The Institute for Clinical and Economic Review (ICER) has published an evidence report evaluating tolebrutinib for non-relapsing secondary progressive multiple sclerosis (nrSPMS). The clinical trial data from the Phase III HERCULES trial showed a 31% reduction in six-month confirmed disability progression (CDP) compared to placebo (HR 0.69, 95% CI 0.55–0.88). This makes tolebrutinib the first disease-modifying therapy (DMT) with potential efficacy in nrSPMS. However, mixed secondary outcomes introduce uncertainty about its long-term net benefit. ICER’s cost-effectiveness analysis suggests tolebrutinib could meet common thresholds at an annual price between $3,250 and $5,900, far below the placeholder price of $115,000.

Reviewing the Clinical Efficacy

Tolebrutinib targets smoldering neuroinflammation by inhibiting Bruton’s tyrosine kinase (BTK). The HERCULES trial involved 1,131 participants with nrSPMS, randomized in a 2:1 ratio to receive tolebrutinib (60 mg/day) or placebo. The primary endpoint was six-month CDP, measured by the Expanded Disability Status Scale (EDSS). Tolebrutinib reduced the risk of six-month CDP by 31% (22.6% vs. 30.7% with placebo; HR 0.69). This effect persisted for up to 45 months. However, secondary outcomes were inconsistent:

• MRI Activity: Tolebrutinib decreased the rate of new/enlarging T2 lesions by 38% (1.84 vs. 2.95 lesions/year).
• Brain Atrophy: No significant change was seen in annualized brain volume loss (−0.81% vs. −0.83%; p = 0.67).
• Upper Limb Function: No improvement was observed in the 9-hole peg test (HR 0.97, 95% CI 0.74–1.29).

These discrepancies suggest tolebrutinib may mitigate inflammatory-driven disability but has limited impact on neurodegeneration in SPMS.

Evaluating Safety Profile and Risk-Benefit

The HERCULES trial reported Grade 3–4 alanine transaminase (ALT) elevations in 4% of tolebrutinib recipients, including a fatal case of acute liver failure. Post hoc analyses suggest weekly liver function testing (LFT) may help mitigate severe outcomes, but real-world adherence is uncertain. Other BTK inhibitors, like ibrutinib, show similar hepatotoxicity risks.

No DMTs are approved for nrSPMS. Siponimod, approved for active SPMS, presents risks of bradycardia and macular edema but lacks hepatotoxicity. Tolebrutinib’s safety profile involves a trade-off: potential benefits versus the need for rigorous monitoring and serious liver risks.

The Epidemiological and Economic Context of SPMS

SPMS affects 22–26% of the 1 million MS patients in the U.S. The financial burden of MS exceeds $85 billion annually, driven by medical costs ($63.3 billion) and lost productivity. Patients with nrSPMS face high costs due to ongoing care needs. Current guidelines lack recommendations for nrSPMS, as existing DMTs target relapsing or active MS. Tolebrutinib addresses a critical gap, but its value depends on balancing efficacy, safety, and cost.

Cost-Effectiveness and Pricing Implications

The ICER model compared tolebrutinib to best supportive care (BSC). At $115,000/year, its cost-effectiveness ratio exceeded $3.4 million per QALY, far above conventional thresholds. A price of $3,250–$5,900/year would align with expectations, but Sanofi’s strategy remains unclear. Tolebrutinib could increase U.S. healthcare expenditures by $1.2–$2.1 billion annually. Payers might impose strict prior authorization criteria, limiting access for underserved populations.

Implications for Health Policy and Practice

Formulary inclusion for tolebrutinib will require price negotiations and value-based contracts tied to real-world outcomes. ICER’s recommended pricing range ($3,250–$5,900) may serve as a benchmark, though industry resistance is likely. Long-term studies are needed to assess tolebrutinib’s impact on wheelchair dependence and mortality. Biomarkers like neurofilament light chain could improve patient selection.

Conclusion

Tolebrutinib presents a groundbreaking option for nrSPMS, delaying disability progression despite incomplete efficacy. Its success depends on addressing safety concerns and achieving affordable pricing. Policymakers must balance innovation with affordability to tackle progressive MS’s economic and social impacts.