The trial of anakinra is underway, while the trial for tolebrutinib is undergoing regulatory review.
A new phase 2a clinical trial paradigm for multiple sclerosis (MS) is underway, evaluating the effects of anakinra and tolebrutinib on 7-Tesla magnetic resonance imaging (MRI) paramagnetic rim lesions (PRL) in 2 studies.1
The 2 open-label studies, 1 evaluating anakinra currently underway (NCT04025554) and the second evaluating tolebrutinib study undergoing regulatory review, were presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021 by Jemima Akinsanya, DO, Neuroimmunology Clinical Fellow, National Institutes of Health, and colleagues.
“No existing treatment for MS is known to resolve ‘chronic active’ or ‘smoldering’ white matter lesions, which can expand over time, may play a role in disease progression, and are identifiable on high-field MRI by their characteristic paramagnetic rims, which indicate iron-laden phagocytes at the lesion edge,” Akinsanya and colleagues wrote.
Anakinra, a recombinant human interleukin-1 receptor antagonist, was approved by the FDA for the treatment of rheumatoid arthritis and Neonatal-Onset Multisystem Inflammatory Disease in 2001.2 The study will evaluate the effects of short-term anakinra of up to 300 mg per day doses on PRL.
It will enroll up to 10 patients with progressive or stable MS with 1 or more PRL and no new lesions or relapse within the past year. Over 12 weeks, patients will receive a scheduled dose escalation of daily self-administered subcutaneous injections with monthly evaluations. Follow-up visits will be conducted 12 weeks after discontinuation.
Tolebrutinib is an investigational, orally available, brain-penetrant Bruton’s tyrosine kinase (TBK) inhibitor. The first cohort in the study will consist of 10 patients that are stable on anti-CD20 antibody therapy and within 3 months of their most recent dose. These patients will initiate tolebrutinib treatment with 60 mg daily while forgoing further anti-CD20 or other disease-modifying therapies (DMTs) for the duration of the trial.
The second cohort will be a non-randomized comparison group of 10 patients choosing to stay on anti-CD20 antibody therapy instead of receiving tolebrutinib. Both cohorts will be followed for 96 weeks, with 7-Tesla scans every 6 months, and the primary outcome of PRL disappearance assessed, blinded, at 48 weeks.
Secondary outcome measures include scores on Expanded Disability Status Scale, 9-hole peg test, Symbol Digit Modalities Test. Immune cell populations, single-cell cerebrospinal fluid (CSF), blood RNA sequencing, and biomarkers such as neurofilament light chain will also be analyzed.
“We aim to induce therapeutic disruption of the dysregulated equilibrium at the edge of chronic active lesions, visualized as either complete or partial resolution of the paramagnetic rim on MRI. Exploratory imaging and biological outcomes will assess whether such disruption, if achieved, will facilitate lesion repair or alter relevant biomarkers in CSF and blood,” Akinsanya and colleagues concluded. “These studies are the first steps toward a novel trial design to explore an emerging outcome measure that may address a critical but unmet clinical need in MS.”
For more coverage of ACTRIMS Forum 2021, click here.