The positive finding on the secondary end point of 6-month confirmed disability worsening supports the data from the phase 3 HERCULES trial in secondary progressive multiple sclerosis.
Jiwon Oh, MD, PhD
Tolebrutinib, a brain-penetrant and bioactive Bruton’s tyrosine kinase (BTK) inhibitor being investigated by Sanofi as a treatment for relapsing multiple sclerosis (MS) that acts on peripheral B cells, has failed to meet its primary end point of reducing annualized relapse rate (ARR) in comparison with teriflunomide (Aubagio; Sanofi), according to the top line results of the phase 3 GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) clinical trials.1,2
Although, importantly, the trials did show positive data on a key secondary end point of pooled 6-month confirmed disability worsening (CDW), significantly delaying the time to onset of worsening.1,2 These late-breaking data were presented by Jiwon Oh, MD, PhD, at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held September 18-20, in Copenhagen, Denmark, alongside those from the phase 3 HERCULES trial (NCT04411641) of the therapy in secondary progressive MS. Oh noted that these data sets are still being analyzed, with additional subgroup and other details planned to be explored in the coming months and years from all 3 endeavors.
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).
“While this is disappointing, there is hope,” Oh said, noting that the results “only go uphill from here” and that the secondary end point data were “of high interest when you think about [the HERCULES data] that [were] presented next… and they’re quite informative for the results that we saw in HERCULES.”
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 time to 6-month confirmed disability improvement (CDI) was also assessed in the pooled data and showed a numerically higher rate for the tolebrutinib arm (13.8%) compared with the teriflunomide arm (12.0%), which was not significant (P = .17). Of note, Oh mentioned that the P values for these secondary end point findings were “technically considered nominal” as a result of the failure on the primary end point and the planned prespecified analyses.
“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,” Robert Fox, MD, a neurologist at the Mellen Center for MS at Cleveland Clinic who presented the results of HERCULES at ECTRIMS, told NeurologyLive®.
“And, although that was a negative trial from the relapsing aspect, it was positive in slowing disability progression and I think it points to, and confirms, what we found in the HERCULES trial of secondary progressive MS,” Fox added.
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Of interest to the audience was that the new gadolinium (Gd) enhancing T1 lesions was higher among those treated with tolebrutinib in both GEMINI 1 (tolebrutinib, 0.53; teriflunomide, 0.29; adjusted rate ratio, 1.86 [95% CI, 1.36-2.55]; P = .0001) and in GEMINI 2 (tolebrutinib, 0.46; teriflunomide, 0.22; adjusted rate ratio, 2.12 [95% CI, 1.50-2.99]; P <.0001). New and enlarging T2 lesions were similar among groups in both trials, with those on tolebrutinib reporting annualized rates of 5.6 and 5.1 and those on teriflunomide reporting rates of 5.2 and 4.4 in GEMINI 1 and 2, respectively (GEMINI 1 adjusted rate ratio, 1.08 [95% CI, 0.88-1.34], P = .46; GEMINI 2 adjusted rate ratio, 1.17 [95% CI, 0.91-1.50], P = .24).
In GEMINI 1 and 2, rates of brain volume loss between the 2 treatment groups were inconsistent—in GEMINI 1, the tolebrutinib group showed a least-squares mean (LSM) difference of 0.20 (95% CI, 0.09-0.30; P = .0002) compared with teriflunomide at end of study, but in GEMINI 2, the LSM at end of study was 0.04 (95% CI, –0.07 to 0.15; P = .43).
“It is also important to note that this rate of total brain atrophy in tolebrutinib-treated patients is approximately 0.3% per year, which is similar to the rate of brain atrophy that is seen in healthy adults,” Oh said in her presentation.
Several audience questions were posed regarding the Gd-enhancing lesions data from GEMINI 1 and 2, as well as HERCULES, to Oh and Fox, including a question posed (as a sort of composite of multiple web-submitted audience inquiries) by one of the session’s moderators, Dalia L. Rotstein, MD, MPH, an assistant professor of medicine at the University of Toronto. Rotstein speculated about the consideration of exploring a combination therapy approach with tolebrutinib along with another disease-modifying therapy (DMT in relapsing MS—prompted by worry about the Gd-positive lesions that were seen with tolebrutinib.
“I think theoretically, and this is of course, pure speculation and my personal opinion,” Oh responded, “combination therapy is interesting just because we are starting to get many different therapies with radically different mechanisms, and especially seeing the results from GEMINI 1 and 2. But from a practical standpoint, combination therapy seems unlikely because of the exorbitant cost.”
Oh continued, saying “I think what we should consider as a field in the future are really smart sequencing strategies. I think we have the benefit of having many therapies that we know are highly effective against relapse disease biology. Maybe we can think about in the future, if somebody has really active aggressive MS, rapidly starting one of these highly effective therapies and then rapidly transitioning—if the concern is ongoing progression—to a therapy that we know is effective, like tolebrutinib.”
After the topline data were announced earlier in September 2024, Erik Wallstroem, MD, PhD, global head of neurology development at Sanofi, sat down with NeurologyLive® to discuss the safety profile of tolebrutinib, emphasizing the need for careful monitoring, particularly during the early months of initiating the therapy. Click the button below to watch his interview.
Regarding safety, there was much interest in the observed elevations of liver enzymes among the tolebrutinib-treated patients—which resulted in an adjustment in liver monitoring strategies across the clinical development program after a clinical hold was placed on the trials in MS and myasthenia gravis by the FDA in June 2022,3 and which has been observed with other investigational BTK inhibitors. There was an elevation 3 times the upper limit of normal (ULN) reported by 5.6% of tolebrutinib-treated patients compared with 6.3% of those on teriflunomide, however, a small proportion of patients (0.5%) experience peak alanine aminotransferase (ALT) levels of 20 times or greater the ULN, all of which occurred within the first 90 days of treatment. All cases of ALT elevation of 3 times the ULN resolved without sequelae. “Once this liver safety signal had been identified, in the entire clinical development program, frequent liver monitoring has been instituted,” Oh noted.
Ultimately, Oh noted that the results of the study are consistent with the hypothesis that acute focal inflammation and smoldering neuroinflammation are 2 distinct biological processes in MS, and that tolebrutinib appears to be effective in reducing disability accumulation—despite its lack of significant separation on relapse activity vs teriflunomide.
“Tolebrutinib represents an unprecedented breakthrough as a potential first-in-disease treatment option with clinically meaningful benefit in disability accumulation,” Houman Ashrafian, MD, PhD, the head of Research & Development at Sanofi, said in a statement.2 “Addressing disability accumulation, thought to be driven by smoldering neuroinflammation, remains the greatest unmet medical need in people with non-relapsing secondary progressive MS today.”
Altogether, the GEMINI trials enrolled 1873 participants (GEMINI 1, n = 974; GEMINI 2, n = 899) across sites in 42 countries between June 25, 2020, and August 8, 2022. The baseline mean age in the combined trial population was 36.5 years with a mean time since diagnosis of 4.3 years. The majority of participants were female (67%), and more than half were treatment-naïve (63%). The population had a mean number of relapses in the year prior to enrollment of 1.2 and a mean Expanded Disability Status Scale (EDSS) score of 2.38 (median, 2.0; IQR, 1.5-3.0), with 34.4% of the combined cohort having Gd-enhancing T1 lesions at baseline.
The trials included individuals between the ages of 18 and 55 years with a diagnosis of relapsing MS, EDSS score of 5.5 or lower, and either 1 or more relapses within the previous year, 2 or more relapses within the previous 2 years, or 1 or more Gd-enhancing T1 brain lesions on MRI within the previous year. Participants were randomly assigned 1:1 to receive oral tolebrutinib in a dose of 60 mg once daily, or oral teriflunomide in a dose of 14 mg once daily, each with a matching placebo.
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