Treatment of PIRA with Nasal Foralumab Dampens Microglial Activation and Stabilizes Clinical Progression in Non-active Secondary Progressive MS
Tarun Singhal1, Jonathan Zurawski1, Steven Cicero1, Steven Vaquerano1, Shipra Dubey1, Taylor Saraceno1, Danielle Howard1, John Sullivan1, Nancy Clementi2, Howard Weiner1, Tanuja Chitnis1
1Brigham and Women's Hospital, 2Clementi & Associates Ltd.
To assess the effect of nasal foralumab, a fully-human anti-CD3 monoclonal-antibody on microglial activation in non-active secondary progressive multiple sclerosis (na-SPMS) with PIRA (progression independent of relapses).

A major unmet need in MS is developing therapy for na-SPMS with PIRA and smoldering inflammation. [F-18]PBR06 is a long half-life PET ligand targeting the 18kiloDalton translocator protein that measures microglial density and is increased in na-SPMS and PIRA. We are using nasal foralumab to treat MS subjects with PIRA in an open-label expanded-access program based on its positive effects in attenuating microglial activation and clinical progression in an animal model of progressive MS.


22 [F-18]PBR06-PET scans were performed in 6 na-SPMS patients with PIRA (3 females) who underwent [F-18]PBR06-PET scans at baseline and at 3 and 6 months following nasal foralumab treatment and in 2 na-SPMS patients with PIRA who underwent a test and a retest [F-18]PBR06-PET scan. A voxel-by-voxel z-score mapping approach was used and sum of z-scores in voxels with z-values>2 was calculated. Longitudinal PET uptake and clinical changes were assessed.

Five of six patients (83%, 95% confidence interval 44%-97%) showed a qualitative reduction on [F-18]PBR06-PET in multiple brain regions after both 3 and 6 months of nasal foralumab treatment. White matter z-scores were reduced by 26-36% in the foralumab treated group at 3 and 6 months, which was >4-5-times higher compared to 6% variability in the test-retest group (PET effect size estimate at 3 months=1.4). Clinically, foralumab-treated patients demonstrated a stable EDSS and improvement in the modified fatigue impact scale.

Nasal foralumab attenuated microglial activation in na-SPMS patients with PIRA at 3 and 6 months, as evaluated by [F-18]PBR06-PET and was associated with clinical stability. Based on these positive results, a double-blind, placebo-controlled dose-ranging study of nasal-foralumab in na-SPMS with [F-18]PBR06-PET as a primary endpoint is underway.