Question

Prof G, could you do an article on what is going on with tolebrutinib in the States? Having a hard time processing the FDA rejection letter. Not sure what this means for the field.

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Prof G’s response

You can download the FDA response here.

This is the informing Genzyme Corporation (Sanofi) that its application for the tolebrutinib cannot be approved in its current form. The primary obstacle to authorisation is a significant risk of severe liver injury, which the FDA believes outweighs the potential clinical benefits.

Despite Sanofi’s attempts to manage this toxicity through intensive monitoring, the FDA identified several “life-threatening cases” during clinical trials. Additionally, the FDA noted substantial uncertainty regarding the drug’s effectiveness across multiple sclerosis subpopulations, particularly in those with inactive disease. To move forward, Sanofi must provide more robust safety data and potentially identify a specific patient group or groups where the therapeutic advantages clearly justify the high risks.

The most critical factor in the FDA’s decision was the risk of severe drug-induced liver injury (DILI). The FDA characterised this risk as “substantial and unusually high” for drug development programmes in general, and specifically for MS therapies. In the Phase 3 development programme, there were 6 cases meeting Hy’s Law criteria (indicators of severe hepatotoxicity) out of approximately 2,700 subjects, including one patient who required a liver transplant and subsequently died.

The FDA noted that even a single Hy’s Law case is a signal of high hepatotoxicity, and most drugs withdrawn from the market for this reason have rates of severe injury far lower than what was observed with tolebrutinib. While DILI is a known class effect of BTK inhibitors, tolebrutinib’s risk of fatal DILI appears to be “among the highest in the class” and exceeds the risk observed with all other approved MS therapies.

The FDA concluded that the proposed Risk Evaluation and Mitigation Strategy (REMS) was insufficient. Although Sanofi implemented weekly liver monitoring, severe liver injury cases continued to occur even under this strict protocol. Consequently, the Agency determined that the benefit-risk assessment must assume severe and potentially fatal DILI cases would occur in a postmarketing setting regardless of monitoring requirements.

The FDA identified significant issues with the efficacy data supporting the proposed indication for non-relapsing secondary progressive MS (nrSPMS). The study population was heterogeneous, containing both “active” and “non-active” SPMS patients, which complicated the assessment of benefit. The treatment effect was largely driven by a small subgroup (13% of enrolled subjects) with baseline gadolinium-enhancing lesions, indicating active SPMS. While the drug showed efficacy here, there are already approved therapies for active SPMS that do not carry the same magnitude of liver risk. Therefore, the benefits in this group were not anticipated to outweigh the severe DILI risk.

For patients without baseline enhancing lesions—the population with the greatest unmet need—the treatment effect was significantly smaller and uncertain. The FDA stated that therapies with greater risks require a “greater magnitude and certainty of benefit” to support approval. The potential benefit in this population was deemed inadequate to justify the severe liver risks.

Their analysis of the data showed that the treatment effect was substantially diminished in patients who had previously tried two or more prior MS therapies. The FDA rejected Sanofi’s claim regarding “slowing disability accumulation independent of relapse activity”. The Agency cited several reasons for this rejection. The concept lacks widely accepted criteria and relies on post hoc analyses. There is limited understanding of whether BTK inhibitors address the underlying pathophysiology of progression. They also highlighted a separate study in primary progressive MS that has recently failed to demonstrate a benefit on its primary endpoint of confirmed disability progression, further undermining the mechanistic rationale for this claim (see Tolebrutinib PPMS trial is negative, 15-Dec-2025). I would counter the latter argument that the PPM population in the Perseus trial differs significantly from the nrSPMS population in the Hercules trial. Ultimately, the FDA could not identify a clinically identifiable population for whom the benefits of tolebrutinib outweighed the “serious and unusually high risk of severe DILI”.

My initial thoughts

This is not the first or last time this has happened with MS DMTs and the FDA. They did the same with natalizumab (Tysabri), alemtuzumab (Lemtrada), and cladribine (Mavenclad) based on PML, secondary autoimmunity & other adverse events (infusion reactions, infections, …) and cancer risk with each DMT, respectively. All these drugs eventually got to market. I am confident there is a way forward.

Defining a more responsive subgroup

The FDA is clearly worried about giving tolebrutinib a wide label for smouldering MS. This is because when you look for it using sensitive measures, for example, cognitive and other neurological stress tests, the majority of people with MS have smouldering disease. This means that the use of tolebrutinib would likely spread like wildfire to most subgroups of MS, and hence, the risk of life-threatening liver toxicity would increase. The FDA determined that, in its present form, a favourable benefit-risk profile could not be established for any patient subpopulation. The challenge for Sanofi is to identify a subgroup that would benefit most from the drug.

Interestingly, in a post-hoc analysis, subjects with early-relapsing MS who had paramagnetic rim lesions (PRLs) responded better to tolebrutinib than those without PRLs. We have yet to see the same data for the PPMS cohort. But if PRLs serve as a prognostic marker in this population, it would make a compelling case for using this biomarker.

Please see the MS-Selfie newsletter on ACTRIMS 2025 Highlights (3-Mar-2026), which covers this analysis.

As you are aware, PRLs are one biomarker of smouldering MS lesions, and their presence is associated with poorer outcomes. PRLs are considered a “red flag” in MS because they represent chronic, smouldering inflammation that actively destroys brain tissue long after the initial attack has passed. While a typical MS lesion stabilises and “heals”, PRLs behave like a slow-burning fire that continues to expand outward, causing progressive damage.

The defining feature of a PRL is a dark ring seen on specific MRI scans (susceptibility-weighted imaging). This ring corresponds to a dense accumulation of iron-laden microglia at the edge of the lesion. Instead of clearing debris and promoting repair, these immune cells remain chronically activated. Iron accumulation causes oxidative stress, which is toxic to neurons and oligodendrocytes (myelin-producing cells). This “toxic rim” slowly eats away at the healthy tissue surrounding the lesion. A proportion of PRLs are also slowly expanding lesions (SELs).

Because these lesions do not shut down as standard lesions do, they are a primary driver of neurodegeneration (brain shrinkage). The ongoing inflammation at the rim severs nerve fibres or axons. Once an axon is lost, it generally cannot be replaced. Patients with multiple PRLs typically show accelerated brain atrophy (shrinkage), particularly in the deep grey matter, which is strongly correlated with physical and cognitive disability.

PRLs are a major biological cause of smouldering MS and PIRA (Progression Independent of Relapse Activity). Traditionally, disability was thought to accumulate via acute relapses (attacks). PRLs cause disability to worsen between attacks. A person with MS may not have a new relapse for years, yet their walking or cognition slowly deteriorates because these smouldering lesions are quietly destroying tissue in the background.

PRLs are associated with poor outcomes because they are difficult to treat. The inflammation in a PRL is trapped behind the blood-brain barrier (BBB). Most standard DMTs work by stopping immune cells from entering the brain from the blood. Since the immune cells in a PRL are already inside the brain and self-perpetuating, these drugs are less effective at stopping smouldering inflammation. Tolebrutinib is the first DMT to show an effect in smouldering MS, presumably by targeting PRLs and other intrathecal processes driving smouldering MS, which is why this FDA response is so devastating for people with MS.

The FDA are also behind the curve when it comes to smouldering MS and are questing whether or not it is a real entity. I suggest they ask people with MS what smouldering MS is. If they read some of the comments on MS-Selfie, they would recognise that this is clearly the unmet need in treating MS and most people with MS, particularly those with advanced MS who identify as ha...