Controversies in Multiple Sclerosis: Discontinuing Disease Modifying Therapies

1. Controversies in Multiple Sclerosis: Discontinuing Disease Modifying Therapies Le H. Hua Eric and Sheila Samson Chair for MS Research Director, Mellen Program for MS Cleveland Clinic Lou Ruvo Center for Brain Health

2. Disclosures • Speaking, consulting, advisory board activities from Biogen, Genzyme, Novartis, Celgene, Genentech and EMD Serono

3. Background • Pathophysiology of MS • Currently available DMTs for MS target the immune system to reduce inflammatory activity • Limited effectiveness of DMTs on progressive processes Mahad et al, 2015

4. MS relapses decreases with age • Retrospective study of 2477 patients in BC, with mean follow up time of 20.6 years. • Relapse rate decreased by 17% every 5 years (between years 5 to 20 post onset) • Increased magnitude of decline with increasing onset age. Tremlett et al, 2008

5. Immune system changes with age • Immunosenescence – changes to the immune system due to normal aging • Thymus involution- reduction in naïve T cells, naïve CD8+> CD4+ • Decreased CTL-mediated cytotoxicity and reduced T cell helper functional activity • Reduced response to infections and vaccinations • Reduction in T cell receptor repertoire • Loss of CD28 (co-stimulatory molecule for T cell effector functions) • Reduction in B cell antibody responses including somatic hypermutation and class switching • Potentially increased risk of infections such as PML or increased risk of cancer • Inflammaging – systemic, chronic, unresolved low grade inflammation • Influenced by chronic antigenic stimulations leading general increase in production of pro-inflammatory cytokines and inflammatory markers • Neuro-degeneration (AD, PD, MS, ALS), cardiovascular diseases, insulin resistance, osteoporosis, age-related macular degeneration

6. Current questions • What is the utility of DMT in progressive MS who have reached certain levels of disability? • Should DMT be stopped in progressive patients? • Should DMT be stopped in stable patients?

7. Prior Discontinuation Studies • Birnbaum, IJMSC 2017 • Prospective observational, single center • Group A – 77 patients, SPMS, no disease activity for at least 2 years, advised to stop • Median age 61 years (47-76), median EDSS 6 • Group B – 17 RMS, stopped DMT on own • Median age 49 years (35-64), median EDSS 2 • 11.7% of group A and 58.5% of group B had recurrent acute disease within 1-2 years of stopping treatment

8. Prior Discontinuation Studies • Bsteh et al, MSJ 2016 • Western Austria – Innsbruck MS Database • 221 DMT discontinuers • Discontinued DMT after at least 12 months use • Follow up for at least 2 years after discontinution • Excluded PP and SP patients • Average age of discontinuation between 36-39 years, mean duration of treatment 4.2 years (CI 3.5-4.9) • 80.5% interferon-beta, 19.5% glatiramer acetate • Mean relapse-free time before discontinuation 3.4 years (CI=3.0-3.7) • 44% of patients had a relapse after DMT discontinuation, and 31% of their cohort restarted DMT with median follow-up 3.8 years.

9. Prior Discontinuation Studies • Kister et al, JNNP 2016 • MSBase registry • DMT stoppers (n=485), no relapses at least 5 years, follow up at least 3 years, did not restart DMT for at least 3 months • DMT stayers (n=854), no disease activity for 5 years at baseline, PS matched age, sex, EDSS, disease duration, and time on treatment • Average age of stoppers 45.1 years (IQR 37.0-51.6) and stayers 43.8 years (IQR 37.1-51.3) • In stoppers, 86% interferon-beta, 11.7% glatiramer acetate • In stayers, 80.7% interferon-beta, 19.3% glatiramer acetate • Relapse rate was 36.4% in stoppers, and 37.8% among stayers • Almost half of the discontinuers (46%) restarted therapy within 2 years. Mean post-discontinuation follow-up 4.85 years. • Interestingly, disability progression was higher in the group that stopped, indicating that DMT continues to have benefit in the younger population who have not yet shown signs of disability progression. In patients who were already showing disability progression, there were no differences between stoppers and stayers.

10. Our study • Focus on age • To understand current clinical practices and implications of stopping DMT in patients with MS over age 60. • To compare clinical and patient-reported outcomes after stopping DMT in older MS patients.

11. Methods • Retrospective, observational chart review • Patients seen at all CCF MS centers (Cleveland, Las Vegas, Weston) • Confirmed MS diagnosis over age 60 • KP data available, 2010-2016 • Discontinuers must have been on DMT for at least 2 years prior to discontinuing and stopped after age 60. Hua et al, MSJ 2019

12. Results • Patient characteristics • 600 patients included • 178 (29.7%) discontinued • Current age, disease duration, treatment duration were significantly different between continuers and discontinuers Hua et al, MSJ 2019

13. Results • MRI characteristics • Similar lesion burden and volume loss • Spinal cord data missing Hua et al, MSJ 2019

14. Results • DMT use • Exposed to 2 DMTs over treatment course • 90.5% of patients exposed to interferons, and 42.2% exposed to glatiramer acetate • 22% exposed to unapproved therapies Hua et al, MSJ 2019

15. Results • Discontinuers (n=178) • 68% provider initiated • 42.1% ambulate independently • 10.7% of discontinuers later reinitiated DMT: • patient preference (N=8; 42.1%) • MRI changes (N=3; 15.8%) • clinical progression (N=4; 21.1%) • provider preference (N=3; 15.8%) • entering clinical trial (N=1; 5.3%) • Only 1 documented relapse in those that discontinued DMT. • No difference in MRI metrics due to low number of disease activity in cohort overall • Median follow up 4.1 years Hua et al, MSJ 2019

16. Results • Time-to-discontinuation model • GA use was a significant predictor of discontinuation compared to interferon (HR 1.46, 95% CI 1.02-2.09, p=0.039) • More DMT starts in RR patients led to increase risk of discontinuation compared to PP (HR 1.99, 95% CI 1.04-3.79; p=0.037) • Disease course, duration of disease, proportion of disease duration on DMT, number of DMT were not significant • By age 72, more than 50% probability to stopping DMT Hua et al, MSJ 2019

17. Results • Time-to-reinitiation model • 178 discontinued, 19 reinitiated • Provider initiated less likely to reinitiate (HR 0.34, 95% CI 0.12-0.97; p=0.044) • Disease course, gender, disease duration, proportion of disease on treatment, DMT at discontinuation, and independent ambulation were not significant • Probability of reinitation four years after discontinuation was 16.1% Hua et al, MSJ 2019

18. Results • Disability changes • PS – 89 discontinuers, median follow-up 576 days. • Lower scores indicate less disability • RR patient had a PS score 2.51 less than PP • Provider-initiated discontinuation was associated with a lower PS compared to patient-initiated, with an average difference of 2.01 • T25FW rate- 83 discontinuers, median follow-up 592 days • Lower rates indicate higher disability • SP had decreasing walking rates by 0.30 feet per second per year compared to RR Hua et al, MSJ 2019

19. Conclusions • DMT discontinuation is more successful when age is considered, compared to disease stability alone, as this can help serve as a surrogate for “burnt out” inflammatory processes and aging immune systems • Limitations • Inability to compare stable pts who no longer need DMT vs progressive pts who no longer need DMT • 200 (33%) total in entire sample; 75 (42.1%) discontinuers; and 125 (29.6%) continuers) in this study were diagnosed long before DMTs became available, and thus were exposed to unapproved immunosuppressive therapies • High efficacy agents not available until much later in disease course for this cohort

20. PROs changes between continuers and discontinuers • Second study looking at impact of discontinuing DMT on patient reported outcomes • Same patient cohort, median follow up time 5.3 years • Outcomes- EQ-5D, PS, T25FW, PHQ9 • 3 treatment groups • Continuers • Discontinuers • Before Discontinuation • After Discontinuation

21. Results • Only ED-5D demonstrated significance over time • Discontinuers with better scores over time • No statistically significant differences in PS, T25FW and PHQ-9, new T2 or GdE lesions • Trend towards greater change in PS in continuers Hua et al, MSRAD 2019

22. Conclusions • Use of patient-reported outcomes are important to understand treatment decisions • Overall, stopping DMT appears to have minimal effect on PROs over time. • EQ-5D worsened more in those who continued DMT vs discontinued • May be driven by use of injectable therapies • Discontinuers may be more stable cohort

23. Discussion • Reassurance regarding stopping DMT in older patients, over 60 • Unclear benefit of DMT in older patients • Balancing risk of infections such as PML and malignancy • Need to continue monitoring for disease activity after discontinuation • Randomized prospective study over age 55 with stable disease underway (ClinicalTrials.gov Identifier: NCT03073603)