FENhance 1 & 2

Fenebrutinib

The parallel FENhance trials reported that investigational fenebrutinib reduced relapses and MRI lesion activity more than teriflunomide in relapsing multiple sclerosis.

Phase
Phase III
Population
Relapsing multiple sclerosis (RMS)
Controlled period
Mar 17, 2021 — Jan 27, 2026

What was compared

Two parallel trialsRandomized 1:1Double-blindDouble-dummy
Intervention

Fenebrutinib

200 mg orally twice daily with matching placebo

Comparator

Teriflunomide

14 mg orally once daily with matching placebo

1,497 randomized across two trialsAt least 96 weeks controlled phase

Primary endpoint

Prespecified outcome

Annualized relapse rate

Minimum 96 weeks in each trial

Outcome figure

Primary endpoint results

Intervention Comparator or reference

FENhance 1 — annualized relapse rate

Adjusted relapses per participant-year

Minimum 96 weeks
Fenebrutinib
0.061
Teriflunomide
0.125

FENhance 2 — annualized relapse rate

Adjusted relapses per participant-year

Minimum 96 weeks
Fenebrutinib
0.054
Teriflunomide
0.130

Fenebrutinib reduced adjusted relapse rates by 51.1% in FENhance 1 (rate ratio 0.49; 95% CI 0.33–0.73; P<0.001) and 58.5% in FENhance 2 (0.42; 95% CI 0.28–0.61; P<0.00001).

Selected secondary outcomes

MRI lesion activity

New T1 gadolinium-enhancing lesions and new or enlarging T2 lesions were significantly reduced in both trials.

12-week composite disability progression

Numerical reductions favored fenebrutinib but the confidence intervals included no difference in both trials.

Study population

Randomized
1,497 randomized across two trials
Age
18–55 years eligible
Sex
66.5% women across both studies
Disability
EDSS 0–5.5
Disease definition
2017 McDonald-defined relapsing multiple sclerosis

Who entered the trial

Key inclusion criteria

  • Defined based on McDonald criteria 2017
  • Baseline EDSS 0–5.5
  • Able to complete protocol-defined walking and upper-limb assessments

Key exclusion criteria

  • Primary progressive MS or non-active secondary progressive MS
  • Active infection or clinically important immune, hepatic, or systemic disease
  • Disease duration over 10 years with baseline EDSS below 2.0

Safety signal

  • Liver-enzyme elevations above three times the upper limit of normal were similar between treatment groups in both trials.
  • One asymptomatic Hy’s Law case occurred in each treatment group in FENhance 1 and resolved after treatment discontinuation.
  • Across the two reporting periods, seven deaths occurred with fenebrutinib and one with teriflunomide; causes and timing varied, and an additional fenebrutinib-arm death occurred later.

Why it mattered

FENhance 1 and 2 provided replicated Phase III evidence that an oral, brain-penetrant, non-covalent BTK inhibitor can outperform an active oral comparator on relapse and MRI outcomes.

Important limitation

Fenebrutinib remains investigational in MS. The current efficacy evidence comes from a conference presentation and sponsor report rather than a peer-reviewed primary paper, and the fatal-event imbalance requires careful regulatory and clinical interpretation.

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