In the 2-year AFFIRM pivotal trial:

Relapsing MS patients received 300 mg TYSABRI every 28 days (n=627) or placebo (n=315). Patients with PPMS, SPMS, and PRMS were excluded.

83% of patients taking TYSABRI had no sustained disability progression for 12 weeks vs 71% with placebo (primary endpoint: 17% vs 29%; p<0.001)1,2

TYSABRI demonstrated 67% relative reduction in ARR vs placebo (secondary endpoint: 0.22 vs 0.67; p<0.001)1,2

LONG-TERM OBSERVATIONAL STUDY OF OVER 6000 PATIENTS REAFFIRMS THE TYSABRI SAFETY PROFILE.3

Study description: TOP is an ongoing, open-label, multinational, multicenter, prospective study observing 6148 patients with RRMS outside of the US receiving 300 mg TYSABRI IV every 4 weeks for 15 years in real-world clinical practice settings. Of the 6148 patients enrolled, 3210 patients have discontinued TYSABRI, and 2117 have withdrawn from TOP. Of the 3210 patients who have discontinued TYSABRI treatment, 1093 remain in TOP. RRMS patients enrolled in TOP are required to be TYSABRI-naïve or to have received ≤3 doses of TYSABRI in their lifetime. This 10-year interim analysis includes data from study initiation (July 2007) through November 1, 2017. 

Study limitations3:

  • The study is ongoing and observational, without randomization or a placebo control group
  • Attrition bias in inherent in long-term observational studies. Analysis of attrition bias is limited by the small number of patients in the <8-year treatment group, which decreased from 1056 at baseline to 389 at 8 years. The decrease occurred at various time points, resulting in varied treatment durations
  • Results should be interpreted with caution, as treatment practices vary by country
  • The longest evaluation of real-world outcomes in patients treated with TYSABRI to date
  • In 2007, Biogen initiated TOP, which assessed real-world safety and efficacy outcomes in patients treated with TYSABRI across the globe and is planned to continue out to 15 years

>85% of patients receiving TYSABRI experienced no SAEs in the 10-year TOP study

INCIDENCE OF SAEs OCCURRING IN ≥10 PATIENTS IN TOP

MedDRA PREFERRED TERM N=6148, n (%)a
Immune reconstitution inflammatory syndrome (IRIS)b 54 (0.9)
Progressive multifocal leukoencephalopathy (PML), confirmed 53 (0.9)
Abortion spontaneous 37 (0.6)
Hypersensitivity 26 (0.4)
Pneumonia 23 (0.4)
Urinary tract infection 20 (0.3)
Fall 19 (0.3)
Depression 18 (0.3)
Epilepsy 18 (0.3)
Herpes zoster 17 (0.3)
Breast cancer 12 (0.2)
Intervertebral disc protrusion 12 (0.2)
Escherichia urinary tract infection 12 (0.2)
Suicide attempt 11 (0.2)
Pulmonary embolism 10 (0.2)
Pyelonephritis 10 (0.2)

Copyright © 2020 Butzkueven H, et al; licensee BMJ is adapted under CC BY-NC.

aEach patient was counted only once within each preferred term. Multiple sclerosis relapse was also reported as an SAE in 20 patients (0.3%).3

bOne case of immune reconstitution inflammatory syndrome was not associated with PML.3

  • SAEs related to hypersensitivity reactions (n=40, <0.7% of patients) included anaphylactic reaction (n=4), anaphylactoid reaction (n=3), anaphylactic shock (n=5), and hypersensitivity (n=28)
  • 12 hepatic events (<0.2% of patients) were reported during the study
  • 30 deaths (<0.5%) were reported during the study
    • Physicians classified 8 deaths as treatment related, which included PML (n=4), IRIS (n=2, one of which was combined with MS relapse), metastatic breast cancer (n=1), and autonomic nervous system imbalance (n=1)

Incidence rates for opportunistic infections, malignancy, and PML were low (~1%)

SERIOUS ADVERSE EVENTS OF INTEREST

OVERALL
EXPOSURE
(26,060 patient-yearsc; N=6148)
FIRST 3 YEARS
ON TREATMENT
(15,773 patient-yearsc; N=6148)
BEYOND 3 YEARS
ON TREATMENT
(10,233 patient-yearsc; N=3719)
Patients with event, n (%) Incidence rate
(95% CI)d,e
Patients with event, n (%) Incidence rate
(95% CI)d,e
Patients with event, n (%) Incidence rate
(95% CI)d,e
Opportunistic infections other than PML
11 (0.18) 0.422
(0.234-0.762)
10 (0.16) 0.634
(0.341-1.178)
1 (0.03) 0.098
(0.014-0.694)
PML, confirmed
53 (0.86) 2.034
(1.554-2.662)
17 (0.28) 1.078
(0.67-1.734)
36 (0.97) 3.518
(2.537-4.877)
Malignancy
63 (1.02) 2.417
(1.889-3.095)
35 (0.57) 2.219
(1.593-3.090)
28 (0.75) 2.736
(1.889-3.963)
OVERALL EXPOSURE
(26,060 patient-yearsc; N=6148)
Patients with event, n% Incidence rate (95% CI)d,e
Opportunistic infections other than PML 11 (0.18) 0.422
(0.234-0.762)
PML, confirmed 53 (0.86) 2.034
(1.554-2.662)
Malignancy 63 (1.02) 2.417
(1.889-3.095)
FIRST 3 YEARS ON TREATMENT
(15,773 patient-yearsc; N=6148)
Patients with event, n% Incidence rate (95% CI)d,e
Opportunistic infections other than PML 10 (0.16) 0.634
(0.341-1.178)
PML, confirmed 17 (0.28) 1.078
(0.67-1.734)
Malignancy 35 (0.57) 2.219
(1.593-3.090)
BEYOND 3 YEARS ON TREATMENT
(10,233 patient-yearsc; N=3719)
Patients with event, n% Incidence rate (95% CI)d,e
Opportunistic infections other than PML 1 (0.03) 0.098
(0.014-0.694)
PML, confirmed 36 (0.97) 3.518
(2.537-4.877)
Malignancy 28 (0.75) 2.736
(1.889-3.963)

Copyright © 2020 Butzkueven H, et al; licensee BMJ is adapted under CC BY-NC.

cBased on the time from the first dose of natalizumab until the last natalizumab dosing date + 6 months.3

dCalculated as (1000 × number of patients with an event) / (total patient-years of follow-up).3

eExact CIs are calculated based on the Poisson distribution.3

  • The most commonly reported opportunistic infection was PML (confirmed; n=53 out of 6148 patients, or ~0.9%), followed by herpes zoster infection (n=3 out of 6148 patients, or 0.05%)
  • Results are in line with the current understanding of the risk factors for PML
    • Prior immunosuppressant use was reported by 26.4% of patients with PML 
    • 97.2% of PML cases (35 out of 36) with reported anti-JCV antibody serostatus 6 months prior to PML development were confirmed positive
    • JCV status was not tested at enrollment in 1809 out of 6148 patients (29.4%) and was missing from 7 patients who were tested at enrollment (0.1%)
    • 67.9% of PML cases (36 out of 53) occurred in patients receiving natalizumab for >3 years
  • Overall, there were 66 patients with 39 types of malignancies
  • Incidence of breast cancer was 0.3% (19 of 6148 patients), or 86.7 per 100,000 patient-years with TYSABRI (95% CI: 52.2-135.4 per 100,000 patient-years)

Results are consistent with the current understanding of PML risk factors

TYSABRI had a sustained impact on disability progression and ARR out to 10 years3,f

Copyright © 2020 Butzkueven H, et al; licensee BMJ is adapted under CC BY-NC.

fCumulative probability of confirmed disability worsening was defined as an increase of ≥1.5 from a baseline score of 0.0, ≥1.0 from a score of 1.0-5.5, or ≥0.5 from a score of ≥6.0, sustained for 24 weeks.3

Median EDSS scores were stable over 10 years

MEDIAN EDSS SCORES IN THE OVERALL STUDY POPULATION FROM ENROLLMENT TO YEAR 10
Year 0
(n=6088)
Year 1
(n=5696)
Year 2
(n=4995)
Year 3
(n=4359)
Year 4
(n=3808)
Year 5
(n=3156)
Year 6
(n=2395)
Year 7
(n=1771)
Year 8
(n=1126)
Year 9
(n=533)
Year 10
(n=208)
Median
EDSS score
3.5
3.0
3.0
3.0
3.0
3.0
3.5
3.5
3.5
4.0
4.0
MEDIAN EDSS SCORES IN THE OVERALL
STUDY POPULATION FROM
ENROLLMENT TO YEAR 10
Median EDSS score
Year 0 (n=6088) 3.5
Year 1 (n=5696) 3.0
Year 2 (n=4995) 3.0
Year 3 (n=4359) 3.0
Year 4 (n=3808) 3.0
Year 5 (n=3156) 3.0
Year 6 (n=2395) 3.5
Year 7 (n=1771) 3.5
Year 8 (n=1126) 3.5
Year 9 (n=533) 4.0
Year 10 (n=208) 4.0
  • At Year 10, very few patients were eligible to be counted due to disability progression measurements (which had to verify sustained progression 6 months after detecting progression), low initial enrollment, and treatment discontinuations

TYSABRI reduced relapses by 88% at Year 1, with low ARRs (≤0.21) sustained out to 10 years3,g

Copyright © 2020 Butzkueven H, et al; licensee BMJ is adapted under CC BY-NC.

gARRs for the year prior to starting natalizumab and the period during which patients were on natalizumab (and ≤84 days after the last dose) were compared using a repeated Poisson model.3

TYSABRI administration early in the treatment course reduced relapses by 88% at Year 1, with low ARR sustained out to 10 years.

  • In the overall population, ARR decreased from 1.99 at baseline to 0.24 after 1 year of TYSABRI treatment, and ARRs remained ≤0.20 out to 10 years. Similar results were observed in the other cohorts:
    • In the ≥8-year treatment cohort, ARR decreased from 2.04 at baseline to 0.21 at Year 1, and ARRs remained ≤0.21 in subsequent years
    • In the <8-year treatment cohort, ARR decreased from 1.97 at baseline to 0.26 at Year 1, and ARRs remained ≤0.21 in subsequent years

ARR decreased by >90% for patients taking TYSABRI, regardless of baseline EDSS3

ARR BY BASELINE EDSS

  • Patients experienced lower ARR when TYSABRI was used at lower baseline EDSS scores (≤3.0)
  • Patients achieved a significant reduction in clinical disease activity, as defined by ARR, regardless of high EDSS scores (≥3.0)

Early use of TYSABRI in patients resulted in a lower ARR than did later use of TYSABRI3

ARR BY NUMBER OF PRIOR DMTs

  • Patients experienced lower ARR when TYSABRI was used earlier in the treatment course (for patients with no prior DMT use vs those who had taken ≥2 prior DMTs)
  • Patients achieved a significant reduction in clinical disease activity, as defined by ARR, regardless of prior use of DMTs (≥1)

ARR was lower in patients who received TYSABRI after ≤1 relapse in the prior year vs >1 relapse3

ARR BY PRIOR RELAPSES

  • Patients experienced lower ARR when TYSABRI was used at lower pre-TYSABRI relapse rates (≤1 relapse in prior year)
  • Patients achieved a significant reduction in clinical disease activity, as defined by ARR, regardless of a higher number of relapses (>1 in prior year)

TYSABRI reduced ARR in the 10-year TOP study when used early
or late in the disease course3

The TOP Study was funded by Biogen.