REMODEL-1 & 2
Remibrutinib
Remibrutinib reduced annualized relapse rates versus teriflunomide in two identically designed trials in relapsing multiple sclerosis.
- Phase
- Phase III
- Population
- Relapsing multiple sclerosis (RMS)
- Controlled period
- Dec 13, 2021 — Jul 22, 2026
What was compared
Remibrutinib
100 mg orally twice daily with matching teriflunomide placebo
n=1,006 across both trialsTeriflunomide
14 mg orally once daily with matching remibrutinib placebo
n=1,001 across both trialsPrimary endpoint
Annualized relapse rate
Confirmed MS relapses per participant-year during up to 30 months of controlled follow-up
Primary endpoint results
REMODEL-1 — annualized relapse rate
Confirmed relapses per participant-year
REMODEL-2 — annualized relapse rate
Confirmed relapses per participant-year
The rate ratio was 0.648 (95% CI 0.453–0.927, P=0.018) in REMODEL-1 and 0.688 (95% CI 0.487–0.972, P=0.034) in REMODEL-2.
Selected secondary outcomes
Annualized lesion rates with remibrutinib versus teriflunomide were 0.94 versus 2.71 in REMODEL-1 and 0.82 versus 2.77 in REMODEL-2 (P<0.0001 in each trial).
In the prespecified combined analysis, the 24-month estimates were 11.7% with remibrutinib and 14.1% with teriflunomide (HR 0.80, 95% CI 0.61–1.04, P=0.090). The difference was not statistically significant.
In the prespecified combined analysis, the 24-month estimates were 7.7% with remibrutinib and 10.5% with teriflunomide (HR 0.70, 95% CI 0.51–0.98, nominal P=0.038).
Who was studied
Key inclusion criteria
- Age 18–55 years
- RMS diagnosis based on McDonald criteria 2017
- Baseline EDSS 0–5.5
- At least 1 relapse in the prior year, at least 2 in the prior 2 years, or at least 1 active gadolinium-enhancing lesion in the year before screening
- Neurologically stable for at least 1 month before both screening and randomization
Key exclusion criteria
- Disease duration over 10 years with EDSS of 2 or less at screening
- Use of specified disease-modifying therapies within protocol-defined washout periods
Participants at baseline
REMODEL-1
| Characteristic | RemibrutinibN=502 | TeriflunomideN=498 |
|---|---|---|
| Age, years — mean ± SD | 38.1 ± 10.0 | 38.3 ± 9.6 |
| Female sex — n (%) | 326 (64.9%) | 340 (68.3%) |
| RRMS — n (%) | 482 (96.0%) | 483 (97.0%) |
| SPMS — n (%) | 20 (4.0%) | 15 (3.0%) |
| Time since first symptoms, years — median (IQR) | 3.7 (1.1–9.3) | 4.0 (0.9–10.6) |
| Time since diagnosis, years — median (IQR) | 1.1 (0.3–6.0) | 1.4 (0.2–7.9) |
| Treatment-naive — n (%) | 319 (63.5%) | 307 (61.6%) |
| Relapses in prior 12 months — mean ± SD | 1.1 ± 0.53 | 1.1 ± 0.52 |
| EDSS — mean ± SD | 2.57 ± 1.4 | 2.56 ± 1.3 |
| Gadolinium-enhancing T1 lesions — mean ± SD | 0.89 ± 2.3 | 1.06 ± 3.8 |
| No gadolinium-enhancing T1 lesions — n/N (%) | 250/354 (70.6%) | 264/367 (71.9%) |
| T2 lesion volume, cm³ — mean ± SD | 10.85 ± 11.7 | 10.97 ± 11.5 |
MRI values are for the MRI analysis set (remibrutinib n=354, teriflunomide n=367).
Source: Wiendl et al., The Lancet 2026, Table 1
REMODEL-2
| Characteristic | RemibrutinibN=504 | TeriflunomideN=503 |
|---|---|---|
| Age, years — mean ± SD | 39.0 ± 10.0 | 39.1 ± 9.4 |
| Female sex — n (%) | 340 (67.5%) | 335 (66.6%) |
| RRMS — n (%) | 495 (98.2%) | 496 (98.6%) |
| SPMS — n (%) | 9 (1.8%) | 7 (1.4%) |
| Time since first symptoms, years — median (IQR) | 3.7 (0.9–9.5) | 3.7 (0.8–9.0) |
| Time since diagnosis, years — median (IQR) | 1.0 (0.3–6.6) | 1.0 (0.2–6.6) |
| Treatment-naive — n (%) | 296 (58.7%) | 289 (57.5%) |
| Relapses in prior 12 months — mean ± SD | 1.1 ± 0.52 | 1.1 ± 0.58 |
| EDSS — mean ± SD | 2.52 ± 1.4 | 2.43 ± 1.3 |
| Gadolinium-enhancing T1 lesions — mean ± SD | 0.94 ± 2.7 | 0.90 ± 2.5 |
| No gadolinium-enhancing T1 lesions — n/N (%) | 225/313 (71.9%) | 219/319 (68.7%) |
| T2 lesion volume, cm³ — mean ± SD | 11.11 ± 12.2 | 11.32 ± 12.0 |
MRI values are for the MRI analysis set (remibrutinib n=313, teriflunomide n=319).
Source: Wiendl et al., The Lancet 2026, Table 1
Safety signal
- In the pooled controlled phase, adverse events occurred in 800 of 1,006 participants (79.5%) with remibrutinib and 816 of 1,001 (81.5%) with teriflunomide. Serious adverse events occurred in 60 (6.0%) and 70 (7.0%), respectively.
- Adverse events led to treatment discontinuation in 31 participants (3.1%) with remibrutinib and 58 (5.8%) with teriflunomide.
- Bleeding events were reported in 128 participants (12.7%) with remibrutinib and 67 (6.7%) with teriflunomide. Serious infections occurred in 23 (2.3%) and 13 (1.3%), respectively.
- New ALT elevations above 3 times the upper limit of normal occurred in 20 participants (2.0%) with remibrutinib and 73 (7.4%) with teriflunomide among those eligible for the laboratory analysis. Neither arm had a case meeting Hy’s law criteria.
- Two deaths occurred in the remibrutinib arm and none in the teriflunomide arm. Investigators assessed both deaths as unrelated to study treatment.
Why it mattered
The two trials independently showed that an oral BTK inhibitor could lower relapse rates compared with an active oral therapy. MRI lesion outcomes also favored remibrutinib in both trials.
Important limitation
The confirmed disability progression results were less conclusive than the relapse results. The prespecified combined 3-month endpoint was nonsignificant, and the 6-month result was nominally significant.