Beyond One Drug: What the Tolebrutinib Decision Teaches Us About Progressive MS Trials.

Reflections on risk, biology, and the trials progressive MS now demands

Feb 03, 2026 – by: Leorah Freeman, MD, PhD

In my last post, I tried to offer a balanced reading of the safety concerns surrounding tolebrutinib by comparing its clinical trial data with that of other FDA-approved BTK inhibitors, by looking back at past MS therapies that faced significant regulatory hurdles, and by clarifying what REMS programs do and do not actually accomplish.

My hope was that, by sharing my interpretation of the available data, I could help put this complex and emotionally charged information into context.

But what has unsettled so many of us after the FDA’s letter is not just the safety signal itself, but the deeper question it forces us to confront:

💡 When a drug carries real risk, should it still be considered for approval, and what degree of evidence do patients deserve in return?

This isn’t just a regulatory question. It’s a moral one. A clinical one.

Progressive MS remains one of the greatest unmet needs in Neurology. For many patients, progression may not be dramatic, but it is devastating. It is slow, grinding, and relentless. Moving becomes harder. Thinking takes more effort. Memory slips away. Fatigue reshapes daily life. Independence narrows quietly, year after year. In that context, the idea that we might only approve therapies with pristine safety profiles begins to feel disconnected from reality. If the standard for approval were zero serious adverse events, many of the therapies we now consider transformative in Neurology, and certainly in Oncology, would never have reached patients.

So yes, risky drugs must remain on the table. For some patients, the alternative is not safety. It is certainty of decline.

We often talk about benefit–risk as if it were a calculation: benefit on one side, risk on the other, weigh them carefully and decide. But benefit–risk is not an exact ratio. Benefit in MS, particularly in progressive MS, is often heterogeneous. It may be modest on average, but meaningful for a subset of patients. Risk, on the other hand, may be rare but catastrophic, falling on a small number of individuals with potentially devastating consequences. Those two realities don’t cancel each other out neatly. The ethical challenge is not deciding whether benefit outweighs risk in the abstract. It’s deciding whether we understand who benefits, who is at risk, and how we can protect patients while offering choice.

Risky therapies may be necessary. They may even be transformative. But the riskier the drug, the higher the bar for clarity on benefit. This is not about demanding certainty. Medicine has never offered that. It is about proportionality. When a drug’s risks are minimal, we can tolerate ambiguity in benefit. A modest effect, a trend in the right direction, or population-level averages may be enough. But as risk increases, especially when that risk includes rare, severe, or irreversible harm, the ethical threshold shifts.

People living with MS deserve more than protection from harm, and more than access to innovation. They deserve to know:

• What kind of benefit is being offered
• How meaningful that benefit may be in daily life
• How likely they personally are to experience it

If this moment pushes our field toward smarter trial designs and greater collaboration to provide our patients with the answers they need, then the delay will not have been entirely wasted. Sometimes the hardest pauses are the ones that move us forward more responsibly.

See more from Dr. Freeman’s substack