Objective Dimethyl fumarate (DMF) and diroximel fumarate (DRF) are oral multiple sclerosis (MS) disease-modifying therapies (DMTs). Absolute lymphocyte count (ALC) dynamics are similar for DMF and DRF, but have not been investigated in patients who switched from DMF to DRF. This retrospective, observational study of the US Komodo Health Claims Database characterized ALC dynamics and outcomes in patients who switched DMF-DRF (“Switchers”) versus patients who stayed on DMF (“Stayers”). Methods Eligible patients aged 18–64 years, with a diagnosis of MS and ≥1 DMT claim during the study period (01Jan201531Aug2022) had ≥1 year on DMF before switching to DRF and ≥6 months on DRF. Switchers were propensity score-matched 1:2 to Stayers. Assessments included ALC, relapses, and infection-related healthcare encounters (HCEs) and healthcare costs (HCCs). Results Of 94 eligible Switchers, 62 were matched with 124 Stayers. Mean (SD) duration of DMF exposure was 36.0 (16.0) months prior to index date/switch and 15.0 (4.9) months post-index date/switch. Over 12 months, mean ALC change from index date was –26.9 % (Switchers) versus +3.5 % (Stayers). In Switchers, mean ALC remained stable thereafter. Proportions remaining relapse-free during 15 months mean follow-up were similar between Switchers (95 %) and Stayers (91 %). Outcomes were similar for annualized rates of infection-related HCEs (mean [SD]: Switchers, 0.70 [1.03]; Stayers, 0.74 [1.57]) and HCCs (mean [SD]: Switchers, $285 [$856]; Stayers, $346 [$2299]). Conclusion Over 12 months, ALC declined by 26.9 % in Switchers but increased by 3.5 % in Stayers. Despite this difference in ALC dynamics, infection-related HCEs and HCCs remained low and comparable between cohorts.

Dimethyl fumarate (DMF) has demonstrated a favorable benefit–risk profile in patients with relapsing–remitting multiple sclerosis (RRMS). Some patients may develop lymphopenia on DMF; therefore, LymphoTEC evaluated absolute lymphocyte count (ALC) reconstitution after DMF discontinuation. LymphoTEC was a retrospective, multicenter study of patients with RRMS in the Observatoire Français de la Sclérose en Plaques registry. Times to ALC reconstitution and lymphopenia were estimated by the Kaplan–Meier method. Univariate and multivariate analyses evaluated factors associated with ALC reconstitution after DMF discontinuation or lymphopenia after DMF initiation. Patients treated with DMF for ≥ 3 months with ≥ 1 ALC in the 6 months before/close to DMF initiation and ≥ 1 ALC during treatment were included. Overall, 1429 RRMS patients were included; 356 patients developed lymphopenia, of whom 183 discontinued DMF. Overall, ALC decreased by 33

Background: Dimethyl fumarate (DMF) has a favorable benefit-risk profile treating people with multiple sclerosis and should be used in pregnant women only if the potential benefits outweigh potential risks to the fetus. Objective: Assess pregnancy outcomes in a completed international registry (TecGistry) of women with MS exposed to DMF. Methods: TecGistry included pregnant women with MS exposed to DMF, with data collected at enrollment, 6-7 months gestation, 4 weeks after estimated due date, and at postpartum weeks 4, 12, and 52. Outcomes included live births, gestational size, pregnancy loss, ectopic/molar pregnancies, birth defects, and infant/maternal death. Results: Of 397 enrolled, median (range) age was 32 years (19-43). Median (range) gestational week at enrollment was 10 (0-39) and at first DMF exposure was 1 (0-13). Median (range) duration of gestational DMF exposure was 5 weeks (0-40). Fifteen (3.8%) spontaneous abortions occurred. Of 360 (89.1%) live births, 323 were full term and 37 were premature. One neonatal death and no maternal deaths occurred. Adjudicator-confirmed EUROCAT birth defects were found in 2.2%. Conclusion: DMF exposure during pregnancy did not adversely affect pregnancy outcomes; birth defects, preterm birth, and spontaneous abortion were in line with rates from the general population.

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic gamma-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once -daily, 14 -day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open -label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the longterm safety and efficacy of zuranolone in adults with MDD are reported. Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17 -item Hamilton Rating Scale for Depression (HAMD-17) total score >= 20 received an initial 30 -mg or 50 -mg 14 -day zuranolone course. HAMD-17 responders (>= 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for <= 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s). Results: As of September 2021, among patients in the 30 -mg (n = 725) and 50 -mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment -emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30 -mg Cohort, 90.9% [448/493]; 50 -mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30 -mg and 50 -mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30 -mg Cohort and 54.8% (80/146) in the 50mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received <= 2 total treatment courses (30 -mg Cohort, 68.5% [335/489]; 50 -mg Cohort, 79.5% [116/146]). Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses.

BACKGROUND:Zuranolone is an oral, once-daily, 14-day treatment course approved for adults with postpartum depression in the United States. AIMS:To assess cognitive effects, pharmacokinetics, and safety of zuranolone, alone or with alprazolam/ethanol. METHODS:This was a phase 1, two-part, two-period, randomized, double-blind, placebo-controlled crossover trial. Participants received zuranolone 50 mg or placebo once daily for 9 days, and additionally received alprazolam (1 mg, Part A), ethanol (males: 0.7 g/kg; females: 0.6 g/kg, Part B), or corresponding placebo on days 1, 5, and 9. Within each part, participants received all treatment combinations. Cognition was assessed using a computerized test battery; pharmacokinetics and safety were also evaluated. RESULTS:All participants (Part A, N = 24; Part B, N = 25) received ⩾1 dose of zuranolone/placebo. Compared to placebo, zuranolone produced small-to-moderate cognitive decline (Cohen's |d| = 0.126-0.76); effects were larger with alprazolam (Cohen's |d| = 0.523-0.93) and ethanol (Cohen's |d| = 0.345-0.88). Zuranolone coadministration with alprazolam (Cohen's |d| = 0.6-1.227) or ethanol (Cohen's |d| = 0.054-0.5) generally worsened cognitive decline when compared with zuranolone alone. Maximal pharmacodynamic effects occurred at approximately 5 h and were resolved by 12 h postbaseline. No pharmacokinetic interactions were observed. Incidence of adverse events was similar between groups; most events were mild or moderate in severity. CONCLUSION:A general small-to-moderate magnitude decline in cognition occurred with zuranolone alone. Coadministration with alprazolam/ethanol increased the magnitude, but not the duration, of effects compared with single-agent administration. Zuranolone prescribers and patients should be aware of the potential for increased central nervous system-depressant effects if coadministered with GABAergic active compounds such as alprazolam and ethanol.

In EVOLVE-MS-1 (NCT02634307), mean absolute lymphocyte count (ALC) on diroximel fumarate (DRF) declined from baseline by approximately 28

Zuranolone is an oral positive allosteric modulator of GABAA receptors. Due to its central nervous system (CNS) activity, zuranolone may impact activities requiring complex cognition, including driving. Evaluate the effect of zuranolone on simulated driving performance. In this randomized, double-blind, active- and placebo-controlled, four-period crossover study, treatments included once-nightly zuranolone 50 mg on days 1–7, zuranolone 50 mg on days 1–6 and zuranolone 100 mg on day 7, zopiclone 7.5 mg on days 1 and 7, and placebo on days 1–7. Driving was assessed using a validated simulator. Primary endpoint was standard deviation of lateral position (SDLP), evaluated 9 h post-dose on days 2 and 8. Secondary endpoints included additional driving assessments, cognitive tests, pharmacokinetics, and safety. Healthy adults (N = 67) enrolled and received ≥ 1 dose. Zuranolone 50 mg increased SDLP versus placebo on days 2 (least squares mean difference [LSMD]: 7.4 cm; p < 0.0001) and 8 (LSMD: 4.6 cm; p = 0.0106). Zuranolone 100 mg evoked a larger increase in SDLP versus placebo on day 8 (LSMD 18.9 cm; p < 0.0001). Reduced performance in other driving assessments and cognition were observed with zuranolone 50 mg on day 2; many resolved by day 8. Despite the SDLP observations, most participants judged themselves capable of driving. Frequent adverse events (≥ 20

Background: Multiple sclerosis (MS) has not been well studied in racial and ethnic minorities, as these populations are typically underrepresented in clinical trials. Black or African Americans comprise similar to 13 % of the US population, yet are represented by as little as 5 % in clinical trials. Differences in disease course and progression have been reported between races and ethnicities, so there is a need to understand the safety and efficacy of disease-modifying therapies (DMTs) in Black patients, to inform evidence-based approaches to treatment in this population. Methods: EVOLVE-MS-1 (NCT0234307) was an open-label, single-arm, phase 3 study assessing the long-term safety, tolerability, and efficacy of diroximel fumarate (DRF) over 96 weeks in adults with relapsing-remitting multiple sclerosis (RRMS). Patients were either newly initiated to DRF or rolled over from completing EVOLVE-MS-2 (NCT03093324). In this post-hoc analysis of the phase 3 EVOLVE-MS-1 study, we evaluate the safety and exploratory efficacy outcomes for DRF in Black and non-Black patient subgroups. Results: Of 1057 patients enrolled, 72 (6.8 %) were Black. In Black vs non-Black patients, mean age was 42 vs 43 years and 75 % vs 72 % were female, respectively. In both groups, median (range) duration of DRF exposure was 1.8 (0.0-2.0) years and mean Expanded Disability Status Scale (EDSS) was 2.7. The most common prior DMTs for both Black vs non-Black patients were interferons (47 % vs 37 %) and glatiramer acetate (36 % vs 24 %). DRF treatment was discontinued in 33 (46 %) Black and 224 (23 %) non-Black patients; most common reasons for discontinuation were withdrawal by patient (n = 11, 15.3 %), adverse events (AEs; n = 7, 9.7 %), and lost to follow-up (n = 7, 9.7 %) in Black patients; AEs (8.2 %) and withdrawal by patient (7.0 %) in non-Black patients. AEs were reported in 90 % Black and 89 % non-Black patients; most AEs were mild or moderate in both groups. Gastrointestinal (GI) AEs were reported in 36 % Black and 32 % non-Black patients; no Black patients discontinued due to GI AEs, vs 7 (0.7 %) non-Black patients. The most commonly reported AE was flushing (18 % Black and 28 % non-Black patients). No AEs of lymphopenia were reported in Black patients compared with 13 % of non-Black patients. Mean absolute lymphocyte count declined from baseline to week 48 by 15 % in Black patients and 29 % in non-Black patients, then plateaued and remained above the lower limit of normal (LLN; 0.91 x 10(9)/L). Adjusted annualized relapse rate (95 % confidence interval) was reduced by 78.2 % (54.6 - 89.5; p < 0.0001) in Black patients, from 12 months before to 96 weeks after DRF treatment; similar to 81.7 % (78.5 - 84.5 %; p < 0.0001) reduction in non-Black patients. Mean number of patients free from confirmed disability progression was 93.4 % by week 48, then 86.2 % vs 90.4 % by week 96 in Black vs non-Black patients, respectively. Conclusion: This study presents the first analysis of safety and efficacy of DRF in Black patients. Relapse rates remained low in Black patients on DRF, consistent with non-Black patients, and there were no new safety signals identified in the Black patient subgroup in EVOLVE-MS-1. Together, these outcomes support DRF as an effective treatment option in Black patients with RRMS.

Background: Diroximel fumarate (DRF) is approved for adults with relapsing-remitting multiple sclerosis (RRMS) in Europe and for relapsing forms of MS in the United States. DRF and dimethyl fumarate (DMF) yield bioequivalent exposure of the active metabolite monomethyl fumarate. Prior studies indicated fewer gastrointestinal (GI)-related adverse events (AEs) with DRF compared with DMF.Objective: To report final outcomes from EVOLVE-MS-1.Methods: EVOLVE-MS-1 was an open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in patients with RRMS. The primary endpoint was safety and tolerability; efficacy endpoints were exploratory.Results: Overall, 75.7% (800/1057) of patients completed the study; median exposure was 1.8 (range: 0.0-2.0) years. AEs occurred in 938 (88.7%) patients, mostly of mild (28.9%) or moderate (50.3%) severity. DRF was discontinued due to AEs in 85 (8.0%) patients, with < 2% discontinuing due to GI or flushing/flushing-related AEs. At Week 96, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (72.7%; p < 0.0001); adjusted annualized relapse rate was 0.13 (95% confidence interval: 0.11-0.15).Conclusion: DRF was generally well tolerated over 2 years, with few discontinuations due to AEs; radiological measures indicated decreased disease activity from baseline. These outcomes support DRF as a treatment option in patients with RRMS.

Objective: 1. To report pregnancy outcomes from women with multiple sclerosis (MS) exposed to diroximel fumarate (DRF) during pregnancy in EVOLVE-MS-1. 2. To describe a prospective, international pregnancy registry of women with MS (BlossoMS). Background: DRF, a next-generation oral fumarate approved for relapsing forms of MS, has the same active metabolite, monomethyl fumarate, and fewer gastrointestinal AEs compared with dimethyl fumarate (DMF). While many patients with MS are women of childbearing potential, there are limited data on developmental risks associated with use of DRF before and during pregnancy. Design/Methods: 1. EVOLVE-MS-1 (NCT02634307) is an open-label, 96-week study assessing DRF safety, tolerability, and efficacy. Any female found to be pregnant while participating in EVOLVE-MS-1 was discontinued from study treatment, but the pregnancy was followed until completion or termination. 2. BlossoMS, anticipated to begin in 2023, aims to evaluate effects of DRF on pregnancy outcomes and compare women with MS exposed to DRF with those exposed to other disease-modifying therapies (DMTs), unexposed to DMTs, and women without MS. Results: Overall, 9 patients in EVOLVE-MS-1 had pregnancies; median (range) age at enrollment was 28 (19–33, n=9) years, median (range) overall DRF exposure in EVOLVE-MS-1 was 306.5 (12–431, n=8) days, and median (range) duration of DRF exposure during pregnancy was 46 (29–101, n=6) days. Of 9 pregnancies, 6 outcomes were live birth without congenital abnormality, including one set of twins; 1 was an elective termination with no known fetal defects; and 2 were spontaneous abortion. Conclusions: We report pregnancy outcomes in women exposed to DRF during pregnancy. It is important to better understand potential pregnancy-related risks associated with use of DRF to help providers and patients with medical decision-making. The BlossoMS registry will provide essential information on the risk of birth defects, congenital abnormalities, and pregnancy outcomes among women with MS exposed to DRF during pregnancy. Disclosure: Dr. Houtchens has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Houtchens has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche . Dr. Houtchens has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Houtchens has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Serono. Dr. Houtchens has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Cravath. Dr. Houtchens has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Beasley . Dr. Houtchens has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Biogen. The institution of Dr. Houtchens has received research support from Genzyme. The institution of Dr. Houtchens has received research support from Biogen. The institution of Dr. Houtchens has received research support from Genentech. The institution of Dr. Wundes has received research support from Benaroya Research Institute . Dr. Osborne has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion. Dr. Osborne has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Biogen. Dr. Osborne has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Bristol Myer Squibb. Dr. Osborne has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Horizon. Dr. Osborne has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Peter Angelos Law Firm. Dr. Osborne has received publishing royalties from a publication relating to health care. Dr. Bozin has received personal compensation for serving as an employee of Biogen. Dr. Bozin has received personal compensation for serving as an employee of Arvelle Therapeutics. Dr. Bozin has stock in Biogen. Filipe Branco has received personal compensation for serving as an employee of Biogen. Filipe Branco has received stock or an ownership interest from Biogen. Hailu Chen has received personal compensation for serving as an employee of Biogen.com. Hailu Chen has received stock or an ownership interest from Biogen.com. Dr. England has received personal compensation for serving as an employee of Biogen. Dr. England has stock in Biogen. Ms. Gerber has received personal compensation for serving as an employee of Biogen. Ms. Gerber has stock in Biogen. Dr. Levin has received personal compensation for serving as an employee of Biogen. Dr. Levin has received stock or an ownership interest from Biogen. Dr. Lin has received personal compensation for serving as an employee of Biogen. Dr. Lin has stock in Biogen. Mr. Scaramozza has received personal compensation for serving as an employee of Biogen. Mr. Scaramozza has stock in Biogen. Mr. Scaramozza has received intellectual property interests from a discovery or technology relating to health care. Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genzyme . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Bayer . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for INC research . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche . Kerstin Hellwig has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Merck . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen . Kerstin Hellwig has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bayer . The institution of Kerstin Hellwig has received research support from Roche . The institution of Kerstin Hellwig has received research support from Merck . The institution of Kerstin Hellwig has received research support from Biogen. The institution of Kerstin Hellwig has received research support from Genzyme . The institution of Kerstin Hellwig has received research support from Novartis . The institution of Kerstin Hellwig has received research support from TEVA.

BackgroundZuranolone is an investigational positive allosteric modulator of synaptic and extrasynaptic GABAA receptors and a neuroactive steroid in clinical development as a once-daily, oral, 14-day treatment course for adults with major depressive disorder or postpartum depression (PPD). The randomized, double-blind, placebo-controlled SKYLARK Study (NCT04442503) demonstrated that zuranolone 50 mg significantly improved depressive symptoms (as assessed by 17-item Hamilton Rating Scale for Depression total score) at Day 15 (primary endpoint; p<0.001) and was generally well tolerated in adults with PPD.MethodsIn the SKYLARK Study, patients were randomized 1:1 to receive zuranolone 50 mg or placebo for 14 days. Safety and tolerability were assessed by the incidence and severity of treatment-emergent adverse events (TEAEs), rates of dose reduction and treatment discontinuation, as well as weight gain and sexual dysfunction.ResultsThe SKYLARK Study assessed safety data from 98 patients treated with zuranolone 50 mg and 98 patients treated with placebo. TEAEs were reported in 66.3% of zuranolone-treated patients and 53.1% of placebo-treated patients. In patients that experienced TEAEs, most reported mild (zuranolone, 50.8%; placebo, 75%) or moderate (zuranolone, 44.6%; placebo, 23.1%) events. The most common (≥5%) TEAEs were somnolence (26.5%), dizziness (13.3%), sedation (11.2%), headache (9.2%), diarrhea (6.1%), nausea (5.1%), urinary tract infection (5.1%), and COVID-19 (5.1%) with zuranolone, and headache (13.3%), dizziness (10.2%), nausea (6.1%), and somnolence (5.1%) with placebo. Dose reduction due to TEAEs was 16.3% in patients receiving zuranolone vs 1.0% in patients receiving placebo; the most common TEAEs (>1 patient) leading to zuranolone dose reduction were somnolence (7.1%), dizziness (6.1%), and sedation (3.1%). Treatment discontinuation due to TEAEs was 4.1% in patients receiving zuranolone vs 2.0% in patients receiving placebo; TEAEs leading to zuranolone discontinuation in >1 patient included somnolence (2.0%). Serious TEAEs were reported in 2.0% of zuranolone-treated and 0% of placebo-treated patients; these included upper abdominal pain (1.0%, [1/98]), peripheral edema (1.0%, [1/98]), perinatal depression (1.0%, [1/98]), and hypertension (1.0%, [1/98]). Per investigators, serious TEAEs were not related to zuranolone. No signals for weight gain or sexual dysfunction were identified.ConclusionsIn adults with PPD, zuranolone 50 mg was generally well tolerated. Most TEAEs were mild or moderate in severity. Dose reduction due to TEAEs mainly resulted from somnolence, dizziness, and sedation, while treatment discontinuation due to TEAEs was low. No signals for weight gain or sexual dysfunction were identified.FundingSage Therapeutics, Inc., and Biogen Inc.

People with multiple sclerosis (pwMS) have an increased risk of infection. As disease-modifying therapies (DMTs) and other treatments may interact with the immune system, there may be concerns about vaccine efficacy and safety. Therefore, it is important to evaluate possible interactions between DMTs and vaccines. The fumarates, dimethyl fumarate, diroximel fumarate, and monomethyl fumarate, are approved for the treatment of relapsing multiple sclerosis. This review assesses the evidence on vaccine response in pwMS treated with fumarates, with a particular focus on COVID-19 vaccines. Treatment with fumarates does not appear to result in blunting of humoral responses to vaccination; for COVID-19 vaccines, particularly RNA-based vaccines, evidence indicates antibody responses similar to those of healthy recipients. While data on the effect of fumarates on T-cell responses are limited, they do not indicate any significant blunting. COVID-19 vaccines impart a similar degree of protection against severe COVID-19 infection for pwMS on fumarates as in the general population. Adverse reactions following vaccination are generally consistent with those observed in the wider population; no additional safety signals have emerged in those on fumarates. Additionally, no increase in relapse has been observed in pwMS following vaccination. In pwMS receiving fumarates, vaccination is generally safe and elicits protective immune responses.

[email protected] (B. Iyoma). Même sécurité d'emploi et d'efficacité du diroximel fumarate (DRF) que le diméthylfumarate (DMF) dont il a le même métabolite actif mais avec une meilleure tolérance GI pour le DRF. Évaluer les flushs et les EI qui leurs sont liés ainsi que les EI GI chez les patients initiant le DRF dans l'étude EVOLVE-MS-1 (groupe de novo). EVOLVE-MS-1 est une étude de phase 3 ouverte, de 96 semaines, évaluant la sécurité d'emploi et l'efficacité du DRF chez des adultes atteints de SEP-RR. Les patients inclus ont soit initié le DRF (groupe de novo) soit complété l'étude EVOLVE-MS-2, phase 3 randomisée, en aveugle, évaluant le DRF ou le DMF pendant 5 semaines (groupes rollover). Les résultats du groupe de novo sur les flushs/EI liés aux flushs et les EI GI seront présentés. Dans le groupe de novo sont inclus 593 patients (56,1 %). Des EI sont survenus chez 519 patients (87,5 %). Des flushs/EI liés aux flushs sont observés chez 49,2 % des patients ; la plupart, légers/modérés, survenant le premier mois de DRF. Le DRF a été arrêté chez 4 patients. Des EI GI sont survenus chez 33,7 % des patients ; la plupart, légers/modérés, survenant le premier mois de DRF. Le DRF a été arrêté chez 5 patients. Dix-sept pour cent et 46 % des participants présentant un EI (flushs et GI, respectivement) ont reçu un traitement concomitant. L'incidence globale des flushs/EI liés aux flushs et EI GI dans les groupes rollover est faible. Peu de participants ont rapporté ces EI après 5 mois de traitement. Ces données sont en adéquation avec le profil de tolérance connu du DRF. Flush/EI liés aux flushs et EI GI sont fréquents, souvent légers/modérés et survenant le premier mois sous DRF. Peu d'arrêts de traitement sont liés aux flushs ou EI GI.

ObjectiveReport pregnancy outcomes from diroximel fumarate (DRF)-exposed women with multiple sclerosis (MS) in EVOLVE-MS-1, and describe a prospective, international pregnancy registry of women with MS (BlossoMS).BackgroundDRF is a next-generation oral fumarate approved for relapsing forms of MS. There are limited data on developmental risks associated with DRF use before and during pregnancy.Design/MethodsEVOLVE-MS-1 (NCT02634307) is an open-label, 96-week study assessing DRF. Any female in EVOLVE-MS-1 found to be pregnant was discontinued from study treatment; the pregnancy was followed until completion/termination. BlossoMS (anticipated 2023 start) will evaluate pregnancy outcomes in DRF-treated women, compared with those on other disease-modifying therapies (DMTs), no DMTs, and women without MS.ResultsOverall, 9 patients in EVOLVE-MS-1 had pregnancies; median (range) age at enrollment was 28 (19–33, n=9) years, overall DRF exposure in EVOLVE-MS-1 was 306.5 (12–431, n=8) days, and duration of DRF exposure during pregnancy was 46 (29–101, n=6) days. Of 9 pregnancies, 6 live births without con- genital abnormality, 1 elective termination with no known fetal defects, and 2 spontaneous abortions were observed.ConclusionsWe report pregnancy outcomes in women exposed to DRF during pregnancy. BlossoMS will provide essential information among DMF-exposed women during pregnancy. Supported: Biogen.

La SEP-pédiatrique représente environ 5 % des cas. Son évolution est souvent plus active que chez l'adulte. Le profil d'efficacité et sécurité du DMF, établi chez l'adulte, est inconnu chez l'enfant. L'étude CONNECT a comparé l'efficacité et la sécurité du DMF et de l'interféron bêta-1a (IFNβ-1a) intramusculaire chez des patients présentant une SEP d'apparition pédiatrique à la semaine (S) 96. CONNECT est une étude ouverte, randomisée, multicentrique, avec contrôle actif, chez des patients présentant une SEP récurrente-rémittente âgés de 10 à < 18 ans traités par DMF ou IFNβ-1a pendant 96S. Le critère d'évaluation principal était la proportion de patients sans nouvelles lésions ou lésions élargies (N/NE) hyper-intenses en T2 à S96 par rapport à l'inclusion. Les critères d'évaluation secondaires incluaient la proportion de patients sans poussée et les événements indésirables (EI). Au total, 150 patients ont été inclus (78 DMF et 72 IFNβ-1a) ; l'âge médian était 15 ans. La proportion de patients sans N/NE hyper-intenses en T2 à S96 était de 16 % pour le DMF vs 5 % pour l'IFNβ-1a. À S96. Les EI les plus fréquents observés chez les patients traités par DMF étaient les douleurs gastro-intestinales et bouffées congestives ; chez les patients traités par IFNβ-1a, il s'agissait de syndromes pseudo-grippaux et céphalées. Un plus grand nombre de patients traités par DMF étaient exempts de lésions T2N/NE à S96 comparés à ceux traités par IFNβ-1a. Le taux annualisé de poussée ajusté était également plus faible pour le DMF vs IFNβ-1a à S96. D'une manière générale, le profil de sécurité et de tolérance chez les patients pédiatriques était conforme à celui observé dans la population adulte.

To describe effectiveness of delayed-release dimethyl fumarate (DMF) for patients with relapsing-remitting multiple sclerosis (RRMS) previously treated with teriflunomide who switched for efficacy or non-efficacy reasons.