Author Of 3 Presentations
P0118 - Neurofilament light chain concentration predicts risk of relapse in participants with relapsing multiple sclerosis in phase 3 ozanimod trials (ID 1211)
Abstract
Background
In patients with multiple sclerosis (MS), neurofilament light chain concentration (NfL-c) is increased in blood and cerebrospinal fluid (CSF). Plasma and CSF NfL-c correlate and may serve as a biomarker for neurologic damage and disease activity in relapsing MS (RMS). Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, reduced annualized relapse rate (ARR) and plasma NfL-c (pNfL-c) vs interferon β-1a (IFN) in phase 3 RMS trials.
Objectives
To expand upon previously reported data showing that baseline (BL) pNfL-c predicts risk of on-treatment relapse, we analyzed the relationship between changes in pNfL-c and on-treatment risk of relapse with ozanimod vs IFN.
Methods
In this exploratory, post hoc analysis, pNfL-c was measured at BL and after 12 and 24 months of treatment with oral ozanimod 0.46 or 0.92 mg/d or intramuscular IFN β-1a 30 µg/wk in the phase 3 SUNBEAM (NCT02294058; ≥12 mo) and RADIANCE (NCT02047734; 24 mo) trials. The effect of treatment on pNfL-c was assessed, as were the relationships between BL pNfL-c and relapse rate and pNfL-c change from BL and ARR. NfL data are reported as median percentage change from BL. Poisson generalized linear models were used to fit the number of relapses as a function of BL pNfL-c and treatment group with an offset for duration. We calculated a predictive model of expected ARR based on median percentage change from BL in pNfL-c.
Results
At end of treatment, median pNfL-c was significantly reduced from BL by 20‒23% (P<0.01) and 23‒27% (P≤0.0001) with ozanimod 0.46 and 0.92 mg, respectively, and by 13‒15% with IFN. Higher BL p-NfL-c was associated with an increase in number of relapses (P<0.0001). Over a 12-month period, participants treated with either dose of ozanimod had significantly fewer relapses than those treated with IFN (P<0.05); the greatest effect was observed with ozanimod 0.92 mg. Further analyses reveal that treatment groups associated with a greater median reduction from BL pNfL-c are also associated with lower ARR. Predictive modeling estimated that a 25% reduction in pNfL-c, similar to that observed with ozanimod 0.92 mg, predicts an ARR (standard error [SE]) of 0.18‒0.23 (0.4); a 13% reduction, which was similar to that observed with IFN, predicts an ARR (SE) of 0.29‒0.37 (0.04).
Conclusions
Our findings further support pNfL-c as a biomarker for RMS disease activity. BL pNfL-c is related to relapse rate, as are changes in pNfL-c during treatment. Ozanimod causes dose-dependent reductions in pNfL-c and ARR compared with IFN.
P0228 - Post-treatment recovery of lymphocyte subsets in healthy volunteers treated with ozanimod (ID 861)
Abstract
Background
Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, was recently approved in the US and EU for the treatment of relapsing forms of MS (RMS). Ozanimod blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in MS is unknown but may involve reduction of lymphocyte migration into the central nervous system. In healthy volunteers (HV) and patients with RMS, ozanimod induces differential reductions in lymphocyte subset counts.
Objectives
To evaluate the recovery of lymphocyte subsets to pre-treatment levels following discontinuation of ozanimod in HV.
Methods
In a phase 1, randomized, double-blind, placebo-controlled study (NCT03694119) in HV (25–55 y), oral ozanimod 1.84 mg/d (2 x the approved dose, n=27) was administered for 28 days, which included a 10-day dose escalation (0.23 mg/d x 4 d, 0.46 mg/d x 3 d, and 0.92 mg/d x 3 d). Lymphocyte subset counts were evaluated at baseline and at 7±2 and 75±10 days after cessation of ozanimod. Lymphocyte subsets were measured using an epigenetic platform and are summarized descriptively as mean (standard deviation [SD]) percentage change from baseline.
Results
At 7±2 days after cessation of ozanimod, total lymphocyte counts were reduced by 52.4% (23.0) from baseline and CD3+ T cells were reduced by 49.7% (20.1). Within the T-cell population, CD4+ (−56.1% [22.5]), CD8+ (−39.3% [24.5]), regulatory T cells (−31.6% [30.3]), and Th17 cells (−36.5% [27.2]) were reduced from baseline. Total B cells (−56.3% [25.3]) and memory B cells (−46.6% [16.5]) were also reduced. At 75±10 days after cessation of ozanimod, total lymphocytes and all subsets had recovered to near baseline values, although at different rates. Total lymphocytes (−18.3% [26.1]) had less recovery than CD3+ (−4.8% [28.0]), CD4+ (−14.5% [27.5]), and CD8+ (−11.0% [26.0]) T cells. Th17 cells (3.8% [33.5]) recovered faster than regulatory T cells (−15.4% [28.8]). Total B cells (−18.6% [25.1]) and memory B cells (−18.9% [24.7]) had recovered less than T cells.
Conclusions
Ozanimod induced differential declines in T and B cell subsets in HV. By the final assessment at 65‒85 days after cessation of ozanimod, all cell populations evaluated showed gradual and variable rates of recovery to near baseline levels, indicative of a return of circulating lymphocytes toward pre-treatment levels.
P0325 - Effect of ozanimod on proportions of leukocyte subsets in patients with relapsing multiple sclerosis (ID 979)
Abstract
Background
Ozanimod is a sphingosine 1-phosphate receptor 1 and 5 modulator that blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.
Objectives
To characterize the phenotype of circulating leukocytes in relapsing multiple sclerosis (RMS) in participants treated with ozanimod.
Methods
In a phase 1, open-label, pharmacokinetic/pharmacodynamic study, 24 participants with RMS were randomized to oral ozanimod 0.46 (n=13) or 0.92 mg/d (n=11) [equivalent to ozanimod HCl 0.5 or 1 mg] for ~12 weeks, including an initial 7-d dose escalation (0.23 mg/d x 4d + 0.46 mg/d x 3d). Key exclusion criteria were active infection, history of chronic infections or immunodeficiency, recent live vaccination, previous lymphocyte-depleting or immunosuppressant therapy, and absolute lymphocyte count <1.0 × 109/L. Exploratory analyses used flow cytometry to characterize proportional changes from baseline in leukocyte subsets on days 28, 56, and 85 in total peripheral blood mononuclear cells (PBMC) and total T cells. Proportional change from baseline is reported using descriptive statistics.
Results
Ozanimod was associated with dose-dependent decreases in absolute numbers of CD4+ and CD8+ T cells. Within the PBMC population, ozanimod was associated with a minimal increase in the proportion of CD8+ TEMRA cells (ozanimod 0.92 mg only) and no change in CD8+ effector memory T (TEM) cells. A decrease in the proportion of CD4+ and CD8+ naive and central memory T (TCM) cells and CD4+ TEM cells was evident. Within the total T cell population, ozanimod was associated with an increase in the proportion of CD4+ TEM cells (ozanimod 0.92 mg only) and CD8+ TEM and TEMRA cells. A decrease in the proportion of CD4+ naive (ozanimod 0.92 mg only) and CD8+ naive cells was observed; CD4+ and CD8+ TCM cells were minimally affected. Changes from baseline were more pronounced with ozanimod 0.92 mg than with ozanimod 0.46 mg.
Conclusions
During ozanimod treatment, the relative frequencies of circulating cell types within total PBMCs and within the remaining T cell population were altered. These shifts in circulating leukocyte proportions support the hypothesis that although ozanimod inhibits trafficking of some subsets of lymphocytes, the remaining circulating cells are still poised to provide immune surveillance.
Presenter Of 3 Presentations
P0118 - Neurofilament light chain concentration predicts risk of relapse in participants with relapsing multiple sclerosis in phase 3 ozanimod trials (ID 1211)
Abstract
Background
In patients with multiple sclerosis (MS), neurofilament light chain concentration (NfL-c) is increased in blood and cerebrospinal fluid (CSF). Plasma and CSF NfL-c correlate and may serve as a biomarker for neurologic damage and disease activity in relapsing MS (RMS). Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, reduced annualized relapse rate (ARR) and plasma NfL-c (pNfL-c) vs interferon β-1a (IFN) in phase 3 RMS trials.
Objectives
To expand upon previously reported data showing that baseline (BL) pNfL-c predicts risk of on-treatment relapse, we analyzed the relationship between changes in pNfL-c and on-treatment risk of relapse with ozanimod vs IFN.
Methods
In this exploratory, post hoc analysis, pNfL-c was measured at BL and after 12 and 24 months of treatment with oral ozanimod 0.46 or 0.92 mg/d or intramuscular IFN β-1a 30 µg/wk in the phase 3 SUNBEAM (NCT02294058; ≥12 mo) and RADIANCE (NCT02047734; 24 mo) trials. The effect of treatment on pNfL-c was assessed, as were the relationships between BL pNfL-c and relapse rate and pNfL-c change from BL and ARR. NfL data are reported as median percentage change from BL. Poisson generalized linear models were used to fit the number of relapses as a function of BL pNfL-c and treatment group with an offset for duration. We calculated a predictive model of expected ARR based on median percentage change from BL in pNfL-c.
Results
At end of treatment, median pNfL-c was significantly reduced from BL by 20‒23% (P<0.01) and 23‒27% (P≤0.0001) with ozanimod 0.46 and 0.92 mg, respectively, and by 13‒15% with IFN. Higher BL p-NfL-c was associated with an increase in number of relapses (P<0.0001). Over a 12-month period, participants treated with either dose of ozanimod had significantly fewer relapses than those treated with IFN (P<0.05); the greatest effect was observed with ozanimod 0.92 mg. Further analyses reveal that treatment groups associated with a greater median reduction from BL pNfL-c are also associated with lower ARR. Predictive modeling estimated that a 25% reduction in pNfL-c, similar to that observed with ozanimod 0.92 mg, predicts an ARR (standard error [SE]) of 0.18‒0.23 (0.4); a 13% reduction, which was similar to that observed with IFN, predicts an ARR (SE) of 0.29‒0.37 (0.04).
Conclusions
Our findings further support pNfL-c as a biomarker for RMS disease activity. BL pNfL-c is related to relapse rate, as are changes in pNfL-c during treatment. Ozanimod causes dose-dependent reductions in pNfL-c and ARR compared with IFN.
P0228 - Post-treatment recovery of lymphocyte subsets in healthy volunteers treated with ozanimod (ID 861)
Abstract
Background
Ozanimod, a sphingosine 1-phosphate receptor 1 and 5 modulator, was recently approved in the US and EU for the treatment of relapsing forms of MS (RMS). Ozanimod blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in MS is unknown but may involve reduction of lymphocyte migration into the central nervous system. In healthy volunteers (HV) and patients with RMS, ozanimod induces differential reductions in lymphocyte subset counts.
Objectives
To evaluate the recovery of lymphocyte subsets to pre-treatment levels following discontinuation of ozanimod in HV.
Methods
In a phase 1, randomized, double-blind, placebo-controlled study (NCT03694119) in HV (25–55 y), oral ozanimod 1.84 mg/d (2 x the approved dose, n=27) was administered for 28 days, which included a 10-day dose escalation (0.23 mg/d x 4 d, 0.46 mg/d x 3 d, and 0.92 mg/d x 3 d). Lymphocyte subset counts were evaluated at baseline and at 7±2 and 75±10 days after cessation of ozanimod. Lymphocyte subsets were measured using an epigenetic platform and are summarized descriptively as mean (standard deviation [SD]) percentage change from baseline.
Results
At 7±2 days after cessation of ozanimod, total lymphocyte counts were reduced by 52.4% (23.0) from baseline and CD3+ T cells were reduced by 49.7% (20.1). Within the T-cell population, CD4+ (−56.1% [22.5]), CD8+ (−39.3% [24.5]), regulatory T cells (−31.6% [30.3]), and Th17 cells (−36.5% [27.2]) were reduced from baseline. Total B cells (−56.3% [25.3]) and memory B cells (−46.6% [16.5]) were also reduced. At 75±10 days after cessation of ozanimod, total lymphocytes and all subsets had recovered to near baseline values, although at different rates. Total lymphocytes (−18.3% [26.1]) had less recovery than CD3+ (−4.8% [28.0]), CD4+ (−14.5% [27.5]), and CD8+ (−11.0% [26.0]) T cells. Th17 cells (3.8% [33.5]) recovered faster than regulatory T cells (−15.4% [28.8]). Total B cells (−18.6% [25.1]) and memory B cells (−18.9% [24.7]) had recovered less than T cells.
Conclusions
Ozanimod induced differential declines in T and B cell subsets in HV. By the final assessment at 65‒85 days after cessation of ozanimod, all cell populations evaluated showed gradual and variable rates of recovery to near baseline levels, indicative of a return of circulating lymphocytes toward pre-treatment levels.
P0325 - Effect of ozanimod on proportions of leukocyte subsets in patients with relapsing multiple sclerosis (ID 979)
Abstract
Background
Ozanimod is a sphingosine 1-phosphate receptor 1 and 5 modulator that blocks the capacity of lymphocytes to egress from lymphoid tissue, reducing the number of lymphocytes in peripheral blood. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown, but may involve reduction of lymphocyte migration into the central nervous system.
Objectives
To characterize the phenotype of circulating leukocytes in relapsing multiple sclerosis (RMS) in participants treated with ozanimod.
Methods
In a phase 1, open-label, pharmacokinetic/pharmacodynamic study, 24 participants with RMS were randomized to oral ozanimod 0.46 (n=13) or 0.92 mg/d (n=11) [equivalent to ozanimod HCl 0.5 or 1 mg] for ~12 weeks, including an initial 7-d dose escalation (0.23 mg/d x 4d + 0.46 mg/d x 3d). Key exclusion criteria were active infection, history of chronic infections or immunodeficiency, recent live vaccination, previous lymphocyte-depleting or immunosuppressant therapy, and absolute lymphocyte count <1.0 × 109/L. Exploratory analyses used flow cytometry to characterize proportional changes from baseline in leukocyte subsets on days 28, 56, and 85 in total peripheral blood mononuclear cells (PBMC) and total T cells. Proportional change from baseline is reported using descriptive statistics.
Results
Ozanimod was associated with dose-dependent decreases in absolute numbers of CD4+ and CD8+ T cells. Within the PBMC population, ozanimod was associated with a minimal increase in the proportion of CD8+ TEMRA cells (ozanimod 0.92 mg only) and no change in CD8+ effector memory T (TEM) cells. A decrease in the proportion of CD4+ and CD8+ naive and central memory T (TCM) cells and CD4+ TEM cells was evident. Within the total T cell population, ozanimod was associated with an increase in the proportion of CD4+ TEM cells (ozanimod 0.92 mg only) and CD8+ TEM and TEMRA cells. A decrease in the proportion of CD4+ naive (ozanimod 0.92 mg only) and CD8+ naive cells was observed; CD4+ and CD8+ TCM cells were minimally affected. Changes from baseline were more pronounced with ozanimod 0.92 mg than with ozanimod 0.46 mg.
Conclusions
During ozanimod treatment, the relative frequencies of circulating cell types within total PBMCs and within the remaining T cell population were altered. These shifts in circulating leukocyte proportions support the hypothesis that although ozanimod inhibits trafficking of some subsets of lymphocytes, the remaining circulating cells are still poised to provide immune surveillance.