Early Use of Erenumab vs Nonspecific Oral Migraine Preventives: The APPRAISE Randomized Clinical Trial.

Importance: Patients with migraine often cycle through multiple nonspecific preventive medications due to poor tolerability and/or inadequate efficacy leading to low adherence and increased disease burden. Objective: To compare the efficacy, tolerability, patient adherence, and patient satisfaction between erenumab and nonspecific oral migraine preventive medications (OMPMs) in patients with episodic migraine (EM) who had previously failed 1 or 2 preventive treatments. Design, Setting, and Participants: The 12-month prospective, interventional, global, multicenter, active-controlled, randomized clinical trial comparing sustained benefit of 2 treatment paradigms (erenumab qm vs oral prophylactics) in adult episodic migraine patients (APPRAISE) trial was a 12-month open-label, multicenter, active-controlled, phase 4 randomized clinical trial conducted from May 15, 2019, to October 1, 2021. This pragmatic trial was conducted at 84 centers across 17 countries. Overall, participants 18 years or older with a 12-month or longer history of migraine, and 4 or more but fewer than 15 monthly migraine days (MMDs) were included. Interventions: Patients were randomized (2:1) to receive erenumab or OMPMs. Dose adjustment was permitted (label dependent). Main Outcomes and Measures: The primary end point was the proportion of patients completing 1 year of the initially assigned treatment and achieving a reduction of 50% or greater from baseline in MMDs at month 12. Secondary end points included the cumulative mean change from baseline in MMDs during the treatment period and the proportion of responders according to the Patients' Global Impression of Change (PGIC) scale at month 12 for patients taking the initially assigned treatment. Results: A total of 866 patients were screened, of whom 245 failed the screening and 621 completed the screening and baseline period. Of the 621 randomized patients (mean [SD] age, 41.3 [11.2] years; 545 female [87.8%]; 413 [66.5%] in the erenumab group; 208 [33.5%] in the OMPM group), 523 (84.2%) completed the treatment phase, and 98 (15.8%) discontinued the study. At month 12, significantly more patients assigned to erenumab vs OMPM achieved the primary end point (232 of 413 [56.2%] vs 35 of 208 [16.8%]; odds ratio [OR], 6.48; 95% CI, 4.28-9.82; P <.001). Compared with OMPMs, treatment with erenumab showed higher responder rate (314 of 413 [76.0%] vs 39 of 208 [18.8%]; OR, 13.75; 95% CI, 9.08-20.83; P <.001) on the PGIC scale (≥5 at month 12). Significant reduction in cumulative average MMDs was reported with erenumab treatment vs OMPM treatment (-4.32 vs -2.65; treatment difference [SE]: -1.67 [0.35] days; P < .001). Substantially fewer patients in the erenumab arm compared with the OMPM arm switched medication (9 of 413 [2.2%] vs 72 of 208 [34.6%]) and discontinued treatment due to adverse events (12 of 408 [2.9%] vs 48 of 206 [23.3%]). No new safety signals were identified. Conclusions and Relevance: Results of this randomized clinical trial demonstrated that earlier use of erenumab in patients with EM who failed 1 or 2 previous preventive treatments provided greater and sustained efficacy, safety, and adherence than continuous OMPM. Trial Registration: ClinicalTrials.gov Identifier: NCT03927144.

Burden of migraine in patients attending Belgian headache specialists: real-world evidence from the BECOME study.

INTRODUCTION: Migraine is a primary headache disorder, which imposes a major burden on the sufferers. The BECOME study (Burden of migrainE in specialist headache Centers treating patients with prOphylactic treatMent failurE) attempted to characterize and assess the prevalence, burden and healthcare resource utilization of migraine patients presenting in specialized headache centers in Europe and Israel. In this paper, we will describe the patient characteristics of the Belgian headache centers. METHODS: The BECOME study was a prospective, non-interventional, cross-sectional study consisting of two parts. In the first part of the study, data were collected from subjects with a diagnosis of migraine. Subsequently, patients with ≥ 4 monthly migraine days (MMD) and ≥ 1 prior preventive treatment failure (PPTF) filled out validated questionnaires to assess the burden of disease. RESULTS: In part 1 of the Belgian study population (N = 806), 45% of patients reported ≥ 8 MMD and 25% had failed ≥ 4 preventive treatments. In part 2 (N = 90), more than 90% of patients reported having severe impact of headache on daily life and having severe migraine-related disability. The impact was the highest for patients with ≥ 15 MMD, however, even within the patient population with < 8 MMD, the burden was significant. Almost 40% of the study population suffered from anxiety. CONCLUSIONS: These findings in the Belgian sample of the BECOME study demonstrate the substantial burden and unmet need for the management of difficult-to-treat migraine.

Prevalence and Burden of Migraine in Switzerland: Cross-Sectional Study in ten Specialised Headache Centres from the BECOME Study.

INTRODUCTION: There is limited real-world evidence on the burden of migraine among patients with prior preventive treatment failure (PPTF). In the BECOME Swiss subanalysis, we aimed to assess current prevalence of PPTF in patients with migraine seen at specialised headache centres in Switzerland and burden of migraine in these patients. Furthermore, we assessed this burden in subgroups stratified by monthly migraine days (MMDs) and number of PPTFs. METHODS: BECOME was a prospective, multicentre, non-interventional two-part study conducted in 17 countries across Europe and Israel. This subanalysis includes patients visiting ten headache specialist centres in Switzerland. In part 1, patients visiting the centres over 3 months were screened by physicians for frequency of PPTF, MMD and other migraine characteristics. Patients with ≥ 1 PPTF and ≥ 4 MMDs were invited to take part in part 2. The primary endpoint was the proportion of patients with ≥ 1 PPTF (part 1). Other endpoints included proportion of patients specified by number of PPTF and MMD (part 1, part 2), and impact of migraine on patient-reported outcomes (PROs; part 2). RESULTS: Patients (1677) from ten Swiss centres were included in part 1, of which 855 (51.0%) reported ≥ 1 PPTF. One hundred fifty-five patients were included in part 2: 6.5% reported ≥ 4 PPTFs and 43.2% reported ≥ 15 MMDs. Mean EuroQoL 5 and EuroQoL visual analogue scale (EQ-VAS) were 0.8 ± 0.2 and 69.6 ± 20.2, respectively, suggesting a mild level of impairment in the daily functioning and self-reported health of the patients. Mean six-item Headache Impact Test (HIT-6) and modified Migraine Disability Assessment (mMIDAS) scores were 63.3 ± 6.5 and 22.7 ± 21.8, respectively, corresponding to severe migraine burden. Patients also reported impairment in work-related productivity and general activities (48.6 ± 22.8) but no associations of anxiety (7.2 ± 4.4) or depression (6.0 ± 4.4) with migraine were noted. Burden of migraine increased with increasing frequency of PPTF and MMD. CONCLUSIONS: Migraine-related quality of life, as well as work productivity are significantly affected in Swiss patients with migraine. Increasing migraine burden is associated with increasing migraine frequency and prior treatment failures.

Safety and tolerability of erenumab in individuals with episodic or chronic migraine across age groups: a pooled analysis of placebo-controlled trials.

BACKGROUND: Erenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, has demonstrated efficacy and safety in the prevention of episodic and chronic migraine. There exists an unmet need to establish the safety of erenumab in older individuals, in view of existing multiple comorbidities, polypharmacy, and age-related physiological changes. This pooled analysis of five large migraine-prevention studies examined the safety of erenumab stratified across age groups, particularly in older populations. METHODS: Pooled and age-stratified analysis of safety data from the 12-week double-blind treatment phase (DBTP) of five randomized, placebo-controlled Phase 2 and 3 studies of erenumab in participants with episodic or chronic migraine across the age groups < 40 years, 40-49 years, 50-59 years, and ≥ 60 years was completed. The safety of erenumab across age groups was determined by assessing safety endpoints including treatment-emergent adverse events (AEs), serious AEs, and events leading to study drug discontinuation. RESULTS: Overall, 3345 participants across five studies were randomized to receive either placebo (n = 1359), erenumab 70 mg (n = 1132) or erenumab 140 mg (n = 854); 3176 (94.9%) completed the DBTP, and 169 (5.1%) discontinued, mainly due to participant decision (110; 3.3%). Overall, 1349 (40.6%), 1122 (33.8%), and 850 (25.6%) participants received at least one dose of placebo, erenumab 70 mg, and erenumab 140 mg, respectively. Incidence of treatment-emergent AEs was similar across all age groups for both doses of erenumab (70 mg or 140 mg) and placebo (< 40 years, 44.0% vs 44.4%; 40-49 years, 42.5% vs 49.2%; 50-59 years, 46.5% vs 41.6%; ≥ 60 years, 43.8% vs 59.4%). Incidence of treatment-emergent serious AEs overall, and stratified by age groups for both doses and placebo was low (< 40 years, 0.9% vs 1.2%; 40-49 years, 1.7% vs 1.9%; and 50-59 years, 1.6% vs 1.1%), with no serious AEs reported in participants aged ≥ 60 years. No deaths were reported. CONCLUSIONS: Erenumab (70 mg or 140 mg) exhibited a similar safety profile compared with placebo across age groups in individuals with episodic or chronic migraine, with no increased emergence of events due to age. Erenumab was well tolerated in older participants with multiple comorbidities, polypharmacy, and age-related physiological changes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifiers: NCT02066415, NCT02456740, NCT02483585, NCT03096834, NCT03333109.

Factors that affect migratory Western Atlantic red knots (Calidris canutus rufa) and their prey during spring staging on Virginia's barrier islands.

Understanding factors that influence a species' distribution and abundance across the annual cycle is required for range-wide conservation. Thousands of imperiled red knots (Calidris cantus rufa) stop on Virginia's barrier islands each year to replenish fat during spring migration. We investigated the variation in red knot presence and flock size, the effects of prey on this variation, and factors influencing prey abundance on Virginia's barrier islands. We counted red knots and collected potential prey samples at randomly selected sites from 2007-2018 during a two-week period during early and peak migration. Core samples contained crustaceans (Orders Amphipoda and Calanoida), blue mussels (Mytilus edulis), coquina clams (Donax variabilis), and miscellaneous prey (horseshoe crab eggs (Limulus polyphemus), angel wing clams (Cyrtopleura costata), and other organisms (e.g., insect larvae, snails, worms)). Estimated red knot peak counts in Virginia during 21-27 May were highest in 2012 (11,959) and lowest in 2014 (2,857; 12-year peak migration [Formula: see text] = 7,175, SD = 2,869). Red knot and prey numbers varied across sampling periods and substrates (i.e., peat and sand). Red knots generally used sites with more prey. Miscellaneous prey ([Formula: see text] = 2401.00/m2, SE = 169.16) influenced red knot presence at a site early in migration, when we only sampled on peat banks. Coquina clams ([Formula: see text] = 1383.54/m2, SE = 125.32) and blue mussels ([Formula: see text] = 777.91/m2, SE = 259.31) affected red knot presence at a site during peak migration, when we sampled both substrates. Few relationships between prey and red knot flock size existed, suggesting that other unmeasured factors determined red knot numbers at occupied sites. Tide and mean daily water temperature affected prey abundance. Maximizing the diversity, availability, and abundance of prey for red knots on barrier islands requires management that encourages the presence of both sand and peat bank intertidal habitats.

Siponimod vs placebo in active secondary progressive multiple sclerosis: a post hoc analysis from the phase 3 EXPAND study.

BACKGROUND: Siponimod 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. METHODS: Post 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. ENDPOINTS: 3-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. RESULTS: Data 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). CONCLUSIONS: In aSPMS, siponimod reduced risk of disability progression and was associated with benefits on cognition and MRI outcomes vs placebo. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01665144.

Long-term efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis: Analysis of EXPAND core and extension data up to >5 years.

BACKGROUND: Siponimod 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. OBJECTIVE: The 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. METHODS: In 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). RESULTS: Continuous 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. CONCLUSION: The 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 NUMBER: NCT01665144.

Effect of siponimod on magnetic resonance imaging measures of neurodegeneration and myelination in secondary progressive multiple sclerosis: Gray matter atrophy and magnetization transfer ratio analyses from the EXPAND phase 3 trial.

BACKGROUND: Magnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS). OBJECTIVE: To examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM). METHODS: Patients with secondary progressive multiple sclerosis (SPMS) received siponimod (2 mg/day; n =1037) or placebo (n = 523). Endpoints included percentage change from baseline to months 12/24 in whole-brain, cGM, and thalamic volumes; change in nMTR from baseline to months 12/24 in NABT, cGM, and NAWM; MTR recovery in newly formed lesions. RESULTS: Compared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity. CONCLUSION: Siponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

Burden of Migraine in Patients With Preventive Treatment Failure Attending European Headache Specialist Centers: Real-World Evidence From the BECOME Study.

INTRODUCTION: Migraine is consistently ranked as one of the most disabling neurological conditions in the world, often causing a substantial impairment of daily activities and quality of life. It also carries a high economic burden of direct and indirect healthcare costs. Patients with difficult-to-treat migraine often cycle through different preventive therapies, but real-world prospective evidence describing the burden of migraine in patients with prior preventive treatment failure (PPTF) in Europe is limited. In BECOME, we aimed to characterize and assess the prevalence and burden of migraine in patients with PPTF attending specialist headache centers in Europe and Israel. Furthermore, we assessed this burden in pre-specified subgroups based on the frequency of monthly migraine days (MMD) and number of PPTFs. METHODS: BECOME was a prospective, non-interventional study conducted in two concurrent parts across 17 countries in Europe and Israel. In part 1, patients visiting the centers over a 3-month period were screened for frequency of PPTF, MMD, and other characteristics. In part 2, patients from part 1 with ≥ 1 PPTF and ≥ 4 MMD were enrolled, and impact of migraine on patient-reported outcomes, and healthcare resource utilization (HRU) were examined. RESULTS: In part 1 (n = 20,837), 62.2% of patients reported ≥ 1 PPTF. In part 2 (n = 2419), 15.3% of patients reported ≥ 4 PPTF. In part 2, the migraine burden measured by the EuroQoL 5 dimensions 5 level (EQ-5D-5L) questionnaire indicated an impact of at least moderate severity in performing usual activities in 26.5% of patients, pain/discomfort in 51.2%, and 26.1% reported being at least moderately anxious/depressed. Most patients reported a severe impact on daily activities and disability due to migraine. Abnormal Hospital Anxiety and Depression subscale scores of ≥ 11 were observed in 29% (anxiety) and 19.8% (depression) of the population. In part 2, analysis of HRU showed 21.2% patients visited an emergency department and 8.4% were hospitalized for headache/migraine in the past year. CONCLUSIONS: This study provides real-world evidence of the high personal, social, and HRU burden of migraine in Europe and Israel.

Erenumab prevents the occurrence of migraine attacks and not just migraine days: Post-hoc analyses of a phase III study.

BACKGROUND: This post-hoc analysis was conducted to evaluate the effect of erenumab on monthly migraine days, monthly migraine attacks, and attack duration in patients with episodic migraine to investigate whether erenumab actually prevents the occurrence of migraine attacks and/or shortens them. METHODS: We conducted a post-hoc analysis of the data from the STRIVE study, in 955 patients with episodic migraine. Relative changes from baseline to mean over months 4, 5 and 6 of the double-blind treatment phase in monthly migraine days, monthly migraine attacks and mean migraine attack duration were assessed. RESULTS: Erenumab reduced monthly migraine days and monthly migraine attacks compared with placebo in a similar way. Erenumab had only a minor impact on shortening the duration of migraine attacks. CONCLUSION: These post-hoc analyses demonstrate that the decrease in monthly migraine days by erenumab is mainly driven by a reduction in the frequency of monthly migraine attacks and to a much lesser extent by shortening the duration of migraine attacks.Trial registration: This study is registered at ClinicalTrials.gov (NCT02456740).

Disability improvement as a clinically relevant outcome in clinical trials of relapsing forms of multiple sclerosis.

BACKGROUND: Disease-modifying therapies (DMTs) can reduce the risk of disability worsening in patients with relapsing forms of multiple sclerosis (RMS). High-efficacy DMTs can lead to confirmed or sustained disability improvement (CDI and SDI). OBJECTIVE AND METHODS: Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.5-1.25 mg/day) on stabilizing or improving disability over ⩽8 years in participants with RMS. CDI and SDI rates were compared between participants initially randomized to fingolimod, interferon (IFNß-1a), or placebo. RESULTS: At 8 years' follow-up in TRANSFORMS, 35.1% (95% confidence interval [CI], 28.2%-43.1%) of assessed participants in the IFNß-1a-fingolimod switch group and 41.9% (36.6%-47.6%) on continuous fingolimod experienced CDI; disability did not worsen in approximately 70%. Similar results were seen in the combined FREEDOMS population. Proportionally fewer TRANSFORMS participants achieved SDI in the IFNß-1a-fingolimod switch group than on continuous fingolimod (5.4% [3.0%-9.5%] vs 14.2% [10.8%-18.4%], p = 0.01). CONCLUSION: CDI and SDI are outcomes of interest for clinical trials and for long-term follow-up of participants with RMS. Monitoring CDI and SDI in addition to disability worsening may facilitate understanding of the therapeutic benefit of RMS treatments.

The spectrum of response to erenumab in patients with chronic migraine and subgroup analysis of patients achieving ≥50%, ≥75%, and 100% response.

OBJECTIVE: To assess the efficacy of erenumab across the spectrum of response thresholds (≥50%, ≥75%, 100%) based on monthly migraine days (MMD) reduction in patients with chronic migraine from a 12-week, randomized study (NCT02066415). METHODS: Patients (n = 667) received (3:2:2) placebo or erenumab 70/140 mg once-monthly. The proportion of patients achieving a given response threshold was assessed. A post-hoc analysis was conducted to contextualize the actual treatment benefit in subgroups of patients achieving (or not) specified response thresholds. Outcome measures included MMD, acute migraine-specific medication treatment days (MSMD) and disability. RESULTS: The proportion of patients responding to erenumab exceeded that of placebo at the ≥50% and ≥75% response thresholds. At month 3, 39.9% and 41.2% of patients on erenumab 70 and 140 mg, respectively, achieved ≥50% response versus placebo (23.5%). Similarly, at month 3, 17.0% and 20.9% of patients on erenumab 70 and 140 mg, respectively, achieved ≥75% response versus placebo (7.8%). Compared with the overall erenumab-treated population (change in MMD: -6.6 [both 70 and 140 mg]), ≥50% responders showed MMD reductions of -12.2/-12.5 for 70 mg/140 mg versus -2.6/-2.2 for those not achieving ≥50% response. ≥75% responders showed MMD reductions of -13.9/-14.8 for 70 mg/140 mg versus -5.0/-4.3 for those not achieving ≥75% response. Relative improvements in MSMD and disability were observed in responders versus overall erenumab-treated population. CONCLUSION: For erenumab-treated patients achieving ≥50% response, the actual reduction in MMD was almost twice that of the overall population. These findings provide context for setting realistic expectations regarding actual treatment benefit experienced by patients responding to treatment.

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.

A comparison of multiple sclerosis disease activity after discontinuation of fingolimod and placebo.

BACKGROUND: Cases of higher-than-expected disease activity have been reported following fingolimod discontinuation. OBJECTIVE: The objective of this paper is to assess the risk of substantially higher-than-expected disease activity post-study drug discontinuation (SDD) at the individual patient level using data from the Phase III, placebo-controlled FREEDOMS and FREEDOMS II trials. METHODS: Baseline gadolinium-enhancing T1-lesion volumes were used to statistically model the expected level of MRI disease activity post-SDD. Patients exceeding this level were classed as "MRI outliers." Patients with an unusually high increase in Expanded Disability Status Scale score, hospitalization for relapse, severe relapse, or relapse with incomplete recovery post-SDD were classed as "clinical outliers." RESULTS: In FREEDOMS, the number of MRI outliers post-SDD was 2/69 (2.9%), 1/65 (1.5%) and 7/83 (8.4%) for the placebo, fingolimod 0.5 mg, and fingolimod 1.25 mg groups, respectively. In FREEDOMS II, the corresponding numbers were 4/72 (5.6%), 6/79 (7.6%) and 3/73 (4.1%). The number of clinical outliers across both trials was low. No consistent evidence of placebo vs fingolimod, dose-related or inter-trial patterns was discernable. CONCLUSION: The low number of clinical and MRI outliers and lack of any discernible pattern within and between trials, including between placebo and fingolimod, argues against a systematic risk of higher-than-expected recurrence of disease activity following discontinuation of fingolimod.

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.

Onset of clinical and MRI efficacy occurs early after fingolimod treatment initiation in relapsing multiple sclerosis.

To minimize the clinical burden associated with multiple sclerosis (MS), early control of focal and diffuse CNS disease activity is a treatment priority. A post hoc analysis was conducted to evaluate the onset of efficacy of fingolimod treatment in patients with relapsing MS. Data from patients who received fingolimod 0.5 mg or placebo during either of two 24-month, double-blind, randomized, parallel-group clinical trials (FREEDOMS and FREEDOMS II) were pooled for analysis. Efficacy outcomes were: time to first confirmed relapse; annualized relapse rate (ARR); proportions of patients free from T1 gadolinium-enhancing lesions or new/newly enlarged T2 lesions; percentage brain volume loss (BVL); and change in Multiple Sclerosis Functional Composite (MSFC) z-score from baseline to 6 months. An early benefit was seen with fingolimod (N = 783) vs. placebo (N = 773) for ARR at both 3 and 6 months (3 months, 0.32 vs. 0.52, p = 0.0015; 6 months, 0.21 vs. 0.45, p < 0.0001). Time to first relapse was also delayed with fingolimod vs. placebo from day 48 onwards. At 6 months, more patients in the fingolimod group than in the placebo group were free from new MRI activity (65.3 vs. 40.5%, p < 0.0001) and had less BVL (37.1% reduction vs. placebo, p < 0.001). MSFC z-score favored fingolimod over placebo at 6 months, with improvements noted in 9-Hole Peg Test and Paced Auditory Serial Addition Test scores. Improvements in outcomes related to relapses, MRI, disability, cognition, and BVL occurred within 6 months of treatment initiation with fingolimod.

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 ß-1a (IFNß-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 IFNß-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 IFNß-1a to fingolimod. CLINICAL TRIAL REGISTRATION NO: NCT00340834.

Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial.

OBJECTIVE: To assess long-term safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Patients completing FTY720 Research Evaluating Effects of Daily Oral Therapy in MS (FREEDOMS) were eligible for this dose-blinded, parallel-group extension study, continuing fingolimod 0.5 mg/day or 1.25 mg/day, or switching from placebo to either dose, randomized 1:1. Efficacy variables included annualized relapse rate (ARR), brain volume loss (BVL), and confirmed disability progression (CDP). Between-group analyses were conducted in the intent-to-treat (ITT) population from FREEDOMS baseline to end of study. Within-group analyses compared years 0-2 (FREEDOMS) and years 2-4 (extension) in the extension ITT population. RESULTS: Of 1,272 patients (FREEDOMS ITT population), 1,033 were eligible, and 920 enrolled in the extension study (continuous-fingolimod: 0.5 mg [n = 331], 1.25 mg [n = 289]; placebo-fingolimod: 0.5 mg [n = 155], 1.25 mg [n = 145]); 916 formed the extension ITT population (n = 330; n = 287; n = 154; n = 145) and 773 (84%) completed. In the continuous-fingolimod groups, ARR was lower (p < 0.0001), BVL was reduced (p < 0.05), and proportionately more patients were free from 3-month CDP (p < 0.05) than in a group comprising all placebo-fingolimod patients. Within each placebo-fingolimod group, ARR was lower (p < 0.001, both) and BVL was reduced after switching (p < 0.01, placebo-fingolimod 0.5 mg). Rates and types of adverse events were similar across groups; no new safety issues were reported. CONCLUSION: Efficacy benefits of fingolimod during FREEDOMS were sustained during the extension; ARR and BVL were reduced after switching. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that long-term fingolimod treatment is well-tolerated and reduces relapse rates, disability progression, and MRI effects in patients with RRMS.

Aphid-encoded variability in susceptibility to a parasitoid.

BACKGROUND: Many animals exhibit variation in resistance to specific natural enemies. Such variation may be encoded in their genomes or derived from infection with protective symbionts. The pea aphid, Acyrthosiphon pisum, for example, exhibits tremendous variation in susceptibility to a common natural enemy, the parasitic wasp Aphidius ervi. Pea aphids are often infected with the heritable bacterial symbiont, Hamiltonella defensa, which confers partial to complete resistance against this parasitoid depending on bacterial strain and associated bacteriophages. That previous studies found that pea aphids without H. defensa (or other symbionts) were generally susceptible to parasitism, together with observations of a limited encapsulation response, suggested that pea aphids largely rely on infection with H. defensa for protection against parasitoids. However, the limited number of uninfected clones previously examined, and our recent report of two symbiont-free resistant clones, led us to explicitly examine aphid-encoded variability in resistance to parasitoids. RESULTS: After rigorous screening for known and unknown symbionts, and microsatellite genotyping to confirm clonal identity, we conducted parasitism assays using fifteen clonal pea aphid lines. We recovered significant variability in aphid-encoded resistance, with variation levels comparable to that contributed by H. defensa. Because resistance can be costly, we also measured aphid longevity and cumulative fecundity of the most and least resistant aphid lines under permissive conditions, but found no trade-offs between higher resistance and these fitness parameters. CONCLUSIONS: These results indicate that pea aphid resistance to A. ervi is more complex than previously appreciated, and that aphids employ multiple tactics to aid in their defense. While we did not detect a tradeoff, these may become apparent under stressful conditions or when resistant and susceptible aphids are in direct competition. Understanding sources and amounts of variation in resistance to natural enemies is necessary to understand the ecological and evolutionary dynamics of antagonistic interactions, such as the potential for coevolution, but also for the successful management of pest populations through biological control.

Fingolimod in relapsing multiple sclerosis: An integrated analysis of safety findings.

BACKGROUND: Fingolimod 0.5mg once daily is the first approved oral therapy for relapsing multiple sclerosis (MS). OBJECTIVE: To report integrated long-term safety data from phase 2/3 fingolimod studies. METHODS: Descriptive safety data are reported from the FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study, a 24-month, randomized, double-blind study comparing fingolimod 0.5mg and 1.25mg with placebo, and an All Studies group (patients who received fingolimod 0.5mg (n=1640) or 1.25-0.5mg (n=1776) in phase 2/3 studies and associated extensions). Relevant post-marketing experience, up to December 2011, is included. RESULTS: The incidence of adverse events (AEs) and serious AEs (SAEs) was similar with fingolimod and placebo in FREEDOMS. In the All Studies group, fingolimod 0.5mg was associated with transient, rarely symptomatic (0.5%), bradycardia and second-degree atrioventricular block on treatment initiation, minor blood pressure increases, frequent (9%) but generally asymptomatic liver enzyme elevations, and macular oedema (0.4%). The incidences of infections (including serious and herpes infections), malignancies, SAEs and treatment discontinuations due to AEs were similar with fingolimod 0.5mg and placebo. CONCLUSION: The safety profile of fingolimod has been well characterized in this large combined trial population. Although infrequent SAEs can occur, there is no increased risk of infections, malignancies or serious cardiovascular events versus placebo.