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.
ABSTRACT
Introduction: Ofatumumab (OMB), a fully human anti-CD20 monoclonal antibody, is indicated for the treatment of adults with relapsing multiple sclerosis (RMS) in the US. Given the ongoing COVID-19 global pandemic, it is important to assess if OMBtreated patients can mount a protective immune response to the COVID-19 vaccine. Objectives/Aims: To assess immune response to non-live COVID-19 mRNA vaccines (Pfizer or Moderna) in RMS patients treated with subcutaneous OMB 20 mg monthly compared to those on interferon or glatiramer acetate. Methods: This is a 3-cohort, multicenter, prospective study in RMS patients (aged 18-55) receiving the mRNA COVID-19 vaccine (NCT04878211). Patients with prior COVID-19 diagnosis, recent infections, and prior treatment with other immunomodulatory disease-modifying therapies will be excluded. Cohort 1 will receive full course (2 doses) of vaccine ≥2 weeks prior to starting OMB. Cohort 2 will receive the full course of vaccine ≥4 weeks after starting OMB. Cohort 3 will receive the full course of vaccine ≥4 weeks after starting interferon or glatiramer acetate. Patients will continue taking their prescribed therapy per their current dosing schedule throughout treatment period (360 days after completion of full course vaccine). All groups will undergo serologic testing prior to vaccination and 14 days after 2nd vaccine dose. Primary endpoint is positive SARS-CoV-2 qualitative IgG antibody assay 14 days after full course vaccination. Key secondary endpoints include immune response to vaccine at other timepoints, immune conversion to vaccine (SARS-CoV-2 qualitative/ quantitative IgG antibody assay), SARS-CoV-2 neutralizing IgG antibody development, and adverse events (AEs) and serious AEs associated with OMB treatment. Exploratory endpoints include frequency of IFNγ positive CD4+ or CD8+ T cells, and T cell reactivity, after stimulation with SARS-CoV-2 peptide. Results: This study plans to enroll up to 66 RMS patients (up to 22 per cohort) at up to 30 US centers. The planned first patient first visit is on May 31, 2021 and study completion is expected by Q4 2022. An interim analysis will be performed once Cohorts 2 and 3 each have ≥10 patients that have had serum drawn 14 days after full course vaccination. Conclusions: This study will contribute to a better understanding of immune responses that occur in OMB-treated RMS patients given a COVID-19 mRNA vaccine.
ABSTRACT
Background: COVID-19, the disease caused by SARS CoV2, causes severe respiratory disease, and rarely multisystem inflammatory syndrome, in some pediatric patients. Little is known about the disease course among patients with pediatric-onset multiple sclerosis. Objectives: To describe the demographic and clinical characteristics of a subgroup of pediatric-onset multiple sclerosis (POMS) patients infected with SARS CoV2. Methods: The Network of Pediatric Multiple Sclerosis Centers (NPMSC), a consortium of 10 US pediatric multiple sclerosis (MS) centers contributes clinical information about POMS patients and demyelinating disorders to a centralized database, the Pediatric Demyelinating Disease Database (PeMSDD), to facilitate research for this rare disorder. In addition to collecting clinical data on clinical course, comorbidities, disease modifying therapy use, and functional status, the NPMSC developed a screening questionnaire to administer to patients during standard of care visits to further evaluate their COVID- 19 status. Additionally POMS patients with confirmed or highly suspected COVID-19, will be assessed for risk factors including smoking use, recent glucocorticoid use, comorbidities;clinical presentation, including symptoms, radiological and laboratory data;COVID-19 treatments and outcomes. POMS patients will also complete the COViMS (COVID-19 Infections in MS & Related Diseases) database, a joint effort of the US National MS Society and the Consortium of MS Centers to capture information on outcomes of people with MS and other central nervous system (CNS) demyelinating diseases (Neuromyelitis Optica Spectrum Disease, or MOG antibody disease) who have developed COVID- 19. Together with data collected from the PeMSDD, we will present comprehensive data on the POMS patient experience with COVID- 19 and compare it to POMS patients without known or suspected COVID-19. Results: Data collection continues. Results available by the meeting due date will describe the demographics, risk factors, treatments and outcomes of POMS with COVID-19. Conclusions: will be drawn pending results of data analysis. We anticipate reporting on demographic data, risk factors, outcomes and any associations with disease modifying therapy.