Long-term Safety and Effectiveness of Natalizumab STRATA MS Study

STRATA Feeder Studies Study Protocol N AFFIRM Natalizumab vs Placebo 942 SENTINEL Natalizumab + IM IFNB-1a vs Placebo + IM IFNB-1a 1171 GLANCE Natalizumab + GA vs Placebo + GA 110 STARSNatalizumab vs SC IFNB-1a vs Placebo 6 Total entering STRATA=1094 O’Connor P, et.al. Neurology. 2014;83:78-86.

Total number enrolled: 1, (22%) patients discontinued 217 (20%) completed initial weeks but did not continue into STRATA extension 632 (58%) remained in STRATA up to week 240 Patient Distribution O’Connor P, et.al. Neurology. 2014;83:78-86.

Patient Characteristics at Entry into STRATA (N=1,094) Mean age (yrs)41.4 Sex (M/F) (%) 31/69 Median EDSS score* 2.5 Median disease duration since diagnosis (yrs) 8 Median no. relapses* 1 Median no. natalizumab doses 32 Median time since last natalizumab infusion (wks) 85 * In year before entry into feeder study O’Connor P, et.al. Neurology. 2014;83:78-86.

Safety Results Adverse events (including PML) were consistent with natalizumab’s known profile Anti-natalizumab antibody and hypersensitivity rates with natalizumab re-exposure – Overall Anti-natalizumab antibodies: 3% Hypersensitivity: 5% – 1 to 2 prior natalizumab doses Anti-natalizumab antibodies: 40% Hypersensitivity: 24% O’Connor P, et.al. Neurology. 2014;83:78-86.

Safety: Patients with PML 8 cases as of 2/9/12; 14 cases as of 8/23/13 Prior to diagnosis – All 14 were anti-JCV antibody-positive at all time points >6 months – All had >2 years natalizumab exposure 5 (36%) had previously received immunosuppressive therapy Natalizumab infusions since reintroduction in STRATA before PML diagnosis: Lifetime natalizumab exposure: infusions O’Connor P, et.al. Neurology. 2014;83:78-86

Patients originally randomized to placebo/other disease-modifying therapy Had similar EDSS scores at feeder study entry to those originally randomized to natalizumab (2.36 vs 2.38) Had significantly higher EDSS scores at STRATA entry (3.13 vs 2.90; P =.027) This difference persisted over 240 weeks in STRATA (3.15 vs 2.79; P =.024) Efficacy Results: EDSS* * Assessed every 24 weeks O’Connor P, et.al. Neurology. 2014;83:78-86

Efficacy Results: Annualized Relapse Rate(ARR) Patients originally randomized to natalizumab had a lower ARR than those randomized to placebo (0.15 vs 0.22) However, reductions beyond week 48 were seen in both groups A statistical difference between groups was seen during the first year (P<.01) and during the overall study (P<.01), but not during other individual years O’Connor P, et.al. Neurology. 2014;83:78-86

Conclusions Natalizumab re-dosing after an extended treatment gap was not associated with a change in immunogenic response for most patients However, the incidence of anti-natalizumab antibodies and hypersensitivity was higher in patients with only 1-2 prior doses, suggesting that a brief exposure followed by an extended treatment gap contributed to a higher risk for these events on re-exposure O’Connor P, et.al. Neurology. 2014;83:78-86

Conclusions PML – All patients had known risk factors Anti-JCV antibodies >6 months prior to diagnosis >2 years of natalizumab exposure – It is unknown whether dosing interruption impacted PML incidence Efficacy results suggest – Earlier treatment may provide a lasting advantage compared with later treatment – Earlier suppression of inflammatory activity may have important clinical benefits O’Connor P, et.al. Neurology. 2014;83:78-86