Tolebrutinib Shows Favorable Long-Term Safety, Efficacy in Relapsing MS Open-Label Extension

Jiwon Oh, MD, PhD

Sanofi’s tolebrutinib, an investigational Bruton tyrosine kinase (BTK) inhibitor, demonstrated a favorable safety profile with low annualized relapse rate (ARR) at 60-mg doses among patients with relapsing multiple sclerosis (RMS) in an 18-month long-term safety (LTS) extension of a phase 2b trial (NCT03996291).¹

The results, presented at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2022, held February 24-26, in West Palm Beach, Florida, also showed that through 72 weeks of treatment with tolebrutinib 60 mg, new gadolinium (Gd)-enhancing lesion counts were low. By weeks 48 and 72, when all patients in the lower dose groups switched to 60-mg doses, investigators noticed a reduction in new Gd-enhancing lesions.

In the original phase 2b study, tolebrutinib demonstrated a dose-dependent reduction in the number of these lesions and was well-tolerated among patients with relapsing-remitting MS (RRMS) or relapsing secondary progressive MS (SPMS).² Following the conclusion of that trial, 125 of the 129 eligible participants continued to the LTS extension study, and 124 completed Part A to transition to Part B. In total, 118 (94%) remained in the study at the August 2021 cut-off.

Led by Jiwon Oh, MD, PhD, staff neurologist, University of Toronto, participants would first enter Part A of the LTS, where they received the same dose (5, 15, 30, or 60 mg/day) of tolebrutinib. Once the dose of 60 mg was selected for the phase 3 trials, participants entered the open-label Part B of the LTS, where they all received tolebrutinib 60 mg/day.

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At week 72, a low number of new Gd-enhancing lesions (mean counts: 0.62 [±1.06]) were observed for those in the 60/60-mg arm, where dosing had not changed. For those in the 5/60-mg, 15/60-mg, and 30/60-mg arms, these lesions were reduced by mean counts of 0.68 (±0.98), 0.86 (±2.42), and 0.47 (±1.33), respectively, at weeks 48 and 72. The investigators also wrote that new/enlarging T2 lesion counts remained low for the 60/60-mg arm through week 24, and increased slightly at weeks 48 and 72.¹

Slowly evolving lesion (SEL) volume, another MRI outcome measure, was 441 (IQR, 69-630), 468 (IQR, 102-1317), 675 (IQR, 150-1230), and 284 (IQR, 168-504) mm3 in the 5/60-, 15/60-, 30/60-, and 60/60-mg arms, respectively, at week 72. Most patients did not demonstrate changes in paramagnetic rim lesion counts.

Most common adverse events (AE) reported were headache (12.8%), COVID-19 (12.8%), nasopharyngitis (10.4%), upper respiratory tract infection (8.0%), and arthralgia (5.6%). There was no dose-dependent relationship observed for treatment-emergent AEs or serious AEs in Part A, and patients who switched to 60-mg tolebrutinib in Part B showed no new safety signals as well.

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 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® in November.

To this point, tolebrutinib has become a well-traveled investigational agent in the MS pipeline. In December 2020, the National Multiple Sclerosis Society announced the therapeutic 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.³

GEMINI 1, a randomized, double-blind study, is evaluating the safety and efficacy of 60-mg tolebrutinib in comparison with oral teriflunomide (Aubagio; Sanofi Genzyme), an already FDA-approved therapy. Patients in that study are randomly assigned to receive either treatment for up to 3 years.

For more coverage of ACTRIMS Forum 2022, click here.

REFERENCES
1. MRI, safety, and efficacy outcomes in patients with relapsing MS: 18-month results from the long-term extension study of tolebrutinib. Presented at ACTRIMS Forum 2022; February 24-26; West Palm Beach, FL. Abstract P102

2. Reich DS, Arnold DL, Vermersch P, et al. Safety and efficacy of tolebrutinib, an oral brain-penetrant BTK inhibitor in relapsing multiple sclerosis: a phase 2b, randomized, double-blind, placebo-controlled trial. Lancet Neurol. Published online August 2021. doi: 10.1016/S1474-4422(21)00237-4

3. MS trial alert: investigators recruiting for two phase 3 trials comparing experimental tolebrutinib with Aubagio in relapsing MS. National Multiple Sclerosis Society. December 10, 2020. Accessed February 23, 2022. https://www.nationalmssociety.org/About-the-Society/News/MS-Trial-Alert-Investigators-Recruiting-for-Two-Ph