A pilot trial for ozanimod therapy in hospitalized COVID19 patients

Background: Sphingosine-1-phosphate (S1P) receptor ligands reduce lung damage and endothelial activation in models of virus-induced pneumonia. Feasibility of initiating S1P receptor ligand therapy during pneumonia needs confirmation. Objective(s): Evaluate safety/efficacy outcomes of ozanimod therapy in COVID-19 patients. Method(s): In a prospective multicentric open-label pilot trial, adults with COVID-19 requiring O were recruited (3 Canadian centres, starting Sept. 2020). Patients were randomized to standard of care (SOC) or SOC + ozanimod (per os). Modified WHO-adapted 6-points ordinal scale for clinical improvement was computed daily and adverse events were recorded. Result(s): As of Jan. 2022, 41 patients (out of 48) were enrolled and 18 received ozanimod. Stratification at randomization balanced groups for risk factors of poor outcome and initial O2 requirement. No serious drug reaction was reported. Asymptomatic bradycardia occurred with ozanimod. So far, 36 patients completed the study-ending phone call (day 90). Ordinal scale-related outcomes are shown in Table 1. Since enrollment is ongoing, data is shown for the whole cohort. Conclusion(s): This small scale trial provides the very first evidence supporting the possibility of initiating S1P receptor ligand therapy during active COVID-19 pneumonia.

An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated disorder of the CNS manifested by recurrent attacks of neurological symptoms (related to focal inflammation) and gradual disability accrual (related to progressive neurodegeneration and neuroinflammation). Sphingosine-1-phosphate-receptor (S1PR) modulators are a class of oral disease-modifying therapies (DMTs) for relapsing MS. The first S1PR modulator developed and approved for MS was fingolimod, followed by siponimod, ozanimod, and ponesimod. All are S1P analogues with different S1PR-subtype selectivity. They restrain the S1P-dependent lymphocyte egress from lymph nodes by binding the lymphocytic S1P-subtype-1-receptor. Depending on their pharmacodynamics and pharmacokinetics, they can also interfere with other biological functions. AREAS COVERED: Our narrative review covers the PubMed English literature on S1PR modulators in MS until August 2022. We discuss their pharmacology, efficacy, safety profile, and risk management recommendations based on the results of phase II and III clinical trials. We briefly address their impact on the risk of infections and vaccines efficacy. EXPERT OPINION: S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS. Aside their established benefit, their place and timing within the long-term DMT strategy in MS, as well as their immunological effects in the new and evolving context of the post-COVID-19 pandemic and vaccination campaigns warrant further study.

Receptor-dependent effects of sphingosine-1-phosphate (S1P) in COVID-19: the black side of the moon.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection leads to hyper-inflammation and amplified immune response in severe cases that may progress to cytokine storm and multi-organ injuries like acute respiratory distress syndrome and acute lung injury. In addition to pro-inflammatory cytokines, different mediators are involved in SARS-CoV-2 pathogenesis and infection, such as sphingosine-1-phosphate (S1P). S1P is a bioactive lipid found at a high level in plasma, and it is synthesized from sphingomyelin by the action of sphingosine kinase. It is involved in inflammation, immunity, angiogenesis, vascular permeability, and lymphocyte trafficking through G-protein coupled S1P receptors. Reduction of the circulating S1P level correlates with COVID-19 severity. S1P binding to sphingosine-1-phosphate receptor 1 (S1PR1) elicits endothelial protection and anti-inflammatory effects during SARS-CoV-2 infection, by limiting excessive INF-α response and hindering mitogen-activated protein kinase and nuclear factor kappa B action. However, binding to S1PR2 opposes the effect of S1PR1 with vascular inflammation, endothelial permeability, and dysfunction as the concomitant outcome. This binding also promotes nod-like receptor pyrin 3 (NLRP3) inflammasome activation, causing liver inflammation and fibrogenesis. Thus, higher expression of macrophage S1PR2 contributes to the activation of the NLRP3 inflammasome and the release of pro-inflammatory cytokines. In conclusion, S1PR1 agonists and S1PR2 antagonists might effectively manage COVID-19 and its severe effects. Further studies are recommended to elucidate the potential conflict in the effects of S1P in COVID-19.

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of relapsing forms of MS. OBJECTIVE: To characterize long-term safety and efficacy of ozanimod. METHODS: Patients with relapsing MS who completed a phase 1‒3 ozanimod trial were eligible for an open-label extension study (DAYBREAK) of ozanimod 0.92 mg/d. DAYBREAK began 16 October 2015; cutoff for this interim analysis was 2 February 2021. RESULTS: This analysis included 2494 participants with mean 46.8 (SD 11.9; range 0.033‒62.7) months of ozanimod exposure in DAYBREAK. During DAYBREAK, 2143 patients (85.9%) had treatment-emergent adverse events (TEAEs; similar in nature to those in the parent trials), 298 (11.9%) had a serious TEAE, and 75 (3.0%) discontinued treatment due to TEAEs. Serious infections (2.8%), herpes zoster infections (1.7%), confirmed macular edema cases (0.2%), and cardiac TEAEs (2.8%) were infrequent. Adjusted annualized relapse rate was 0.103 (95% confidence interval, 0.086‒0.123). Over 48 months, 71% of patients remained relapse free. Adjusted mean numbers of new/enlarging T2 lesions/scan and gadolinium-enhancing lesions were low and similar across parent trial treatment subgroups. CONCLUSIONS: This long-term extension of ozanimod trials confirmed a favorable safety/tolerability profile and sustained benefit on clinical and magnetic resonance imaging measures of disease activity.

SARS-CoV-2 vaccine response in RMS patients treated with ozanimod and other DMTs

Objective: To describe antibody and T-cell responses to the three SARS-CoV-2 vaccines available in the United States (U.S.) in patients with relapsing multiple sclerosis (RMS) on ozanimod or other disease modifying therapies (DMTs). Background: SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is a novel, zoonotic coronavirus that emerged in late 2019 in patients with pneumonia of unknown cause;the disease caused by SARS-CoV-2 is termed COVID-19 (coronavirus disease 2019). Recent reports have suggested that RMS patients on certain DMTs may have a blunted humoral response to the available COVID-19 vaccinations. Sphingosine-1-phosphate (S1P) receptor modulators may control RMS via sequestration of circulating lymphocytes, thus raising questions about vaccination response in RMS on ozanimod and other S1P receptor modulators. Design/Methods: Prospective observational trial following patients with RMS who are going to be vaccinated against COVID-19. The primary endpoint is the proportion of subjects treated with ozanimod with SARS-CoV-2 anti-spike IgG positivity (Elecsys® Anti-SARS-CoV-2) 4 weeks after full vaccination as compared to pre-vaccination levels. To ensure a geographic distribution across the U.S., RMS patients were recruited online (under the care of various neurologists), and all study-related proceures were performed at the patient's home. Results: Descriptive statistics of antibody and T-cell response for sixty subjects (30 treated with ozanimod and 30 treated with various other FDA-approved RMS DMTs) assessed prior to and 28 days after full vaccination will be presented. Additionally, all subjects will complete follow-up questionnaires every 3 months until a year has passed from the second (or only) vaccine dose Conclusions: In this study, RMS patients treated with ozanimod had an antibody and T-cell response to the three available COVID-19 vaccines in the U.S. This trial is ongoing, with 48- weeks of follow-up expected in December 2022.

Lowered COVID-19 mRNA vaccine antibody response in MS patientstreated with B-cell depleting and S1P-receptor-targeting therapies compared to controls: interim analysis

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.