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Link to original article: Neurology Today (lww.com)
The fully human anti-CD3 antibody foralumab attenuates microglial activation in patients with non-active secondary progressive multiple sclerosis (na-SPMS) with progression independent of relapse (PIRA), according to a small pilot study presented at the AAN Annual Meeting, held in Denver in April.
“PIRA is a major unmet need in multiple sclerosis [MS],” said lead author Tarun Singhal, MD, MBBS, associate professor of neurology at Harvard Medical School. “None of the disease-modifying therapies we currently have are approved for this category of progressive MS patients.” A systematic review published in JAMA Neurology last October found that PIRA is the most frequent manifestation of disability accumulation across the full spectrum of traditional MS phenotypes.
One of the mechanisms thought to contribute to na-SPMS with PIRA is innate immune activation of microglial cells and astrocytes, for which there historically have been no good biomarkers in humans. To measure the activity of foralumab in a group of six na-SPMS patients with PIRA, Dr. Singhal and his colleagues used PET scans with [F18]PBR06, a novel ligand that targets the 18-kDa-translocator protein which is overexpressed on activated microglia/macrophages.
“This ligand has a long half-life and is therefore feasible for multicenter studies and potential clinical use, unlike a number of other PET ligands,” he said.
Five of the six patients (83 percent; 95 percent confidence interval 44 to 97 percent) showed a qualitative reduction on [F18]PBR06-PET in multiple brain regions at both three and six months after initiation of treatment with nasal foralumab. White matter z-scores were reduced by 26 to 36 percent in the foralumab group at these time points, which was more than four to five times higher than the 6 percent variability seen in two patients with PIRA who did not receive nasal foralumab but underwent testing and retesting with [F18]PBR06-PET.
“We are encouraged by the magnitude of change we see, particularly in these patients’ white matter, and do not think it’s just random noise,” Dr. Singhal said.
Clinically, the investigators also noted that foralumab-treated patients demonstrated stable disability scores on the Extended Disability Status Scale and improvement in the modified fatigue impact scale at three and six months.
Since submitting the abstract for presentation at the AAN Annual Meeting, Dr. Singhal said, they have gathered additional data now that most of the participants have been treated for nearly 12 months.
“My general impression is that patients have remained clinically stable and/or improved on these metrices, but we are compiling the additional clinical information in detail,” he said.
“Obviously, this is a very small sample size, and there is no reported data on safety. But if this agent proves to be useful and safe in larger trials, this study will be looked at as the first evidence that we can have some kind of impact in this form of MS, which is the most intractable form to treat,” says John Corboy, MD, FAAN, an endowed chair in neurology and director of the Rocky Mountain Multiple Sclerosis Center at the University of Colorado Anschutz Medical Campus.
“We do not have any recognized approaches to try to alter microglial activation at present, which everyone agrees at this point in time is relevant throughout the life of a patient with MS. Even ocrelizumab [Ocrevus] for primary progressive MS has modest impact, so the potential here is great, and the proof of principle that you can alter the microglia is a real punchline.”
Dr. Corboy cautioned that [F18]PBR06-PET is a novel technique and not commonly used in clinical practice, so understanding its true significance and what impact it might have on clinical function is challenging. “Nonetheless, it is a proof of concept as to whether you can show a benefit using this oral agent to bind and turn off these active microglia.”
The investigators are now studying nasal foralumab in a larger group of patients within an expanded access program, and a phase 2, double-blind, placebo-controlled, dose-ranging study of the agent also is underway using [F18]PBR06-PET as a primary endpoint.
“We are also committed to confirming these findings with further quantitative approaches,” Dr. Singhal said.
Disclosures: Dr. Singhal received personal compensation for serving as a consultant for Novartis and on a scientific advisory or data safety monitoring board for Genentech. His institution has received research support from Novartis and the US Department of Defense.
• AAN Annual Meeting Abstract S31.002: Singhal T, Zurawski J, Cicero S, et al. Treatment of PIRA with nasal foralumab dampens microglial activation and stabilizes clinical progression in non-active secondary progressive MS.