We have the top-line results of the MS SMART trial.
This trial compared the effects of riluzole, amiloride and fluoxetine and placebo in secondary progressive MS in a phase II trial.
This indicates that ....
322 - Primary analysis of a randomised, placebo-controlled, phase 2 study of the Bruton's tyrosine kinase inhibitor evobrutinib (M2951) in patients with relapsing multiple sclerosis
Absence of Epstein-Barr virus seronegativity in a large cohort of patients with early multiple sclerosis. S. Abrahamyan et al.
Background: The strong association of multiple sclerosis (MS) and Epstein-Barr virus (EBV) infection raises the question whether there might be EBV seronegative patients with MS at all.
Objective: To determine the rate of EBV seronegativity in a large and well-characterized cohort of patients with a clinically isolated syndrome (CIS) or early relapsing-remitting (RR)MS.
Methods: Epstein-Barr nuclear antigen-1 (EBNA-1) antibodies were measured by a chemiluminescent assay (CLIA) in serum samples of 901 patients (median [interquartile range] age 33 [27-41] years, 69.9% females) with a CIS (n = 380) or early RRMS (n = 521) from the German National MS cohort. In EBNA-1 antibody seronegative patients, antibodies to the EBV viral capsid antigen (VCA) were measured by CLIA. EBNA-1 and VCA antibody double seronegative patients were analysed by an EBV immunoblot.
This trial compared the effects of riluzole, amiloride and fluoxetine and placebo in secondary progressive MS in a phase II trial.
This indicates that ....
324 - MS-SMART Trial: a multi-arm phase 2b randomised, double blind, parallel group, placebo-controlled clinical trial comparing the efficacy of three neuroprotective drugs in secondary progressive multiple sclerosis [NCT01910259]
Background: Reducing the disability gradient in progressive multiple sclerosis is a fundamental aim. A strong therapeutic pipeline at phase 2 is a key part of this work.
Objectives: We aimed to carry out a multi-arm phase 2 trial in secondary progressive multiple sclerosis (SPMS) which would determine if drugs targeting different candidate pathways in the pathobiology of progression, which had early phase 2a success, could reduce whole brain atrophy. The drugs chosen with postulated mechanisms were: amiloride (acid-sensing ion channel-1 antagonist - reducing calcium and sodium influx), fluoxetine (increased production of brain-derived neurotrophic factor; enhanced astrocyte glycogenolysis) and riluzole (reduction in glutamate release; antagonism of voltage gated sodium channels).
Methods: 445 patients with SPMS were randomised 1:1:1:1 to 96 weeks of treatment with amiloride (5mg bd), fluoxetine (20mg bd), riluzole (5mg bd) or matched placebo. The study took place at 13 neuroscience centres around the UK. The major entry criteria were SPMS progressing over at least the previous 2 years, age 25-65 years, EDSS 4.0-6.5, not taking disease modifying treatment, no recent relapse activity or significant depression. Patients, healthcare professionals and those assessing outcomes were blinded to treatment assignment. The primary outcome was the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalization, of Atrophy (SIENA) method. Major Secondary outcomes were: (i) to establish that a multi-arm trial strategy is an efficient way of screening drugs in SPMS. (ii) evaluate anti-inflammatory drug activity using the count of new and enlarging T2 lesions. (iii) examine for evidence of pseudo-atrophy by MRI. (iv) examine for clinical efficacy as measured by clinician and patient reported outcomes.
Results: 557 patients were screened and 445 randomised. The median EDSS was 6.0 (IQR 6.0 to 6.5). Other baseline characteristics were [mean (SD)] age 54 yrs (7), 67% female, MS duration 22 yrs (10), SPMS duration 8 yrs (6), Paced Auditory Serial Addition Test 38.5 (14.8), and Symbol Digit Modalities Test 44.2 (12.4). The 96 week primary and major secondary outcomes will be presented.
Conclusions: A multi-arm strategy is viable, can significantly speed up phase 2 activity and interrogate the biology of progression in vivo.Complicance was about 75% and There was no effect on slowing of brain volume of any agent and so MS SMART was not so SMART as it failedThere was no effect on atrophy There have been negative trials of all three agents since the inception of the study. Very disappointing.However, I say we need to put inhibition of the immune response at the bottom of the pyramid.
Objectives: We aimed to carry out a multi-arm phase 2 trial in secondary progressive multiple sclerosis (SPMS) which would determine if drugs targeting different candidate pathways in the pathobiology of progression, which had early phase 2a success, could reduce whole brain atrophy. The drugs chosen with postulated mechanisms were: amiloride (acid-sensing ion channel-1 antagonist - reducing calcium and sodium influx), fluoxetine (increased production of brain-derived neurotrophic factor; enhanced astrocyte glycogenolysis) and riluzole (reduction in glutamate release; antagonism of voltage gated sodium channels).
Methods: 445 patients with SPMS were randomised 1:1:1:1 to 96 weeks of treatment with amiloride (5mg bd), fluoxetine (20mg bd), riluzole (5mg bd) or matched placebo. The study took place at 13 neuroscience centres around the UK. The major entry criteria were SPMS progressing over at least the previous 2 years, age 25-65 years, EDSS 4.0-6.5, not taking disease modifying treatment, no recent relapse activity or significant depression. Patients, healthcare professionals and those assessing outcomes were blinded to treatment assignment. The primary outcome was the percentage brain volume change (PBVC) between baseline and 96 weeks, derived from structural MR brain imaging data using the Structural Image Evaluation, using Normalization, of Atrophy (SIENA) method. Major Secondary outcomes were: (i) to establish that a multi-arm trial strategy is an efficient way of screening drugs in SPMS. (ii) evaluate anti-inflammatory drug activity using the count of new and enlarging T2 lesions. (iii) examine for evidence of pseudo-atrophy by MRI. (iv) examine for clinical efficacy as measured by clinician and patient reported outcomes.
Results: 557 patients were screened and 445 randomised. The median EDSS was 6.0 (IQR 6.0 to 6.5). Other baseline characteristics were [mean (SD)] age 54 yrs (7), 67% female, MS duration 22 yrs (10), SPMS duration 8 yrs (6), Paced Auditory Serial Addition Test 38.5 (14.8), and Symbol Digit Modalities Test 44.2 (12.4). The 96 week primary and major secondary outcomes will be presented.
Conclusions: A multi-arm strategy is viable, can significantly speed up phase 2 activity and interrogate the biology of progression in vivo.Complicance was about 75% and There was no effect on slowing of brain volume of any agent and so MS SMART was not so SMART as it failedThere was no effect on atrophy There have been negative trials of all three agents since the inception of the study. Very disappointing.However, I say we need to put inhibition of the immune response at the bottom of the pyramid.
COI We were part of the the study
However, we had more positive data with a B cell and macrophage activation inhibitor in active MS
X. Montalban et al.
Background: Evobrutinib (M2951) is a highly specific, irreversible, oral inhibitor of Bruton´s tyrosine kinase (BTK) that functionally impairs activation of B-cells and macrophages in vivo and may be effective in autoimmune disease. This study (NCT02975349) evaluated evobrutinib in clinically and radiologically active RMS.
Methods: In this double-blind, placebo (PBO)-controlled, 48-wk, Ph 2 study, patients (pts) aged 18-65 years with RRMS or SPMS with superimposed relapses were randomised to evobrutinib 25mg QD (QD= ONCE A DAY), 75mg QD, 75mg BID (BID = TWICE A DAY), PBO or open-label dimethyl fumarate (240mg BID; reference arm). The primary endpoint was the sum of T1 Gd+ lesions at wks 12, 16, 20, and 24. Key secondary endpoints included annualised relapse rate (ARR) at wk 24 and safety. Primary analysis (evobrutinib groups versus PBO) was planned when all pts reached 24 wks of treatment or prematurely discontinued.
Results: 243 (91%) of 267 randomised pts completed 24 wks of treatment. Baseline characteristics were balanced across groups. Mean (SD) total T1 Gd+ lesions (wks 12-24) was 4.07 (5.76), 5.23 (12.52), 1.69 (4.69) and 1.39 (3.85) in the PBO, evobrutinib 25mg QD, 75mg QD and 75mg BID groups, respectively. T1 Gd+ lesions per scan were significantly reduced with evobrutinib 75mg QD (lesion rate ratio [RR]=0.38; p=0.01) and 75mg BID (RR=0.48; p=0.05), but not 25mg QD (RR=1.54; p=0.22) vs PBO; a dose-response relationship was seen (p=0.003). A trend towards a reduction in ARR (unadjusted [95% CI]) was seen with evobrutinib 75mg QD (0.13 [0.03-0.38]; p=0.15) and BID (0.08 [0.01-0.30]; p=0.10) vs PBO (0.33 [0.14-0.64]), with evidence of dose-response (p=0.03). Rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were comparable with evobrutinib 25 and 75mg QD and PBO, but higher with evobrutinib 75mg BID (driven by asymptomatic increases in liver transaminases). Grade 3 TEAEs were more frequent with evobrutinib 75mg BID; most were asymptomatic, reversible transaminase elevations with no Hy's Law cases. There were no serious infections with evobrutinib and no other emerging safety signals.
Conclusions: The primary endpoint was met, with evobrutinib 75mg QD and 75mg BID significantly reducing the number of T1 Gd+ lesions vs PBO. In this 24 wk analysis, evobrutinib led to numerical and clinically relevant decreases in ARR, with evidence of a dose response and a manageable safety profile. These data support a role for evobrutinib in MS, warranting evaluation in larger trials.
Methods: In this double-blind, placebo (PBO)-controlled, 48-wk, Ph 2 study, patients (pts) aged 18-65 years with RRMS or SPMS with superimposed relapses were randomised to evobrutinib 25mg QD (QD= ONCE A DAY), 75mg QD, 75mg BID (BID = TWICE A DAY), PBO or open-label dimethyl fumarate (240mg BID; reference arm). The primary endpoint was the sum of T1 Gd+ lesions at wks 12, 16, 20, and 24. Key secondary endpoints included annualised relapse rate (ARR) at wk 24 and safety. Primary analysis (evobrutinib groups versus PBO) was planned when all pts reached 24 wks of treatment or prematurely discontinued.
Results: 243 (91%) of 267 randomised pts completed 24 wks of treatment. Baseline characteristics were balanced across groups. Mean (SD) total T1 Gd+ lesions (wks 12-24) was 4.07 (5.76), 5.23 (12.52), 1.69 (4.69) and 1.39 (3.85) in the PBO, evobrutinib 25mg QD, 75mg QD and 75mg BID groups, respectively. T1 Gd+ lesions per scan were significantly reduced with evobrutinib 75mg QD (lesion rate ratio [RR]=0.38; p=0.01) and 75mg BID (RR=0.48; p=0.05), but not 25mg QD (RR=1.54; p=0.22) vs PBO; a dose-response relationship was seen (p=0.003). A trend towards a reduction in ARR (unadjusted [95% CI]) was seen with evobrutinib 75mg QD (0.13 [0.03-0.38]; p=0.15) and BID (0.08 [0.01-0.30]; p=0.10) vs PBO (0.33 [0.14-0.64]), with evidence of dose-response (p=0.03). Rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were comparable with evobrutinib 25 and 75mg QD and PBO, but higher with evobrutinib 75mg BID (driven by asymptomatic increases in liver transaminases). Grade 3 TEAEs were more frequent with evobrutinib 75mg BID; most were asymptomatic, reversible transaminase elevations with no Hy's Law cases. There were no serious infections with evobrutinib and no other emerging safety signals.
Conclusions: The primary endpoint was met, with evobrutinib 75mg QD and 75mg BID significantly reducing the number of T1 Gd+ lesions vs PBO. In this 24 wk analysis, evobrutinib led to numerical and clinically relevant decreases in ARR, with evidence of a dose response and a manageable safety profile. These data support a role for evobrutinib in MS, warranting evaluation in larger trials.
So another B ell reagent appears to be positive in relapsing MS.
Finally
Everybody with MS has been infected with MS, if you have a negative serology testing using additional metods made this 100%. In the mathed control it was 95%.
Background: The strong association of multiple sclerosis (MS) and Epstein-Barr virus (EBV) infection raises the question whether there might be EBV seronegative patients with MS at all.
Objective: To determine the rate of EBV seronegativity in a large and well-characterized cohort of patients with a clinically isolated syndrome (CIS) or early relapsing-remitting (RR)MS.
Methods: Epstein-Barr nuclear antigen-1 (EBNA-1) antibodies were measured by a chemiluminescent assay (CLIA) in serum samples of 901 patients (median [interquartile range] age 33 [27-41] years, 69.9% females) with a CIS (n = 380) or early RRMS (n = 521) from the German National MS cohort. In EBNA-1 antibody seronegative patients, antibodies to the EBV viral capsid antigen (VCA) were measured by CLIA. EBNA-1 and VCA antibody double seronegative patients were analysed by an EBV immunoblot.
Results: Antibodies to EBNA-1 were detected in 839 of 901 patients with CIS/RRMS. Of the 62 EBNA-1 antibody seronegative patients, 45 had antibodies to VCA. Of the 17 remaining patients, all had antibodies to EBV as detected by EBV immunoblot. Thus, all 901 (100%) patients with CIS/RRMS investigated in this study were EBV seropositive.
Conclusions: The absence of EBV seronegativity in this large cohort of patients with early MS provides further evidence for a crucial role of EBV in MS and suggests that a negative EBV serology in a patient with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
Conclusions: The absence of EBV seronegativity in this large cohort of patients with early MS provides further evidence for a crucial role of EBV in MS and suggests that a negative EBV serology in a patient with suspected inflammatory central nervous system disease should alert clinicians to consider diagnoses other than MS.
So until Next year Bye from ECTRIMS 2018