Tolebrutinib Shows Positive Results in Slowing Disability Progression for Non-Relapsing Secondary Progressive MS in Phase 3 HERCULES Trial

Newly announced late-breaking results from the phase 3 HERCULES trial (NCT04411641) showed that tolebrutinib (Sanofi), a Bruton’s tyrosine kinase (BTK) inhibitor, had a significant effect on disability accumulation compared with placebo in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). Presented at the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 18-20, in Copenhagen, Denmark, the findings from this trial are the first to reveal a significant slowing of disability progression in this patient population, for which there is a large unmet need.^1,2

In the trial, findings showed that tolebrutinib delayed the time to onset of 6-month confirmed disability progression (CDP), the primary end point, by 31% compared with placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026) in patients with nrSPMS. Additional results of the secondary end points revealed that the number of patients who experienced confirmed disability improvement increased by nearly 2-fold, 10% for those treated with tolebrutinib compared with 5% those in the placebo group (HR, 1.88; 95% CI, 1.10-3.21; nominal P = .021).

“Up to this point, we have over 20 approved therapies that help relapsing MS, meaning they reduce relapses and relapsing forms of MS. But at this point, we don't have any therapies that effectively slow the little-by-little progression we see in secondary progressive MS. What's exciting to me about these results from the HERCULES trial is that we finally have identified a therapy that slows progression of disability in a population of patients without relapses, the non-relapsing, secondary progressive MS population,” lead author Robert J. Fox, MD, a staff neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, told NeurologyLive^®.

HERCULES comprised of 1131 patients aged between 18 to 60 years with nrSPMS (mean age was, 48.9 years; women, 62%) and Expanded Disability Status Scale (EDSS) score of 3.0–6.5. Eligible participants also had inclusive, documented proof of disability progression in the prior 12 months and no clinical relapses in the prior 24 months before screening. In the study, investigators randomized participants 2:1 to receive 60-mg once daily oral tolebrutinib or matching placebo. The primary end point of the trial was time to onset of 6-month CDP, as measured by EDSS, and secondary end points included other measures of disability, MRI outcomes and safety.

Top Clinical Takeaways

Tolebrutinib delayed the onset of 6-month confirmed disability progression by 31% compared with placebo among patients with nrSPMS.
Nearly twice as many patients treated with tolebrutinib experienced confirmed disability improvement compared with those on placebo.
Although liver enzyme elevations were reported as a adverse effect, most cases resolved without further intervention, with safety remaining a key focus in ongoing evaluations.

The mean time since relapsing-remitting MS symptom onset reported was 17.3 years, and the mean time since the most recent relapse observed was 7.5 years. A majority of the patients included in the study had previously received at least 1 disease-modifying therapy (77%) and the mean EDSS score was 5.53 at baseline (median 6.0; interquartile range 5.0–6.3). At baseline, 12.8% of patients in HERCULES had gadolinium-enhancing T1 lesions and the cohort had a mean T2 lesion volume of 18.9 cm3 (SD, 14.6).

“These results are really important to me as a practicing neurologist because every day I see patients with secondary progressive MS for whom have no treatments. They have gradual, little by little, decline in their walking function, in their arm function, in their cognitive function. I really have no therapies offered to them at this point, and this looks to have promised to be an effective therapy,” Fox added. “The biggest takeaway is that we have finally identified a therapy that slows the insidious progression of secondary progressive MS, that little by little decline in function for which up to this point, we've had no effective treatments. Finally, we have hope to slow this form of the disease.”

In the preliminary analysis of HERCULES, investigators reported a slight increase of some adverse events among tolebrutinib-treated patients. Researchers noted that liver enzyme elevations (>3xULN) were experienced by 4.1% of patients who received tolebrutinib compared with 1.6% in the placebo group, which is an adverse effect previously reported with other BTK inhibitors in MS. In addition, 0.5% of patients in the tolebrutinib group had peak ALT increases of >20xULN, all which occurred in the first 90 days of treatment. All of the cases of liver enzyme elevations, with the exception of one, resolved without any further medical intervention needed.

Before researchers implemented more stringent monitoring in the revised study protocol, 1 patient in the tolebrutinib arm received a liver transplant and died because of post-operative complications. Up to now, Fox and colleagues noted that this implementation of more frequent monitoring has mitigated such serious liver sequelae. In the trial, other deaths were evaluated as unrelated to the study treatment by investigators; reported deaths were similar across the placebo and tolebrutinib arms at 0.3%.

Additional late-breaking data of tolebrutinib from the phase 3 GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) trials presented by lead author Jiwon Oh, MD, PhD, staff neurologist and medical director of the Barlo Multiple Sclerosis Program at St Michaels Hospital, at ECTRIMS 2024 showed that the treatment failed to meet its primary end point of reducing annualized relapse rate (ARR) in comparison with teriflunomide (Aubagio; Sanofi). Although, importantly, the trials did show positive data on a key secondary end point of pooled 6-month CDW, significantly delaying the time to onset of worsening.^3,4

All told, on the primary end point of ARR, the pooled data from the 2 trials indicated no significant difference between the teriflunomide group (n = 940) and the tolebrutinib-treated group (n = 933), both of which recorded rates of 0.12. The overall ARR rate ratio was 1.03 (95% CI, 0.84-1.25; P = .80). In GEMINI 1, those respective rates for the teriflunomide group (n = 488) and the tolebrutinib group (n = 486) were 0.12 and 0.13, respectively, for an ARR rate ratio of 1.06 (95% CI, 0.81-1.39; P = 0.67). Likewise, in GEMINI 2, the rates for the teriflunomide group (n = 452) and the tolebrutinib group (n = 447) were both 0.11, respectively, for an ARR rate ratio of 1.00 (95% CI, 0.75-1.32; P = .98).

Regarding the secondary end points of time to 6-month CDW, the pooled data showed a 29% risk reduction (HR, 0.71; 95% CI, 0.53-0.95; P = .023) for the tolebrutinib group (9.9%) compared with the teriflunomide group (13.2%). When exploring time to 3-month CDW, there was a 27% risk reduction (HR, 0.73; 95% CI, 0.57-0.94; P = .018) for the tolebrutinib group (14.7%) compared with the teriflunomide group (18.5%).

“The GEMINI trials gave confirmation of what we saw in HERCULES in that although there was no reduction in the annualized relapse rate in the patients treated with tolebrutinib versus teriflunomide, we did see a slowing of the disability progression. We saw a reduction in the proportion of patients with sustained progression of disability,” Fox said. “Although that was a negative trial from the relapsing aspect, it was positive in slowing disability progression. This points to and confirms what we found in the HERCULES trial of secondary progressive MS.”