AFFIRM
Natalizumab
AFFIRM showed large effects of natalizumab monotherapy on relapses, disability progression, and MRI activity in relapsing MS.
- Phase
- Phase III
- Population
- Relapsing-remitting multiple sclerosis (RRMS)
- Controlled period
- Nov 2001 — Nov 2004
What was compared
Natalizumab
300 mg intravenous infusion every 4 weeks
n=627Placebo
Matching intravenous infusion every 4 weeks
n=315Primary endpoint
Clinical relapse and sustained disability progression
Relapse at 1 year; disability at 2 years
Primary endpoint results
Annualized clinical relapse rate
Relapses per participant-year
12-week sustained disability progression
Participants with progression (%)
68% lower clinical relapse rate at 1 year and 42% lower risk of sustained disability progression at 2 years.
Selected secondary outcomes
Mean 1.9 with natalizumab versus 11.0 with placebo over 2 years.
92% fewer with natalizumab at years 1 and 2.
Who was studied
Key inclusion criteria
- Age 18–50 years
- Relapsing MS diagnosis based on McDonald criteria 2001
- Baseline EDSS 0–5.0
- At least 1 documented relapse in the previous 12 months
- MRI lesions consistent with MS
Key exclusion criteria
- PPMS, SPMS, or progressive-relapsing MS
- Relapse within 50 days before randomization
- Cyclophosphamide or mitoxantrone in the previous year
- Interferon, glatiramer acetate, cyclosporine, azathioprine, methotrexate, or intravenous immunoglobulin in the previous 6 months
- More than 6 months of previous interferon or glatiramer acetate treatment
Participants at baseline
| Characteristic | NatalizumabN=627 | PlaceboN=315 |
|---|---|---|
| Age, years — mean ± SD | 35.6 ± 8.5 | 36.7 ± 7.8 |
| Female sex — n (%) | 449 (72%) | 211 (67%) |
| MS duration, years — median (range) | 5.0 (0–34) | 6.0 (0–33) |
| EDSS — mean ± SD | 2.3 ± 1.2 | 2.3 ± 1.2 |
| Relapses in previous 12 months — mean ± SD | 1.53 ± 0.91 | 1.50 ± 0.77 |
| Gadolinium-enhancing lesions — mean ± SD | 2.2 ± 4.7 | 2.0 ± 4.8 |
SD: standard deviation; EDSS: Expanded Disability Status Scale.
Source: Polman et al., NEJM 2006, Table 1
Safety signal
- Fatigue and allergic reactions were more frequent with natalizumab.
- Serious hypersensitivity occurred in 1% of natalizumab-treated participants.
- The controlled trial was not large or long enough to define rare opportunistic infection risk.
Later safety context
Later regulatory context (2006): the FDA label included a boxed warning for progressive multifocal leukoencephalopathy (PML) and restricted distribution through TOUCH. This broader safety experience is separate from the AFFIRM controlled results above.
FDA, Tysabri label, 2006 ↗Why it mattered
AFFIRM demonstrated that targeting leukocyte entry into the central nervous system could substantially reduce relapses and confirmed disability progression. It established natalizumab as a major monoclonal-antibody treatment strategy, while later safety experience made treatment-specific risk assessment essential.
Important limitation
Rare but serious risks cannot be inferred from AFFIRM alone; its efficacy findings must be separated from safety knowledge accumulated outside this monotherapy trial.