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Background: Dimethyl fumarate (DMF) demonstrated favorable benefit–risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension. Objective: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE. Methods: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0–2), then DMF (Years 3–10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years. Results: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04–10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF ( n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120–0.169)), while for PBO/DMF ( n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0–2 years, 0.330 (95% CI, 0.266–0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118–0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening. Conclusion: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF’s positive benefit/risk profile for long-term RRMS treatment.

ImportanceWith few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS).ObjectiveTo compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon β-1a (IFNβ-1a) in POMS.Design, Setting, and ParticipantsThe CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021.InterventionsPatients were randomized to DMF or IFNβ-1a.Main Outcomes and MeasuresThe primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group.ResultsAmong 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNβ-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNβ-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNβ-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNβ-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNβ-1a; the rate ratio for DMF vs IFNβ-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNβ-1a.Conclusions and RelevanceThis study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon β-1a. DMF was well tolerated.Trial RegistrationClinicalTrials.gov Identifier: NCT02283853

In the last decade there has been a significant increase in the literature discussing the use of benefit-risk methods in medical product (including devices) development. Government agencies, medical product industry groups, academia, and collaborative consortia have extensively discussed the advantages of structured benefit-risk assessments. However, the abundance of information has not resulted in a consistent way to utilize these findings in medical product development. Guidelines and papers on methods, even though well structured, have not led to a firm consensus on a clear and consistent approach. This paper summarizes the global landscape of benefit-risk considerations for product- or program-level decisions from available literature and regulatory guidance, providing the perspectives of three stakeholder groups-regulators, collaborative groups and consortia, and patients. The paper identifies key themes, potential impact on benefit-risk assessments, and significant future trends.

BackgroundBlack/African-American participants are underrepresented in clinical trials but can experience a greater burden of disease, such as multiple sclerosis, than other racial groups in the United States. A phase 1, open-label, 2-period crossover study that demonstrated bioequivalence of subcutaneous (SC) and intramuscular (IM) injection of peginterferon beta-1a in healthy volunteers enrolled a similar proportion of Black/African-American and White participants, enabling a subgroup analysis comparing these groups.MethodsPeginterferon beta-1a 125 μg was administered by SC or IM (1:1) injection, followed by a 28-day washout period before a second injection using the alternate method. Primary endpoints were maximum observed concentration (Cmax) and area under the concentration-time curve from Hour 0 to infinity (AUCinf). Secondary endpoints included safety, tolerability, and additional pharmacokinetic and pharmacodynamic parameters.FindingsThis analysis included 70 (51.5%) Black and 59 (43.3%) White participants. Black participants exhibited a 29.8% higher geometric mean Cmax of peginterferon beta-1a than White participants following SC administration and demonstrated similar values following IM administration. Black participants displayed 31.0% versus 11.8% higher geometric mean AUCinf values than White participants with SC versus IM administration. Neopterin dynamics and safety signals were similar between groups, with numerically fewer adverse events reported among Black participants.ConclusionsNo clinically meaningful differences were identified between Black and White participants in pharmacokinetics/pharmacodynamics or safety related to peginterferon beta-1a administration, indicating that no change in dosing regimen is warranted for Black patients with MS.FundingFunding for medical writing support was provided by Biogen Inc. (Cambridge, MA, USA).

ObjectiveIn the pivotal DEFINE and CONFIRM trials for dimethyl fumarate (DMF), patterns of brain volume changes were different, potentially due to low sample sizes and because MRIs were analyzed at two different reading centers. We evaluated effects of DMF on brain volume change in patients with multiple sclerosis (MS) through reanalysis of pooled images from DEFINE/CONFIRM trials in one reading center.MethodsMRIs from DEFINE/CONFIRM at weeks 0, 24, 48, and 96 from patients randomized to twice-daily DMF or placebo (PBO) were reanalyzed at the Cleveland Clinic to measure brain parenchymal fraction (BPF). To account for pseudoatrophy, brain volume estimates were re-baselined to calculate changes for weeks 48–96.ResultsAcross studies, 301 and 314 patients receiving DMF and PBO, respectively, had analyzable MRIs. In weeks 0–48, mean ± SE percentage change in BPF was −0.44 ± 0.04 vs. −0.34 ± 0.04% in DMF vs. PBO, respectively, whereas in weeks 48–96, mean ± SE percentage change in BPF was −0.27 ± 0.03 vs. −0.41 ± 0.04% in DMF vs. PBO, respectively. The mixed-effect model for repeated measures showed similar results: in weeks 48–96, estimated change (95% confidence interval) in BPF was −0.0021 (−0.0027, −0.0016) for DMF vs. −0.0033 (−0.0039, −0.0028) for PBO (35.9% reduction; p = 0.0025).ConclusionsThe lower rate of whole brain volume loss with DMF in this pooled BPF analysis in the second year vs. PBO is consistent with its effects on relapses, disability, and MRI lesions. Brain volume changes in the first year may be explained by pseudoatrophy effects also described in other MS clinical trials.

Black/African American participants are underrepresented in clinical trials for multiple sclerosis but can experience a greater burden of disease than other racial groups in the United States. A phase 1, open-label, crossover study that demonstrated bioequivalence of subcutaneous and intramuscular injection of peginterferon β-1a in healthy volunteers enrolled similar proportions of Black and White participants, enabling a post hoc subgroup analysis comparing these groups.Peginterferon β-1a (125 μg) was administered by subcutaneous or intramuscular injection, followed by a washout period before a second injection using the alternative method. The primary pharmacokinetic and pharmacodynamic endpoints were maximum observed concentration (CThis analysis included 70 (51.5%) Black and 59 (43.3%) White participants. Peginterferon β-1a CNo clinically meaningful differences were identified between Black and White participants related to peginterferon β-1a administration, supporting the approved dose of 125 μg/mL peginterferon β-1a. Future clinical studies should include sufficiently diverse populations to ensure accurate assessments of treatment response.Funding for medical writing support was provided by Biogen (Cambridge, MA, USA).

IntroductionDimethyl fumarate (DMF) is not recommended during pregnancy and should only be used if the potential benefit justifies potential foetal risk. Given limited pregnancy data, the UK and Ireland have enrolled DMF-exposed pregnant women in an ongoing international registry assessing pregnancy outcomes. In the general population, 62% of pregnancies end in live birth, 22% in abortion, and 16% in foetal loss, with similar rates in multiple sclerosis (MS) patients.MethodsWomen with MS exposed to DMF since the first day of their last menstrual period before con- ception/during pregnancy were included. UK/Ireland Coordinating Centres liaised directly with patients and healthcare providers.ResultsAs of March 2021, 403 patients (19 UK/Ireland) were enrolled. Of 350 reported pregnancy outcomes (19 UK/Ireland), 329 (94%) represented live births (100% UK/Ireland). Of 326 infants with known gestational age,298 births (91%) were full-term (100% UK/Ireland) and 28 (9%) premature (28 weeks). There was one neonatal death. Nine infants (2 UK/Ireland) had EUROCAT-confirmed birth defects.ConclusionsThe observations are consistent with MS and general populations.SupportBiogen. Disclosures on poster.

IntroductionDimethyl fumarate (DMF) is not recommended for use during pregnancy and should only be used if the potential benefit justifies the potential foetal risk. Given limited pregnancy data, the UK and Ireland have enrolled DMF-exposed pregnant women in an ongoing international registry assessing pregnancy outcomes. Generally, pregnancies end in live birth (62%), abortion (22%), or foetal loss (16%), with similar rates in MS patients.MethodsPregnant women with MS exposed to DMF since the first day of their last menstrual period before conception/during pregnancy were included. UK/Ireland Coordinating Centres liaise directly with patients and healthcare providers.ResultsAs of May 2020, 345 patients (18 UK/Ireland) were enrolled. Of the reported 351 pregnancy outcomes (18 UK/Ireland), 277 (79%) represented live births (17 UK/Ireland) and 74 (21%) foetal loss. Of infants with known gestational age (n=274), 249 births (91%) were full-term (17 UK/Ireland) and 25 (9%) premature (28 weeks). No infant or maternal deaths were reported. Ten infants (4%) (2 UK/Ireland) had confirmed birth defects.ConclusionsObserved safety signals were consistent with MS and general populations.SupportBiogen. Disclosures: Included on poster 81david.rog@srft.nhs.uk

Introduction DMF a montre un profil benefice–risque favorable dans les essais et en pharmacovigilance. DMF est recommande chez les femmes enceintes que si le benefice justifie le risque pour le fœtus. Objectifs Fournir les issues de grossesses et des donnees d’exposition au DMF chez des femmes atteintes de SEP traitees par DMF dans un registre international prospectif en cours ( NCT01911767 , TecGistry). Patients et methodes TecGistry inclut des femmes des le premier jour de leurs dernieres regles avant la conception ou durant la grossesse. Les donnees ont ete obtenues a l’inclusion, a 6 − 7 mois de gestation, 4 semaines apres la date de naissance estimee et 4, 12 et 52 semaines apres celle-ci. Les criteres d’evaluation incluaient les naissances vivantes, les avortements, les grossesses ectopiques/molaires, les malformations et anomalies congenitales, et les deces de meres et de nourrissons post-accouchement. Resultats Au total, 345 patientes etaient inscrites. La semaine gestationnelle mediane a la premiere exposition au DMF etait de 1 (plage : 0, 13) et de 9 a l’inclusion (0, 39,3). La duree d’exposition mediane du fœtus au DMF etait de 5 (0, 40) semaines. Parmi les arrets de traitement, un etait du a un EI grave. Sur les resultats connus, 277 etaient des naissances vivantes, 19 pertes fœtales dont 1 grossesse molaire et 1 grossesse ectopique. Discussion Un deces neonatal mais aucun maternel n'a ete rapporte. Sur les 274 nouveau-nes d’âge gestationnel connu, 249 (91 %) etaient a terme et 25 (9 %) prematures ( Conclusion Les issues de grossesses observees correspondaient aux rapports precedents et ne depassaient pas celles observees dans les populations de SEP et generale. Aucun autre signal de securite n’a ete identifie.

Background and ObjectivesOral delayed-release dimethyl fumarate (DMF) is not recommended during pregnancy and should only be used if the potential benefit justifies the potential fetal risk. Although DMF was well tolerated in clinical trials with consistent safety results in postmarketing surveillance, data are limited in pregnant women. The objective was to provide pregnancy outcomes and DMF exposure information from an interim analysis from a prospective, international registry (TecGistry; NCT01911767).MethodsWomen exposed to DMF from the first day of their last menstrual period before conception or during pregnancy were evaluated. Data were obtained at enrollment; 6−7 months' gestation; 4 weeks after estimated due date; and 4, 12, and 52 weeks after birth. Outcomes included live births, gestational size, pregnancy loss, birth defects, and infant or maternal death after delivery. Outcomes were analyzed cumulatively from October 30, 2013 (the start of TecGistry), to April 8, 2020.ResultsOf 345 enrolled patients, median (range) age was 32 (20–43) years. The mean (SD) duration of gestational weeks of DMF exposure was 4.9 (3.8). Most infants were full-term at birth (n = 249/274; 91%) and of average gestational size (n = 190/232; 82%). Of 351 outcomes, 277 were live births; 17 (5%) spontaneous abortions (95% confidence interval [CI] 2.6%–7.1%), including 1 (DiscussionInterim results from this large registry indicate that early DMF exposure was not significantly associated with adverse pregnancy outcomes. Outcomes are consistent with previous smaller reports and with the general population.Trial Registration InformationTecGistry; clinical trial registration number: NCT01911767.

Background: Reversible lymphocyte count reductions have occurred following daclizumab beta treatment for relapsing–remitting multiple sclerosis. Objective: To analyse total and differential lymphocyte levels and relationship with infection status. Methods: In DECIDE, blood samples were collected at 12-week intervals from daclizumab beta- ( n = 919) or intramuscular interferon beta-1a–treated ( n = 922) patients. Infections/serious infections were assessed proximate to grade 2/3 lymphopenia or low CD4+/CD8+ T-cell counts. Total safety population (TSP) data were additionally analysed from the entire clinical development programme ( n = 2236). Results: Over 96 weeks in DECIDE, mean absolute lymphocyte count (ALC), CD4+ and CD8+ T-cell counts decreased +/CD8+ T-cell counts were similar regardless of infection status. TSP data were consistent with DECIDE. Conclusion: When observed, ALC and CD4+/CD8+ T-cell count decreases in daclizumab beta–treated patients were generally mild-to-modest, reversible upon treatment discontinuation and not associated with increased risk of infections, including opportunistic infections.

Introduction Le DMF est un traitement pour les formes remittentes recurrentes de sclerose en plaques (SEP-RR) ; les donnees d’ENDORSE, extension aux etudes DEFINE/CONFIRM, ont permis un suivi > 10 ans. Objectifs Nous rapportons la securite et l’efficacite du DMF chez des patients atteints de SEP-RR traites par DMF et suivis pendant 13 ans dans ENDORSE (NCT00835770). Patients et methodes L’incidence des EI graves (EIG), les interruptions dues a des EI, le taux annualise de poussees (TAP) et le score de l’echelle de handicap (EDSS) ont ete evalues. Les patients ont ete traites par DMF 240 mg 2 fois par jour : placebo (PBO, annees 0 a 2/DMF, annees 3 a 10) ou en continu (DMF/DMF). Resultats Au total, 1736 patients etaient inclus/avaient recu ≥ 1 dose de DMF. Trente-deux pour cent presentaient des EIG (poussee ou chute majoritairement). Il y a eu un cas de LEMP. L’incidence d’autres infections/graves reste stable. Pour les patients traites en continu (n = 501), le TAP est reste bas (0,141[IC95 % : 0,119–0,167]), alors que pour les patients sous PBO/DMF (n = 249), il a diminue suite au DMF (TAP 0 a 2 ans, 0,330[IC95 % : 0,266–0,408] ; TAP global, 0,149[IC95 % : 0,116–0,190]). Discussion Soixante pour cent de patients sous DMF/DMF et 66 % sous PBO/DMF n’ont pas eu de poussees. Patients avec des scores EDSS ≤ 3,5 : 413/479 (86 %) DMF/DMF (179/217[82 %]PBO/DMF) annee 2 ; 173/226 (77 %) DMF/DMF (67/90[74 %]PBO/DMF) annee 10. Soixante-douze pour cent et 73 % des patients DMF/DMF et PBO/DMF, respectivement, n’ont pas eu de progression confirmee du handicap a 24 semaines sur 10 ans. Conclusion Ces donnees de securite et d’efficacite chez les patients suivis pendant 13 ans appuient le DMF comme option a long terme pour les patients atteints de SEP-RR.

Background Peginterferon beta-1a and teriflunomide are both first-line disease-modifying therapies (DMTs) approved for the treatment of relapsing multiple sclerosis (RMS); however, no head-to-head trials have directly compared their clinical efficacy. We performed a matching-adjusted comparison of individual patient data from the peginterferon beta-1a pivotal phase 3 study, ADVANCE, and its extension study, ATTAIN, with pooled aggregated data from the teriflunomide pivotal phase 3 studies, TEMSO and TOWER. Methods A total of 512 patients randomized to subcutaneous (SC) peginterferon beta-1a 125 mcg every 2 weeks in ADVANCE and 731 patients randomized to teriflunomide 14 mg daily (359 from TEMSO and 372 from TOWER) were matched on key baseline characteristics. After matching, weighted annualized relapse rate (ARR) and 24-week confirmed disability worsening (CDW) were calculated and compared for peginterferon beta-1a– and teriflunomide-treated patients. A subset analysis comparing weighted ARR in patients who were newly diagnosed with RMS (diagnosis ≤1 year before study enrollment and disease-modifying therapy naive) was also performed. Results After matching, the peginterferon beta-1a and teriflunomide treatment groups were identically matched across baseline characteristics. The proportion of patients in the overall study populations with 24-week CDW at 108 weeks was significantly lower in the peginterferon beta-1a group than the teriflunomide group both before matching (8.5% vs 12.6%; P = 0.0249) and after matching (8.4% vs 12.6%; P = 0.0323). ARR at 108 weeks was numerically lower with peginterferon beta-1a than with teriflunomide both before matching (0.278 vs 0.354; P = 0.1326) and after matching (0.257 vs 0.354; P = 0.0510). Newly diagnosed patients treated with peginterferon beta-1a had numerically lower ARR than patients treated with teriflunomide both at 108 weeks (before matching: 0.225 vs 0.270; P = 0.587; after matching: 0.201 vs 0.270; P = 0.384) and at 5 years (before matching: 0.150 vs 0.196; after matching: 0.142 vs 0.196). Conclusions In this matching-adjusted comparison of patients with RMS from three phase 3 trials, a significantly lower proportion of patients treated with SC peginterferon beta-1a 125 mcg every 2 weeks than with oral teriflunomide 14 mg once daily had 24-week CDW at 108 weeks. In addition, in both the overall population and newly diagnosed patient subgroups, ARR at 108 weeks was numerically lower with peginterferon beta-1a than with teriflunomide. The numerically lower ARR in newly diagnosed patients treated with peginterferon beta-1a compared with those treated with teriflunomide was sustained through up to 5 years of treatment.

Introduction Peginterferon beta-1a and glatiramer acetate (GA) have been studied in different clinical studies, and head-to head efficacy comparisons are lacking. Objectives Compare peginterferon beta-1a vs. GA on clinical efficacy endpoints at 2 years in patients from ADVANCE and CONFIRM using PSM. Patients and methods PSM (1:1) based on key baseline characteristics was performed on 512 peginterferon beta-1a patients and 350 GA patients. Outcomes included annualised relapse rate (ARR), which was assessed using negative binomial regression, and 12-week and 24-week confirmed disability worsening (CDW), which were evaluated using the Kaplan–Meier method and Cox proportional hazards modeling. Results After matching, 336 patients were included. At 2 years, patients treated with peginterferon beta-1a had a significantly lower ARR (0.204 vs. 0.282; rate ratio 0.724; P = 0.0453), a significantly lower probability of 12week CDW (10,0 % vs. 14.6 %; hazard ratio (HR) 0.625; P = 0,0476), and a numerically lower probability of 24-week CDW (7.7 % vs. 10.6 %; HR 0.684; P = 0.171) compared with patients treated with GA. Discussion NA. Conclusion Peginterferon beta-1a showed significantly better clinical outcomes in terms of relapses and 12 week disability worsening compared to GA over 2 years.

Introduction Chronic black holes (BHs) indicate severe tissue injury and are used as a biomarker of therapeutic outcomes in relapsing-remitting multiple sclerosis (RRMS). Objectives Evaluate the effect of peginterferon beta-1a every 2 weeks on the number of chronic BHs that evolve from acute lesions over 2 years. Patients and methods ADVANCE was a 2-year, double-blind phase 3 trial of peginterferon beta-1a in 1512 patients with RRMS. The number of BHs at week 96 that evolved from new/enlarging T2-weighted (NET2) lesions at 24 or 48 weeks or gadolinium-enhancing (Gd + ) lesions (at baseline, 24 weeks, or 48 weeks) were compared. The adjusted annualized relapse rate (ARR) by BH conversion status was also assessed. Results ADVANCE included 231 newly diagnosed and 281 non-newly diagnosed patients in the continuous-treatment group and 229 newly diagnosed and 271 non-newly diagnosed patients in the delayed-treatment group. At week 96, the continuous-treatment ITT patients had fewer BHs that evolved from NET2 lesions at week 24 or week 48 than the delayed-treatment ITT patients in both newly diagnosed (P Discussion The results are similar for the BHs that evolved from the Gd+ lesions detected at baseline, week 24 or week 48 in newly diagnosed (P Conclusion The lower risk of chronic BHs with peginterferon beta-1a therapy suggests the potential to provide treatment benefits to patients with RRMS by reducing long-term disability.

This paper is concerned with testing association between marker genotypes and traits with variable age at onset. Two methods are proposed, one which makes use of both age-at-ascertainment and age-at-onset information, and one which may be applied when only age-at-ascertainment information is available. (Here, by age-at-ascertainment, is meant the subject’s age when presence of onset and age at onset are determined; for subjects who have died or are otherwise censored before ascertainment, the censoring time should be used instead). Adjustment for confounding due to population stratification is carried out by conditioning on observed traits and parental genotypes, or, if complete parental genotypes are not available, by conditioning on observed traits and the minimal sufficient statistics under the null hypothesis for the parental genotypes. Proportional hazards regression models and logistic regression models are used to motivate the methods, but correct type I error rates result even if the models are not correct. An illustrative example is described.