Tysabri Observational Program Research Articles

014 Long-term effectiveness of natalizumab for RRMS: UK and global interim results from TYSABRI observational program

IntroductionThe TYSABRI Observational Program (TOP) is a large, ongoing observational study in relapsing- remitting multiple sclerosis (RRMS) patients treated with natalizumab. Country-specific data on relapse and disability outcomes, alongside global data, can provide information on natalizumab’s effectiveness in local practice.MethodsAnnualised relapse rate (ARR) and cumulative probability of 24-week confirmed disability worsening (CDW; increase in Expanded Disability Status Scale [EDSS] score ≥1.5 from a baseline of 0.0,≥1.0 from a baseline between 1.0–5.5, or ≥0.5 from a baseline of ≥6.0) and improvement (CDI; decrease≥1.0 from a baseline EDSS score ≥2.0) were analysed in TOP UK (n=134) and global (N=6295) cohorts using data from July 2007 to November 2018. Updated data (as of November 2019) will be presented.ResultsARR decreased in UK patients from 2.21 in the year before initiation to 0.19 on natalizumab (P<0.0001), consistent with a global decrease from 2.00 to 0.21 (P<0.0001). At 7 years, probabilities of CDW and CDI were, respectively, 26.2% and 35.3% in UK patients and 27.9% and 32.1% globally.ConclusionsThese TOP UK results show disease control that is generally consistent with global TOP results, supporting natalizumab’s long-term effectiveness in real-world settings.SupportBiogen. Disclosures: Included on the poster.richard.nicholas@btinternet.com

023 Relapse outcomes with natalizumab Q4W vs switch to Q6W

IntroductionThe approved dosing of natalizumab (300 mg infusion every 4 weeks [Q4W]) is associated with risk of progressive multifocal leukoencephalopathy. This analysis from the TYSABRI Observational Program (TOP) compared relapse outcomes in patients who switched to natalizumab every 6 weeks (Q6W) after 1 year of Q4W with patients who remained on Q4W.MethodsEligible TOP patients had ≥1 year of natalizumab Q4W. Treatment duration-matched Q6W and Q4W patients (191 pairs) were compared by propensity score matching (PSM). Negative binomial model-estimated annualised relapse rate (ARR) and Kaplan-Meier-estimated relapse risk were compared during the post-switch and exposure-matched follow-up periods.ResultsAfter PSM, 135 pairs of Q6W and Q4W patients were included. Mean treatment duration was4.4 years in both groups. There was no difference in ARR (Q6W: 0.231 [95% confidence interval (CI), 0.145–0.367]; Q4W: 0.254 [0.160–0.402]; P=0.774) or relapse risk (hazard ratio [95% CI], 1.021 [0.583–1.789]; P=0.940) between groups.ConclusionsNo significant difference in relapse outcomes was observed between patients who switched4t6o Q6W and those who remained on Q4W. An ongoing randomized prospective trial of Q4W vs Q6W will inform further on the effectiveness of natalizumab Q6W. Support: Biogen.peiran.ho@biogen.com

Conversion to Non-Active Secondary Progressive Multiple Sclerosis (SPMS) in Patients Who Discontinued or Remained on Natalizumab in the Real-World TYSABRI Observational Program (TOP) (2505)

Conversion to Non-Active Secondary Progressive Multiple Sclerosis (SPMS) in Patients Who Discontinued or Remained on Natalizumab in the Real-World TYSABRI Observational Program (TOP) (2505)

No evidence for loss of natalizumab effectiveness with every-6-week dosing: a propensity score–matched comparison with every-4-week dosing in patients enrolled in the Tysabri Observational Program (TOP)

Background:Extended interval dosing of natalizumab is associated with significantly lower progressive multifocal leukoencephalopathy risk compared with every-4-week (Q4W) dosing in patients with relapsing-remitting multiple sclerosis. Previous studies have suggested that natalizumab effectiveness is maintained in patients who switch from Q4W to extended interval dosing but have been limited by a lack of well-matched patient cohorts.Methods:Tysabri Observational Program (TOP) data as of November 2019 were used to identify patients with relapsing-remitting multiple sclerosis treated with natalizumab Q4W and those with a single physician-indicated dosing change from Q4W to every-6-week (Q6W) dosing after ⩾1 year of Q4W treatment. Patients were propensity score matched at the time of the switch from Q4W to Q6W dosing. Clinical outcomes (annualized relapse rate and probability of remaining relapse free or free of 24-week confirmed disability worsening) and safety outcomes were assessed for the two cohorts.Results:This study included 219 pairs of propensity score–matched Q6W and Q4W patients. Annualized relapse rates were similar for Q6W (0.150) and Q4W (0.157) patients. The probability of remaining relapse free [hazard ratio = 1.243 (95% confidence interval = 0.819–1.888); p = 0.307] and of remaining free of 24-week confirmed disability worsening [hazard ratio = 0.786 (95% confidence interval = 0.284–2.176); p = 0.644] did not differ significantly between Q6W and Q4W patients. Summarized safety results for the matched Q6W and Q4W patients are also presented.Conclusion:These real-world findings in well-matched patient cohorts from TOP demonstrate that natalizumab effectiveness is maintained in patients who switch to Q6W dosing after ⩾1 year of Q4W dosing.ClinicalTrials.gov identifier:NCT00493298

Real-world disability improvement in patients with relapsing–remitting multiple sclerosis treated with natalizumab in the Tysabri Observational Program

Background: Natalizumab has been associated with disability improvement as indicated by a confirmed Expanded Disability Status Scale (EDSS) score decrease. Objective: The aim of this study was to characterize disability improvement in patients in the Tysabri Observational Program (TOP), an ongoing observational study of relapsing–remitting multiple sclerosis patients initiating natalizumab in clinical practice. Methods: TOP data as of November 2018 were included. Confirmed disability improvement (CDI) was defined as a decrease ⩾1.0 confirmed 24 weeks later from a baseline EDSS score ⩾2.0. Confirmed functional system (FS) improvement was defined as a decrease ⩾1.0 confirmed 24 weeks later from a baseline score ⩾1.0 in that FS. Results: Of 5384 patients, 1287 (23.9%) had CDI; 51.8% experienced CDI in the first treatment year. Among patients with CDI, 56.6% had CDI ⩾1.5 points; 34.4% had CDI ⩾2.0 points. The cumulative probability of maintaining improvement 8 years after the CDI event was 52.6%. At treatment initiation, 5363 patients (85.2%) had impairment in ⩾1 FS. At 8 years, the cumulative probability of confirmed improvement in any FS was 88.8% and ranged from 38.3% to 58.6% in individual FS. Conclusion: These results highlight disability improvement as a potential benefit of natalizumab treatment. Improvements across all FS demonstrate the range of functional improvement.

Clinical outcomes in patients who discontinue natalizumab therapy after 2 years in the Tysabri® Observational Program (TOP)

Background: Natalizumab is a highly efficacious therapy for relapsing–remitting multiple sclerosis (RRMS). Patients who discontinue natalizumab may experience return of MS disease activity. Objective: The aim of this study was to analyze predictors of post-natalizumab disease activity return. Methods: The Tysabri® Observational Program (TOP) is an ongoing observational study of natalizumab-treated RRMS patients. Patients discontinuing natalizumab are encouraged to remain in TOP. Results: Analyses included 3221 TOP patients. After ⩾2 years on natalizumab, relapse risk was twice as high for patients who switched to an oral therapy (n = 660, hazard ratio (HR) = 2.18, p < 0.001) and three times as high for patients who switched to an injectable therapy (n = 95, HR = 3.02, p < 0.001) as for those who stayed on natalizumab (n = 2466). Relapse rates after switching remained below pre-natalizumab rates. In patients who switched to an oral therapy, higher relapse risk was predicted by longer washout time, more pre-natalizumab relapses, higher Expanded Disability Status Scale score at natalizumab initiation, and shorter natalizumab treatment duration. Conclusion: Patients who stayed on natalizumab had better clinical outcomes than those who switched to an oral or injectable therapy after ⩾2 years on natalizumab. These results highlight modifiable risk factors for disease activity return (e.g. natalizumab treatment duration and washout duration) to consider when making treatment decisions.

Transition to non-active secondary progressive multiple sclerosis (SPMS) after up to 9.5 years of natalizumab treatment in the real-world TYSABRI Observational Program (TOP) (2802)

Transition to non-active secondary progressive multiple sclerosis (SPMS) after up to 9.5 years of natalizumab treatment in the real-world TYSABRI Observational Program (TOP) (2802)

Long-term safety and effectiveness of natalizumab treatment in clinical practice: 10 years of real-world data from the Tysabri Observational Program (TOP)

ObjectiveThe Tysabri Observational Programme (TOP), which began >10 years ago, is an open-label, multinational, prospective observational study evaluating the long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis patients.MethodsThese...

Real-world data from over 10 years in the TYSABRI® Observational Program: Long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis patients

Introduction The TYSABRI Observational Program (TOP) began > 10 years ago to inform on long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis (RRMS) patients in clinical practice. Objectives Report an interim analysis of safety and effectiveness in patients with up to 10 years of natalizumab treatment in TOP, an open-label, multinational, prospective, observational study. Patients and methods Annualised relapse rates (ARRs) for the year prior to starting natalizumab and on natalizumab (and ≤ 84 days post discontinuation) were compared using a repeated Poisson model. Confirmed Expanded Disability Status Scale (EDSS) worsening, and improvement, while on natalizumab were estimated by Kaplan–Meier analysis. Serious adverse events (SAEs) were assessed at clinical visits. Results As of November 2017, TOP included 6149 patients. ARR while on natalizumab was reduced by 89.4% (from 1.99 pre- natalizumab to 0.21 on natalizumab; P Discussion At 10 years, cumulative probabilities of 24-week–confirmed EDSS worsening and improvement were 32.9% and 35.5%, respectively. Overall, 828 of 6149 patients (13.5%) experienced ≥ 1 SAE (most commonly reported by system organ class: infections and infestations, 253 patients [4.1%]). Conclusion This analysis reinforces the consistent effectiveness—particularly when used earlier in the disease and treatment course–and the established safety profile of natalizumab, now assessed over 10 years.

THUR 171 Natalizumab effectiveness and safety in top uk patients

IntroductionThe TYSABRI® Observational Program (TOP) is an ongoing, global open-label study enrolling natalizumab-treated relapsing-remitting multiple sclerosis patients in real-world settings. Country-specific data can provide information on natalizumab’s benefit-risk in local clinical practice.MethodsClinical outcomes in UK and rest of world (ROW) TOP patients were compared.ResultsAs of May 2016, 134 UK and 5793 ROW patients were enrolled in TOP. Mean baseline Expanded Disability Status Scale (EDSS) score was 4.27 in the UK and 3.45 in ROW. Mean years on natalizumab was 3.52 in the UK and 3.04 in ROW. Annualized relapse rate (ARR) decreased by 89.7% (from 2.21 pre-natalizumab to 0.23 post natalizumab initiation; p&lt;0.0001) in the UK and by 89.0% (from 1.99 to 0.22; p&lt;0.0001) in ROW. In both cohorts, ARR decrease by baseline EDSS score was 91.0%–93.2% for &lt;3.0 and 87.3%–88.9% for ≥3.0; mean EDSS score change from baseline over 6 years was &lt;1.0. Overall, 9 of 134 UK patients (6.7%) experienced ≥1 serious adverse event.ConclusionsNatalizumab demonstrated similar effectiveness in the UK and ROW cohorts. Safety in the UK cohort was consistent with natalizumab’s established safety profile.SupportBiogenDisclosuresRN: grant/travel support from Biogen; KR, SL, SFSF, CS: Biogen employees.

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting

BackgroundThough the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. MethodsTOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. ResultsOf the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). ConclusionsIn TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Longer duration of natalizumab exposure may lessen return of disease activity following a switch from natalizumab to an oral therapy: modelling real-world data from relapsing-remitting multiple sclerosis (RRMS) patients in the TYSABRI® Observational Program (TOP) (P6.379)

Longer duration of natalizumab exposure may lessen return of disease activity following a switch from natalizumab to an oral therapy: modelling real-world data from relapsing-remitting multiple sclerosis (RRMS) patients in the TYSABRI® Observational Program (TOP) (P6.379)

Real-world improvement across functional systems (FS) in relapsing-remitting multiple sclerosis (RRMS) patients treated with natalizumab in the TYSABRI® Observational Program (TOP) (P6.383)

Real-world improvement across functional systems (FS) in relapsing-remitting multiple sclerosis (RRMS) patients treated with natalizumab in the TYSABRI® Observational Program (TOP) (P6.383)

Greater sensitivity to multiple sclerosis disability worsening and progression events using a roving versus a fixed reference value in a prospective cohort study

Background: Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses. Objective: To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ≈5.5 years from the Tysabri® Observational Program (TOP). Methods: TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks. Measures of increasing disability were assessed using as a reference either study baseline score or a “roving” system that resets the reference score after ⩾24- or ⩾48-week confirmation of a new score. Results: This analysis included 5562 patients. Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively). Conclusion: In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease.

In treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS), initiating natalizumab earlier is associated with greater disability improvement than delaying treatment: real-world results from the TYSABRI® Observational Program (TOP) (P6.350)

In treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS), initiating natalizumab earlier is associated with greater disability improvement than delaying treatment: real-world results from the TYSABRI® Observational Program (TOP) (P6.350)

Real-World Relapsing-Remitting Multiple Sclerosis (RRMS) Patients in the Tysabri® Observational Program (TOP) Who Discontinued Natalizumab: Why They Stopped, Which Therapies They Switched To, and How Their Disease Activity Changed (P2.399)

Real-World Relapsing-Remitting Multiple Sclerosis (RRMS) Patients in the Tysabri® Observational Program (TOP) Who Discontinued Natalizumab: Why They Stopped, Which Therapies They Switched To, and How Their Disease Activity Changed (P2.399)

Real-World Safety and Efficacy of Natalizumab after Switching from Other Disease-Modifying Therapies (DMTs): Data from the Tysabri® Observational Program (TOP) (P2.069)

Real-World Safety and Efficacy of Natalizumab after Switching from Other Disease-Modifying Therapies (DMTs): Data from the Tysabri® Observational Program (TOP) (P2.069)

Comparative efficacy of first-line natalizumab vs IFN-β or glatiramer acetate in relapsing MS.

We compared efficacy and treatment persistence in treatment-naive patients with relapsing-remitting multiple sclerosis (RRMS) initiating natalizumab compared with interferon-β (IFN-β)/glatiramer acetate (GA) therapies, using propensity score-matched cohorts from observational multiple sclerosis registries. The study population initiated IFN-β/GA in the MSBase Registry or natalizumab in the Tysabri Observational Program, had ≥3 months of on-treatment follow-up, and had active RRMS, defined as ≥1 gadolinium-enhancing lesion on cerebral MRI at baseline or ≥1 relapse within the 12 months prior to baseline. Baseline demographics and disease characteristics were balanced between propensity-matched groups. Annualized relapse rate (ARR), time to first relapse, treatment persistence, and disability outcomes were compared between matched treatment arms in the total population (n = 366/group) and subgroups with higher baseline disease activity. First-line natalizumab was associated with a 68% relative reduction in ARR from a mean (SD) of 0.63 (0.92) on IFN-β/GA to 0.20 (0.63) (p [signed-rank] < 0.0001), a 64% reduction in the rate of first relapse (hazard ratio [HR] 0.36, 95% confidence interval [CI] 0.28-0.47; p < 0.001), and a 27% reduction in the rate of discontinuation (HR 0.73, 95% CI 0.58-0.93; p = 0.01), compared with first-line IFN-β/GA therapy. Confirmed disability progression and area under the Expanded Disability Status Scale-time curve analyses were not significant. Similar relapse and treatment persistence results were observed in each of the higher disease activity subgroups. This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse and treatment persistence outcomes compared to first-line IFN-β/GA. This needs to be balanced against the risk of progressive multifocal leukoencephalopathy in natalizumab-treated patients. This study provides Class IV evidence that first-line natalizumab for RRMS improves relapse rates and treatment persistence outcomes compared to first-line IFN-β/GA.

Comparative efficacy of switching to natalizumab in active multiple sclerosis.

ObjectiveTo compare treatment efficacy and persistence in patients who switched to natalizumab versus those who switched between glatiramer acetate (GA) and interferon-beta (IFNβ) after an on-treatment relapse on IFNβ or GA using propensity score matched real-world datasets.MethodsPatients included were registered in MSBase or the TYSABRI Observational Program (TOP), had relapsed on IFNβ or GA within 12 months prior to switching to another therapy, and had initiated natalizumab or IFNβ/GA treatment ≤6 months after discontinuing prior therapy. Covariates were balanced across post switch treatment groups by propensity score matching at treatment initiation. Relapse, persistence, and disability measures were compared between matched treatment arms in the total population (n = 869/group) and in subgroups defined by prior treatment history (IFNβ only [n = 578/group], GA only [n = 165/group], or both IFNβ and GA [n = 176/group]).ResultsCompared to switching between IFNβ and GA, switching to natalizumab reduced annualized relapse rate in year one by 65–75%, the risk of first relapse by 53–82% (mean follow-up 1.7–2.2 years) and treatment discontinuation events by 48–65% (all P ≤ 0.001). In the total population, switching to natalizumab reduced the risk of confirmed disability progression by 26% (P = 0.036) and decreased the total disability burden by 1.54 EDSS-years (P < 0.0001) over the first 24 months post switch.InterpretationUsing large, real-world, propensity-matched datasets we demonstrate that after a relapse on IFNβ or GA, switching to natalizumab (rather than between IFNβ and GA) led to superior outcomes for patients in all measures assessed. Results were consistent regardless of the prior treatment identity.

NATALIZUMAB FOR RELAPSING-REMITTING MS IN THE UK TOP COHORT

Introduction The TYSABRI® Observational Program (TOP) is a global, open-label study of natalizumab for relapsing-remitting multiple sclerosis (RRMS) in clinical practice. Methods Baseline characteristics were summarised. On-therapy annualised relapse rates (ARRs) were compared with baseline. Results As of 01 May 2013, 122 patients were enrolled in the United Kingdom (UK) and 5122 patients were enrolled globally. Median duration of RRMS was 5.4 years in the UK and 7.3 years globally. Mean numbers of relapses in the 2 years prior to natalizumab treatment were 3.22 in the UK and 2.85 globally. Mean baseline Expanded Disability Status Scale (EDSS) scores were 4.2 in the UK and 3.5 globally. Median Multiple Sclerosis Severity Scores (MSSS) were 6.2 in the UK versus 4.9 globally (p Conclusions The UK Cohort appears to have more aggressive disease, as evidenced by higher MSS score and higher ARR history. Despite this similar significant reductions in ARR were observed in the UK-specific and global cohorts. Supported by Biogen Idec Ltd. RN: grant support and support for travel to conferences from Biogen Idec Ltd. JH: employee of Biogen Idec Ltd.