Phase II Clinical Trial: Tolebrutinib

EP: 1.BTK Inhibitor Overview

EP: 2.BTK Inhibitor Clinical Development

EP: 3.Phase II Clinical Trial: Evobrutinib

EP: 4.Phase II Clinical Trial: Fenebrutinib

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EP: 5.Phase II Clinical Trial: Tolebrutinib

EP: 6.BTKi Safety Data

EP: 7.BTKi Safety Concerns

EP: 8.BTKi Mechanism of Action

EP: 9.BTKi Effect on Chronic Active Lesions

EP: 10.BTKi Treatment: Clinical Measures

EP: 11.BTKi Treatment Paradigm

Jiwon Oh, MD, PhD, FRCPC: I'm just going to, before we move on, to discuss other aspects of BTK inhibitors, summarize, briefly, the phase 2B clinical trial that evaluated tolebrutinib in people with relapsing multiple sclerosis. So, like the evobrutinib phase 2B clinical trial, the tolebrutinib phase 2B clinical trial actually looked at multiple doses of tolebrutinib that ranged from 5 milligrams to 60 milligrams daily.

But it was a very interesting study design. I would say a very efficient study design because there was both a placebo run-in and run-out period that was for a duration of 4 weeks. And this allowed the evaluation of 4 different doses of tolebrutinib over a period of 16 weeks. So, at the end of the 16-week period, tolebrutinib at the highest dose did meet the primary endpoint, which, like the evobrutinib phase 2 clinical trial, was evaluating for a reduction in T1 gadolinium-enhancing lesions.

Specifically, the 60 milligram dose of tolebrutinib reduced T1 gadolinium-enhancing lesions by about 85%. In addition, there were reductions, as expected, in new and enlarging T2 lesions. Although similar to the evobrutinib phase 2 clinical trial, clinical endpoints were not the primary endpoint and the study was not powered to detect a difference, it was very clear that the annualized relapse rate reduced, particularly with people on the tolebrutinib at 60 milligrams, and Expanded Disability Status Scale [EDSS] scores remained stable.

Like the evobrutinib program, the tolebrutinib phase 2B clinical trial then went into an open-label extension, and the extension has now followed patients for up to 3 years, and those results were recently reported at the 2023 European Committee for Treatment and Research in Multiple Sclerosis [ECTRIMS] meeting. Over the 3-year follow-up period, it's reassuring because the annualized relapse rate remained low, EDSS scores also remained stable, and the rate of formation of new T1 gadolinium-enhancing lesions or new T2 lesions also remained low.

One thing to note, with the tolebrutinib extension program, initially, people went into long-term extension part A, during which they continued on the same dose of tolebrutinib that they had been on during the phase 2B trial, so this was one of the doses that ranged between 5 milligrams and 60 milligrams. In long-term extension part B, this is when everybody went on the 60-milligram dose of tolebrutinib.

People will continue in the open-label extension, and these data will be valuable to be assured of continuing efficacy as well as safety with tolebrutinib.

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