ABSTRACT
Introduction: There are no effective treatments for non-active secondary progressive MS (SPMS), which is mediated by compartmentalized CNS inflammation, including activated microglia. We found that fully human anti-CD3 intranasal monoclonal antibody (Foralumab) suppressed disease in a chronic EAE model by dampening microglia and astrocyte inflammation. Nasal Foralumab does not enter the bloodstream or brain. A dose-finding study of nasal Foralumab in controls dosed at 10ug, 50ug and 250ug for 5 days found the drug to be safe with immune effects seen at 50ug. COVID patients dosed with 100ug of nasal Foralumab for 10 days was well-tolerated and exhibited positive effects on blood markers and lung inflammation. Objective(s): To determine if nasal Foralumab has a therapeutic effect on patients with non-active SPMS. Method(s): Two patients were identified with non-active SPMS and sustained clinical progression, despite use of approved DMT. EA1 is a 61-year-old male diagnosed for over 20 years and EA2 is a 42-year-old male diagnosed for 8 years, both last treated with ocrelizumab for 3 years. Treatment occurs in 3-week cycles with intranasal Foralumab 50ug/day administered 3x/week for 2 weeks with 1 week rest. Each cycle, clinical and neurological assessments are repeated, and imaging is repeated every 3 months. Result(s): EA1 has completed 6 months and EA2 has completed 3 months of treatment. To date, there have been no adverse reactions, local irritation, or laboratory abnormalities, and symptom progression has subsided. EA1 is feeling more stable, subjectively, and has noted improvement in lower extremity strength. EDSS, pyramidal motor score and T25FW have stabilized or improved. SDMT and 9HPT were stable during treatment. Microglial activation as measured by [F-18]PBR06 PET scan was significantly reduced 3 months after the start of nasal Foralumab, and this reduction was sustained after 7-week washout and at 6 months. Serum protein measurements of cytokines showed reduction of IFN-gamma, IL-18, IL-1s and IL-6 levels (Olink assay). Cellular immune studies showed increase in CD8 naive cells and decrease in CD8 effector cells, and alteration in gene expression as measured by single cell RNA sequencing. EA2 3-month laboratory and imaging results are pending and will be presented. Conclusion(s): Nasal Foralumab in non-active SPMS patients treated for at least 3 months reduced microglial activation, decreased levels of proinflammatory cytokines, and had positive clinical effects.
ABSTRACT
Introduction: IC14 (atibuclimab) is a monoclonal anti-CD14 antibody that may target T-regulatory (T-reg) cell function. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 for a single cycle of treatment. We provided longterm treatment with IC14 to 17 individuals with ALS via an expanded access protocol (EAP) and documented target engagement, safety, and disease endpoints. Method(s): Participants received intravenous IC14 every two weeks. Consistent with FDA guidelines, participants were ineligible for clinical trials and the EAP was inclusive of a broad population. Participants unable to travel to MGH due to the COVID-19 pandemic or disease progression, were transitioned to infusions in-home or local clinics. Blood samples for hematology, chemistry, and coagulation were collected to monitor safety. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) was administered monthly to track disease progression. Respiratory function was measured through slow vital capacity tests -data for this is limited due to the COVID-19 pandemic. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), soluble CD14, and antidrug antibodies (ADA). Ex vivo T regulatory functional assays were performed with five participants. Result(s): Participants received IC14 for up to 103 weeks (average: 30.1 weeks, range: 1-103 weeks). Treatmentemergent adverse events were uncommon, mild, and self-limited. There were 18 serious adverse events (SAEs) which were related to disease progression and unrelated (17) or likely unrelated (1) to IC14. Three participants died due to disease progression. Most participants achieved >80% monocyte mCD14 RO on a 14-day dosing schedule, although one individual required more frequent dosing (every 10 days) to achieve >80% RO. ADA were detected in only one participant and were transient, low titer, and non-neutralizing. Tregs were isolated from the available longitudinal samples and assayed for suppression of CD4 T cell proliferation and cytokine production versus baseline T-reg activity. Conclusion(s): IC14 administration to ALS patients was safe and well tolerated in this EAP, with no significant changes in laboratory tests and no drug-related SAEs. Measuring RO guided dosing frequency. Preliminary data suggest IC14 enhanced T-reg activity. Additional placebo-controlled trials are required to determine the efficacy of IC14 in ALS.