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HERCULES

Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis

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Year of Publication: 2025

Authors: Robert J. Fox, Amit Bar-Or, Anthony Traboulsee, ..., Daniel S. Reich

Journal: New England Journal of Medicine

Citation: N Engl J Med 2025; DOI: 10.1056/NEJMoa2415988

Link: https://doi.org/10.1056/NEJMoa2415988

Clinical Question

Does tolebrutinib, an oral brain-penetrant BTK inhibitor, slow disability progression in patients with nonrelapsing secondary progressive multiple sclerosis?

Bottom Line

In participants with nonrelapsing secondary progressive multiple sclerosis, tolebrutinib significantly reduced the risk of disability progression compared to placebo, representing the first approved treatment for this population with unmet medical need.

        Major Points
        First positive phase 3 trial in nonrelapsing secondary progressive MS
Tolebrutinib is an oral, brain-penetrant BTK inhibitor targeting both peripheral and CNS B cells and microglia
31% reduction in risk of 6-month confirmed disability progression (primary endpoint)
24% reduction in risk of 3-month confirmed disability progression
38% reduction in new/enlarging T2 lesions annually
23% reduction in 20% worsening on timed 25-foot walk
88% increase in disability improvement sustained for 6 months
All disability progression events were independent of relapses
Median follow-up of 133 weeks across both groups
Event-driven trial design continuing until ~288 disability progression events
Liver enzyme elevations were the main safety concern (4.0% vs 1.6% ALT >3x ULN)
Most liver enzyme elevations were mild-moderate and resolved without sequelae
No approved treatments existed previously for nonrelapsing SPMS

      

Design

Study Type: Phase 3, double-blind, placebo-controlled, event-driven, randomized trial

Randomization: 1

Blinding: Double-blind with matching placebo

Enrollment Period: October 23, 2020 - January 12, 2023

Follow-up Duration: Event-driven (median 133 weeks)

Centers: 264

Countries: 31

Sample Size: 1131

Analysis: Intention-to-treat using Cox proportional-hazards model with hierarchical testing

Inclusion Criteria

Age 18-60 years
Secondary progressive MS per 2017 McDonald criteria
No clinical relapses in 24 months before screening
EDSS score 3.0-6.5 at screening
Documented disability progression in previous 12 months
Adjudication committee confirmation of nonrelapsing SPMS diagnosis

Exclusion Criteria

Relapsing forms of multiple sclerosis
Primary progressive multiple sclerosis
Recent use of disease-modifying therapies (washout required)
Significant liver dysfunction
Other contraindications to study drug

Arms

Field	Tolebrutinib Group	Control
Intervention	Tolebrutinib 60mg once daily orally with meal	Matching placebo tablet once daily with meal
Duration	Event-driven (median 133 weeks)	Event-driven (median 133 weeks)

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Confirmed disability progression sustained for ≥6 months	Primary	30.7% (116/377)	22.6% (171/754)	0.69	0.003
Confirmed disability progression sustained for ≥3 months	Secondary	34.2% (129/377)	27.6% (208/754)	0.76	0.01
Annualized rate of new/enlarging T2 lesions	Secondary	2.95	1.84	0.62 (relative rate)	0.01
20% increase in 9-hole peg test sustained ≥3 months	Secondary	19.6%	19.0%	0.97	0.84
20% increase in timed 25-foot walk sustained ≥3 months	Secondary	49.6%	41.1%	0.77	Point estimate only (hierarchical testing)
Disability improvement sustained ≥6 months	Secondary	4.5%	8.6%	1.88	Point estimate only (hierarchical testing)
Any adverse event	Adverse	293/375 (78.1%)	613/752 (81.5%)	N/A	N/A
Serious adverse events	Adverse	39/375 (10.4%)	113/752 (15.0%)	N/A	N/A
ALT >3x upper limit normal	Adverse	6/372 (1.6%)	30/741 (4.0%)	N/A	N/A
Deaths	Adverse	1/375 (0.3%)	2/752 (0.3%)	N/A	N/A
Treatment discontinuation due to AE	Adverse	11/375 (2.9%)	29/752 (3.9%)	N/A	N/A

Subgroup Analysis

Consistent treatment effects across predefined subgroups including age, geographic region, baseline EDSS, and other demographic factors

Criticisms

Higher rate of serious adverse events with tolebrutinib vs placebo
Liver enzyme elevations requiring monitoring, including one case requiring liver transplant
Event-driven design may have led to earlier stopping than optimal for some secondary endpoints
Hierarchical testing meant some secondary endpoints could only be reported as point estimates
Open-label extension phase not described in detail
Limited long-term safety data beyond median 133 weeks
Mechanism of action on chronic active lesions not directly demonstrated

Funding

Sanofi

Based on: HERCULES (New England Journal of Medicine, 2025)

Authors: Robert J. Fox, Amit Bar-Or, Anthony Traboulsee, ..., Daniel S. Reich

Citation: N Engl J Med 2025; DOI: 10.1056/NEJMoa2415988

Content summarized and formatted by NeuroTrials.ai.

HERCULES

(2025)

Objective

Tolebrutinib - Assess whether tolebrutinib affects disease progression independent of relapse activity in participants with nonrelapsing secondary progressive multiple sclerosis.

Study Summary

• Tolebrutinib significantly reduced risk of 6-month confirmed disability progression vs placebo in nonrelapsing secondary progressive MS
• First BTK inhibitor to show efficacy in progressive MS

Intervention

Oral tolebrutinib 60mg once daily vs matching placebo, both taken with meals, in patients with no clinical relapses in the 24 months before screening.

Inclusion Criteria

Age 18-60 years with secondary progressive MS per 2017 McDonald criteria, no relapses in 24 months before screening, EDSS 3.0-6.5, documented disability progression in previous 12 months.

Study Design

Arms: Tolebrutinib vs Placebo (2:1 randomization)

Patients per Arm: 754 tolebrutinib, 377 placebo

Outcome

• Primary endpoint: 22.6% tolebrutinib vs 30.7% placebo had 6-month confirmed disability progression (HR 0.69, P=0.003). <br>• 3-month confirmed disability progression: 27.6% vs 34.2% (HR 0.76, P=0.01). <br>• New/enlarging T2 lesions: 1.84 vs 2.95 annually (relative rate 0.62, P=0.01). <br>• SAEs: 15.0% vs 10.4%. ALT >3x ULN: 4.0% vs 1.6%. <br>• First approved treatment for nonrelapsing secondary progressive MS.

Bottom Line

Major Points

First positive phase 3 trial in nonrelapsing secondary progressive MS
Tolebrutinib is an oral, brain-penetrant BTK inhibitor targeting both peripheral and CNS B cells and microglia
31% reduction in risk of 6-month confirmed disability progression (primary endpoint)
24% reduction in risk of 3-month confirmed disability progression
38% reduction in new/enlarging T2 lesions annually
23% reduction in 20% worsening on timed 25-foot walk
88% increase in disability improvement sustained for 6 months
All disability progression events were independent of relapses
Median follow-up of 133 weeks across both groups
Event-driven trial design continuing until ~288 disability progression events
Liver enzyme elevations were the main safety concern (4.0% vs 1.6% ALT >3x ULN)
Most liver enzyme elevations were mild-moderate and resolved without sequelae
No approved treatments existed previously for nonrelapsing SPMS

Study Design

Study Type: Phase 3, double-blind, placebo-controlled, event-driven, randomized trial
Randomization: Yes
Blinding: Double-blind with matching placebo
Sample Size: 1131
Follow-up: Event-driven (median 133 weeks)
Centers: 264

Primary Outcome

Definition: Confirmed disability progression sustained for ≥6 months

Control	Intervention	HR/OR	P-value
30.7% (116/377)	22.6% (171/754)	0.69 (0.55 to 0.88)	0.003

Limitations & Criticisms

Higher rate of serious adverse events with tolebrutinib vs placebo
Liver enzyme elevations requiring monitoring, including one case requiring liver transplant
Event-driven design may have led to earlier stopping than optimal for some secondary endpoints
Hierarchical testing meant some secondary endpoints could only be reported as point estimates
Open-label extension phase not described in detail
Limited long-term safety data beyond median 133 weeks
Mechanism of action on chronic active lesions not directly demonstrated

Citation

N Engl J Med 2025; DOI: 10.1056/NEJMoa2415988

View Original Publication →

HERCULES

Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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