With deep expertise in biopharmaceutical research and development, Ivan Kairatov has a front-row seat to the breakthroughs and setbacks that define modern medicine. He joins us to dissect the recent turbulence in the multiple sclerosis (MS) treatment landscape, where a promising new class of drugs has run into significant safety hurdles, forcing a re-evaluation of risk, reward, and the future of therapy. Our conversation will explore the fallout from Sanofi’s recent clinical trial failures, the delicate balance between best-in-class efficacy and potential patient harm, the evolving regulatory climate for new MS drugs, and the exciting, fundamentally different therapeutic approaches emerging on the horizon.
The FDA recently rejected Sanofi’s tolebrutinib, citing that its benefits may not outweigh potentially fatal liver risks. What does this specific safety concern signal for the entire BTK inhibitor class, and how might other developers proactively address these risks in their ongoing clinical trials?
When a regulatory body like the FDA uses potent language like “potentially fatal liver risks” to issue a rejection, it’s not just a note to one company; it’s a warning shot fired across the bow of the entire drug class. This decision effectively raises the safety bar for every other BTK inhibitor in development for multiple sclerosis. It tells the industry that the agency sees a concerning pattern and will apply intense scrutiny to any similar drug. For other developers, this means their clinical trial designs must now be bulletproof when it comes to liver safety. They need to implement more frequent and rigorous monitoring, establish crystal-clear protocols for when to stop treatment at the first sign of trouble, and be prepared to prove that their specific molecule has a meaningfully better safety profile. It’s a clear signal that just being effective is no longer enough; demonstrating a manageable and favorable risk profile is now the central challenge.
Roche’s fenebrutinib also faced a clinical hold due to liver safety signals but has since shown strong efficacy data against established therapies. How do you weigh the potential “best-in-disease” efficacy of these drugs against this recurring safety concern? Please walk us through that risk-benefit analysis.
This is the classic, razor’s-edge calculation we constantly face in drug development. On one side, you have Roche’s data, which is incredibly compelling. They’re reporting what they call “unprecedented results,” significantly reducing the annualized relapse rate over 96 weeks and showing performance on par with Ocrevus, the only approved drug for primary progressive MS. That’s a massive potential benefit for patients who feel trapped by their disease. On the other side, you have the shadow of drug-induced liver injury, serious enough to trigger a clinical hold. The critical factor in this analysis is reversibility. The reports state that patients recovered after they stopped taking fenebrutinib. If you can prove that the liver toxicity is detectable early through diligent monitoring and, crucially, that it’s completely reversible upon cessation, then you can build a strong case. You argue that for a patient facing progressive, irreversible neurological decline, a manageable and reversible side effect is a worthwhile trade-off for a “best-in-disease” level of efficacy.
Beyond BTK inhibitors, research is advancing on remyelination drugs, an mRNA vaccine for the Epstein-Barr virus, and even CAR T-cell therapy. How do these fundamentally different mechanisms complement or compete with existing MS treatments, and which approach do you believe holds the most promise for patients?
These emerging therapies represent a monumental shift from simply managing MS to fundamentally altering its course. For decades, our best tools, including BTK inhibitors, have focused on suppressing the immune system’s attack. But a remyelination drug like CNM-AU8 isn’t competing with that approach; it’s complementing it by aiming to repair the nerve damage that has already been done. Imagine a future where one drug stops the attack and another rebuilds the defenses—that’s a paradigm shift. Similarly, Moderna’s mRNA vaccine targeting the Epstein-Barr virus is an entirely different strategy, attempting to neutralize a long-suspected trigger for the disease itself. CAR T-cell therapy is perhaps the most ambitious, seeking to reset the immune system entirely. While all are exciting, I believe the most transformative near-term promise lies in therapies that repair damage. For the millions already living with the effects of MS, a drug that could help restore lost function would be nothing short of miraculous.
Sanofi’s leadership expressed surprise at the FDA’s “change in direction” regarding tolebrutinib. From your perspective, what does this event reveal about the current regulatory climate for new MS drugs, particularly for conditions where patients have limited options but potential treatment risks are high?
That expression of surprise from Sanofi is incredibly illuminating. It suggests that the regulatory ground is shifting beneath the industry’s feet. Historically, for debilitating diseases with high unmet need, the FDA might have allowed for a wider latitude on the risk-benefit spectrum. However, the rejection of tolebrutinib indicates a hardening stance, especially when a class-wide safety issue emerges. The agency is essentially communicating that even if patients have limited options, a pattern of serious toxicity across multiple drugs in a class is a red line. This forces developers to generate impeccable, unambiguous data. It tells us that regulators are less willing to approve a “me-too” drug if it carries the known baggage of its predecessors, unless it also brings a truly dramatic and undeniable leap in efficacy. The era of assuming a smoother path for a high-unmet-need indication may be closing.
What is your forecast for the multiple sclerosis treatment landscape over the next five years?
My forecast is a move from a strategy of containment to one of restoration and precision. Over the next five years, I expect we will see one or two BTK inhibitors cross the finish line, but they will come with strict monitoring protocols and be targeted to specific patient subsets. The bigger story, however, will be the maturation of these novel mechanisms. We will see pivotal data from remyelination agents that could, for the first time, offer a way to reverse nerve damage, not just slow its progression. The Epstein-Barr virus hypothesis will also face its big test with data from Moderna’s vaccine, potentially opening a new front in the war on MS. We are on the cusp of moving beyond a monolithic reliance on immune suppression and toward a multi-pronged, personalized approach that combines controlling inflammation, repairing the nervous system, and possibly even neutralizing the disease’s original triggers. The future of MS treatment will be far more complex, but infinitely more hopeful.
