] in the glatiramer acetate group). CONCLUSIONS AND RELEVANCE: Fingolimod, 0.5 mg, demonstrated superior clinical efficacy compared with glatiramer acetate, 20 mg, and had a superior benefit-risk profile compared with fingolimod, 0.25 mg, in adult participants with relapsing-remitting multiple sclerosis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01633112.

Switching to fingolimod in PREFERMS: Effect of treatment history and naïvety on clinical, MRI and treatment satisfaction outcomes✰.

BACKGROUND: Injectable disease-modifying therapies (iDMTs) are often used as first-line treatments for relapsing multiple sclerosis. Fingolimod is frequently used following treatment with iDMTs. Whether prior iDMT treatment impacts the effectiveness of subsequent fingolimod therapy is unclear. Here, we assessed switching from iDMTs to fingolimod, and the impact of treatment history on fingolimod escalation using data from the 12-month 'Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease-modifying thErapies in adults with Relapsing-remitting Multiple Sclerosis' (PREFERMS). The study design and results at the end of randomized treatment (EoRT) in PREFERMS have been published. METHODS: Both treatment-naïve patients and those who had previously received an iDMT were eligible for enrolment in PREFERMS, and one treatment switch was permitted on study. Pre-specified exploratory analyses compared outcomes in those randomized to fingolimod or to an iDMT at end of study (EoS), which included time spent on randomized and on switch treatment. Post hoc exploratory analyses (unadjusted for multiplicity owing to the large number of comparisons) among patients randomized to an iDMT who switched to fingolimod, compared outcomes longitudinally before (EoRT) and after (EoS) switching, and compared outcomes at EoRT and EoS among subgroups stratified by iDMT-treatment history. Outcomes included brain volume, various measures of gadolinium-enhancing [Gd+] lesion counts, annualized relapse rate (ARR), Symbol Digit Modalities Test (SDMT) score, patient-reported treatment satisfaction using the Medication Satisfaction Questionnaire (MSQ) and adverse event (AE) rates. RESULTS: At EoS, 255 of 439 patients randomized to an iDMT had switched to fingolimod and 27 of 436 patients randomized to fingolimod had switched to an iDMT. By EoS, 44.2% of total treatment exposure in the iDMT group was to fingolimod and the mean time spent on fingolimod in this group was 220 days (approximately 7 months). Outcomes in the fingolimod group at EoS (brain volume, changes in Gd+ lesion counts, ARR, oral SDMT score and MSQ score) were similar to those seen at EoRT, but in the iDMT group these outcomes were more favorable at EoS than at EoRT and were similar to rates seen in the fingolimod group. Among patients who switched from iDMT to fingolimod, there were longitudinal improvements in ARR (EoRT, 0.3 [95% confidence interval (CI), 0.2-0.4]; EoS, 0.2 [0.1-0.3]; odds ratio, 0.5 [0.3-0.9]) and in treatment satisfaction (proportion of patients with MSQ > 5; EoRT, 67.4%; EoS, 90.4%; odds ratio, 5.7 [95% CI, 3.4-9.4]) after fingolimod treatment, and changes in brain volume, Gd+ lesion count, and AEs or AEs causing discontinuation were also more favorable at EoS than at EoRT. In all patient groups stratified by iDMT-treatment history, differences in outcomes narrowed or disappeared after fingolimod treatment. CONCLUSION: These analyses indicate that patients in PREFERMS had improved outcomes within months of switching to fingolimod from an iDMT and that improvements occurred irrespective of the number of iDMTs previously administered. These data provide a unique opportunity to explore clinical, radiological and safety outcomes associated with a range of clinically relevant treatment pathways.

Extended treatment with fingolimod for relapsing multiple sclerosis: the 14-year LONGTERMS study results.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease that may require decades of ongoing treatment. Therefore, the long-term safety and efficacy of disease-modifying therapies is an important consideration. METHODS: The LONGTERMS study evaluated the safety and efficacy of fingolimod in patients with relapsing MS (RMS) with up to 14 years of exposure. This phase IIIb, open-label extension study included patients aged ⩾ 18 years with confirmed RMS diagnosis who completed previous phase II/III/IIIb core/extension studies of fingolimod. Patients received fingolimod 0.5 mg orally once daily; safety and efficacy (clinical and magnetic resonance imaging) were the main outcomes. RESULTS: Of 4086 patients from the core studies who entered LONGTERMS, 3480 (85.2%) completed the study. The median age (range) was 38 (17-65) years and median fingolimod exposure was 944.5 (range 75-4777) days. Overall, 85.5% of patients experienced at least one adverse event (AE); most common AEs (⩾10%) were viral upper respiratory tract infection (17.3%), headache (13.3%), hypertension (11.0%) and lymphopenia (10.7%). Among patients with serious AEs (12.6%), basal cell carcinoma and MS relapse (0.9% each) were most frequently reported. The aggregate annualized relapse rate decreased from 0.22 (in years 0-2) to 0.17 (years 0-10); 45.5% of patients remained relapse free after 10 years. At year 10, 63.2% of patients were free from 6-month confirmed disability worsening. CONCLUSION: This long-term observational study of patients treated for up to 14 years with fingolimod confirmed its established safety profile with no new safety concerns. Patients with RMS receiving fingolimod had sustained low levels of disease activity and progression. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01201356.

Treatment retention on fingolimod compared with injectable multiple sclerosis therapies in African-American patients: A subgroup analysis of a randomized phase 4 study.

BACKGROUND: Suboptimal persistence with injectable disease-modifying therapies (iDMTs; interferon beta-1a/b, glatiramer acetate) is common in patients with relapsing forms of multiple sclerosis (MS), reducing the effectiveness of these agents. Adherence to, and persistence with, an effective therapy is important for patient populations at increased risk of rapid disease progression. African-American individuals with multiple sclerosis may experience a more aggressive disease course than Caucasian patients, with a greater risk of developing ambulatory difficulties and other disabilities, and may also have a diminished response to some disease-modifying therapies compared with patients of other ethnicities. Retention on oral fingolimod and on iDMTs was evaluated in a post hoc analysis of data from African-American patients in the parallel-group, 48-week 'Prospective, Randomized, active-controlled, open-label study to Evaluate patient retention on Fingolimod versus approved first-line disease modifying thErapies in adults with Relapsing-remitting Multiple Sclerosis' (PREFERMS). METHODS: In PREFERMS, patients with relapsing-remitting MS aged 18-65 years with an Expanded Disability Status Scale score ≤6 enrolled at 117 US study sites were treatment-naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day:preselected iDMT) using an interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier, for efficacy or safety reasons only. The primary outcome was patient retention on randomized treatment over 48 weeks. In this post hoc analysis of African-American patients in PREFERMS, outcome variables included rate of patient retention on randomized treatment, reasons for discontinuing randomized treatment, patient-reported treatment satisfaction, and safety. Clinical and radiographic outcomes such as annualized relapse rate, brain volume loss, and lesion count changes were also investigated. RESULTS: In PREFERMS, 141 of 875 patients (16.1%) randomized to a study drug were African-American. Analysis of data for the full analysis set of 67 patients receiving fingolimod and 69 receiving iDMTs showed that the retention rate over 48 weeks was significantly higher with fingolimod than with iDMTs (80.6% [n = 54] vs 30.4% [n = 21]; between-group difference: 50.2%; 95% confidence interval 35.8-64.6%; p < 0.0001). The most common treatment switch was from an iDMT to fingolimod for injection-related reasons, and patient satisfaction was greater with fingolimod than with iDMTs. Adverse events were consistent with the respective prescribing information for each treatment. CONCLUSION: In PREFERMS, fingolimod was associated with better treatment retention than iDMTs in African-American patients. Optimal outcomes in the management of multiple sclerosis depend on good persistence with treatment, and this is particularly important in patient populations at increased risk of a rapidly progressing disease course.

Phase IV study of retention on fingolimod versus injectable multiple sclerosis therapies: a randomized clinical trial.

OBJECTIVE: In relapsing-remitting multiple sclerosis (RRMS), suboptimal adherence to injectable disease-modifying therapies (iDMTs; interferon ß-1a/b, glatiramer acetate) is common, reducing their effectiveness. Patient retention on oral fingolimod and iDMTs was evaluated in PREFERMS, a randomized, parallel-group, active-controlled, open-label, 48-week study. METHODS: Patients were included if they had RRMS, were aged 18-65 years and had Expanded Disability Status Scale score up to 6, enrolled at 117 US study sites, were treatment naïve or had received only one iDMT class. Patients were randomized 1:1 (fingolimod 0.5 mg/day; preselected iDMT) by interactive voice-and-web-response system without blinding, followed up quarterly, and allowed one study-approved treatment switch after 12 weeks, or earlier for efficacy or safety reasons. The primary outcome was patient retention on randomized treatment over 48 weeks. Secondary endpoints included patient-reported outcomes, brain volume loss (BVL), and cognitive function. RESULTS: Analysis of 433/436 patients receiving fingolimod and 428/439 receiving iDMTs showed that patient retention rate was significantly higher with fingolimod than with iDMTs [352 (81.3%) versus 125 (29.2%); 95% confidence interval 46.4-57.8%; p < 0.0001]. The most common treatment switch was from iDMT to fingolimod for injection-related reasons. Patient satisfaction was greater and BVL less with fingolimod than with iDMTs, with no difference in cognitive function. Adverse events were consistent with established tolerability profiles for each treatment. CONCLUSIONS: In RRMS, fingolimod was associated with better treatment retention, patient satisfaction and BVL outcomes than iDMTs. Patients may persist with iDMTs, but many may switch treatment if permitted. Treatment satisfaction fosters adherence, a prerequisite for optimal outcomes.

Impact of a switch to fingolimod versus staying on glatiramer acetate or beta interferons on patient- and physician-reported outcomes in relapsing multiple sclerosis: post hoc analyses of the EPOC trial.

BACKGROUND: The Evaluate Patient OutComes (EPOC) study assessed physician- and patient-reported outcomes in individuals with relapsing multiple sclerosis who switched directly from injectable disease-modifying therapy (iDMT; glatiramer acetate, intramuscular or subcutaneous interferon beta-1a, or interferon beta-1b) to once-daily, oral fingolimod. Post hoc analyses evaluated the impact of a switch to fingolimod versus staying on each of the four individual iDMTs. METHODS: Overall, 1053 patients were randomized 3:1 to switch to fingolimod or remain on iDMT. The primary endpoint was the change in Treatment Satisfaction Questionnaire for Medication (TSQM) Global Satisfaction score. Secondary endpoints included changes in scores for TSQM Effectiveness, Side Effects and Convenience subscales, Beck Depression Inventory-II (BDI-II), Fatigue Severity Scale (FSS), Patient-Reported Outcome Indices for Multiple Sclerosis (PRIMUS) Activities, 36-item Short-Form Health Survey (SF-36) Mental Component Summary (MCS) and Physical Component Summary (PCS) and mean investigator-reported Clinical Global Impressions of Improvement (CGI-I). All outcomes were evaluated after 6 months of treatment. RESULTS: Changes in TSQM Global Satisfaction scores were superior after a switch to fingolimod when compared with scores in patients remaining on any of the iDMTs (all p <0.001). Likewise, all TSQM subscale scores improved following a switch to fingolimod (all p <0.001), except when compared with glatiramer acetate for the TSQM Side Effects subscale (p = 0.111). FSS scores were found to be superior for fingolimod versus remaining on subcutaneous interferon beta-1a and interferon beta-1b, BDI-II scores were significantly improved for fingolimod except for the comparison with intramuscular interferon beta-1a, and SF-36 scores were superior with fingolimod compared with remaining on interferon beta-1b (MCS and PCS; p = 0.030 and p = 0.022, respectively) and subcutaneous interferon beta-1a (PCS only; p = 0.024). Mean CGI-I scores were superior with fingolimod when compared with continuing treatment with any of the iDMTs (all p <0.001). CONCLUSIONS: After 6 months, a switch to fingolimod showed superiority compared with remaining on each iDMT for a range of patient- and physician-reported outcomes, including global satisfaction with treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT01216072 .

Efficacy and safety of fingolimod in Hispanic patients with multiple sclerosis: pooled clinical trial analyses.

INTRODUCTION: The disease characteristics of multiple sclerosis (MS) appear to differ between Hispanic and Caucasian patients, with Hispanic patients having a younger age at onset, and a higher prevalence of optic nerve and spinal cord involvement. Fingolimod, the first-in-class oral sphingosine 1-phosphate receptor modulator approved for the treatment of relapsing MS, has been shown to significantly reduce annualized relapse rates (ARRs), lesion-based magnetic resonance imaging (MRI) activity, confirmed disability, and brain volume loss, compared with placebo or intramuscular interferon beta-1a (IFNß-1a IM) in randomized, double-blind, controlled clinical studies. Here, the efficacy and safety profile of fingolimod in Hispanic patients was compared to that observed in the overall study populations. METHODS: This was a post hoc analysis of relapses and safety data for Hispanic patients with relapsing-remitting MS (RRMS) randomized to receive daily fingolimod 0.5 mg, weekly IFNß-1a IM (30 mg) or placebo, in the phase 3, controlled FREEDOMS, FREEDOMS II, and TRANSFORMS fingolimod studies. The ARR was estimated for each treatment group; only relapses that were confirmed by an independent examining neurologist were included in these analyses. Safety assessments included the incidence of adverse events and serious adverse events. RESULTS: Eligible Hispanic patients aged 18-55 years (n=181) had been treated as follows: fingolimod 0.5 mg (n=89), IFNß-1a IM (n=65), and placebo (n=27). Hispanic patients treated with fingolimod for up to 2 years had lower ARRs (ARR: 0.22, 95% confidence interval [CI]: 0.14-0.35) than those receiving placebo (ARR: 0.46, 95% CI: 0.24-0.88) or IFNß-1a IM (ARR: 0.34, 95% CI: 0.18-0.63), with relative reductions of 52% and 35%, respectively. A transient decrease in heart rate that started to attenuate 6 h after fingolimod administration was observed, consistent with the well-characterized pharmacologic effect following fingolimod treatment initiation. No cases of symptomatic bradycardia were reported in Hispanic patients. The incidence of first-degree atrioventricular block was low and similar across all treatment groups (3.1-4.5%). The safety profile of fingolimod in Hispanic patients was consistent with that reported in the overall population of each study. CONCLUSION: Overall, this study demonstrates that fingolimod is efficacious and well tolerated in Hispanic patients with RRMS.

Long-term safety of rivastigmine in parkinson disease dementia: an open-label, randomized study.

OBJECTIVE: This study investigated the long-term safety of rivastigmine (12 mg/d capsules, 9.5 mg/24 h patch) and effects on motor symptoms in patients with mild-to-moderately severe Parkinson disease dementia. METHODS: This was a 76-week, prospective, open-label, randomized study in patients aged 50 to 85 years. Primary outcomes included incidence of, and discontinuation due to, predefined adverse events (AEs) potentially arising from worsening of Parkinson disease motor symptoms with capsules. Secondary outcomes included frequency of AEs/serious AEs. Efficacy outcomes included Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), Neuropsychiatric Inventory (NPI-10), and Mattis Dementia Rating Scale (MDRS). RESULTS: Five hundred eighty-three patients were randomized to rivastigmine capsules (n = 295) or patch (n = 288). Incidence of predefined AEs was 36.1% for capsules, 31.9% for patch; discontinuation due to worsening of motor symptoms was 4.4% and 2.4%, respectively. Most common AEs were nausea (capsules, 40.5%; patch, 8.3%), tremor (24.5%; 9.7%), fall (17.0%; 20.1%), vomiting (15.3%; 2.8%), and application site erythema (0%; 13.9%). Significant efficacy in favor of capsules was observed at weeks 24 to 76 on MDRS; 24 and 76 on NPI-10; weeks 52 and 76 on ADCS-ADL. In patients with Mini-Mental State Examination (MMSE) greater than 21, no differences in efficacy on MDRS and ADCS-ADL were observed at any time point; significant differences in favor of capsules were maintained in patients with MMSE less than or equal to 21. CONCLUSIONS: This study supports the long-term safety of rivastigmine in Parkinson disease dementia. The rate of worsening of motor symptoms was in the range expected due to the natural progression of Parkinson disease, no new or unexpected safety issues emerged in the long-term.