Effectiveness and safety of opicapone in Parkinson’s disease patients with motor fluctuations: the OPTIPARK open-label study

Background The efficacy and safety of opicapone, a once-daily catechol-O-methyltransferase inhibitor, have been established in two large randomized, placebo-controlled, multinational pivotal trials. Still, clinical evidence from routine practice is needed to complement the data from the pivotal trials. Methods OPTIPARK (NCT02847442) was a prospective, open-label, single-arm trial conducted in Germany and the UK under clinical practice conditions. Patients with Parkinson’s disease and motor fluctuations were treated with opicapone 50 mg for 3 (Germany) or 6 (UK) months in addition to their current levodopa and other antiparkinsonian treatments. The primary endpoint was the Clinician’s Global Impression of Change (CGI-C) after 3 months. Secondary assessments included Patient Global Impressions of Change (PGI-C), the Unified Parkinson’s Disease Rating Scale (UPDRS), Parkinson’s Disease Questionnaire (PDQ-8), and the Non-Motor Symptoms Scale (NMSS). Safety assessments included evaluation of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). Results Of the 506 patients enrolled, 495 (97.8%) took at least one dose of opicapone. Of these, 393 (79.4%) patients completed 3 months of treatment. Overall, 71.3 and 76.9% of patients experienced any improvement on CGI-C and PGI-C after 3 months, respectively (full analysis set). At 6 months, for UK subgroup only (n = 95), 85.3% of patients were judged by investigators as improved since commencing treatment. UPDRS scores at 3 months showed statistically significant improvements in activities of daily living during OFF (mean ± SD change from baseline: − 3.0 ± 4.6, p < 0.0001) and motor scores during ON (− 4.6 ± 8.1, p < 0.0001). The mean ± SD improvements of − 3.4 ± 12.8 points for PDQ-8 and -6.8 ± 19.7 points for NMSS were statistically significant versus baseline (both p < 0.0001). Most of TEAEs (94.8% of events) were of mild or moderate intensity. TEAEs considered to be at least possibly related to opicapone were reported for 45.1% of patients, with dyskinesia (11.5%) and dry mouth (6.5%) being the most frequently reported. Serious TEAEs considered at least possibly related to opicapone were reported for 1.4% of patients. Conclusions Opicapone 50 mg was effective and generally well-tolerated in PD patients with motor fluctuations treated in clinical practice. Trial registration Registered in July 2016 at clinicaltrials.gov (NCT02847442)

Assessing the impact of persistency for disease-modifying therapies in a German registry for multiple sclerosis

Aim: To identify, characterize, and compare outcomes of patients with high persistency (HP) and low persistency (LP). Methods: Study data came from MS disease registry of the doctors-run German NeuroTransData(NTD) network of neurologists and psychiatrists capturing demographic, clinical history, and clinical variables during outpatient visits. Inclusion criteria were patients with RRMS, treatment naïve or 1 switch, and with one future visit after therapy start. Only patients with an index date (i.e., therapy start) after 1 January 2009 were retained.From patient distribution, HP was defined as continuous exposure time of at least two years, while LP was less than two years. Propensity Score Matching was performed on age, sex, relapses, baseline EDSS, and time since MS manifestation for 1 year pre-index. Cox regression was used to compare time to first relapse and time to 12-week confirmed disability progression (CDP). Results: In total, 2,367 patients were matched for HP and LP cohorts. The mean [standard deviation (SD), interquartile range (IQR)] for age was 38.3 (10.7; 29.9-46.4) years, 0.7 relapses in the past year (0.8; 0-1), mean baseline EDSS was 2.0 (1.5;1-3), and symptoms manifestation time was 6.6 years (sd:7.2; 0.96-10.3); 76.2% were females. Mean (SD; IQR) DMT exposure time in years was 0.78 years (0.57;0.29-1.2) for the LP cohort and 4.7 (2.2;2.9-6.2) for the HP cohort.The use of DMTs was: 49.1% on injectables, 40.5% on orals, 2.2% on infusions (excluding monoclonal antibodies) and 8.2% on monoclonal antibodies. Using Cox Regression, the hazard ratio (95% CI) on time to relapse for LP versus HP cohort was 1.4 (1.3-1.5) (Wald p value: < 0.001). For time to first CDP, it was 1.2 (1.0-1.3) (Wald p value: 0.011). Conclusion: HP had better outcomes on time to first relapse than matched LP cohort. The minor difference in CDP risk between two cohorts may be due to 2 years limited follow-up. These findings support the importance of identifying appropriate DMTs for individual patients with due consideration to their underlying disease characteristics in maintaining treatment persistency and improved outcomes

Is there an impact of early initiation of disease-modifying therapies in patients with relapsing-remitting multiple sclerosis in the German registry?

Aim: To compare the characteristics and outcomes of patients who initiate disease modifying treatments (DMTs) early compared to later over a 5-year period. Methods: Data came from NeuroTransData (NTD) MS registry run by a network of Germany-wide neurologists. Study included patients initiating DMTs between Jan 1, 2009, and Oct 1, 2021. Patient cohorts were defined based on the time of initiation of their first DMT relative to the date of RRMS diagnosis: Cohort 1 ( 12 months to 24 months to < 5 years, n=788), and Cohort 4 treatment (more than 5 years, n=1604). Results: There were no meaningful differences in age, time since symptoms manifestation, or EDSS across the cohorts at time of first DMT initiation (index). Relapse activity appeared to be a leading reason for DMT initiation with at least one relapse experienced 1-year pre-index by 43.6% patients in cohort 1 compared to 31.3%, 27.2% and 18.1% of patients in cohorts 2,3,4, respectively. Glatiramer acetate/interferons were most used in cohort 1 (74.4%) and least in cohort 4 (54.5%). The use of other DMTs, including monoclonal antibodies, increased with delayed time to DMT initiation. For cohorts 1 and 2, average (SD) annual relapse rate (ARR) was 0.4 (0.6) and 0.3 (0.6) at year 1 but declined to 0.08 (0.3) and 0.1 (0.3) by year 5, respectively. In vontrast, average ARR mean (SD) was in a narrow range for cohorts 3 [0.1 (0.4)- 0.2 (0.5)] and 4 [0.05 (0.2)-0.1 (0.3)] through the study period. EDSS for patients delaying DMTs numerically worsened than those who initiated early over 5 years [e.g., mean (SD) worsening from 1.3 (1.1) at year 1 to 1.9 (1.6) at year 5 in cohort 3 compared to stable EDSS of 1.5 over 5 years in cohort 1]. EDSS results must be interpreted with caution due to high level of missingness. Conclusions: Neurologists appear to make a reasonable prognosis regarding potential changes in patients’ EDSS status over a 5-year period and whether to initiate treatment or wait and see clinical changes. A potential trade-off with the wait and see approach is that more efficacious treatments are used as initial therapy. Nevertheless, the benefit: risk of such treatments may be an important consideration along with other disease-related factors in individualizing patient treatment decisions

Safety, Patient-Reported Well-Being, and Physician-Reported Assessment of Walking Ability in Patients with Multiple Sclerosis for Prolonged-Release Fampridine Treatment in Routine Clinical Practice: Results of the LIBERATE Study

Background: Prolonged-release fampridine (PR-FAM) 10-mg tablet twice daily is the only approved pharmacological treatment for improvement of walking ability in adults with multiple sclerosis (MS). LIBERATE assessed the safety/effectiveness of PR-FAM in the real-world. Objectives: The aim of this study was to collect additional safety data, including the incidence rate of seizures and other adverse events (AEs) of interest, from patients with MS taking PR-FAM in routine clinical practice (including patients aged ≥ 65 years and those with pre-existing cardiovascular risk factors). Other objectives included change over time in patient-reported evaluation of physical and psychological impact of MS while taking PR-FAM, and change over time in physician-reported assessment of walking ability in MS patients taking PR-FAM. Methods: Patients with MS newly prescribed PR-FAM were recruited (201 sites, 13 countries). Demographic/safety data were collected at enrolment through 12 months. Physician-rated Clinical Global Impression of Improvement (CGI-I) scores for walking ability, and Multiple Sclerosis Impact Scale-29 (MSIS-29) were assessed. Results: Safety analysis included 4646 patients with 3534.8 patient-years of exposure; median (range) age, 52.6 (21–85) years, 87.3% < 65 years, and 65.7% women. Treatment-emergent AEs (TEAEs) were reported in 2448 (52.7%) patients, and serious TEAEs were reported in 279 (6.0%) patients, of whom 37 (< 1%) experienced treatment-emergent serious AEs (TESAEs) considered related to PR-FAM. AEs of special interest (AESI) occurred in 1799 (38.7%) patients, and serious AESI in 128 (2.8%) patients. Seventeen (< 1%) patients experienced actual events of seizure. Overall, 1158 (24.9%) patients discontinued treatment due to lack of efficacy. At 12 months, a greater proportion of patients on-treatment had improvement from baseline in CGI-I for walking ability versus those who discontinued (61% vs. 11%; p < 0.001). MSIS-29 physical impact score improved significantly for patients on-treatment for 12 months versus those who discontinued (mean change, baseline to 12 months: − 9.99 vs. − 0.34 points; p < 0.001). Results were similar for MSIS-29 psychological impact. Conclusion: No new safety concerns were identified in this real-world study, suggesting that routine risk-minimization measures are effective. CGI-I and MSIS-29 scores after 12 months treatment with PR-FAM treatment show clinical benefits consistent with those previously reported. Trial Registration: ClinicalTrials.gov: NCT01480063

The Multiple Sclerosis Data Alliance Catalogue Enabling Web-Based Discovery of Metadata from Real-World Multiple Sclerosis Data Sources

Background: One of the major objectives of the Multiple Sclerosis Data Alliance (MSDA) is to enable better discovery of multiple sclerosis (MS) real-world data (RWD). Methods: We implemented the MSDA Catalogue, which is available worldwide. The current version of the MSDA Catalogue collects descriptive information on governance, purpose, inclusion criteria, procedures for data quality control, and how and which data are collected, including the use of e-health technologies and data on collection of COVID-19 variables. The current cataloguing procedure is performed in several manual steps, securing an effective catalogue. Results: Herein we summarize the status of the MSDA Catalogue as of January 6, 2021. To date, 38 data sources across five continents are included in the MSDA Catalogue. These data sources differ in purpose, maturity, and variables collected, but this landscaping effort shows that there is substantial alignment on some domains. The MSDA Catalogue shows that personal data and basic disease data are the most collected categories of variables, whereas data on fatigue measurements and cognition scales are the least collected in MS registries/cohorts. Conclusions: The Web-based MSDA Catalogue provides strategic overview and allows authorized end users to browse metadata profiles of data cohorts and data sources. There are many existing and arising RWD sources in MS. Detailed cataloguing of MS RWD is a first and useful step toward reducing the time needed to discover MS RWD sets and promoting collaboration. Int J MS Care. 2021;23:261-268

Ofatumumab versus Teriflunomide in Multiple Sclerosis

BACKGROUND: Ofatumumab, a subcutaneous anti-CD20 monoclonal antibody, selectively depletes B cells. Teriflunomide, an oral inhibitor of pyrimidine synthesis, reduces T-cell and B-cell activation. The relative effects of these two drugs in patients with multiple sclerosis are not known. METHODS: In two double-blind, double-dummy, phase 3 trials, we randomly assigned patients with relapsing multiple sclerosis to receive subcutaneous ofatumumab (20 mg every 4 weeks after 20-mg loading doses at days 1, 7, and 14) or oral teriflunomide (14 mg daily) for up to 30 months. The primary end point was the annualized relapse rate. Secondary end points included disability worsening confirmed at 3 months or 6 months, disability improvement confirmed at 6 months, the number of gadolinium-enhancing lesions per T1-weighted magnetic resonance imaging (MRI) scan, the annualized rate of new or enlarging lesions on T2-weighted MRI, serum neurofilament light chain levels at month 3, and change in brain volume. RESULTS: Overall, 946 patients were assigned to receive ofatumumab and 936 to receive teriflunomide; the median follow-up was 1.6 years. The annualized relapse rates in the ofatumumab and teriflunomide groups were 0.11 and 0.22, respectively, in trial 1 (difference, -0.11; 95% confidence interval [CI], -0.16 to -0.06; P<0.001) and 0.10 and 0.25 in trial 2 (difference, -0.15; 95% CI, -0.20 to -0.09; P<0.001). In the pooled trials, the percentage of patients with disability worsening confirmed at 3 months was 10.9% with ofatumumab and 15.0% with teriflunomide (hazard ratio, 0.66; P = 0.002); the percentage with disability worsening confirmed at 6 months was 8.1% and 12.0%, respectively (hazard ratio, 0.68; P = 0.01); and the percentage with disability improvement confirmed at 6 months was 11.0% and 8.1% (hazard ratio, 1.35; P = 0.09). The number of gadolinium-enhancing lesions per T1-weighted MRI scan, the annualized rate of lesions on T2-weighted MRI, and serum neurofilament light chain levels, but not the change in brain volume, were in the same direction as the primary end point. Injection-related reactions occurred in 20.2% in the ofatumumab group and in 15.0% in the teriflunomide group (placebo injections). Serious infections occurred in 2.5% and 1.8% of the patients in the respective groups. CONCLUSIONS: Among patients with multiple sclerosis, ofatumumab was associated with lower annualized relapse rates than teriflunomide. (Funded by Novartis; ASCLEPIOS I and II ClinicalTrials.gov numbers, NCT02792218 and NCT02792231.)