1. Are stable MS patients who stop their disease-modifying therapy (DMT) at increased risk for relapses and disability progression compared to patients who continue on DMTs? A propensity-score matched analysis of the MSBase registrants Ilya Kister 1, Tim Spelman 2,3, Raed Alroughani 4, Jeannette Lechner-Scott 5, Pierre Duquette 6, Francois Grand’Maison 7, Mark Slee 8, Alessandra Lugaresi 9, Michael Barnett 10, Pierre Grammond 11, Gerardo Iuliano 12, Raymond Hupperts 13, Maria Trojano 14 & Helmut Butzkueven 2,3 on behalf of the MSBase Study Group. 1 NYU Multiple Sclerosis Care Center, Department of Neurology, NYU School of Medicine, New York, USA; 2. Department of Neurology, Royal Melbourne Hospital, Parkville, Australia; 3 Department of Medicine (RMH), The University of Melbourne, Parkville, Australia; 4 Amiri Hospital, Kuwait City, Kuwait; 5 John Hunter Hospital, Newcastle, Australia; 6 Hôpital Notre Dame, Montreal, Canada; 7 Neuro Rive-Sud, Hôpital Charles LeMoyne, Québec, Canada; 8 Flinders Medical Centre, Adelaide, Australia; 9 MS Center, Department of Neuroscience, Imaging and Clinical Sciences, University ‘G. d’Annunzio’, Chieti, Italy; 10 Brain and Mind Research Institute, Sydney, Australia; 11 Centre de réadaptation déficience physique Chaudière-Appalache, Levis, Canada; 12 Ospedali Riuniti di Salerno, Salerno, Italy; 13 Orbis Medical Centre, Sittard-Geleen, The Netherlands; 14 Department of Basic Medical sciences, Neuroscience and Sense Organs, University of Bari, Italy

2. Disclosures No targeted funding provided for the study The MSBase Registry is operated by the independent MSBase Foundation, a non profit organisation based in Melbourne, Australia. MSBase acknowledges financial contributions to support the MSBase Registry from Biogen Idec, Novartis, Merck Serono, Genzyme Sanofi and CSL.

3. Thanks to… the MSBase Investigators and their Patients, who made the study possible; MSBase Scientific Leadership Group, which granted request for statistical support for the study; Dr Tim Spelman, co- first author, who carried out the statistical analyses

4. Background

5. We know a lot about starting DMTs From www.msdiscovery.org (with permission)www.msdiscovery.org

6. “ Identified 4,359 unique citations … No studies directly assessed continuing versus discontinuing DMT in comparable populations. Providers and MS patients … have little information to guide decisions regarding discontinuing DMT.” Butler et al. Decisional Dilemmas in Discontinuing Prolonged Disease-Modifying Treatment for Multiple Sclerosis. Agency for Healthcare Research and Quality (US); 2015 Apr. Report No.: 15-EHC012-EF. …but little about stopping DMTs

7.  Stopping Natalizumab in RRMS  disease reactivation Kaufman et al. Radiologic MS disease activity during natalizumab treatment interruption : findings from RESTORE. J Neurol. 2015 Feb;262(2):326-36 Kappos et al. Switching from natalizumab to fingolimod: A randomized, placebo- controlled study in RRMS. Neurology. 2015 ;85:29  Stopping (lowering dose?) IFNb in active RRMS  disease reactivation Siger A, et al. Discontinuation of interferon beta therapy in multiple sclerosis patients with high pre-treatment disease activity leads to prompt return to previous disease activity. J Neurol Sci. 2011 ;303:50. Prosperini et al. From high- to low-frequency administered interferon-beta for multiple sclerosis: a multicenter study. Eur Neurol. 2014;71:233 What we do know:

8.  Some treatments in RRMS  prolonged remission “effects of alemtuzumab on disability [were seen] even … 4 years after dosing.” Coles AJ et al. Alemtuzumab more effective than interferon β-1a at 5-year follow- up of CAMMS223 clinical trial. Neurology. 2012 3;78(14):1069-78. “AHSCT is associated with long-lasting suppression of inflammation and … brain atrophy after the second year following treatment.” Roccatagliata et al. The long-term effect of AHSCT on MRI measures of MS evolution: a 5-year follow-up study. Mult Scler. 2007;13(8):1068-70. What we do know:

9. Thus, in patients with ongoing inflammatory activity (relapses, MRI lesions), stopping some of the DMTs leads to disease reactivation. What about patients without evidence of ongoing inflammatory disease activity? – Should DMTs be continued indefinitely?

10. Pros (continue) v Cons (don’t) Relapses can occur even in older patients ~30% of SPMS pts had relapses. Paz Soldán et al. Relapses and disability accumulation in progressive multiple sclerosis. Neurology. 2015. We cannot reliably predict who will have post-DMT relapses We don’t know whether stopping DMT in itself has a detrimental effect on subsequent disease course ‘If it ain’t broke, don’t fix it’ DMTs not proven to be of benefit to patients without active disease Little data on DMTs effective in older patients (excluded from RCTs) Benefit/risk ratio of DMTs likely decreases as relapse rates decline with age. Tremlett et al. Relapses in multiple sclerosis are age- and time-dependent. JNNP 2008. Little data on long-term safety of DMTs Is it good use of medical resources? Clinical equipoise ∆

11. Study Objectives

12. 1. To chart ‘post first line DMT’ disease course; 2. To understand predictors of ‘post DMT’ relapse, confirmed disability progression and DMT restart; 3. To compare risk of relapse and confirmed disability progression in DMT ‘stoppers’ and propensity score matched DMT ‘stayers’

13. Inclusion/exclusion criteria Satisfied Poser or McDonald criteria for MS Age ≥18 yrs Treated for ≥3 yrs with first-line DMT prior to stop No relapses for ≥5 yrs prior to DMT stop Follow up ≥3 yrs after DMT stop Did not restart DMT for ≥3 months after stopping No pregnancy during follow up

14. Methods

15. Data MSBase Outcomes First relapse Three-month confirmed disability progression Treatment restart Methods: Analysis of predictors – “stoppers” only – Cox Shared Frailty Model Analysis of “stoppers” vs propensity score matched “stayers – marginal Cox model Evaluation: Hazard proportionality: Analysis of scaled Schoenfeld residuals Rosenbaum Sensitivity Analysis for unmeasured confounding

16. Results

17. Baseline Characteristic StopStay P-value n=426n=852 Age, years, median (IQR)45.1 (37.0, 51.6)43.8 (37.1, 51.3)0.29 Female sex, n (%)305 (71.6)599 (70.3)0.63 Disease duration, years, median (IQR)13.7 (9.2, 20.1)13.1 (9.1, 18.4)0.05 EDSS, median (IQR)3.5 (2, 6)3.5 (2, 5.5)0.12 # pre-baseline DMD starts – median (IQR) 1 (1, 2) 0.10 Proportion disease duration on treatment – median (IQR) 0.6 (0.6, 0.8)0.6 (0.4, 0.8)0.26 # of pre-baseline DMD starts / disease duration - mean (SD) 0.1 (0.1) 0.20 Duration of follow up period, years, median (IQR) 4.85 (3.75, 6.86)5.02 (3.81, 6.96) Demographic Characteristics of DMT Stoppers and Stayers

18. Demographic Characteristics of DMT Stoppers, con’t

19. ‘Post DMT’ disease course

20. During post-discontinuation period [ median 4.85 yrs]:  155 / 426 (36.4%) DMT stoppers experienced a clinician-reported relapse  131 / 426 (30.8%) stoppers sustained 3-month disability progression  46 / 426 (13.2%) stoppers had both relapses and confirmed disability progression  203 / 426 (47.7%) stoppers restarted DMT after mean (SD) 2.24 (1.97) years

21. Predictors of relapse, progression and DMT restart

22. Predictors of relapse among DMT stoppers Male sex Age (units = 10 years) EDSS Disease duration (years) Number of pre-baseline DMD starts Proportion disease duration on treatment DMD stopped Avonex Betaseron Copaxone Rebif Multivariate aHR (95% CI) p-value 0.75 (0.62, 0.92) 0.005 0.87 (0.80, 0.95) 0.001 Every 10 years older at baseline  25% reduction in relapse rate Every 1 point higher EDDS  13% reduction in relapse rate Thus, younger and less disabled patients were at higher risk of relapse

23. Predictors of confirmed disability progression among DMT stoppers Multivariate aHR (95% CI) p-value 1.32 (1.08, 1.62) 0.008 2.10 (1.19, 3.72) 0.011 Male sex Age (units = 10 years) EDSS Disease duration (years) Number of pre-baseline DMD starts Proportion disease duration on treatment DMD stopped Avonex Betaseron Copaxone Rebif Betaseron Every 10 years older at baseline  32% increase in confirmed disability progression rate Prior Betaseron  increased risk of disability progression

24. Predictors of DMT restart among DMT stoppers Multivariate aHR (95% CI) p-value 0.76 (0.64, 0.91) 0.002 0.87 (0.81, 0.94) <0.001 1.70 (1.14, 2.54) 0.009 1.57 (1.09, 2.25) 0.015 Male sex Age (units = 10 years) EDSS Disease duration (years) Number of pre-baseline DMD starts Proportion disease duration on treatment DMD stopped Avonex Betaseron Copaxone Rebif Avonex Rebif Every 10 years older at baseline  24% reduction in DMT restart rate Every 1 point higher EDSS  13% reduction in DMT restart Prior Avonex and Rebif  increased DMT restart rate Older, more disabled patients had lower DMT restart rates

25. Comparing disease course in ‘DMT stoppers’ and ‘DMT stayers’

26. Time to relapse and confirmed disability progression in DMT Stayers (reference) v. DMT Stoppers: Cox Proportional Hazards Regression Time to first relapse HR (95% CI) p-value 1.002 (0.83, 1.21) 0.985 Time to confirmed disability progression HR (95% CI) p-value 1.47 (1.18, 1.84) 0.001 DMT stoppers and stayers had same relapse rates, but DMT stoppers had higher rates of disability progression then stayers

27. Kaplan-Meier: Time to Relapse

28. Kaplan-Meier: Time to Progression

29. Conclusions

30.  Relapses do occur in patient even after a prolonged relapse-free period – 36% of DMT stoppers experienced relapses during ~5-year follow up – Relapses were more likely in the younger and less disabled patients  Relapse rate was same for DMT stoppers and stayers – Stopping DMT in patients with no relapses for >5 years, does not appear to put them at risk for relapses  Rate of progression was faster in DMT stoppers compared to stayers – This effect was seen mostly >2 years after DMT stopped

31. Limitations

32. Observational study – Selection bias; eg. patient who stop DMT and ‘doing well’ may beless likely to follow up – Unmeasured confounders; DMT stoppers may be inherently ‘faster progressors’ than stayers EDSS is not sensitive to changes in cognition Progression may manifest in cognitive domain rather than motor/ambulation No MRI data to corroborate clinical data

33. What’s next?

34. PI: Prof. John Corboy, University of Colorado - Denver 6 (or more) sites across the United States Inclusion criteria: MS patients ≥55 years old; no relapses/new lesions for ≥5 years on DMTs Outcome measures: EDSS, SDMT, PRO, MRI Duration: 3 years PCORI* Funds Randomized Discontinuation Trial in MS * “The Patient-Centered Outcomes Research Institute (PCORI), an independent nonprofit, nongovernmental agency authorized by the US Congress… mandate to improve the quality and relevance of evidence available to help patients, caregivers, clinicians, employers, insurers, and policy makers make informed health decisions. Specifically, we fund comparative clinical effectiveness research...”