In the phase 3 PERSEUS trial, BTK inhibitor tolebrutinib did not significantly reduce disability progression compared with placebo in patients with primary progressive multiple sclerosis.
Late-breaking data from the phase 3 PERSEUS trial (NCT04458051) showed that tolebrutinib (Sanofi), an investigational Bruton tyrosine kinase (BTK) inhibitor,
“My initial reaction is ‘puzzled’ because we saw a reduced risk of disability progression with tolebrutinib in HERCULES and GEMINI I/II, so I was expecting to see the same in PERSEUS. So why the difference? For one, the outcome was different: composite progression with PERSEUS rather than Expanded Disability Status Scale (EDSS)," senior author
In the study, presented at the
“Indeed, the EDSS outcome trended favorably, with HR = 0.86, but not statistically significant. Also, the characteristics of these patients is much different than other PPMS trials such as 2 large ocrelizumab trials – ORATORIO and O’HAND,” added Fox, staff neurologist at
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PERSEUS was a randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven trial that assessed the efficacy and safety of tolebrutinib in individuals living with PPMS. Eligible participants were aged 18 to 55 years, and had a diagnosis of PPMS according to the 2017 McDonald criteria, an EDSS score of 2.0 to 6.5 at screening, positive cerebrospinal fluid findings, and no access to, intolerance of, or perceived lack of efficacy with ocrelizumab (Ocrevus; Genentech).
In the trial, participants were randomly assigned 2:1 to receive tolebrutinib 60 mg or placebo, administered orally once daily with food. The primary end point was time to onset of 6-month composite CDP (cCDP), defined by worsening on the EDSS, Timed 25-Foot Walk, or 9-Hole Peg Test. Authors noted that secondary end points included additional disability measures, MRI outcomes, and safety assessments.
All told, a total of 767 participants were enrolled into the study. The mean age for participants was 45.3 years, and the mean time since PPMS diagnosis was 4.2 years. Overall, 54% of participants were men and 83% were White. At baseline, the mean EDSS score was 4.9 (median, 5.0), and 59% of participants were treatment naïve. On MRI, 89% of participants had no gadolinium-enhancing lesions at baseline. Among those who underwent susceptibility-sensitive imaging, 63% had at least 1 paramagnetic rim lesion at baseline.
Researchers reported that only 3% of patients with PPMS treated with tolebrutinib experienced liver enzyme elevations more than 5 times the upper limit of normal and 1 patient met Hy law criteria for liver injury. In addition, authors observed that the discontinuation rate was 24.6% of participants in the tolebrutinib arm and 22.7% of patients in the placebo arm. In a company update, Sanofi noted that, based on the phase 3 PERSEUS data, a regulatory submission for tolebrutinib in PPMS is not expected.2
“As for my thoughts regarding BTK inhibitors in general, I remain optimistic that this class will be found helpful in MS, but it’s clear that different drugs within the class work differently. As we look to compare across trials, we’ll want to try to adjust for differences in patient characteristics between the trials,” Fox told NeurologyLive®.
Editor’s Note: Fox has disclosed that he has received consulting fees from Sanofi for advisory roles related to the PERSEUS trial.
