new research suggests. After 12 weeks of treatment, MRI revealed the drug, a Bruton tyrosine kinase inhibitor, was associated with a 93% reduction in new gadolinium-enhancing lesions and an 89% reduction in new and enlarging T2 lesions, compared with placebo.
Dr. Anthony Traboulsee
The analysis supports that tolebrutinib is as effective in this group of patients with highly active relapsing remitting MS as it is in the overall patient population, study investigator said Anthony Traboulsee, MD, professor and research chair of the MS Society of Canada at the University of British Columbia, Vancouver.
“What is additionally exciting is that this effect was seen within a relatively short period of time – within 3 months. This will be important for patients and physicians to know how soon to expect a treatment to work if they have high-risk baseline features,” he added.
The findings were presented at the 2021 annual meeting of the American Academy of Neurology.
New drug class
BTK inhibitors are a new class of oral therapies, and phase 2 trials in patients with relapsing remitting MS show they are safe and effective. BTK inhibitors modulate B lymphocytes without causing depletion, thus reducing the risk for lymphopenia or immunoglobulin depletion.
Tolebrutinib is a covalent, irreversible BTK inhibitor that penetrates the central nervous system well. In a previous randomized, double-blind, phase 2b trial, it was well tolerated and was associated with a dose-dependent reduction in new or enlarging 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 disease course, the investigators examined tolebrutinib’s efficacy and safety in patients with highly active disease who were participants in the phase 2b trial. This subgroup analysis had been predefined in the study’s statistical analysis plan.
The investigators defined highly active disease as one relapse in the year before screening and one or more gadolinium-enhancing lesions on MRI performed within 6 months before screening, or nine or more T2 lesions at baseline, or two or more relapses in the year before screening.
Of the 130 participants enrolled in the study, 61 (47%) met criteria for highly active disease at baseline. These patients represented 44% of the placebo group (29 of 66 participants) who later crossed over to tolebrutinib treatment.
At baseline, demographics in patients with highly active disease were similar to those of the overall study population, although it was slightly younger with slightly shorter disease duration, slightly less disability, and a greater likelihood of gadolinium-enhancing lesions at baseline versus the overall 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 study’s primary objective was to examine the dose-response relationship after 12 weeks of treatment with tolebrutinib.
Good safety, tolerability
After 12 weeks, the mean number of new gadolinium-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 30-mg group, and 0.08 in the 60-mg group. The corresponding measurements in 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 60-mg group.
After 12 weeks, numbers of new or enlarging T2 lesions among patients with highly active disease were 1.09 (5 mg), 0.89 (15 mg), 0.75 (30 mg) and 0.15 (60 mg). The corresponding measurements in 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 disease and in the overall population, said Dr. Traboulsee.
No adverse events were linked to the study drug. One patient with highly active disease who received 60 mg of tolebrutinib had transient elevated ALT levels greater than three times the upper limit of normal. This patient also previously had elevated ALT at baseline.
One serious adverse event occurred during the study. One patient was hospitalized for MS relapse. The patient had been assigned to the 60-mg dose of tolebrutinib. The patient recovered and remained on study treatment.
Two independent studies have indicated that BTK inhibition is an effective treatment approach for relapsing remitting MS. The main advantage of tolebrutinib is its ability to penetrate the CNS.
“Most, if not all, MS therapies mostly affect the peripheral immune system, preventing autoreactive lymphocytes crossing the blood-brain barrier and causing damage,” said Dr. Traboulsee.
Therapies that enter the CNS can target abnormal immune cells, including microglia that are believed to promote disease progression. “If this is an important target, then we now have a highly CNS-penetrant drug that could potentially change the course of progression,” said Dr. Traboulsee.
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 though, it is the clinical outcomes in the phase 3 programs that are essential to know where to place tolebrutinib in the future care of relapsing and progressive forms of MS.”
Not an unmet need
Commenting on the findings, Joseph R. Berger, MD, professor of neurology and associate chief of the MS division at the University of Pennsylvania, Philadelphia, said there are several available treatments that effectively suppress clinical and radiologic evidence of acute inflammation in relapsing remitting MS.
Dr. Joseph Berger
“Any new drug that is to be added to that pharmacological armamentarium should have distinct advantages over what is currently available. Treating relapsing remitting MS is not, in my opinion, an unmet need in MS; treating progressive disease is,” he said.
Dr. Berger said that tolebrutinib appears to be better than placebo in suppressing disease activity, particularly at higher doses. “However, the study is small – only 61 patients,” noted Dr. Berger, who was not involved in the study.
In addition, disease activity was assessed after 4 weeks with placebo and at 12 weeks with tolebrutinib treatment.
“As there is a regression to the mean with respect to disease activity, the interpretation of the apparent response to tolebrutinib needs to be tempered with that in mind,” said Dr. Berger.
Evaluating how tolebrutinib compares with other BTK inhibitors will require a head-to-head trial. “I’d be more interested in whether the drug has an effect on progressive disease,” Dr. Berger concluded.
The study was supported by Sanofi Genzyme, which is developing tolebrutinib. Dr. Traboulsee has received research grant support, honoraria for consulting, and honoraria for participating in a speakers’ bureau from Sanofi Genzyme. Dr. Berger disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.