Tolebrutinib, a potent inhibitor of Bruton tyrosine kinase that can cross the blood-brain barrier, is currently being investigated as a potential treatment for multiple sclerosis (MS). The phase 2b trial (NCT03889639) included a double-blind phase (DBP) and involved participants with relapsing MS. During the 12-week DBP, tolebrutinib demonstrated favorable tolerability and exhibited a dose-dependent reduction in new gadolinium (Gd)-enhancing T1 lesions as well as new/enlarging T2 lesions. To further evaluate the long-term safety and efficacy of tolebrutinib, the LTS16004 study (NCT03996291) was initiated as an extension of the phase 2b trial. This ongoing study focuses on participants who completed the initial trial. The primary objective of the LTS extension study was to assess the magnetic resonance imaging (MRI) outcomes at week 96, representing a two-year study duration. These MRI outcomes provide valuable insights into the impact of tolebrutinib on disease progression and lesion activity in participants with MS.
The extension study consisted of two parts: Part A, where participants continued receiving their DBP dose (5, 15, 30, or 60 mg/day) in a double-blinded manner, and Part B, an open-label extension where all participants received a dose of 60 mg/day. The study assessed various magnetic resonance imaging (MRI) outcomes, including the number of new gadolinium-enhancing T1 lesions, new or enlarging T2 lesions, changes in T2 lesion volume from baseline, slowly evolving lesions (SELs), and paramagnetic rim lesions (PRLs). As of the cutoff date of February 18, 2022 (week 96), 114 participants (90.5%) remained enrolled in the study. At the start of the DBP, the registered participants had a mean age of 37.7 ± 9.6 years, and 69% were women. The 60/60-mg dose arm consistently showed low numbers of new gadolinium-enhancing lesions throughout the study period. In the lower-dose arms, the number of these lesions decreased from week 48 to week 96 (mean ± SD: 0.85 ± 2.5, 0.41 ± 0.91, 0.90 ± 2.16, 0.31 ± 0.66 in the 5/60-mg, 15/60-mg, 30/60-mg, 60/60-mg arms, respectively). The count of new or enlarging T2 lesions remained low in the 60/60-mg arm. T2 lesion volume change was minimal in the 60/60-mg arm at week 96 compared to baseline (mean ± SD: 0.38 ± 2.11 cm3). The median volume of slowly evolving lesions (SELs) at week 96 varied across the different dose arms (247.5 mm3 for the 5/60-mg arm, 258 mm3 for the 15/60-mg arm, 570 mm3 for the 30/60-mg arm, and 244.5 mm3 for the 60/60-mg arm). The count of paramagnetic rim lesions (PRLs) remained unchanged in 18 participants, while a few participants had an increase in PRLs corresponding to new T2 lesions.
The results demonstrate that the tolebrutinib 60/60-mg arm consistently had low numbers of new gadolinium-enhancing lesions. Furthermore, lower-dose arms showed a reduction in these lesions over time. These findings highlight the effectiveness of the 60/60-mg dose of tolebrutinib for the long-term management of MS.
