R. Fox
Cleveland ClinicAuthor Of 3 Presentations
FC02.02 - Update on the risk estimates of progressive multifocal leukoencephalopathy related to fingolimod
Abstract
Background
Progressive multifocal leukoencephalopathy (PML) is a serious and potentially fatal complication of some multiple sclerosis (MS) disease-modifying therapies, including fingolimod. Precise estimates and risk stratification tools are not available for fingolimod-related PML.
Objectives
To estimate the global risk of PML in MS patients receiving fingolimod, and to investigate the effect of treatment duration and age on the risk of PML.
Methods
The number of PML cases identified from the manufacturer safety database, attributed to fingolimod by expert adjudication (based on criteria published by Berger et al. in 2014) as of 28 February 2020, was compared with the estimated global number of fingolimod-treated patients at risk (overall, by treatment duration, and by assumed age at fingolimod treatment initiation).
Results
It was estimated that approximately 299,600 patients were treated with fingolimod globally as of 28 February 2020, corresponding to >778,900 patient-years (PYs) of exposure. Of the 188 suspected PML cases reported during fingolimod treatment, 37 confirmed cases were clearly attributed to fingolimod through expert adjudication. In 17 cases, PML was attributed to previous natalizumab treatment. The remaining 134 cases either had inadequate information to confirm the diagnosis of PML or were classified as either possible or not PML. The estimated incidence rate was 4.75 (95% confidence interval [CI]: 3.34; 6.55) per 100,000 PYs. The estimated crude incidence was 0.12 (95% CI: 0.09–0.17) per 1,000 patients. The incidence of PML appears to increase with treatment duration and approach a plateau at approximately 0.13 per 1,000 patients during Year 5, after which data were scarce. Incidence of PML appears to increase between 30 and 50 years of age and then stabilize but the exact shape of the relationship with age is uncertain due to wide CIs, underlying assumptions, and other unknown confounding factors. For both treatment duration and age at treatment initiation, the precision of the incidence estimates was low due to the small number of cases.
Conclusions
PML risk associated with fingolimod is low. Although, the estimated risk of fingolimod-associated PML appears to increase with cumulative exposure, the precise pattern of this relationship remains uncertain. There may be an increase in PML risk with increased age at treatment initiation, although the exact pattern of this possible relationship is also uncertain.
FC02.05 - Safety and Efficacy in Patients Treated With Dimethyl Fumarate and Followed For 13 Years: Final Results of ENDORSE
Abstract
Background
DMF is a well-established therapy for relapsing forms of multiple sclerosis (RMS); data from ENDORSE, an extension to phase 3 studies DEFINE and CONFIRM, has enabled >10 years follow-up.
Objectives
We report safety/efficacy of DMF in patients with RMS treated with DMF and followed for 13 years in ENDORSE (NCT00835770) (2 years DEFINE/CONFIRM, and >10 years ENDORSE).
Methods
Incidence of serious AEs (SAEs), discontinuations due to AEs, annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg BID: placebo (PBO)/DMF (PBO, years 0–2 /DMF, years 3–10) or continuously (DMF/DMF). Efficacy outcomes were assessed in patients up to 10 years due to sample size considerations. For lymphocyte analysis, data from first DMF exposure were analysed for patients in DEFINE/CONFIRM/ENDORSE.
Results
At 23 January 2020, 1736 patients enrolled/received ≥1 dose DMF. Of 1736 patients, 760 completed. Patients were followed for a median (min,max) of 6.76(0.04,10.98) years in ENDORSE, and 2 years in DEFINE/CONFIRM. Overall, 551 (32%) patients experienced SAEs; most were MS relapse and fall. There was one case of PML in this study. There was no increased incidence of other infections or serious infections. Sixteen percent (n=282) patients discontinued due to AEs; 2% relapse, 2% disease progression, and 4% GI disorders. ALC decreased over the first 48 weeks, and then remained generally stable for the majority of the study. The proportion of patients with other AEs of special interest (including opportunistic infection, malignancy, and serious herpes zoster) was similar regardless of ALC. For patients continuously treated (n=501), overall ARR remained low (0.141[95% CI, 0.119,0.167]), while for PBO/DMF patients (n=249) ARR decreased after initiating DMF (ARR 0–2 years, 0.330[95% CI, 0.266,0.408]; ARR overall, 0.149[95% CI, 0.116,0.190]). Overall, 60% of DMF/DMF and 66% of PBO/DMF patients remained relapse-free; 20% and 17% of patients had 1 relapse, respectively. Walking abilities were maintained throughout the study; the number of patients with EDSS scores ≤3.5 was 413/479(86%) DMF/DMF (179/217[82%] PBO/DMF) at Year 2, and 173/226(77%) DMF/DMF (67/90[74%] PBO/DMF) at Year 10. Seventy-two percent and 73% of DMF/DMF and PBO/DMF patients, respectively, had no 24-week confirmed disability progression over 10 years.
Conclusions
These safety and efficacy data in patients followed for 13 years, support DMF as a long-term option for patients with RMS.
SS02.02 - Comparison of COVID-19 outcomes between racial groups in the COViMS registry
Abstract
Background
Risk factors previously identified for worse outcomes with SARS-CoV-2 infections include older age, male sex and specific comorbid conditions. An increased risk for poorer COVID-19 outcomes in people with multiple sclerosis (MS) are similar to the general population, but less is known about outcomes in minority groups with MS.
Objectives
To evaluate differences in outcomes of SARS-CoV-2 infection in non-Hispanic White and Black persons with multiple sclerosis.
Methods
COViMS is a North American registry for health care providers to report persons with MS who are infected with SARS-CoV-2, the virus that causes COVID-19 (cases). Cases are reported after 7 days and when the outcome of infection is reasonably certain. MS and clinically isolated syndrome cases were categorized using the Center for Disease Control and Prevention races (non-Hispanic Whites, and Black). Comorbidities related to COVID-19 outcomes were collected. Clinical outcomes examined were mortality alone, mortality and/or admissions to the intensive care unit (ICU) and mortality, ICU admissions and/or hospitalization. Age-adjusted mortality rates as of August 3, 2020 and 95% confidence intervals (CI) were calculated. Multivariable logistic regression was used to assess adjusted differences between races using odds ratios (OR) and 95% CIs. Covariates included sex, age, smoking (current, past, never), MS clinical course (relapsing, progressive), disease duration, ambulation (fully ambulatory, walks with assistance, non-ambulatory), individual comorbidities (cardiovascular disease, cerebrovascular disease, chronic kidney disease, chronic lung disease, diabetes, hypertension, morbid obesity), and disease modifying therapy use (yes vs no).
Results
Of 734 patients reported, 421 (57.4%) Whites, and 194 (26.5%) Black patients were reported. Black cases were more likely to be younger (p=0.002), never smokers (p=0.002), have shorter MS duration (p<0.001), a relapsing MS course (p=0.03) and have comorbidities (p<0.001) compared to Whites. A higher proportion of Black patients had hypertension (40.2% vs 19.5%, p<0.001), and morbid obesity (17.0% vs 9.5%, p=0.007). Mortality rates increased with age and were not statistically different between Whites and Blacks (p=0.156). Black race was associated with increased odds of mortality and/or ICU admission (OR 3.8 [95%CI: 1.60, 8.96], p=0.002) and mortality, ICU admission and/or hospitalization (OR 2.0 [95%CI: 1.14, 3.54], p=0.016) after adjustment for covariates.
Conclusions
Within the COViMS registry, Black MS patients were younger and more likely to have comorbidities than White MS patients. Black MS patients had an increased risk for poorer outcomes compared to Whites even after adjusting for comorbidities at the time of COVID-19.
Presenter Of 1 Presentation
FC02.02 - Update on the risk estimates of progressive multifocal leukoencephalopathy related to fingolimod
Abstract
Background
Progressive multifocal leukoencephalopathy (PML) is a serious and potentially fatal complication of some multiple sclerosis (MS) disease-modifying therapies, including fingolimod. Precise estimates and risk stratification tools are not available for fingolimod-related PML.
Objectives
To estimate the global risk of PML in MS patients receiving fingolimod, and to investigate the effect of treatment duration and age on the risk of PML.
Methods
The number of PML cases identified from the manufacturer safety database, attributed to fingolimod by expert adjudication (based on criteria published by Berger et al. in 2014) as of 28 February 2020, was compared with the estimated global number of fingolimod-treated patients at risk (overall, by treatment duration, and by assumed age at fingolimod treatment initiation).
Results
It was estimated that approximately 299,600 patients were treated with fingolimod globally as of 28 February 2020, corresponding to >778,900 patient-years (PYs) of exposure. Of the 188 suspected PML cases reported during fingolimod treatment, 37 confirmed cases were clearly attributed to fingolimod through expert adjudication. In 17 cases, PML was attributed to previous natalizumab treatment. The remaining 134 cases either had inadequate information to confirm the diagnosis of PML or were classified as either possible or not PML. The estimated incidence rate was 4.75 (95% confidence interval [CI]: 3.34; 6.55) per 100,000 PYs. The estimated crude incidence was 0.12 (95% CI: 0.09–0.17) per 1,000 patients. The incidence of PML appears to increase with treatment duration and approach a plateau at approximately 0.13 per 1,000 patients during Year 5, after which data were scarce. Incidence of PML appears to increase between 30 and 50 years of age and then stabilize but the exact shape of the relationship with age is uncertain due to wide CIs, underlying assumptions, and other unknown confounding factors. For both treatment duration and age at treatment initiation, the precision of the incidence estimates was low due to the small number of cases.
Conclusions
PML risk associated with fingolimod is low. Although, the estimated risk of fingolimod-associated PML appears to increase with cumulative exposure, the precise pattern of this relationship remains uncertain. There may be an increase in PML risk with increased age at treatment initiation, although the exact pattern of this possible relationship is also uncertain.