Research drug tolebrutinib effectively reduces brain injury in patients with very active relapse-remission multiple sclerosis (RRMS), suggests new research.
After 12 weeks of treatment, MRI revealed that the drug, a Bruton tyrosine kinase (BTK) inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and a reduction in 89%. % of new and increasing T2 lesions compared with placebo.
The analysis supports that tolebrutinib is as effective in this group of patients with highly active recurrent-remitting MS as in the overall patient population, according to study researcher Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia in Vancouver said Medscape Medical News.
“What’s additionally exciting is that this effect was seen in a relatively short period of time, within three months. This will be important for patients and doctors to know how long they expect a treatment to work if they have baseline characteristics. high risk, “he added.
He the results were presented at the 2021 annual virtual meeting of the American Academy of Neurology (AAN) virtual.
New class of drugs
BTK inhibitors are a new class of oral therapies and phase 2 trials in patients with SMRR show that they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk of lymphopenia or immunoglobulin depletion.
Tolebrutinib is a covalent and irreversible BTK inhibitor that penetrates well into the central nervous system (CNS). In a randomized, double-blind, pre-randomized phase 2b trial, it was well tolerated and associated with dose-dependent reduction in new or increasing MRI lesions. Of the four doses studied, the 60 mg dose was the most effective.
Because highly active MS is associated with a more aggressive course of disease, the researchers examined the efficacy and safety of tolebrutinib in patients with highly active disease who participated in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.
The researchers defined the highly active disease as a relapse the year before screening and one or more MRI gadolinium lesions performed in the 6 months prior to screening, or nine or more T2 lesions at baseline or two or more relapses l ‘year prior to screening.
Of the 130 participants enrolled in the study, 61 (47%) met the criteria for highly active disease at baseline. These patients accounted for 44% of the placebo group (29 of 66 participants) who later switched to tolebrutinib treatment.
Initially, demographics in patients with highly active disease were similar to those in the overall study population, although they were slightly younger, with a slightly shorter disease duration, a slightly shorter disability, and a higher probability. of lesions that improved gadolinium at baseline, compared with the total study population.
The proportion of patients with highly active disease was 36% in the 5 mg group, 59% in the 15 mg group, 48% in the 30 mg group, and 44% in the 60 mg group.
The main objective of the study was to examine the dose-response relationship after 12 weeks of tolebrutinib treatment.
Good safety, tolerability
After 12 weeks, the mean number of new gadolini-enhancing lesions in patients with highly active disease was 0.82 in the 5 mg group, 0.50 in the 15 mg group, 0.38 in the the 30 mg group and 0.08 in the 60 mg group. group mg. Measurements for the overall study population were 1.39 in the 5 mg group, 0.77 in the 15 mg group, 0.76 in the 30 mg group, and 0.13 in the 5 mg group. 60 mg group.
After 12 weeks, the number of new or increasing T2 lesions in patients with highly active disease was 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg), and 0. 15 (60 mg). Measurements for the overall population were 1.90 (5 mg), 1.32 (15 mg) 1.30 (30 mg), and 0.23 (60 mg).
Tolebrutinib had excellent safety and tolerability in patients with highly active diseases and in the general population, Traboulsee said.
No adverse events were related to the study drug. A patient with highly active disease who received 60 mg of tolebrutinib had elevated transient levels of the enzyme alanine aminotransferase (ALT) above three times the upper limit of normal. This patient also had elevated ALT at baseline.
A serious adverse event occurred during the study. One patient was hospitalized for relapse of MS. He had been assigned a dose of tolebrutinib of 60 mg. The patient recovered and remained in study treatment.
Two independent studies have indicated that BTK inhibition is an effective treatment approach for recurrent-remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.
“Most, if not all, of MS therapies mostly affect the peripheral immune system, preventing self-reactive lymphocytes from crossing the blood-brain barrier and causing damage,” Traboulsee said.
Therapies entering the CNS can target abnormal immune cells, including microglia that are thought to promote disease progression. “If this is an important goal, we now have a highly penetrating CNS drug that could change the course of progression,” Traboulsee said.
Serum biomarkers and advanced imaging data collected during the phase 2 trial could help clarify the mechanisms of disease progression and the effects of tolebrutinib, he added.
“Ultimately, however, it is the clinical outcomes of phase 3 programs that are essential to know where to place tolebrutinib in the future treatment of recurrent and progressive forms of MS.”
It is not an unmet need
Commenting on the findings of Medscape Medical News, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania in Philadelphia, said there are several treatments available that effectively suppress the clinical and radiological evidence of acute inflammation in SMRR.
“Any new drug added to this pharmacological armament should have different advantages over what is currently available. The treatment of RRMS is not, in my opinion, an unmet need in MS; the treatment of progressive disease is, ”he said.
Berger said tolebrutinib appears to be better than placebo at suppressing disease activity, especially at higher doses. “However, the study is small, only 61 patients,” noted Berger, who did not participate in the study.
In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.
“Because there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib should be moderated with this in mind,” Berger said.
To evaluate the comparison of tolebrutinib with other BTK inhibitors, a head-to-head trial will be required. “I would be more interested if the drug has effects on progressive disease,” Berger concluded.
The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Traboulsee has received research grants, advice fees and fees for participating in a Sanofi Genzyme speaker office. Berger has not disclosed any relevant financial relationship.
2021 Annual Meeting of the American Academy of Neurology (AAN): Summary S25.004. Filed April 20, 2021.