1. © 2014 Direct One Communications, Inc. All rights reserved. 1 Natalizumab and Dimethyl Fumarate: A Fresh Take on Pivotal Trials and Reports from Ongoing Monitoring Carolyn Bevan, MD, MS Multiple Sclerosis Center, University of California, San Francisco, School of Medicine, San Francisco, California A REPORT FROM THE 29TH CONGRESS OF THE EUROPEAN COMMITTEE FOR TREATMENT AND RESEARCH IN MULTIPLE SCLEROSIS (ECTRIMS 2013)

2. © 2014 Direct One Communications, Inc. All rights reserved. 2 Introducing a New Endpoint: Disease Activity-Free Status Disease activity-free status (DAFS) is a composite endpoint defined by: » Freedom from relapse » Zero progression of the Expanded Disability Status Scale (EDSS) score over 12 weeks » Lack of gadolinium-enhancing or new/enlarging lesions on MRI over a period of 2 years. DAFS is an adaptation of a similar outcome measure used in clinical research studies of rheumatoid arthritis; its application in multiple sclerosis (MS) research carries similar significance in terms of advancement of the ability to control the disease. Havrdova E et al, Neurology 2010;74:S3

3. © 2014 Direct One Communications, Inc. All rights reserved. 3 Natalizumab

4. © 2014 Direct One Communications, Inc. All rights reserved. 4 AFFIRM Study AFFIRM was a phase 3, multicenter, placebo- controlled, 2-year randomized clinical trial involving 600 patients with relapse-remitting MS (RRMS) given natalizumab and 304 given placebo. Study participants were divided into subgroups according to age, disease duration, number of relapses experienced in the past year, EDSS score, and total gadolinium-enhancing lesions detected. In all subgroups, a significantly greater proportion of patients given natalizumab than those given placebo achieved freedom from disease activity over 2 years (P  0.0005). Havrdova E et al, Neurology 2010;74:S3

5. © 2014 Direct One Communications, Inc. All rights reserved. 5 AFFIRM Study In natalizumab-treated patients, a greater proportion of people who were younger or who had shorter disease duration, fewer relapses in the prior year, lower EDSS scores, and fewer gadolinium-enhanced lesions at baseline reached DAFS. In patients who received placebo, only those with fewer gadolinium-enhanced lesions achieved a higher proportion of DAFS. The odds ratios of achieving DAFS in the second year in patients favored natalizumab were significantly greater with an EDSS score < 3.0 than among those having an EDSS score  3.0 at baseline. Polman CH et al, N Engl J Med. 2006;354:899

6. © 2014 Direct One Communications, Inc. All rights reserved. 6 Tysabri Observational Program (TOP) TOP is an ongoing, multinational, open-label, 10-year prospective study of DAFS among 2,595 patients with RRMS who were treated with natalizumab. The majority of patients in all subgroups reached DAFS at 2 years of natalizumab therapy. As observed in the AFFIRM population, a greater proportion of patients with lower EDSS scores, fewer relapses, and fewer gadolinium-enhancing lesions at baseline reached DAFS at 2 years of natalizumab treatment, suggesting that treating patients who are earlier in their disease course and less disabled may increase the odds of achieving DAFS. Kappos L et al, AAN 2012, Abstract P04.133

7. © 2014 Direct One Communications, Inc. All rights reserved. 7 Relapses in Patients on Natalizumab A post hoc analysis of data from the AFFIRM study showed that patients treated with natalizumab experienced a reduction in relapse severity and post- relapse disability when compared with placebo. Natalizumab-treated patients with an increase in EDSS score  0.5 point during relapse had a 55% increased cumulative probability of complete recovery from relapse relative to the placebo group. In addition, when compared with the placebo group, natalizumab-treated patients with an increase in EDSS score of  1 point during relapse had a 67% increased cumulative probability of full recovery. Lublin FD et al, ECTRIMS 2013, Abstract P524

8. © 2014 Direct One Communications, Inc. All rights reserved. 8 TYSTART Trial Data on 168 German patients with RRMS who were treated with natalizumab for 12 months showed: » Stabilization of the mean EDSS score (3.6  1.7 at 12 months vs 3.5  1.7 at baseline) » Improvement in the mean Fatigue Severity Score (FSS) from 4.1  1.7 at baseline to 2.2  2.1 at 12 months. Two patients experienced a relapse of MS on therapy. Only four serious adverse events (SAEs) occurred. Of 228 JC virus-antibody tests, 28.1% were positive. None of the patients developed progressive multifocal leukoencephalopathy (PML). Kallmann B et al, ECTRIMS 2013, Abstract P1066

9. © 2014 Direct One Communications, Inc. All rights reserved. 9 Discontinuation of Natalizumab Therapy Of the 1,017 patients in the Danish registry given natalizumab for longer than 24 weeks, 392 discontinued therapy. Within the first 1–3 months after discontinuing natalizumab, patients returned to their pretreatment relapse rate. They subsequently returned to their on-treatment relapse rate, presumably because they began using another disease-modifying therapy. These findings suggest that the “immune overshoot” described in earlier reports is the exception. Sørensen PS et al, ECTRIMS 2013, Abstract P1058

10. © 2014 Direct One Communications, Inc. All rights reserved. 10 Dimethyl Fumarate

11. © 2014 Direct One Communications, Inc. All rights reserved. 11 Post Hoc Analyses: DEFINE and CONFIRM Trials In a post hoc analysis of DAFS in patients with RRMS treated with dimethyl fumarate in the pivotal DEFINE and CONFIRM trials: » The proportion of patients with no measured overall disease activity at 2 years was 23% in patients treated twice daily as well as those treated three times a day, as compared with 11% in the placebo group. » Patients who had been treated with dimethyl fumarate were twice as likely to have no measured overall disease activity at 6 months, 1 year, and 2 years. These findings reflected promising advances in the treatment of RRMS. Gold R et al, N Engl J Med. 2012;367:1098; Fox RJ et al, N Engl J Med. 2012;367:1087; Havrdova E et al, ECTRIMS 2013, Abstract P521

12. © 2014 Direct One Communications, Inc. All rights reserved. 12 In both studies, dimethyl fumarate was shown to be effective whether patients previously had been treated with interferon beta-1a or glatiramer acetate. Similar therapeutic benefits of dimethyl fumarate were shown in the integrated population as well as its component studies, with an: » Adjusted annualized relapse rate of about 50% » Approximately 30% reduction in confirmed disability progression » 85% reduction in gadolinium-enhanced lesion activity » 80% reduction in the number of new or enlarging T2 hyperintense lesions Post Hoc Analyses: DEFINE and CONFIRM Trials Hutchinson M et al, ECTRIMS 2013, Abstract P563; Hutchinson M et al, ECTRIMS 2013, Abstract P1013

13. © 2014 Direct One Communications, Inc. All rights reserved. 13 ENDORSE Study: Four-Year Follow-Up Among 1,736 patients enrolled in ENDORSE who were treated with dimethyl fumarate for 4 years, the relapse rate remained low, as did the proportion of patients who relapsed at 4 years (36.2%). Among the group treated with dimethyl fumarate twice daily for 4 years, 15.4% experienced disease progression. The groups of patients initially on placebo or glatiramer acetate and transitioned to dimethyl fumarate for the first 2 years of the ENDORSE study showed similar clinical outcomes when compared with the group treated for 4 years. Gold R et al, ECTRIMS 2013, Abstract P538

14. © 2014 Direct One Communications, Inc. All rights reserved. 14 ENDORSE Study: Four-Year Follow-Up The mean number of new/enlarging T2 hyperintense lesions (1.3) and new non-enhancing T1 hypointense lesions (0.6) remained low in patients treated with dimethyl fumarate two or three times daily. The number of new gadolinium-enhanced lesions also remained low in both populations. In patients switched from placebo or glatiramer acetate to dimethyl fumarate, MRI measures approached those of the group treated with dimethyl fumarate in the phase 3 studies. Miller DH et al, ECTRIMS 2013, Abstract P1004

15. © 2014 Direct One Communications, Inc. All rights reserved. 15 ENDORSE Study: Four-Year Follow-Up Flushing and adverse gastrointestinal (GI) events were more frequent among patients treated with dimethyl fumarate than among those given placebo. Diarrhea occurred in 8% of patients who continued on dimethyl fumarate and 13% of those who were switched from placebo to dimethyl fumarate. Other adverse events occurring in  10% of patients receiving dimethyl fumarate in the ENDORSE study included nasopharyngitis, urinary tract infections, headache, upper respiratory tract infections, back pain, and upper abdominal pain. Phillips JT et al, ECTRIMS 2013, Abstract P996

16. © 2014 Direct One Communications, Inc. All rights reserved. 16 ENDORSE Study: Four-Year Follow-Up In all, 27% of patients experienced MS relapse in the continuing on dimethyl fumarate, compared with 27% in the prior-placebo group and 20% in the prior-glatiramer acetate group. A total of 4%–6% of patients who continued on dimethyl fumarate discontinued therapy due to adverse events, as did 14%–23% of patients who were switched from placebo to dimethyl fumarate. The incidence of malignancies in the group continued on dimethyl fumarate was 1%, with no evidence of increased risk of malignancy. Phillips JT et al, ECTRIMS 2013, Abstract P996

17. © 2014 Direct One Communications, Inc. All rights reserved. 17 Laboratory Abnormalities In the ENDORSE study, mean WBC and lymphocyte counts declined in patients switched from placebo to dimethyl fumarate and remained stable among those who continued on dimethyl fumarate. Elevated AST and ALT levels at least three times the upper limit of normal were noted in < 2% of patients, and there were no cases of drug-induced liver injury. Proteinuria, microalbuminuria, and hematuria were the most commonly observed renal adverse events, occurring in at least 3% of patients in all treatment groups. Phillips JT et al, ECTRIMS 2013, Abstract P996

18. © 2014 Direct One Communications, Inc. All rights reserved. 18 Laboratory Abnormalities An integrated analysis of the data from the DEFINE, CONFIRM, and ENDORSE studies revealed that in patients treated with dimethyl fumarate, mean WBC counts fell by 11% and mean lymphocyte counts fell by 30% through week 48 of treatment; they later plateaued but remained within normal limits through the remainder of the 96 weeks. Grade 3/4 lymphopenia was observed in a higher percentage of patients in the dimethyl fumarate group than in the placebo group. The incidence of grade 3/4 lymphopenia increased through week 48 and then stabilized. Fox RJ et al, ECTRIMS 2013, Abstract P1018

19. © 2014 Direct One Communications, Inc. All rights reserved. 19 Laboratory Abnormalities Importantly, there was no increased incidence of infections or serious infections associated with development of lymphopenia during the monitoring period, and no opportunistic infections were observed. In patients with lymphopenia who discontinued dimethyl fumarate, lymphocyte counts rose after discontinuation, but they did not return to pretreatment baseline levels 4 weeks after treatment discontinuation, the significance of which is unclear, but it could influence decisions about switching to other medications that also may cause lymphopenia. Fox RJ et al, ECTRIMS 2013, Abstract P1018

20. © 2014 Direct One Communications, Inc. All rights reserved. 20 Conclusion Natalizumab continues to demonstrate consistent efficacy in both clinical and imaging outcomes. Its influence on recovery after an active relapse is even more intriguing. Although natalizumab is a powerful and effective drug, the risk of PML requires careful monitoring. In addition, patients should be closely monitored for recurrence of their previous level of aggressive disease activity after discontinuing the drug. Dimethyl fumarate is a meaningful new addition to the growing list of oral therapies for MS. It effectively treats both clinical and radiographic disease. Its long-term safety is currently being elucidated.