Ray Zhang

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Anti-TWEAK Monoclonal Antibody in Patients With Rheumatoid Arthritis

BACKGROUND Persistent upregulation of signaling by cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) through its receptor fibroblast growth factor-inducible molecule-14 (Fn14) promotes chronic inflammation and tissue destruction. OBJECTIVE The aim of this study was to explore the safety and tolerability of the TWEAK-blocking monoclonal antibody BIIB023 and determine its pharmacokinetics and effects on TWEAK pathway pharmacodynamic markers in rheumatoid arthritis (RA). METHODS Phase I, first-in-human, 2-part, multicenter, double-blind, dose-escalation study. Patients were randomized to a single dose of BIIB023 (0.03-20 mg/kg) (n = 38) or placebo (n = 15) as an add-on to methotrexate. Three open-label cohorts of RA patients taking background disease-modifying antirheumatic drugs and stable tumor necrosis factor (TNF) inhibitor therapy (n = 12) received a single-dose of BIIB023 of 2, 10, or 20 mg/kg and were assessed over 70 days. RESULTS The incidence of treatment-emergent adverse events for the BIIB023 monotherapy cohorts and open-label cohorts of BIIB023 as add-on therapy to TNF inhibitors compared with placebo were 47% and 50% versus 33%, respectively. Serum exposure to BIIB023 increased in a dose-dependent manner from 0.03 to 20 mg/kg, but not in direct proportion to dose level. After administration, the time course of BIIB023 serum concentration was multiphasic and showed expedited elimination when levels decreased to < 10 µg/mL. Serum-soluble TWEAK levels were suppressed at all dose levels by 6 hours post-dose and recovered to baseline between days 7 and 28. A trend toward downward modulation of serum biomarkers of inflammatory response was suggested in monocyte chemoattractant protein 1, inducible protein 10, macrophage inflammatory protein 1β, and tissue inhibitor of metalloproteinase 1 in the BIIB023 group versus placebo. CONCLUSIONS Single-dose BIIB023 showed a favorable safety and tolerability profile in RA. Suppression of serum-soluble TWEAK for ≤ 28 days was observed and downward trends in serum biomarkers suggested.

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.

Efficacy of delayed-release dimethyl fumarate in relapsing-remitting multiple sclerosis: integrated analysis of the phase 3 trials

Obtain a more precise estimate of the efficacy of delayed‐release dimethyl fumarate (DMF; also known as gastro‐resistant DMF) in relapsing multiple sclerosis (MS) and examine the consistency of DMFs effects across patient subgroups stratified by baseline demographic and disease characteristics.

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study

Objective: To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study. Methods: CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort). Results: DMF BID and TID produced significant and consistent reductions vs placebo in the number of new or enlarging T2-hyperintense lesions and new nonenhancing T1-hypointense lesions after 1 and 2 years of treatment and in the number of Gd+ lesions at week 24, year 1, and year 2. Lesion volumes were also significantly reduced. Reductions in brain atrophy and MTR changes with DMF relative to placebo did not reach statistical significance. Conclusions: The robust effects on MRI active lesion counts and total lesion volume in patients with RRMS demonstrate the ability of DMF to exert beneficial effects on inflammatory lesion activity in multiple sclerosis, and support DMF therapy as a valuable new treatment option in RRMS. Classification of evidence: This study provides Class I evidence of reduction in brain lesion number and volume, as assessed by MRI, over 2 years of delayed-release DMF treatment.

Relapses Requiring Intravenous Steroid Use and Multiple-Sclerosis-related Hospitalizations: Integrated Analysis of the Delayed-release Dimethyl Fumarate Phase III Studies.

PURPOSE The purpose was to report the effects of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on the number of relapses requiring intravenous (IV) steroids and multiple sclerosis (MS)-related hospitalizations using integrated data from the Phase III DEFINE and CONFIRM studies. METHODS DEFINE and CONFIRM were randomized, double-blind, placebo-controlled, multicenter studies that evaluated the efficacy and safety of DMF over a 2-year period in patients with relapsing-remitting MS (RRMS). Patients were randomized (1:1:1) to receive oral DMF 240 mg BID or TID, placebo, or glatiramer acetate (CONFIRM only). Eligible subjects (aged 18-55 years) had an EDSS score of 0-5.0 and experienced either ≥1 relapse in the 12 months or had ≥1 gadolinium-enhanced lesion on brain MRI in the 6 weeks, before randomization. Data DEFINE and CONFIRM were pooled and analyzed using a negative binomial regression model (adjusted for study and region). Data obtained after subjects switched to an alternative MS therapy were not included in the analysis. Only relapses confirmed by the Independent Neurology Evaluation Committee were included in the analysis of relapses requiring IV steroids. FINDINGS The study population (intention-to-treat) comprised 2301 patients who received either placebo (n = 771), DMF BID (n = 769), or DMF TID (n = 761). Baseline demographic and disease characteristics were generally well balanced among treatment groups. Throughout the 2-year studies, the total number of relapses treated with methylprednisolone was 402, 221, and 209 in the placebo, DMF BID, and DMF TID groups, respectively. A smaller proportion of patients in the DMF BID (168 of 769 [21.8%]) and DMF TID (151 of 761 [19.8%]) groups experienced ≥1 relapse requiring IV steroids compared with the placebo group (284 of 771 [36.8%]). The total number of MS-related hospitalizations over 2 years was 136, 94, and 74 in the placebo, DMF BID, and DMF TID groups. A smaller proportion of patients in the DMF BID (73 of 769 [9.5%]) and DMF TID (57 of 761 [7.5%]) groups had ≥1 MS-related hospitalization compared with the placebo group (104 of 771 [13.5%]). IMPLICATIONS DMF is an effective and well tolerated therapy for RRMS. In addition to clinical benefits, the use of DMF may be associated with reduced patient burden and health economic savings, resulting from a decrease in resource utilization associated with relapses. ClinicalTrials.gov identifiers: NCT00420212 and NCT00451451.

Safety and Tolerability of Delayed-Release Dimethyl Fumarate Administered with Interferon Beta or Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis

BACKGROUND Delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) is indicated for relapsing multiple sclerosis (MS). The objective of this study was to explore the safety and tolerability of DMF when administered with interferon beta (IFNβ) or glatiramer acetate (GA). METHODS Patients with relapsing-remitting MS receiving established therapy with the same dose of IFNβ or GA for at least 12 months continued their prescribed therapy for 2 months (monotherapy period) and then received DMF 240 mg three times daily in addition to their prescribed MS therapy for 6 months (add-on therapy period). Safety and magnetic resonance imaging outcomes were monitored monthly. RESULTS During the add-on therapy period, in the DMF+IFNβ (n = 57) and DMF+GA (n = 47) groups, the overall incidence of adverse events was 95% and 100%, respectively; the most common adverse events were flushing, diarrhea, and abdominal pain. In both groups, mean lymphocyte counts decreased but remained within normal limits, and hepatic transaminase levels increased transiently; no case met Hys law criteria. There was no overall increased risk of infection. In both groups, gadolinium-enhancing lesion activity and new/enlarging T2 lesions decreased compared with the monotherapy period (exploratory endpoints). CONCLUSIONS The safety profile of DMF taken with IFNβ or GA was acceptable and consistent with the known safety profile of DMF monotherapy.

Evaluation of Disability Progression as an Endpoint in Clinical Trials for Relapsing-Remitting Multiple Sclerosis (RRMS): Comparison of the Define and Confirm Studies

• Several approved therapies have shown results that are inconsistent in terms of statistical significance on this endpoint when evaluated in 2 pivotal RRMS trials for superiority versus the same comparator.4-9 • The estimated effects of a given therapy on this endpoint across trials may be influenced by various factors, including differences in study designs, baseline characteristics of the enrolled populations, and endpoint definitions.10

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