Prof. Tony Traboulsee talks to Physician’s Weekly about his study of tolebrutinib

Presented at the American Academy of Neurology (AAN) 2021 Annual Meeting, Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia in Vancouver, demonstrated that the role of Bruton’s tyrosine kinase (BTK) signaling in modulating inflammation in microglial cells can be modulated using brain-penetrant BTK inhibitors in patients with highly active multiple sclerosis (MS). Phase 2b trial results demonstrated that tolebrutinib was well tolerated and identified a dose-dependent reduction in new/enlarging MRI lesions. This treatment may suppress microglia-driven neuroinflammation in MS progression [1].

Bruton tyrosine kinase (BTK) is a non-receptor cytoplasmic tyrosine kinase expressed in B-lymphocytes, myeloid cells and platelets. BTK-inhibitors (BTKi) are used to treat patients with B-cell malignancies and autoimmune diseases including multiple sclerosis (MS), and have even been proposed as novel antithrombotic therapeutic, for example, in patients with severe COVID-19
For MS, neuroinflammation in the brain and spinal cord is driven largely by CNS-resident microglia, and this process has been proposed as a significant contributor to disability accumulation in patients with MS [2]. BTK is expressed in microglia, as well as B-lymphocytes and monocytes/macrophages found in the periphery [3]. Preclinical and early clinical data has suggested that brain-penetrant BTKi may provide therapeutic benefit within the CNS by targeting innate and adaptive immunity, associated with disease progression in MS [4]. Tolebrutinib is an oral irreversible covalent BTKi which crosses the blood–brain barrier and is in development to treat MS [5].

Tolebrutinib binds covalently and irreversibly to Cys-481 in the ATP binding site of BTK, which offers several advantages over reversible inhibitors. Primarily, irreversible binding increases biochemical efficiency for target disruption, enabling sustained effects which are required for clinical efficacy. A recent preclinical report showed that tolebrutinib inhibits myelin loss in a cuprizone-induced mouse model of MS-like demyelination [6]. The data from this study support the notion that microglial BTKi by tolebrutinib protected the myelin sheaths in this in vivo MS model. The researchers demonstrated that tolebrutinib bound to BTK in microglia cells with an IC50 of 0.7 nM, whereas it inhibited B-cell receptor stimulation in whole blood with an IC50 of 10 nM. In humans, a phase 1 study saw rapid absorption (Tmax=1 hour) of tolebrutinib, and a maximal plasma concentration of 46 nM (21 ng/mL) with BTK occupancy of 93–97% in peripheral blood cells. Tolebrutinib was also detectable in cerebrospinal fluid. Although diarrhea was a common adverse event at higher doses, the drug was generally well tolerated, and bleeding was not observed [7].

Anthony Traboulsee, MD

Neurologist, Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia in Vancouver, presented a subgroup analysis of patients with relapsing MS and highly active disease (HAD) in the 16-week tolebrutinib phase 2b study (NCT03889639) [1]. This was a randomized, double-blind, placebo-controlled, cross-over, dose-ranging trial (n=130). HAD was defined as having a single relapse in the year prior to screening together with ≥1 gadolinium (Gd)-enhancing lesion on MRI performed within 6 months prior to screening, or ≥9 T2 lesions at baseline, or ≥2 relapses in the year prior to screening, and 61 patients (47%) met HAD criteria at baseline which were included in this prespecified analysis. Furthermore, MS patients with HAD composed 44% of the placebo cohort (29/66) who later crossed over to tolebrutinib treatment. HAD patients were distributed across each tolebrutinib dose arm (12/33 [36%] received 5mg, 19/32 [59%] received 15mg, 16/33 [48%] received 30mg, and 14/32 [44%] received 60mg). The primary outcome was the number if new Gd-enhancing lesions at 4 weeks versus placebo. Secondary endpoints were the number of new or enlarging T2-lesions at 4 weeks versus placebo, as well as safety.

After 4 weeks of placebo treatment, the HAD subgroup had a mean number of 0.89 Gd-enhancing lesions and 1.44 new/enlarging T2 lesions. After 12 weeks of tolebrutinib treatment, new Gd-enhancing lesions in the HAD subgroups were reduced by 93% when compared to placebo, and was dose-dependent; mean numbers were 0.82 (5 mg; not significant), 0.5 (15 mg; not significant), 0.38 (30 mg; not significant), and 0.08 (60 mg; p=0.003). Likewise, respective numbers of new/enlarging T2 lesions were reduced by 89% compared with placebo, with mean numbers being 1.09 (5 mg; not significant), 0.89 (15 mg; not significant), 0.75 (30 mg; not significant), and 0.15 (60 mg; p=0.0104). Tolebrutinib was well tolerated over 12 weeks. The significant efficacy effects observed at 60mg dose was also seen in the overall study population, with 85% reduction of new Gd-enhancing lesions (p=0.0178), and 89% reduction of new/enlarging T2 lesions (p=0.001).

Safety profiles in patients meeting HAD criteria were consistent with the overall study population, and 12-week exposure to tolebrutinib was well tolerated. No patient discontinued tolebrutinib or the study as a result of adverse events. A single patient from the 60mg treatment group experienced a relapse of MS and required hospitalization, although this patient recovered and remained in the study uninterrupted. Another patient had transiently elevated liver enzymes, but again, this normalized quickly and the patient remained in the study. Overall, the safety profile in HAD patients did not differ. Prof. Traboulsee concluded that HAD patients, typically considered difficult to treat, appear to respond at least as well, if not better to tolebrutinib treatment than MS patients with less active disease.

In an interview, Prof. Traboulsee told Physician’s Weekly: “What we found is that the drug in the phase 2 trial was just as effective in that high-risk population as it was in the general population of the study. And that is very encouraging that we know it is a potential broad-spectrum medication for very active MS as well as average MS, but also that it works quite quickly. This study reached its outcome at 3 months of drug exposure, which is considered quite fast in terms of efficacy in the MS world. So it has been very exciting to see this development of yet another potential drug for treatment of MS that is well-tolerated, appearing to be very effective and very safe. Where the real unmet need for MS is -beyond having more tolerable, effective drugs- is really trying to deal with progressive forms of multiple sclerosis. I think we are at the threshold of finding better medications for progressive MS. The future for MS treatment, I think, is very optimistic.”

1. Traboulsee A et al. Efficacy and Safety of Tolebrutinib in Patients With Highly Active Relapsing MS: Subgroup Analysis of the Phase 2b Study. AAN 2021 , 17-22 April, 2021. Abstract 004.
2. Voet S, Prinz M, van Loo G. Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology. Trends Mol Med. 2019 Feb;25(2):112-123.
3. Ito M, Shichita T, Okada M, Komine R, Noguchi Y, Yoshimura A, Morita R. Bruton’s tyrosine kinase is essential for NLRP3 inflammasome activation and contributes to ischaemic brain injury. Nat Commun. 2015 Jun 10;6:7360.
4. Francesco M, et al. PRN2246, a potent and selective blood brain barrier penetrating BTK inhibitor, exhibits efficacy in central nervous system immunity. ECTRIMS 2017. Poster P989.
5. Smith PF, et al. Phase 1 Clinical Trial of PRN2246 (SAR442168), a Covalent BTK Inhibitor Demonstrates Safety, CNSExposure and Therapeutic Levels of BTK Occupancy. ACTRIMS 2019. Poster 072.
6. Gruber R, et al. Decoding Bruton’s tyrosine kinase signalling in neuroinflammation. MSVirtual 2020, Abstract P0311.
7. von Hundelshausen P, Siess W. Bleeding by Bruton Tyrosine Kinase-Inhibitors: Dependency on Drug Type and Disease. Cancers (Basel). 2021 Mar 4;13(5):1103.