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
Objective: Assess the SARS-CoV2 Spike antibody response in multiple sclerosis (MS) patients on high efficacy immunotherapies. Background: There is limited knowledge about SARS-CoV2 mRNA vaccine response in MS patients on immunotherapy. Design/Methods: Patients with MS, aged 18-65, on fingolimod, siponimod, ofatumumab, or ocrelizumab for at least 3 months prior to first mRNA SARS-CoV2 vaccine (Pfizer or Moderna) were offered enrollment. A cohort of healthy controls who received the mRNA vaccines were also enrolled. Blood samples for the SARS-CoV2 Spike antibody (Anti-SARS-CoV2 S, RocheElecsys) were collected 2-3 months after the second mRNA vaccine. The proportion who seroconverted (antibody>0.4 U/ml), and SARS-CoV2 Spike antibody levels were assessed. Results: A total of 39 MS patients (6 fingolimod, 33 ocrelizumab) and 31 controls were included in this interim analysis. 33%(13/39) of MS patients seroconverted, compared to 100%(31/31) in the control group, with an estimated risk difference of -0.67,(95% confidence interval: -0.81, -0.52;Fisher's exact test, p=9.0∗10-10 ). There was no difference in seroconversion rates between MS patients who received the Pfizer (34%, 10/29) versus the Moderna vaccine (30%, 3/10) (95% confidence interval -0.38, 0.29;Fisher's exact test=1). Seroconversion was found in 100% (31/31) of controls, 66.7% (4/6) of fingolimod-treated patients, and 27.3% (9/33) of ocrelizumab-treated patients (three group comparison, Fisher's exact test p-value =2.7∗10 -10). The median Spike antibody level was <0.4 U/ml in MS patients, and 1,663 U/ml in controls (Wilcoxon rank sum test, p-value= 1.0∗10-12 ). The median Spike antibody level in the ocrelizumab group was <0.4 U/ml, 3.45 U/ml in the fingolimod group, and 1,663 U/ml in the control group (Kruskal Wallis test, p-value=5.9∗10-12 ). Total IgG correlated with Spike antibody levels in the ocrelizumab-treated group only (Spearman correlation, p=0.025). Conclusions: MS patients on ocrelizumab and fingolimod have significantly lower rates of seroconversion, and lower median Spike antibody levels in response to the mRNA SARS-CoV2 vaccines compared to controls.
ABSTRACT
Introduction: SARs-CoV-19 infection (COVID-19) is associated with various neurologic symptoms. A full range of neurologic outcomes in patients with multiple sclerosis (MS) and related disorders (MSRD) following COVID-19 illness is not well understood. Objectives: To investigate neurologic outcomes in patients with MSRD post COVID-19. Methods: This was a retrospective medical records review study of adult patients with MSRD who had confirmed COVID-19 infection at the Brigham MS Center, between March 9, 2020 and April 1, 2021. We reviewed demographics, MS history, COVID-19 outcomes, neurologic symptoms, and MRI data. Neurologic worsening post-COVID-19 was defined as having a relapse, pseudo-relapse, new brain MRI activity, worsening of preexisting MS symptoms, or development of other long-term neurologic symptoms. Results: 111 patients, 85 (77%) females, with a mean [SD] age of 49 [12.2] years, and a mean [SD] EDSS of 3.4 [2.7] were identified. 72 (65%) had relapsing remitting MS, 21 (19%) had secondary and 8 (7%) had primary progressive MS, 2 (2%) had clinically isolated syndrome, and 8 (7%) had related disorders. 17 (15%) patients were asymptomatic, 63 (57%) had mild COVID-19 defined as symptoms not requiring hospitalization, 22 (20%) had moderate COVID-19 requiring hospitalization, 3 (3%) had severe COVID-19 requiring ICU admission, 2 (2%) died due to COVID-19 and 4 (4%) had unknown COVID-19 outcomes. 85 (77%) completely recovered from COVID-19. 41 patients (37%) had neurologic worsening post COVID-19. Of those with neurologic worsening, 19 (46%) had pseudo-relapses, 2 (4.8%) had relapses, and 27 (66%) patients reported worsening of preexisting MS symptoms, or other new longterm neurologic symptoms at the last follow up visit. 55 patients had brain MRI scans post COVID-19 with a mean [SD] between MRI and infection of 144.6 [107.8] days. 5 patients had new lesions on T2 or T1Gd+ scans. Neurologic worsening was associated with moderate or severe COVID-19 (p=0.0006), treatment for COVID-19 (p=0.0061), and incomplete COVID-19 recovery (p=0.0267) but not with age, sex, MS type, ethnicity, disease duration, EDSS, vitamin D use, or type or presence of disease modifying therapy. Conclusions: COVID-19 severity and lack of complete systemic recovery was associated with new or worsening neurologic symptoms in 37% of MSRD patients.