scholarly journals Diroximel Fumarate Demonstrates an Improved Gastrointestinal Tolerability Profile Compared with Dimethyl Fumarate in Patients with Relapsing–Remitting Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III EVOLVE-MS-2 Study

CNS Drugs ◽  
2020 ◽  
Vol 34 (2) ◽  
pp. 185-196 ◽  
Author(s):  
Robert T. Naismith ◽  
◽  
Annette Wundes ◽  
Tjalf Ziemssen ◽  
Elzbieta Jasinska ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dimethyl Fumarate ◽  
Phase Iii ◽  
Tolerability Profile ◽  
Double Blind ◽  
Relapsing Remitting ◽  
Gastrointestinal Tolerability ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

Randomized, double-blind, placebo-controlled study of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis: a categorical disability trend analysis

2002 ◽  
Vol 8 (1) ◽  
pp. 10-14 ◽  
Author(s):  
C Liu ◽  
L D Blumhardt
Keyword(s):  
Multiple Sclerosis ◽  
Disease Duration ◽  
Significant Proportion ◽  
Phase Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Immunomodulatory Therapies

The treatment effects of recent immunomodulatory therapies on disease progression in relapsing-remitting multiple sclerosis (MS) have been mostly established from ‘confirmed progression’ endpoints. However, the reliability of this outcome measure is poor and a significant proportion of patients may be erroneously classified. We previously proposed the area under disability/time curves to quantify in-trial disability changes, but although these have advantages, they lack information on the direction of change. We have therefore performed disease trend analyses and categorical classifications using serial Expanded Disability Status Scale (EDSS) scores from the 533 complete datasets in a double-blind, randomized, placebo-controlled, phase III trial of subcutaneous interferon β-1a (IFNβ-1a) (PRISMS study). We found significant treatment benefits for IFNβ-1a on in-trial disability course (P=0.002). Therapeutic advantages remained when relapse-related assessments were excluded (P=0.018). Post hoc analyses demonstrated that IFNβ-1a was mainly effective in both increasing the proportion of patients with a ‘stable’ course and reducing those with prolonged, disabling deteriorations. Baseline disease duration and EDSS levels, but not MRI lesion load, predicted the subsequent disability trends. Mean ‘numbers needed to treat’ (NNTs) to obtain preferred disability courses were reduced in patients with shorter disease duration. These results have important implications for the targeting of immunomodulatory therapies in MS.

scholarly journals Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: Final ENDORSE study results

2021 ◽  
pp. 135245852110379
Author(s):  
Ralf Gold ◽  
Douglas L Arnold ◽  
Amit Bar-Or ◽  
Robert J Fox ◽  
Ludwig Kappos ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Adverse Events ◽  
Dimethyl Fumarate ◽  
Phase Iii ◽  
Study Results ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis

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.

Randomized, double-blind, placebo-controlled study of subcutaneous interferon beta-Ia in relapsing-remitting multiple sclerosis: a categorical disability trend analysis

2002 ◽  
Vol 8 (1_suppl) ◽  
pp. 10-14 ◽  
Author(s):  
C. Liu ◽  
LD Blumhardt
Keyword(s):  
Multiple Sclerosis ◽  
Disease Duration ◽  
Significant Proportion ◽  
Phase Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Relapsing Remitting Multiple Sclerosis ◽  
Immunomodulatory Therapies

The treatment effects of recent immunomodulatory therapies on disease progression in relapsing-remitting multiple sclerosis (MS) have been mostly established from 'confirmed progression' endpoints. However, the reliability of this outcome measure is poor and a significant proportion of patients may be erroneously classified. We previously proposed the area under disability/time curves to quantify in-trial disability changes, but although these have advantages, they lack information on the direction of change. We have therefore performed disease trend analyses and categorical classifications using serial Expanded Disability Status Scale (EDSS) scores from the 533 complete datasets in a double-blind, randomized, placebo-controlled, phase III trial of subcutaneous interferon β-1a (IFNβ-1a) (PRISMS study). We found significant treatment benefits for IFNβ-1a on in-trial disability course (P=0.002). Therapeutic advantages remained when relapse-related assessments were excluded (P=0.018). Post hoc analyses demonstrated that IFNβ-la was mainly effective in both increasing the proportion of patients with a 'stable' course and reducing those with prolonged, disabling deteriorations. Baseline disease duration and EDSS levels, but not MRI lesion load, predicted the subsequent disability trends. Mean 'numbers needed to treat' (NNTs) to obtain preferred disability courses were reduced in patients with shorter disease duration. These results have important implications for the targeting of immunomodulatory therapies in MS. Multiple Sclerosis (2002) 8, 10-14

scholarly journals Diroximel fumarate (DRF) in patients with relapsing–remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study

2019 ◽  
Vol 26 (13) ◽  
pp. 1729-1739 ◽  
Author(s):  
Robert T Naismith ◽  
Jerry S Wolinsky ◽  
Annette Wundes ◽  
Christopher LaGanke ◽  
Douglas L Arnold ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dimethyl Fumarate ◽  
Tolerability Profile ◽  
Open Label ◽  
Phase 3 ◽  
Relapsing Remitting ◽  
Remitting Multiple Sclerosis ◽  
Monomethyl Fumarate ◽  
Favorable Safety ◽  
Relapsing Remitting Multiple Sclerosis

Background: Diroximel fumarate (DRF) is a novel oral fumarate for patients with relapsing–remitting multiple sclerosis (RRMS). DRF and the approved drug dimethyl fumarate yield bioequivalent exposure to the active metabolite monomethyl fumarate; thus, efficacy/safety profiles are expected to be similar. However, DRF’s distinct chemical structure may result in a differentiated gastrointestinal (GI) tolerability profile. Objective: To report interim safety/efficacy findings from patients in the ongoing EVOLVE-MS-1 study. Methods: EVOLVE-MS-1 is an ongoing, open-label, 96-week, phase 3 study assessing DRF safety, tolerability, and efficacy in RRMS patients. Primary endpoint is safety and tolerability; efficacy endpoints are exploratory. Results: As of March 2018, 696 patients were enrolled; median exposure was 59.9 (range: 0.1–98.9) weeks. Adverse events (AEs) occurred in 84.6% (589/696) of patients; the majority were mild (31.2%; 217/696) or moderate (46.8%; 326/696) in severity. Overall treatment discontinuation was 14.9%; 6.3% due to AEs and <1% due to GI AEs. At Week 48, mean number of gadolinium-enhancing lesions was significantly reduced from baseline (77%; p < 0.0001) and adjusted annualized relapse rate was low (0.16; 95% confidence interval: 0.13–0.20). Conclusion: Interim data from EVOLVE-MS-1 suggest DRF is a well-tolerated treatment with a favorable safety/efficacy profile for patients with RRMS.

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