Long-term Safety and Effectiveness of Natalizumab

STRATA MS Study

STRATA Feeder Studies Study Protocol NAFFIRM Natalizumab vs Placebo 942

SENTINEL Natalizumab + IM IFNB-1a vs Placebo + IM IFNB-1a

1171

GLANCE Natalizumab + GA vs Placebo + GA

110

STARS Natalizumab vs SC IFNB-1a vs Placebo

6

Total entering STRATA=1094O’Connor P, et .al. Neurology. 2014;83:78-86.

Total number enrolled: 1,094• 245 (22%) patients discontinued• 217 (20%) completed initial 24-48 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 studyO’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: 33-91

• Lifetime natalizumab exposure: 34-111 infusionsO’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 weeksO’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 benefitsO’Connor P, et .al. Neurology. 2014;83:78-86