PDF: Evobrutinib Phase 2
(2019)Objective
Evobrutinib 25 mg/day, 75 mg/day, or 75 mg twice daily — to evaluate whether a selective oral Bruton's tyrosine kinase (BTK) inhibitor reduces MRI lesion activity in relapsing multiple sclerosis.
Study Summary
• Lower (25 mg) and twice-daily (75 mg BID) doses did not significantly reduce lesions, and no evobrutinib dose reduced annualized relapse rate or EDSS progression vs placebo, suggesting a non-linear dose-response and an MRI-only signal in this short phase 2 study.
• Liver aminotransferase elevations with evobrutinib supported cautious phase 3 development — which later failed to confirm benefit over teriflunomide in the GEMINI pivotal studies.
Intervention
Oral evobrutinib 25 mg once daily, 75 mg once daily, or 75 mg twice daily, vs placebo, with open-label dimethyl fumarate 240 mg twice daily as a reference arm. 24-week blinded phase; placebo patients rolled to 25 mg evobrutinib for additional 24-week blinded extension.
Inclusion Criteria
Adults with relapsing multiple sclerosis with clinical and imaging evidence of active disease.
Study Design
Arms: Evobrutinib 25 mg daily vs 75 mg daily vs 75 mg BID vs Placebo vs open-label DMF (1:1:1:1:1)
Patients per Arm: ~53 per arm (total N=267)
Outcome
• Rate ratio vs placebo: 1.45 (25 mg, p=0.32), 0.30 (75 mg daily, p=0.005), 0.44 (75 mg BID, p=0.06)
• Unadjusted ARR at week 24: placebo 0.37, 25 mg 0.57, 75 mg daily 0.13, 75 mg BID 0.08, DMF 0.20
• No significant effect on EDSS change at any dose
• Liver aminotransferase elevations observed with evobrutinib — drove caution in subsequent development
Clinical Question
Does oral evobrutinib, a selective BTK inhibitor, reduce MRI lesion activity, relapses, or disability in relapsing multiple sclerosis?
Bottom Line
In this phase 2 trial in relapsing MS, evobrutinib 75 mg once daily reduced cumulative gadolinium-enhancing MRI lesions by ~70% vs placebo (rate ratio 0.30; p=0.005), but the 25-mg and 75-mg BID doses did not, and none reduced annualized relapse rate or EDSS progression. Liver enzyme elevations were observed. This established proof-of-concept for BTK inhibition in MS and enabled phase 3 development (subsequently negative in the GEMINI trials).
Major Points
- Phase 2, multicenter, randomized, double-blind, placebo-controlled trial at 56 centers in Europe and Russia, March 2017 to July 2018
- 267 adults with relapsing MS randomized 1:1:1:1:1 to placebo, evobrutinib 25 mg/day, evobrutinib 75 mg/day, evobrutinib 75 mg twice daily, or open-label dimethyl fumarate (DMF) 240 mg twice daily as a reference
- 24-week blinded placebo-controlled phase; placebo group then crossed to evobrutinib 25 mg/day for a further 24-week blinded extension
- Primary endpoint: cumulative (total) gadolinium-enhancing T1 MRI lesions at weeks 12, 16, 20, and 24
- Key secondary: annualized relapse rate; change from baseline in EDSS at week 24
- Mean cumulative lesions: 3.85 (placebo), 4.06 (25 mg), 1.69 (75 mg daily), 1.15 (75 mg BID), 4.78 (DMF)
- Rate ratios vs placebo: 1.45 (25 mg; p=0.32), 0.30 (75 mg daily; p=0.005), 0.44 (75 mg BID; p=0.06)
- Only the 75 mg once-daily dose met the primary endpoint — non-linear dose-response considered pharmacologically plausible
- Unadjusted ARR at week 24: 0.37 (placebo), 0.57 (25 mg), 0.13 (75 mg daily), 0.08 (75 mg BID), 0.20 (DMF)
- No significant effect on EDSS change from baseline at any evobrutinib dose
- Liver aminotransferase elevations observed with evobrutinib — a warning signal carried into phase 3 design
- This was the first BTK inhibitor MS trial to show any MRI signal and enabled phase 3 program (GEMINI)
- Subsequent phase 3 GEMINI I/II trials (2023) were NEGATIVE — evobrutinib failed to beat teriflunomide on ARR, discontinuing development for MS
Study Design
- Study Type
- Phase 2, multicenter, randomized, double-blind, placebo-controlled with open-label reference arm
- Randomization
- Yes
- Blinding
- Double-blind for placebo and evobrutinib arms; DMF open-label reference arm
- Sample Size
- 267
- Follow-up
- 24-week blinded + 24-week blinded extension
- Centers
- 56
- Countries
- Europe (multiple), Russia
Primary Outcome
Definition: Cumulative (total) number of gadolinium-enhancing T1 MRI lesions at weeks 12, 16, 20, and 24
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 3.85 mean lesions (placebo) / 4.78 (DMF open-label reference) | 1.69 (evobrutinib 75 mg once daily) / 1.15 (75 mg BID) / 4.06 (25 mg once daily) | - (Rate ratio vs placebo: 0.30 (75 mg daily); 0.44 (75 mg BID); 1.45 (25 mg)) | p=0.005 (75 mg QD); p=0.06 (75 mg BID); p=0.32 (25 mg) |
Limitations & Criticisms
- Short 24-week blinded phase insufficient for durable disease-modification claims
- Non-linear dose-response (75 mg daily significant; 75 mg BID borderline) questioned but pharmacologically plausible with covalent inhibitor
- Small sample per arm (~53)
- DMF as open-label reference is not a gold-standard MS trial comparator
- MRI signal did not translate to relapse or EDSS benefit in the short follow-up
- Liver enzyme signal raised safety concerns
- Subsequent phase 3 (GEMINI I/II 2023) was NEGATIVE — highlighting the limitation of short MRI-based phase 2 trials as predictors of clinical benefit
Citation
N Engl J Med 2019;380(25):2406-2417