The Bruton tyrosine kinase inhibitor has been evaluated in 2 phase 3 trials, GEMINI 1 and GEMINI 2 (NCT04410978; NCT04410991), in patients with relapsing-remitting and relapsing secondary progressive MS.
IN A PHASE 2B SETTING, tolebrutinib demonstrated dose-dependent reduction of GdE lesions among patients with relapsing-remitting multiple sclerosis (MS) or relapsing secondary progressive MS (SPMS).
In clinical trials that have featured patients with relapsing MS (RMS), SPMS, and primary progressive MS (PPMS), Sanofi’s tolebrutinib has become a well-traveled investigational agent in the MS pipeline. In December 2020, the National Multiple Sclerosis Society announced that the Bruton tyrosine kinase (BTK) inhibitor is being evaluated in 4 phase 3 trials, GEMINI 1 and GEMINI 2 (NCT04410978; NCT04410991) in patients with relapsing forms of MS, HERCULES (NCT04411641) in non-relapsing SPMS, and PERSEUS (NCT04458051) in PPMS.1
Each study includes 900 participants, aged 18 to 55 years, with various forms of RMS. GEMINI 1, a randomized, double-blind study, is evaluating the safety and efficacy of 60-mg oral tolebrutinib in comparison with oral teriflunomide (Aubagio; Sanofi Genzyme), an already FDA-approved therapy. Patients in the study are randomly assigned to receive either treatment for up to 3 years (FIGURE).
By acting as a BTK inhibitor, tolebrutinib is designed to reduce the activation of B cells, immune cells that play a role in the response that affects the brain and spinal cord in MS. “If you look at the compound itself, you have to look to look at brain penetration as one aspect. You have to look at specificity and potency as well,” Erik Wallström, MD, PhD, senior vice president and global head of the Neurology Department at Sanofi Genzyme, told NeurologyLive®.
“We do think tolebrutinib is a nice combination of those. It’s not the most selective, but it’s quite selective. It’s one of the most brain penetrant and quite potent. That combination makes us believe that we can achieve levels in the brain that are pharmacologically relevant,” Wallström added.
The trial’s primary outcome measure is the annualized adjudicated relapse rate. Other secondary outcome measures include confirmed disability worsening (CDW), time to onset of CDW, total number of new and/or enlarging T2 hyperintense lesions, and total number of gadolinium-enhancing (GdE) T1 hyperintense lesions. Investigators will also assess quality of life, safety, and laboratory biomarkers of immune and nervous system activity.
There has been a sizeable amount of data on tolebrutinib up to this point. In August, findings from a phase 2b study (NCT03889639) showed that treatment with the agent was well tolerated and had a dose-dependent reduction in the number of new GdE lesions among patients with relapsing-remitting MS or relapsing SPMS. This was a 16-week, double-blind, placebo-controlled, crossover, dose-finding trial that assigned 130 participants to tolebrutinib 5 mg (n = 33), 15 mg (n = 32), 30 mg (n = 33), and 60 mg.2
Cohort 1 received tolebrutinib for 12 weeks, then matched placebo for 4 weeks, whereas those in cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. An exponential model showed a dose-response relationship between tolebrutinib and new GdE lesions, which was used to reject the null hypothesis of a flat dose-response curve (test statistic, 2.47; P = .03). The 60-mg dose was the most efficacious, with an observed mean number of lesions of 0.13 (standard deviation [SD], 0.43) compared with 1.03 (SD, 2.50) for placebo. Furthermore, 28 of the 31 participants (90%) who received the 60-mg dose had no new GdE lesions after 12 weeks of treatment, compared with 44 of 59 participants (75%) in the cohort 2 placebo period observed at week 4.
At the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, October 13 to 15, 2021, additional data from the 1-year open-label extension of the phase 2b study were presented. The trial investigators observed no new safety signals among the 125 patients enrolled, and the most common treatment-emergent adverse events were headache (10%), COVID-19 (9%), upper respiratory tract infection (8%), and nasopharyngitis (7%).3
“Those data look quite aligned with the phase 2b data, which is good, because we don’t want surprises,” Wallström said. He went on to explain how dose finding has been crucial for tolebrutinib’s development. “An observation that one should keep in mind when looking at BTK inhibitors across the class is that those findings are not trivial. It was [somewhat a case of] ‘You may have surprises.’ With the 60-mg dose, we’re quite confident based on the phase 2 data. We’ve also looked at exposure vs MRI effects.”
Sanofi is conducting multiple trials of tolebrutinib including HERCULES (NCT04411641), a phase 3 study that assesses the drug in up to 1290 patients with nonrelapsing SPMS. PERSEUS (NCT04458051) is another phase 3 study testing the efficacy of the agent in 990 adults with PPMS. Both studies are anticipated to be completed in August 2024.