In the 2-year AFFIRM pivotal trial:

Relapsing MS patients received 300 mg TYSABRI IV 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 physical 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

RESULTS FROM 10-YEAR
TYSABRI OBSERVATIONAL PROGRAM (TOP) STUDY

TYSABRI was further studied in the ongoing TOP study. The 10-year interim results found:

A decade of well-understood efficacy and safety observed in ~6000 real-world patients taking TYSABRI3

Study description: TOP is an ongoing, open-label, multinational, observational, 10-year prospective study with planned continued follow-up for up to 15 years, assessing the long-term safety and efficacy of TYSABRI in 6148 patients with relapsing MS in clinical practice. Eligible RRMS patients met criteria for a TYSABRI prescription in their respective countries and had 3 or fewer TYSABRI infusions before enrollment in the TOP study. Patients receive TYSABRI 300 mg intravenously every 4 weeks.3,4

  • Primary endpoint is long-term safety (incidence and type of serious AEs)
  • This interim analysis included data from study initiation (July 2007) through November 2017. Patients enrolled in TOP at various time points, resulting in varied treatment duration. Median duration of TYSABRI therapy was 38 doses (range: 1-135) and median follow-up time was 62 months (range: 1-130)3
  • Data were collected at regular clinical visits every 6 months, and data entry was Web based. Patients who discontinued TYSABRI were encouraged to remain in the study4
  • ARRs were estimated using a negative binomial model. Time to and cumulative probabilities of progression and improvement were analyzed using the Kaplan-Meier method4

Study limitations3:

  • The study is ongoing and observational, without randomization or a placebo control group
  • Of the 6148 patients enrolled, 3210 patients discontinued TYSABRI but remained in TOP, and 2117 withdrew from TOP

10-year data show real-world safety findings (incidence/type of SAEs) were consistent with previous studies of TYSABRI—No new safety concerns were identified3

Incidence of SAEs occurring in ≥10 patients in TOP

  • Overall, 13.5% of patients experienced ≥1 SAE; 4.7% had ≥1 SAE reported to be treatment related. There were 30 deaths (0.5%)
MedDRA PREFERRED TERM N=6148, N (%)a
Immune reconstitution inflammatory syndrome (IRIS) 54 (0.9)
Progressive multifocal leukoencephalopathy (PML), confirmed 52 (0.8)
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)
Suicide attempt 11 (0.2)
Escherichia urinary tract infection 10 (0.2)
Pulmonary embolism 10 (0.2)
Pyelonephritis 10 (0.2)

Adapted from the European Committee for Treatment & Research in Multiple Sclerosis.

  • SAEs were assessed at clinical visits beginning with the first dose of TYSABRI
  • SAEs that occurred up to 6 months after the last TYSABRI infusion were included, except for PML and death, which were included after the first dose, irrespective of the date of occurrence

Serious Adverse Events of Interest3

TYSABRI Serious Adverse Events of Interest
TYSABRI Serious Adverse Events of Interest

Incidence rates for OI, malignancy, and PML were low (~1%) and were similar during the first 3 years on treatment and beyond, as indicated by overlapping confidence intervals.

  • The most commonly reported OI was PML (confirmed or suspected; n=59), followed by herpes zoster infection (n=2)
  • The most commonly reported malignancies were breast cancer (including intraductal proliferative breast lesion and invasive ductal breast carcinoma; n=21), papillary thyroid cancer (n=4), and basal cell carcinoma (n=3)
  • The safety profile over 10 years is consistent with previous studies, with no new safety concerns identified

At 10 years, ARR reductions on TYSABRI were ~90% for all patient subgroups, regardless of prior treatmentb

  • ARR reductions from baseline were evaluated based on number of relapses in the prior year, number and type of previous DMT, and baseline EDSS score

ON-THERAPY ARR IN TYSABRI-TREATED PATIENTS ACCORDING TO
NUMBER OF RELAPSES IN PRIOR YEAR AND NUMBER OF PREVIOUS DMTs

On-therapy ARR in TYSABRI-treated patients according to number of relapses in prior year and number of previous DMTs
On-therapy ARR in TYSABRI-treated patients according to number of relapses in prior year and number of previous DMTs

ON-THERAPY ARR IN TYSABRI-TREATED PATIENTS
ACCORDING TO BASELINE EDSS SCORE

On-therapy ARR in TYSABRI-treated patients according to baseline EDSS score
On-therapy ARR in TYSABRI-treated patients according to baseline EDSS score

Adapted from Kappos et al. ECTRIMS poster P908. Oct. 10-12, 2018. Berlin, Germany.
Error bars indicate 95% confidence intervals.

  • Patients experienced lower ARR when TYSABRI was used:
    • At lower baseline EDSS scores (<3.5)
    • At lower pre-TYSABRI relapse rates (≤1 relapse in prior year)
    • Earlier in the treatment course (for treatment-naïve patients and those who are transitioning therapy)

Early use of TYSABRI in the disease course showed reduced ARR at 10 years

 

TOP data showed greater effect on ARR when TYSABRI was used with no prior DMT vs those who have taken prior oral or injectable therapies

ON THERAPY ARR IN TYSABRI-TREATED PATIENTS
ACCORDING TO TYPE OF PREVIOUS DMT

On-therapy ARR in TYSABRI-treated patients according to previous DMT
On-therapy ARR in TYSABRI-treated patients according to previous DMT
Type of DMTs Used Prior to TYSABRI Initiation

Adapted from Kappos et al. ECTRIMS poster P908. Oct. 10-12, 2018. Berlin, Germany.

  • 94.1% decrease in ARR at 10 years compared with the year prior to TYSABRI initiation in treatment-naïve patients

At 10 years, ARR reductions on TYSABRI were nearly 95% in treatment-naïve patients

 

TYSABRI also benefited patients when initiated later in the disease course

  • Patients achieved significant reductions in clinical disease activity, as defined by ARR, regardless of:
    • High EDSS scores (≥3.5)
    • Higher number of relapses (>1 in prior year)
    • Prior use of DMTs (>1)

Used from the start or initiated later, TOP 10 shows TYSABRI is safe and effective at any stage of the relapsing disease course

75% of patients had no confirmed disability worsening at 9 years

  • 25% of patients had confirmed disability worseningc

RRMS=relapsing-remitting multiple sclerosis; SAE=serious adverse event; OI=opportunistic infection; DMT=disease-modifying therapy; ARR=annualized relapse rate; EDSS=Expanded Disability Status Scale; CI=confidence interval.
 

aEach patient was counted only once within each preferred term. Multiple sclerosis was also reported as an SAE in 15 patients.3

bARRs 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

cCumulative 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 ≥6.0, sustained for 24 weeks.3