Comparably low disease activity during Natalizumab treatment in patients who remained on or who later discontinued Natalizumab suggests limited attrition bias in the TYSABRI® observational program
ECTRIMS Online Library. Spelman T. 09/13/19; 278592; P1391
Tim Spelman
Tim Spelman
Contributions
Abstract

Abstract: P1391

Type: Poster Sessions

Abstract Category: Therapy - Long-term treatment monitoring

T. Spelman1, L. Kappos2, H. Butzkueven3,4, M. Trojano5, H. Wiendl6, I. Chang7, N. Campbell7, P.-R. Ho7, S. Licata7, on behalf of the TOP investigators

1Department of Medicine and Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia, 2Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland, 3Department of Neuroscience, Central Clinical School, Alfred Campus, 4Department of Neurology, Box Hill Hospital, Monash University, Melbourne, VIC, Australia, 5Department of Basic Medical Science, Neuroscience, and Sense Organs, University of Bari, Bari, Italy, 6Department of Neurology, University of Münster, Münster, Germany, 7Biogen, Cambridge, MA, United States

Introduction: The TYSABRI Observational Program (TOP) 10-year interim analysis demonstrated long-term control of disease activity with natalizumab (N=6148). Longitudinal real-world studies provide valuable information on benefit-risk assessment but are subject to attrition bias from patients' selectively discontinuing due to lack of efficacy.
Objectives: To assess effects of attrition bias due to selective discontinuation on effectiveness outcomes in TOP.
Methods: Data from July 2007 to November 2017 were analysed in patients with ≥ 8 years of treatment (n=491) and patients who enrolled > 8 years before the data cut but discontinued prior to 8 years of treatment (n=1056). Annualized relapse rates (ARRs) were assessed with a Poisson model. Kaplan-Meier-estimated cumulative probabilities of 24-week-confirmed disability worsening (CDW) and 24-week-confirmed disability improvement (CDI) were analysed, with censoring after natalizumab discontinuation.
Results: Baseline characteristics of the ≥ 8-year and < 8-year treatment cohorts were similar, yet the ≥ 8-year cohort initiated natalizumab earlier in the disease course, as indicated by their younger age, lower baseline EDSS score, and shorter disease duration. A higher percentage of ≥ 8-year patients had negative baseline JC virus serostatus. Reasons for discontinuation were similar to the overall population; 10.3% of < 8-year patients discontinued due to reported lack of efficacy compared with only 6.7% overall. In year 1, ARR decreased from 2.04 to 0.21 (89.7%) in the ≥ 8-year cohort and from 1.97 to 0.26 (86.8%) in the < 8-year cohort. Yearly ARRs thereafter remained ≤ 0.21 in both cohorts. For patients who discontinued, ARRs in the year before discontinuation remained < 0.17 and were similar to ARRs in the same treatment epoch in those who remained on natalizumab. Cumulative probabilities of CDW at 8 years were similar in the ≥ 8-year (27.8%) and < 8-year (25.3%) cohorts. The cumulative probability of CDI at 8 years appeared greater in the ≥ 8-year cohort (43.1%) than the < 8-year cohort (30.9%).
Conclusions: On-natalizumab ARRs and probabilities of CDW were similarly low for patients who discontinued or remained on natalizumab for ≥ 8 years, and discontinuations for efficacy reasons were not common. Results suggest that attrition bias does not account for the observed long-term effectiveness of natalizumab in TOP.
Disclosure: TS: honoraria for consultancy and funding for travel from Biogen, Novartis.
LK: institution (University Hospital Basel) received and used exclusively for research support steering committee, advisory board, consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi, Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; grants from Bayer HealthCare, Biogen, F. Hoffmann-La Roche, Merck, Novartis, the European Union, the Roche Research Foundations, the Swiss Multiple Sclerosis Society, the Swiss National Research Foundation.
HB: Institution (Monash university) received compensation for consulting, talks, advisory/steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health; research support from Novartis, Biogen, Roche, Merck, NHMRC, Pennycook Foundation, MSRA. HB received compensation for same activities from Oxford Health Policy Forum, Merck, Biogen, Novartis.
MT: compensation for consulting from Biogen, Merck Serono, Novartis, Roche; speaker honoraria from Biogen, Merck Serono, Novartis, Sanofi-Genzyme, Teva, Roche; research grants from Biogen, Merck Serono, Novartis, Roche.
HW: honoraria from AbbVie, Actelion, Alexion, Biogen, Cognomed, Evgen, F. Hoffmann-La Roche, MedDay, Merck Serono, Novartis, Roche Pharma AG, Sanofi Genzyme, Teva; research support from Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi.
IC, NC, P-RH, SL: employees of and own stock and/or stock options in Biogen.
The TOP study is funded by Biogen. Biogen also funded the writing support for this abstract, which was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

Abstract: P1391

Type: Poster Sessions

Abstract Category: Therapy - Long-term treatment monitoring

T. Spelman1, L. Kappos2, H. Butzkueven3,4, M. Trojano5, H. Wiendl6, I. Chang7, N. Campbell7, P.-R. Ho7, S. Licata7, on behalf of the TOP investigators

1Department of Medicine and Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC, Australia, 2Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital and University of Basel, Basel, Switzerland, 3Department of Neuroscience, Central Clinical School, Alfred Campus, 4Department of Neurology, Box Hill Hospital, Monash University, Melbourne, VIC, Australia, 5Department of Basic Medical Science, Neuroscience, and Sense Organs, University of Bari, Bari, Italy, 6Department of Neurology, University of Münster, Münster, Germany, 7Biogen, Cambridge, MA, United States

Introduction: The TYSABRI Observational Program (TOP) 10-year interim analysis demonstrated long-term control of disease activity with natalizumab (N=6148). Longitudinal real-world studies provide valuable information on benefit-risk assessment but are subject to attrition bias from patients' selectively discontinuing due to lack of efficacy.
Objectives: To assess effects of attrition bias due to selective discontinuation on effectiveness outcomes in TOP.
Methods: Data from July 2007 to November 2017 were analysed in patients with ≥ 8 years of treatment (n=491) and patients who enrolled > 8 years before the data cut but discontinued prior to 8 years of treatment (n=1056). Annualized relapse rates (ARRs) were assessed with a Poisson model. Kaplan-Meier-estimated cumulative probabilities of 24-week-confirmed disability worsening (CDW) and 24-week-confirmed disability improvement (CDI) were analysed, with censoring after natalizumab discontinuation.
Results: Baseline characteristics of the ≥ 8-year and < 8-year treatment cohorts were similar, yet the ≥ 8-year cohort initiated natalizumab earlier in the disease course, as indicated by their younger age, lower baseline EDSS score, and shorter disease duration. A higher percentage of ≥ 8-year patients had negative baseline JC virus serostatus. Reasons for discontinuation were similar to the overall population; 10.3% of < 8-year patients discontinued due to reported lack of efficacy compared with only 6.7% overall. In year 1, ARR decreased from 2.04 to 0.21 (89.7%) in the ≥ 8-year cohort and from 1.97 to 0.26 (86.8%) in the < 8-year cohort. Yearly ARRs thereafter remained ≤ 0.21 in both cohorts. For patients who discontinued, ARRs in the year before discontinuation remained < 0.17 and were similar to ARRs in the same treatment epoch in those who remained on natalizumab. Cumulative probabilities of CDW at 8 years were similar in the ≥ 8-year (27.8%) and < 8-year (25.3%) cohorts. The cumulative probability of CDI at 8 years appeared greater in the ≥ 8-year cohort (43.1%) than the < 8-year cohort (30.9%).
Conclusions: On-natalizumab ARRs and probabilities of CDW were similarly low for patients who discontinued or remained on natalizumab for ≥ 8 years, and discontinuations for efficacy reasons were not common. Results suggest that attrition bias does not account for the observed long-term effectiveness of natalizumab in TOP.
Disclosure: TS: honoraria for consultancy and funding for travel from Biogen, Novartis.
LK: institution (University Hospital Basel) received and used exclusively for research support steering committee, advisory board, consultancy fees from Actelion, Addex, Bayer HealthCare, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer HealthCare, Biogen, Merck, Novartis, Sanofi, Teva; support of educational activities from Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; grants from Bayer HealthCare, Biogen, F. Hoffmann-La Roche, Merck, Novartis, the European Union, the Roche Research Foundations, the Swiss Multiple Sclerosis Society, the Swiss National Research Foundation.
HB: Institution (Monash university) received compensation for consulting, talks, advisory/steering board activities from Biogen, Merck, Novartis, Genzyme, Alfred Health; research support from Novartis, Biogen, Roche, Merck, NHMRC, Pennycook Foundation, MSRA. HB received compensation for same activities from Oxford Health Policy Forum, Merck, Biogen, Novartis.
MT: compensation for consulting from Biogen, Merck Serono, Novartis, Roche; speaker honoraria from Biogen, Merck Serono, Novartis, Sanofi-Genzyme, Teva, Roche; research grants from Biogen, Merck Serono, Novartis, Roche.
HW: honoraria from AbbVie, Actelion, Alexion, Biogen, Cognomed, Evgen, F. Hoffmann-La Roche, MedDay, Merck Serono, Novartis, Roche Pharma AG, Sanofi Genzyme, Teva; research support from Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi.
IC, NC, P-RH, SL: employees of and own stock and/or stock options in Biogen.
The TOP study is funded by Biogen. Biogen also funded the writing support for this abstract, which was provided by Ashfield Healthcare Communications (Middletown, CT, USA).

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