Nuwan Kurukulasuriya

Efficacy and safety of BG-12 (dimethyl fumarate) and other disease-modifying therapies for the treatment of relapsing–remitting multiple sclerosis: a systematic review and mixed treatment comparison

Abstract Objective: Currently, direct comparative evidence or head-to-head data between BG-12 (dimethyl fumarate) and other disease-modifying treatments (DMTs) is limited. This study is a systematic review and data synthesis of published randomized clinical trials comparing the efficacy and safety of existing DMTs to BG-12 for relapsing–remitting multiple sclerosis (RRMS). Methods: A systematic review was conducted by searching MEDLINE, EMBASE, and the Cochrane Library for English-language publications from 1 January 1960 to 15 November 2012. Clinicaltrials.gov, metaRegister of Controlled Trials, and conference proceedings from relevant annual symposia were also hand searched. Two independent reviewers collected and extracted data, with discrepancies reconciled by a third reviewer. Included studies were randomized controlled trials (RCTs) of DMTs (interferon [IFN] beta-1a, IFN beta-1b, glatiramer acetate [GA], BG-12, fingolimod, natalizumab, and teriflunomide) in adults with RRMS. Mixed treatment comparisons were conducted to derive the relative effect size for the included treatments. Annualized relapse rate (ARR), disability progression, and safety outcomes were assessed. Results: BG-12 240 mg twice a day (BID) significantly reduces ARR compared to placebo (rate ratio: 0.529 [95% CI: 0.451–0.620]), IFNs (0.76 [95% CI: 0.639–0.904]), GA (0.795 [95% CI: 0.668–0.947]), and teriflunomide 7 mg and 14 mg (0.769 [95% CI: 0.610–0.970] and 0.775 [95% CI: 0.614–0.979]), and does not show a significant difference when compared to fingolimod. Only natalizumab was significantly superior to BG-12 in reducing ARR. BG-12 also demonstrated favorable results for disability and safety outcomes. Conclusion: Based on indirect comparison, BG-12 offers an effective oral treatment option for patients with RRMS with an overall promising efficacy and safety profile compared to currently approved DMTs. Key limitations of the systematic review were the large heterogeneity in patients enrolled and the variability in the definition of outcomes in included trials.

Long-term effects of delayed-release dimethyl fumarate in multiple sclerosis: Interim analysis of ENDORSE, a randomized extension study

Background: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit–risk profile for patients with relapsing–remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM. Objective: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE). Methods: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID. Results: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1–5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia. Conclusion: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.

Delayed-Release Dimethyl Fumarate and Pregnancy: Preclinical Studies and Pregnancy Outcomes from Clinical Trials and Postmarketing Experience

IntroductionDelayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) is an oral agent for the treatment of relapsing forms of multiple sclerosis (MS). No formal studies of DMF were conducted in pregnant women, although pregnancies have occurred during clinical trials and in the postmarketing setting.MethodsPreclinical developmental and reproductive toxicology studies were performed with DMF in rats and rabbits. As of March 26, 2014, the DMF clinical development program included a total of 4132 subjects consisting of 2898 patients with MS, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers. Subjects were required to use reliable contraception and immediately discontinue treatment in the event of pregnancy.ResultsAnimal studies showed no evidence of impaired fertility or teratogenicity with DMF. Overall as of June 30, 2014, 63 pregnancies were reported in clinical trials. Outcomes are known for 39 of 42 subjects receiving DMF and include 26 live births (67%), three spontaneous abortions (8%), and 10 elective terminations (26%); follow-up is ongoing in 2 cases and one patient was lost to follow-up. The incidence of spontaneous abortion in subjects exposed to DMF was consistent with the expected rate of early pregnancy loss in the general population (12–22%). A total of 135 pregnancies were reported in the postmarketing setting (spontaneous and solicited reports). Outcomes are known for 30 cases and include 10 live births, 13 spontaneous abortions, and 5 elective terminations; follow-up is ongoing in 103 cases and 2 patients have been lost to follow-up.ConclusionAlthough data are limited and all known exposures have occurred in the first trimester, no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to DMF has been observed.FundingBiogen, Inc.

Efficacy and safety of delayed-release dimethyl fumarate in patients newly diagnosed with relapsing–remitting multiple sclerosis (RRMS)

Background: Delayed-release dimethyl fumarate (DMF) demonstrated efficacy and safety in the Phase 3 DEFINE and CONFIRM trials. Objective: To evaluate delayed-release DMF in newly diagnosed relapsing–remitting multiple sclerosis (RRMS) patients, in a post-hoc analysis of integrated data from DEFINE and CONFIRM. Methods: Patients included in the analysis were diagnosed with RRMS within 1 year prior to study entry and naive to MS disease-modifying therapy. Results: The newly diagnosed population comprised 678 patients treated with placebo (n = 223) or delayed-release DMF 240 mg BID (n = 221) or TID (n = 234). At 2 years, delayed-release DMF BID and TID reduced the annualized relapse rate by 56% and 60% (both p < 0.0001), risk of relapse by 54% and 57% (both p < 0.0001), and risk of 12-week confirmed disability progression by 71% (p < 0.0001) and 47% (p = 0.0085) versus placebo. In a subset of patients (MRI cohort), delayed-release DMF BID and TID reduced the mean number of new or enlarging T2-hyperintense lesions by 80% and 81%, gadolinium-enhancing lesion activity by 92% and 92%, and mean number of new non-enhancing T1-hypointense lesions by 68% and 70% (all p < 0.0001 versus placebo). Flushing and gastrointestinal events were associated with delayed-release DMF. Conclusion: Delayed-release DMF improved clinical and neuroradiological outcomes relative to placebo in newly diagnosed RRMS patients.

Oral BG-12 (dimethyl fumarate) for relapsing–remitting multiple sclerosis: a review of DEFINE and CONFIRM

Introduction: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of the central nervous system involving inflammation, chronic demyelination and axonal loss. MS affects more than 2 million people worldwide. Areas covered: This article aims to summarize the findings from two pivotal 2-year, randomized, double-blind, placebo-controlled, Phase III studies of BG-12 (dimethyl fumarate) for relapsing–remitting MS (RRMS): DEFINE (Determination of the Efficacy and Safety of Oral Fumarate in RRMS) and CONFIRM (Comparator and an Oral Fumarate in RRMS). Results from both studies demonstrated that BG-12 provides clinical and radiological efficacy over 2 years across a range of outcomes. These results were apparent as early as 12 weeks and sustained over the course of both studies. BG-12 was found to have an acceptable safety profile, with a similar overall incidence of adverse events across all treatment groups. Expert opinion: The combination of robust efficacy, ease of administration and established safety profile is unique to a new therapy in MS. Findings from the pivotal Phase III studies support BG-12 as a potential initial oral treatment for patients with RRMS or as an alternative to other currently available therapies.

Cladribine tablets for the treatment of relapsing–remitting multiple sclerosis

Introduction: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system leading to progressive neurodegeneration and disability. Until 2010, all approved disease-modifying drugs for MS required parenteral administration, which is associated with suboptimal adherence. It was anticipated that new approaches to treatment, including oral agents such as cladribine tablets, may improve adherence. In 2011, the development of cladribine tablets was stopped following negative feedback from the EMA and FDA. Areas covered: This article provides an overview of the chemistry, mechanism of action and pharmacological properties of cladribine tablets therapy, and highlights the rationale for its development as an oral treatment for MS. Key efficacy and safety data from the pivotal Phase III CLARITY study are presented, providing context for the opinion received from the regulatory agencies. Expert opinion: Despite the promising efficacy data observed in the cladribine tablets clinical trial program, regulatory agencies identified a potential risk of increased malignancies, and raised concerns about the implications of sustained lymphocyte depletion. Following the feedback received from the regulatory agencies, Merck Serono made the decision to withdraw the agent from the regulatory approval process. The experience gained will benefit other research efforts to address the outstanding unmet treatment needs of patients with relapsing MS.

Effect of Aspirin Pretreatment or Slow Dose Titration on Flushing and Gastrointestinal Events in Healthy Volunteers Receiving Delayed-release Dimethyl Fumarate

PURPOSE In Phase III trials, delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated significant efficacy and an acceptable safety profile in patients with relapsing-remitting multiple sclerosis. The purpose of the present study was to examine 2 potential mitigation strategies for flushing and gastrointestinal (GI) events associated with DMF treatment: aspirin (ASA) 325 mg pretreatment for flushing, and slow dose titration of DMF for flushing and GI events. METHODS The 8-week study included 173 healthy volunteers randomized to 4 groups; 172 underwent dosing. The placebo group (n = 44) received placebo ASA 30 minutes before placebo DMF (weeks 1-4), then placebo DMF alone (weeks 5-8). The DMF without ASA group (n = 43) and the DMF with ASA group (n = 43) received placebo ASA or ASA, respectively, 30 minutes before DMF (weeks 1-4), then DMF alone (weeks 5-8); in both groups, DMF was dosed at 120 mg BID (week 1) and 240 mg BID (weeks 2-8). The slow dose titration DMF group (n = 42) received DMF 120 mg once daily (week 1), 120 mg BID (week 2), 240 mg in the morning/120 mg in the evening (week 3), and 240 mg BID (weeks 4-8). Subjects recorded information about flushing and GI-related events by using an eDiary and numerical rating scales. FINDINGS Flushing and GI-related events were reported in all groups and were mostly rated as mild or moderate in severity. Flushing events were generally ~1 hour in duration and, for most subjects with flushing, initially occurred the first day of study treatment. The duration of GI-related events and time to first GI-related event varied by event type. ASA reduced the incidence, severity, and number of flushing events without affecting duration or time to first flushing event, and had no adverse effect on GI-related events. Dose titration of DMF had no significant effect on flushing or GI events. No subjects discontinued the study due to flushing events. One subject (2%) in the placebo group, 3 subjects (7%) in the DMF without ASA group, 6 subjects (14%) in the DMF with ASA group, and 2 subjects (5%) in the slow dose titration DMF group discontinued treatment because of GI events. IMPLICATIONS ASA pretreatment may mitigate flushing associated with DMF, with no adverse effect on GI events. Dose titration of DMF did not have a significant effect on flushing or GI events and is being evaluated further in ongoing clinical trials. ClinicalTrials.gov identifier: NCT01568112.

Cladribine tablets for relapsing–remitting multiple sclerosis: Efficacy across patient subgroups from the phase III CLARITY study

BACKGROUND In the phase III CLARITY study, treatment with cladribine tablets at cumulative doses of 3.5 or 5.25mg/kg over 96 weeks led to significant reductions in annualized relapse rates (ARR) versus placebo in patients with relapsing-remitting multiple sclerosis. Further post hoc analyses of CLARITY study data were conducted to determine the efficacy of cladribine tablets across patient subgroups stratified by baseline characteristics. METHODS Relapse rates over the 96-week CLARITY study were analyzed in cohorts stratified by demographics; disease duration; treatment history and disease activity at baseline. RESULTS In the intent-to-treat population (n=437, 433 and 456 in the placebo, cladribine 3.5 and 5.25mg/kg groups, respectively), treatment with cladribine tablets 3.5 and 5.25mg/kg led to consistent improvements in ARR versus placebo in patients stratified by gender; age (≤40/>40 years); disease duration (<3/3-10/>10 years); prior disease-modifying drug treatment (treated/naïve); relapses in the prior year (≤1/2/≥3); Expanded Disability Status Scale score (<3.5/≥3.5); T1 gadolinium-enhancing lesions (presence, absence); and T2 lesion volume (≤median/>median) at baseline (all P≤0.05 for reduction in the relative risk of relapse [cladribine tablets versus placebo]). Significant effects were also observed in patients who had only one relapse in the year prior to study entry (n=306, 303 and 323 in the placebo, cladribine 3.5 and 5.25mg/kg groups, respectively) and who were further stratified according to other measures of disease activity at baseline. CONCLUSIONS Treatment with cladribine tablets provides consistent reductions in ARR compared with placebo across the spectrum of baseline demographics and disease characteristics represented in the CLARITY study.

Efficacy for remyelination and safety of anti-lingo-1 monoclonal antibody (biib033) in acute optic neuritis: results from the renew study

Introduction: Anti-LINGO-1 is a monoclonal antibody antagonist of LINGO-1, an oligodendrocyte differentiation and myelination suppressor. RENEW (NCT01721161) aimed to determine the efficacy and safety of anti-LINGO-1 for CNS remyelination. Methods: Subjects with a first unilateral acute optic neuritis episode were treated with high-dose steroids and randomized to 100 mg/kg anti-LINGO-1 IV or placebo every 4 weeks. Nerve conduction latency recovery using full-field visual evoked potential (FF-VEP) in the affected eye over time versus unaffected eye at baseline was used to assess remyelination (pre-specified primary endpoint). Retinal neuroprotection was studied by measuring the thickness of the retinal nerve fiber and ganglion cell layers using spectral-domain optical coherence tomography (SD-OCT) and change in low-contrast letter acuity (LCLA). Patient-reported outcomes (PRO) were also assessed. Between-treatment comparisons were evaluated by ANCOVA and mixed-effect model repeated measure in subjects who completed the study and did not miss >1 study dose or receive MS modifying therapy (pre-specified per-protocol population; n=69/82 subjects randomized). Safety/tolerability were evaluated in those who received ≥1 study dose and included adverse event (AE) and clinical laboratory result assessments. at Week 32. 54% of anti-LINGO-1 subjects had normal/near normal latency at Week 24 (affected eye FF-VEP latency ≤10% worse than the fellow eye) versus 27% of the placebo group (P=0.04). Additional subgroup analyses and PRO data will be presented. No treatment differences were observed in SD-OCT and LCLA. 34/41 in each group experienced any AE, serious AEs (SAE) occurred in 2 placebo and 5 anti-LINGO-1 subjects, with treatment-related SAEs reported in 3 subjects. Conclusions: Improvement in FF-VEP latency is consistent with the first evidence of remyelination in a Phase 2 trial. Anti-LINGO-1 was generally well tolerated. Introduction: Our goal was to determine whether the beneficial effects of acetazolamide (ACZ) in improving vision continues from months 6 to 12 in participants of the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). Methods: In the IIHTT, after 6 months of a weight management program and either placebo or maximally tolerated ACZ, subjects transitioned from study drug to ACZ unless their papilledema resolved. The main outcome was the change in MD from Month 6 to Month 12 in the study eye, groups based on treatment at study entry and after 6 mos. – 1) ACZ to ACZ n = 34, 2) placebo to ACZ n = 35, 3) ACZ to no treatment n = 20, and 4) placebo to no treatment n = 12. Results: The placebo subjects …

Neuroradiological efficacy of oral BG-12 for relapsing–/INS;remitting multiple sclerosis (RRMS): Integrated analysis of the Phase 3 DEFINE and CONFIRM studies

WCN 2013 No: 2276 Topic: 6 — MS & Demyelinating Diseases Neuroradiological efficacy of oral BG-12 for relapsing–remitting multiple sclerosis (RRMS): Integrated analysis of the Phase 3 DEFINE and CONFIRM studies R.J. Fox, D.H. Miller, R. Gold, D. Macmanus, T. Yousry, A. Bar-Or, R. Zhang, N.C. Kurukulasuriya, V. Viglietta, M. Stephan, K.T. Dawson, D.L. Arnold. Mellen Center forMultiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA; Institute of Neurology, University College London, London, UK; St. Josef Hospital, Ruhr University, Bochum, Germany; Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada; Biogen Idec, Weston, MA, USA Background: Oral BG-12 (dimethyl fumarate) demonstrated positive clinical and neuroradiological efficacy and an acceptable safety profile in the Phase 3 DEFINE and CONFIRM trials. Objective: To present the results of a pre-specified, integrated analysis of DEFINE and CONFIRM, conducted to obtain a more precise estimate of the therapeutic effect of BG-12 on MRI endpoints. Patients and methods: Eligible patients were aged 18–55 years and had a diagnosis of RRMS (McDonald criteria) and an Expanded Disability Status Scale score of 0–5.0. In DEFINE, patients were randomized 1:1:1 to receive BG-12 240 mg twice (BID) or three times daily (TID) or placebo. In CONFIRM, patients were randomized 1:1:1:1 to receive BG-12 240 mg BID or TID, placebo, or glatiramer acetate (reference comparator). MRI was performed in a subset of patients at sites with validated MRI capability. Results: A total of 1,046 patients (MRI cohort) were randomized and received placebo (n = 347), BG-12 BID (n = 345), or BG-12 TID (n = 354). At 2 years, BG-12 BID and TID reduced the number of new/newly enlarging T2-hyperintense lesions by 78% and 73%, respectively; new non-enhancing T1-hypointense lesions by 65% and 64%, respectively; and the odds of having more gadoliniumenhancing lesions by 83% and 70%, respectively, as compared to placebo (all comparisons p b 0.0001). Conclusion: The results of the integrated analysis demonstrate consistent benefits of both dosing regimens of BG-12 on MRI activity. Alongside strong clinical efficacy and an acceptable safety profile, these results suggest that BG-12 has the potential to become a valuable oral treatment option for RRMS patients. doi:10.1016/j.jns.2013.07.1345 Abstract — WCN 2013 No: 2316 Topic: 6 — MS & Demyelinating Diseases BG-12 effects on quality of life in relapsing–remitting ms patients: Integrated analysis of the Phase 3 DEFINE and CONFIRM studies WCN 2013 No: 2316 Topic: 6 — MS & Demyelinating Diseases BG-12 effects on quality of life in relapsing–remitting ms patients: Integrated analysis of the Phase 3 DEFINE and CONFIRM studies M. Kita, R.J. Fox, R. Gold, G. Giovannoni, J.T. Phillips, S.P. Sarda, J. Kong, N.C. Kurukulasuriya, V. Viglietta, S.I. Sheikh, K.T. Dawson, L. Kappos. Virginia Mason Multiple Sclerosis Center, Seattle, WA; Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH, USA; St. Josef Hospital, Ruhr University, Bochum, Germany; Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University, London, UK; Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, USA; Biogen Idec, Weston, MA, USA; Department of Neurology, University Hospital Basel, Basel, Switzerland Background: Oral BG-12 (dimethyl fumarate) demonstrated clinical and neuroradiological efficacy and an acceptable safety profile in the Phase 3 DEFINE and CONFIRM studies. Objective: To report the results of a pre-specified, integrated analysis of health-related quality of life (HRQoL) endpoints in DEFINE and CONFIRM. Patients and methods: HRQoL endpoints assessed in both studies were the Short Form-36 (SF-36) Physical and Mental Component Summary (PCS/MCS) scales, global assessment of well-being visual analog scale (VAS), and the EuroQOL-5D (EQ-5D) VAS. Higher scores indicated better HRQoL. Results: A total of 2,301 patients were randomized to receive placebo (n = 771) or BG-12 240 mg twice (BID; n = 769) or three times daily (TID; n = 761). Physical and mental health and functioning were significantly improved with BG-12 versus placebo. At 2 years, mean SF-36 PCS scores increased from baseline by 0.47 (BID) and 0.43 (TID) versus a reduction of −1.05 (placebo; both p b 0.0001). SF-36 MCS scores increased by 0.31 (BID) and 0.63 (TID) versus a reduction of −0.60 (placebo; p = 0.0246 and p = 0.0107, respectively). BG-12-treated patients reported a significantly better sense of well-being and perception of health status than placebotreated patients. Mean changes from baseline to 2 years with BID and TID versus placebo were −0.3 and +0.1 versus −4.0 for global wellbeing VAS (both p b 0.0001) and −0.90 and −0.31 versus −3.37 for EQ-5D VAS (p = 0.0011 and p = 0.0002, respectively). Conclusion: BG-12 treatment resulted in significant improvements in physical and mental aspects of health and functioning, general well-being, and overall health status compared with placebo in RRMS patients. doi:10.1016/j.jns.2013.07.1346 Abstract — WCN 2013 No: 2304 Topic: 6 — MS & Demyelinating Diseases Gastrointestinal tolerability events in relapsing–remitting multiple sclerosis patients treated with BG-12 (dimethyl fumarate): Integrated analysis of DEFINE and CONFIRM WCN 2013 No: 2304 Topic: 6 — MS & Demyelinating Diseases Gastrointestinal tolerability events in relapsing–remitting multiple sclerosis patients treated with BG-12 (dimethyl fumarate): Integrated analysis of DEFINE and CONFIRM E. Havrdova, J.T. Phillips, K. Selmaj, R. Gold, R.J. Fox, G. Giovannoni, A. Pace, M. Novas, N.C. Kurukulasuriya, C. Hotermans, L. Meltzer, K.T. Dawson. Department of Neurology, Charles University in Prague, 1st Abstracts / Journal of the Neurological Sciences 333 (2013) e358–e421 e368