Bristol-Myers Squibb Company

Author Of 3 Presentations

Clinical Trials Poster Presentation

P0228 - Post-treatment recovery of lymphocyte subsets in healthy volunteers treated with ozanimod (ID 861)

Speakers
Presentation Number
P0228
Presentation Topic
Clinical Trials

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.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0325 - Effect of ozanimod on proportions of leukocyte subsets in patients with relapsing multiple sclerosis (ID 979)

Speakers
Presentation Number
P0325
Presentation Topic
Disease Modifying Therapies – Mechanism of Action

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.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0343 - Inhibition of drug transporter breast cancer resistance protein has no effect on the pharmacokinetics of major active metabolites of ozanimod (ID 1170)

Speakers
Presentation Number
P0343
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, was recently approved in the US and EU for the treatment of relapsing forms of multiple sclerosis. A previous study showed that co-administration of ozanimod with cyclosporine had no effect on ozanimod exposure but doubled the exposure of the minor active metabolites, RP101988 and RP101075 (the direct precursor of the major active metabolite CC112273). CC112273 and its interconverting active metabolite CC1084037 were not monitored in that study. A new study (NCT04149678) was conducted to further investigate this potential drug-drug interaction, particularly on the major active metabolites.

Objectives

This study’s primary objective was to evaluate the effect of cyclosporine, the index inhibitor of breast cancer resistance protein (BCRP), on the pharmacokinetics (PK) of ozanimod, CC112273, CC1084037, and RP101988.

Methods

In this phase 1, randomized, parallel-group, open-label study (NCT04149678), 40 healthy adult subjects were enrolled and randomly assigned to 1 of 2 treatment groups (20 per group). Group A received a single oral dose of ozanimod 0.46 mg, and group B received a single oral dose of ozanimod 0.46 mg plus a single oral dose of cyclosporine 600 mg. PK blood samples were collected up to 336 hours postdose, and PK parameters for ozanimod, CC112273, CC1084037, and RP101988 were calculated. Point estimates and 90% confidence intervals (CIs) for the geometric mean ratio between treatment groups (B vs A) for maximum concentration (Cmax) and overall exposure (AUC0-last) were determined with an analysis of variance.

Results

Cyclosporine increased exposure of the minor active metabolite RP101988 approximately 2-fold. Point estimates and 90% CIs for RP101988 Cmax and AUC0-last were 1.96 (1.70, 2.25) and 1.75 (1.47, 2.09), respectively. However, cyclosporine had no effect on ozanimod and its major active metabolites. Point estimates and 90% CIs between treatments for ozanimod, CC112273, and CC1084037 Cmax were 1.01 (0.88, 1.15), 0.87 (0.75, 1.003), and 0.99 (0.87, 1.14), respectively. Point estimates and 90% CIs between treatments for ozanimod, CC112273, and CC1084037 AUC0-last were 1.07 (0.92, 1.26), 1.02 (0.85, 1.22), and 1.11 (0.71, 1.72), respectively.

Conclusions

Results from this new study indicate that coadministration of ozanimod with inhibitors of BCRP had no effect on the exposure of ozanimod and its major active metabolites.

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