Commentary
Video
The HERCULES trial demonstrates tolebrutinib's potential to slow disability progression in non-relapsing secondary progressive multiple sclerosis, offering a new treatment option for patients with limited therapeutic choices.
In an interview with Pharmacy Times®, Robert Fox, MD, FAAN, staff neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, discussed the HERCULES trial, which evaluated tolebrutinib (Sanofi) as a potential treatment for non-relapsing secondary progressive multiple sclerosis (nrSPMS), a condition currently lacking effective therapies. The discussion was based on Fox's presentation, "Tolebrutinib Versus Placebo in Non-relapsing Secondary Progressive Multiple Sclerosis: Efficacy and Safety Results from the Phase 3 HERCULES Trial," showcased during the Clinical Trials Plenary Session on April 8 at the American Academy of Neurology 2025 Annual Meeting and Exposition.
The HERCULES trial revealed a 31% slowdown in disability progression in patients with nrSPMS treated with tolebrutinib compared with placebo, marking a significant advancement in MS treatment, according to Fox, who was the lead investigator in the study. While promising, the therapy requires careful monitoring, particularly for potential respiratory infections and liver enzyme elevations during the first 3 months of treatment. Fox explains how pharmacists and members of a patient care team can play a role in optimizing treatment with tolebrutinib for patients with nrSPMS.
Pharmacy Times: Could you provide an overview of the results of the HERCULES trial?
1. Tolebrutinib showed a 31% reduction in disability progression for patients with non-relapsing secondary progressive MS.
2. The drug requires close monitoring, with potential side effects including increased respiratory infections and liver enzyme elevations.
3. The FDA is expected to make a decision on tolebrutinib's approval by the end of September, with the medication having received breakthrough therapy status.
Robert Fox, MD, FAAN: Currently, we have over 20 FDA-approved therapies for multiple sclerosis (MS), but these therapies really focus on the relapsing phase of the disease, the early stages of MS. A large proportion of our patients have secondary progressive MS without relapses, what we call non-relapsing secondary progressive MS (nrSPMS), and right now, we have no therapies with demonstrated efficacy in SPMS when there are no relapses. nrSPMS represents a significant unmet need in the treatment of MS. The HERCULES trial sought to see if tolebrutinib (Sanofi) was an effective therapy in nrSPMS. It was a placebo-controlled trial where over 1100 patients were randomized to receive either tolebrutinib or a placebo and followed over time. The primary outcome was confirmed disability progression, which was 6-month confirmed progression on the Expanded Disability Status Scale (EDSS), which is a standard outcome scale in MS.
Pharmacy Times: How could these results impact current treatment guidelines for nrSPMS?
Fox: The primary outcome of the HERCULES trial was met, in that there was a 31% slowing of disability progression in patients treated with tolebrutinib compared with placebo. This is great news for our patients, because right now, we don't have any treatments that slow disability progression, and now finally, we do.
Pharmacy Times: How might the results of the HERCULES trial with tolebrutinib inform pharmacists’ counseling efforts for patients with non-relapsing secondary progressive MS?
Fox: The results of this trial found that tolebrutinib does slow progression of disability in patients with nrSPMS. That's encouraging news, but there are some safety issues to appreciate and recognize when patients, providers, and pharmacists may be considering this therapy for treatment of nrSPMS. Overall, there was a slightly higher rate of infections, particularly respiratory infections like COVID-19 and upper respiratory infections, seen in patients treated with tolebrutinib compared to placebo. Also, there was an increased rate of liver enzyme elevation. Four percent of patients treated with tolebrutinib had an elevation of 3 times the upper limit of normal or higher elevation in liver enzymes. Importantly, there was a smaller proportion, 0.5% or 1 in 200 patients, who had a very severe elevation, a 20-times upper limit of normal or higher elevation in liver enzymes. Now, the good news with that is that it always happened within the first 3 months of treatment, so that provides a target window for us to have very intensive monitoring, weekly liver enzyme monitoring. The management of that is also very straightforward--we just tell patients to stop tolebrutinib. But we do need to recognize it, and so the frequent liver enzyme testing in the first 3 months of treatment is a very important aspect in counseling patients.
Pharmacy Times: As tolebrutinib and similar agents emerge in the nrSPMS space, how do you see the pharmacist’s role evolving in treatment selection, adherence support, and multidisciplinary care for this patient population?
Fox: There are many Bruton tyrosine kinase (BTK) inhibitors that are in development in MS, and they have different penetration into the brain. Some stay in the periphery, and some not only are in the periphery but also go into the brain and spinal cord. Based on the early results of several BTK trials, it seems like one needs to have a BTK inhibitor that goes into the brain and spinal cord in order to slow down progression of disability. That will be an important aspect to watch as additional BTK inhibitors are developed in MS.
Pharmacy Times: Is there anything else that you would like to add?
Fox: Currently, tolebrutinib is under review by the US FDA, and it has been given accelerated breakthrough therapy status. That's great news, because it means by the end of September, we expect to get a decision from the regulators regarding the clinical approval of tolebrutinib.
