No difference in radiologic outcomes for natalizumab patients treated with extended interval dosing compared with standard interval dosing: Real-world evidence from MS PATHS

BACKGROUND: Extended interval dosing (EID; average dosing interval approximately every 6 weeks) of natalizumab is associated with significantly lower risk of progressive multifocal leukoencephalopathy than standard interval dosing (SID; every 4 weeks) in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies, though limited, suggest that natalizumab effectiveness is generally maintained in patients who switch to EID after initiation of stable treatment with SID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a collaborative, multicenter learning health system that generates real-world clinical and MRI data using highly standardized acquisition protocols. We compared MRI outcomes in MS PATHS patients treated with natalizumab EID versus SID. We also compared MRI outcomes in patients treated with natalizumab (EID and/or SID) versus injectable MS platform therapy. METHODS: Natalizumab infusion data from the TOUCH Prescribing Program database and MS PATHS MRI assessment data from seven US sites as of July 23, 2020, were used to identify patients with relapsing-remitting MS who had received natalizumab EID or SID in the interval between two MRI scans (an MRI segment). Patients who received injectable platform MS therapy between two MRI scans were also identified. MRI data were used to determine the incidence rate and odds of developing new or enlarging T2 lesions, annualized percentage change in T2 lesion volume (T2LV), and annualized percentage change in brain parenchymal fraction (BPF). MRI outcomes were compared for 1) natalizumab EID treatment versus natalizumab SID treatment, 2) natalizumab treatment (EID + SID) versus platform therapy, and 3) natalizumab EID versus platform therapy. Propensity score-based weighting or matching were used to balance covariates at the start of MRI segments for all comparisons. RESULTS: The MRI outcomes observed with natalizumab EID treatment did not differ significantly from those observed with natalizumab SID treatment. The odds ratio for any new or enlarging T2 lesion was 1.07 (95% confidence interval [CI]: 0.93, 1.24; p = 0.355), and the rate ratio (95% CI) for new or enlarging T2 lesions was 1.62 (0.93, 2.82; p = 0.090). Differences (95% CI) between EID and SID patients in mean annualized percentage change in T2LV and BPF were 1.56% (-3.77%, 6.90%; p = 0.566) and -0.11% (-0.25%, -0.10%; p = 0.096), respectively. Conversely, when MRI outcomes in natalizumab and platform therapy patients were compared, there were significant differences favoring natalizumab in all assessments: the odds of any new or enlarging T2 lesion (odds ratio: 0.69 [95% CI: 0.64, 0.75]; p\u3c0.001), the incidence rate of new or enlarging T2 lesions (rate ratio: 0.47 [95% CI: 0.37, 0.61]; p\u3c0.001), annualized percentage change (decrease) in T2LV (difference: -3.68% [95% CI: -7.06%, -0.30%]; p = 0.033), and annualized percentage change (increase) in BPF (difference: 0.22% [95% CI: 0.16%, 0.29%]; p\u3c0.001). Results of the subgroup comparison of natalizumab EID patients with platform therapy patients were similar to those of the overall-natalizumab-group-versus-platform-therapy comparison. CONCLUSIONS: The results indicate that natalizumab EID and SID provide comparable real-world effectiveness on quantitative MRI metrics. These data further demonstrate that natalizumab EID can provide superior real-world effectiveness to injectable platform therapy on quantitative MRI metrics

Efficacy and tolerability of dimethyl fumarate in White-, African- and Hispanic- Americans with multiple sclerosis

Background: Dimethyl fumarate (DMF) was approved by the US Food and Drug Administration (FDA) for treatment of relapsing–remitting multiple sclerosis (RRMS) based on two phase III randomized clinical trials (RCTs). There were not enough non-White patients enrolled in these RCTs to allow for subgroup analysis based on race. Efficacy and tolerability of DMF therapy across various racial groups is unknown. Methods: Retrospective chart review was performed on all patients with RRMS who were started on DMF in two tertiary multiple sclerosis (MS) clinics. Efficacy and tolerability of DMF was compared across three self-identified racial groups: White-American (WA), African-American (AA) and Hispanic-American (HA). Results: A total of 390 RRMS patients were included in the study: 261 (66.9%) WA, 69 (17.7%) AA and 52 (13.3%) HA. When comparing ‘pre-DMF’ (1 year) and ‘on DMF’ (mean follow up of 14 months) periods, statistically significant reduction in rates of annualized relapses (WA from 0.44 to 0.19, AA from 0.39 to 0.15, and HA from 0.39 to 0.14; no differences between groups), new T2 lesions (WA from 45% to 23%, AA from 39% to 23%, HA from 52% to 26%; no difference between groups), and Gd+ lesions (WA from 25% to 13%, AA from 24% to 7%, HA from 23% to 12%; no difference between groups) were seen. DMF was relatively well tolerated across all groups, with an overall discontinuation rate of 20% (no difference between the three groups). Conclusion: Efficacy of DMF in our clinic population did not differ across three major ethnic groups, WA, AA and HA, and was comparable with results observed in the pivotal studies. These ‘real-life’ data suggest that race is not a factor that needs to be taken into account when initiating DMF

Nocturia in Patients With Multiple Sclerosis.

International audienceThe prevalence of nocturia in patients with multiple sclerosis (MS) is high, ranging from 20.9% to 48.8% in this population. Its underlying pathophysiology is complex and different from the non-neurogenic population. In the MS population, the pathophysiology may involve neurogenic lower urinary tract dysfunction (NLUTD) such as detrusor overactivity (NDO), detrusor-sphincter dyssynergia, or detrusor underactivity resulting in reduced bladder capacity. Nocturnal polyuria is also a significant contributor to the pathogenesis of nocturia in MS patients and may be the result of specific mechanisms such as nocturnal hypertension through autonomic cardiovascular dysfunction or lack of diurnal variation of antidiuretic hormone production (ADH) due to demyelinating lesions of the spinal cord. Nocturia might be particularly burdensome in MS patients by contributing to fatigue, a common and highly debilitating symptom in this population. There is likely a complex and multidirectional relationship between nocturia, other sleep disorders, and fatigue in the MS population that has yet to be explored. The assessment of nocturia in MS should rely upon a thorough history and physical examination. Urinalysis should be done to rule out urinary tract infection, a frequency-volume chart might help elucidating the underlying mechanisms, and post-void residual volume may be of interest to screen for urinary retention that could be asymptomatic in MS patients. Other tests such as urodynamics or polysomnography are indicated in selected patients. The treatment should be tailored to the underlying cause. The first steps involve behavioral interventions and treatment of cofactors. When possible, the predominant mechanism should be addressed first. In case of predominant NDO, antimuscarinics and beta-3 agonists should be offered as a first-line treatment and intradetrusor injections of botulinum toxin as a second-line treatment. In cases of incomplete bladder emptying, clean-intermittent self-catheterization is often used as part of multiple other interventions. In cases of nocturnal polyuria, desmopressin may be offered, inclusive of use of newer formulations (desmopressin acetate nasal spray, desmopressin orally disintegrated tablet) in countries where they are approved

Nocturia in Patients With Multiple Sclerosis.

International audienceThe prevalence of nocturia in patients with multiple sclerosis (MS) is high, ranging from 20.9% to 48.8% in this population. Its underlying pathophysiology is complex and different from the non-neurogenic population. In the MS population, the pathophysiology may involve neurogenic lower urinary tract dysfunction (NLUTD) such as detrusor overactivity (NDO), detrusor-sphincter dyssynergia, or detrusor underactivity resulting in reduced bladder capacity. Nocturnal polyuria is also a significant contributor to the pathogenesis of nocturia in MS patients and may be the result of specific mechanisms such as nocturnal hypertension through autonomic cardiovascular dysfunction or lack of diurnal variation of antidiuretic hormone production (ADH) due to demyelinating lesions of the spinal cord. Nocturia might be particularly burdensome in MS patients by contributing to fatigue, a common and highly debilitating symptom in this population. There is likely a complex and multidirectional relationship between nocturia, other sleep disorders, and fatigue in the MS population that has yet to be explored. The assessment of nocturia in MS should rely upon a thorough history and physical examination. Urinalysis should be done to rule out urinary tract infection, a frequency-volume chart might help elucidating the underlying mechanisms, and post-void residual volume may be of interest to screen for urinary retention that could be asymptomatic in MS patients. Other tests such as urodynamics or polysomnography are indicated in selected patients. The treatment should be tailored to the underlying cause. The first steps involve behavioral interventions and treatment of cofactors. When possible, the predominant mechanism should be addressed first. In case of predominant NDO, antimuscarinics and beta-3 agonists should be offered as a first-line treatment and intradetrusor injections of botulinum toxin as a second-line treatment. In cases of incomplete bladder emptying, clean-intermittent self-catheterization is often used as part of multiple other interventions. In cases of nocturnal polyuria, desmopressin may be offered, inclusive of use of newer formulations (desmopressin acetate nasal spray, desmopressin orally disintegrated tablet) in countries where they are approved

Exploratory clinical efficacy and patient-reported outcomes from NOVA: A randomized controlled study of intravenous natalizumab 6-week dosing versus continued 4-week dosing for relapsing-remitting multiple sclerosis

Background: Natalizumab (TYSABRI®) 300 mg administered intravenously every-4-weeks (Q4W) is approved for treatment of relapsing-remitting multiple sclerosis but is associated with increased risk of progressive multifocal leukoencephalopathy (PML). Extended natalizumab dosing intervals of approximately every-6-weeks (Q6W) are associated with a lower risk of PML. Primary and secondary clinical outcomes from the NOVA randomized clinical trial (NCT03689972) suggest that effective disease control is maintained in patients who were stable during treatment with natalizumab Q4W for ≥12 months and who then switched to Q6W dosing. We compared additional exploratory clinical and patient-reported outcomes (PROs) from NOVA to assess the efficacy of Q6W dosing. Methods: Prespecified exploratory clinical efficacy endpoints in NOVA included change from baseline in Expanded Disability Status Scale (EDSS) score, Timed 25-Foot Walk (T25FW), dominant- and nondominant-hand 9-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT). Exploratory patient-reported outcome (PRO) efficacy endpoints included change from baseline in the Treatment Satisfaction Questionnaire for Medication (TSQM), Neuro-QoL fatigue questionnaire, Multiple Sclerosis Impact Scale (MSIS-29), EuroQol 5 Dimensions (EQ-5D-5 L) index score, Clinical Global Impression (CGI)–Improvement (patient- and clinician-assessed) and CGI-Severity (clinician-assessed) rating scales. Estimated proportions of patients with confirmed EDSS improvement were based on Kaplan-Meier methods. Estimates of mean treatment differences for Q6W versus Q4W in other outcomes were assessed by least squares mean (LSM) and analyzed using a linear mixed model of repeated measures or ordinal logistic regression (CGI-scale). Results: Exploratory clinical and patient-reported outcomes were assessed in patients who received ≥1 dose of randomly assigned study treatment and had ≥1 postbaseline efficacy assessment (Q6W group, n = 247, and Q4W group, n = 242). Estimated proportions of patients with EDSS improvement at week 72 were similar for Q6W and Q4W groups (11.7% [19/163] vs 10.8% [17/158]; HR 1.02 [95% confidence interval [CI], 0.53–1.98]; P = 0.9501). At week 72, there were no significant differences between Q6W and Q4W groups in LSM change from baseline for T25FW (0.00, P = 0.975), 9HPT (dominant [0.22, P = 0.533] or nondominant [0.09, P = 0.862] hand), or SDMT (−1.03, P = 0.194). Similarly, there were no significant differences between Q6W and Q4W groups in LSM change from baseline for any PRO (TSQM, −1.00, P = 0.410; Neuro-QoL fatigue, 0.52, P = 0.292; MSIS-29 Psychological, 0.67, P = 0.572; MSIS-29 Physical, 0.74, P = 0.429; EQ-5D-5 L, 0.00, P = 0.978). For the EQ-5D-5 L, a higher proportion of Q6W patients than Q4W patients demonstrated worsening (≥0.5 standard deviation increase in the EQ-5D-5 L index score; P = 0.0475). From baseline to week 72 for Q6W versus Q4W, odds ratio (ORs) of LSM change in CGI scores did not show meaningful differences between groups (CGI-Improvement [patient]: OR [95% CI] 1.2 [0.80–1.73]; CGI-Improvement [physician]: 0.8 [0.47–1.36]; CGI-Severity [physician]: 1.0 [0.71–1.54]). Conclusions: No significant differences were observed in change from baseline to week 72 between natalizumab Q6W and Q4W groups for all exploratory clinical or PRO-related endpoints assessed. For the EQ-5D-5 L, a higher proportion of Q6W than Q4W patients demonstrated worsening

Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial

Background: Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis. Methods: We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18–60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972. Findings: Between Dec 26, 2018, and Aug 30, 2019, 605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0·20 (95% CI 0·07–0·63) in the once every 6 weeks group and 0·05 (0·01–0·22) in the once every 4 weeks group (mean lesion ratio 4·24 [95% CI 0·86–20·85]; p=0·076) under the primary estimand, and 0·31 (95% CI 0·12–0·82) and 0·06 (0·01–0·31; mean lesion ratio 4·93 [95% CI 1·05–23·20]; p=0·044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (≥25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic. Interpretation: We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Funding: Biogen

Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial

Background Treatment with natalizumab once every 4 weeks is approved for patients with relapsing-remitting multiple sclerosis, but is associated with a risk of progressive multifocal leukoencephalopathy. Switching to extended-interval dosing is associated with lower progressive multifocal leukoencephalopathy risk, but the efficacy of this approach is unclear. We aimed to assess the safety and efficacy of natalizumab once every 6 weeks compared with once every 4 weeks in patients with relapsing-remitting multiple sclerosis.Methods We did a randomised, controlled, open-label, phase 3b trial (NOVA) at 89 multiple sclerosis centres across 11 countries in the Americas, Europe, and Western Pacific. Included participants were aged 18-60 years with relapsing-remitting multiple sclerosis and had been treated with intravenous natalizumab 300 mg once every 4 weeks with no relapses for at least 12 months before randomisation, with no missed doses in the previous 3 months. Participants were randomly assigned (1:1), using a randomisation sequence generated by the study funder and contract personnel with interactive response technology, to switch to natalizumab once every 6 weeks or continue with once every 4 weeks. The centralised MRI reader, independent neurology evaluation committee, site examining neurologists, site backup examining neurologists, and site examining technicians were masked to study group assignments. The primary endpoint was the number of new or newly enlarging T2 hyperintense lesions at week 72, assessed in all participants who received at least one dose of assigned treatment and had at least one postbaseline MRI, relapse, or neurological examination or efficacy assessment. Missing primary endpoint data were handled under prespecified primary and secondary estimands: the primary estimand included all data, regardless of whether participants remained on the assigned treatment; the secondary estimand classed all data obtained after treatment discontinuation or study withdrawal as missing. Safety was assessed in all participants who received at least one dose of study treatment. Study enrolment is closed and an open-label extension study is ongoing. This study is registered with EudraCT, 2018-002145-11, and ClinicalTrials.gov, NCT03689972.Findings Between Dec 26, 2018, and Aug 30,2019,605 patients were assessed for eligibility and 499 were enrolled and assigned to receive natalizumab once every 6 weeks (n=251) or once every 4 weeks (n=248). After prespecified adjustments for missing data, mean numbers of new or newly enlarging T2 hyperintense lesions at week 72 were 0.20 (95% CI 0.07-0-63) in the once every 6 weeks group and 0.05 (0.01-0-22) in the once every 4 weeks group (mean lesion ratio 4.24 [95% CI 0.86-20-85]; p=0.076) under the primary estimand, and 0.31 (95% CI 0.12-0-82) and 0.06 (0.01-0-31; mean lesion ratio 4.93 [95% CI 1.05-23.20]; p=0.044) under the secondary estimand. Two participants in the once every 6 weeks group with extreme new or newly enlarging T2 hyperintense lesion numbers (>= 25) contributed most of the excess lesions. Adverse events occurred in 194 (78%) of 250 participants in the once every 6 weeks group and 190 (77%) of 247 in the once every 4 weeks group, and serious adverse events occurred in 17 (7%) and 17 (7%), respectively. No deaths were reported. There was one case of asymptomatic progressive multifocal leukoencephalopathy (without clinical signs) in the once every 6 weeks group, and no cases in the once every 4 weeks group; 6 months after diagnosis, the participant was without increased disability and remained classified as asymptomatic.Interpretation We found a numerical difference in the mean number of new or newly enlarging T2 hyperintense lesions at week 72 between the once every 6 weeks and once every 4 weeks groups, which reached significance under the secondary estimand, but interpretation of statistical differences (or absence thereof) is limited because disease activity in the once every 4 weeks group was lower than expected. The safety profiles of natalizumab once every 6 weeks and once every 4 weeks were similar. Although this trial was not powered to assess differences in risk of progressive multifocal leukoencephalopathy, the occurrence of the (asymptomatic) case underscores the importance of monitoring and risk factor consideration in all patients receiving natalizumab. Copyright (C) 2022 Elsevier Ltd. All rights reserved