Contributions
Abstract: P945
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Background: Despite the recent approval of several new agents with unique mechanisms of action for patients with Relapsing Multiple Sclerosis (RMS), there are still a significant proportion of patients that have continued disease activity despite treatment. This unmet need has created an opportunity for assessment of rational combination therapies in this patient population, a common strategy for other diseases including Type 2 diabetes and cancer.
Objective: This study assessed the potential benefit of combining ozanimod, which is in Phase 3 clinical development for RMS and is a selective modulator of sphingosine-1-phosphate 1 and 5 receptors (S1P1R, S1P5R), with dimethyl fumarate (DMF), proposed to modulate Nrf2, in a mouse model of Experimental Autoimmune Encephalitis (EAE).
Methods: Combination therapies were assessed in the MOG35-55 peptide-induced mouse model of EAE. Mice were treated either prophylactically at the time of immunization or therapeutically when first clinical signs of disease observed. Endpoints included paralysis score, CNS histopathology and lymphocyte function in ex vivo recall experiments.
Results: Therapeutically administered ozanimod[HW1] (0.6mg/kg PO QD) significantly reduced the End Clinical Score (Vehicle = 3.2 ± 0.25, Ozanimod = 2.1 ± 0.16, p=0.001), while DMF (15mg/kg PO BID) demonstrated no significant effect (DMF = 3.1 ± 0.26). In addition, splenocytes isolated from ozanimod-treated mice were devoid of IFN-g, TNF-a and IL-17A production, while splenocytes from DMF treated mice were fully competent. Histopathological analysis also demonstrated greater reductions in spinal cord inflammation in mice treated with ozanimod compared to DMF.
Interestingly, in combination, there was clear synergy [RC(2] between ozanimod and DMF when analyzing End Clinical Scores (Vehicle = 3.2 ± 0.25, Combination = 1.5 ± 0.23, p< 0.0001), Mean Maximal Score (Vehicle = 3.5 ± 0.16, ozanimod = 3.2 ± 0.09, DMF = 3.5 ± 0.14, Combination = 2.8 ± 0.17, p=0.001) and in assessments of demyelination within the spinal cord. Furthermore, we determined that the benefits of combining ozanimod with DMF were still observed when DMF was reduced from BID to QD dosing.
Conclusions: These data suggest there may be clinical benefit of combination therapy for ozanimod with DMF in RMS. This combination may also allow for reduced dosing frequency of DMF, which may overcome some of its tolerability and compliance issues.
Disclosure: FL Scott and K Taylor are employees of Celgene Corp and have no conflict of interest.
RJ Peach is a consultant to Celgene Corp and has no conflict of interest.
Abstract: P945
Type: Poster
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Background: Despite the recent approval of several new agents with unique mechanisms of action for patients with Relapsing Multiple Sclerosis (RMS), there are still a significant proportion of patients that have continued disease activity despite treatment. This unmet need has created an opportunity for assessment of rational combination therapies in this patient population, a common strategy for other diseases including Type 2 diabetes and cancer.
Objective: This study assessed the potential benefit of combining ozanimod, which is in Phase 3 clinical development for RMS and is a selective modulator of sphingosine-1-phosphate 1 and 5 receptors (S1P1R, S1P5R), with dimethyl fumarate (DMF), proposed to modulate Nrf2, in a mouse model of Experimental Autoimmune Encephalitis (EAE).
Methods: Combination therapies were assessed in the MOG35-55 peptide-induced mouse model of EAE. Mice were treated either prophylactically at the time of immunization or therapeutically when first clinical signs of disease observed. Endpoints included paralysis score, CNS histopathology and lymphocyte function in ex vivo recall experiments.
Results: Therapeutically administered ozanimod[HW1] (0.6mg/kg PO QD) significantly reduced the End Clinical Score (Vehicle = 3.2 ± 0.25, Ozanimod = 2.1 ± 0.16, p=0.001), while DMF (15mg/kg PO BID) demonstrated no significant effect (DMF = 3.1 ± 0.26). In addition, splenocytes isolated from ozanimod-treated mice were devoid of IFN-g, TNF-a and IL-17A production, while splenocytes from DMF treated mice were fully competent. Histopathological analysis also demonstrated greater reductions in spinal cord inflammation in mice treated with ozanimod compared to DMF.
Interestingly, in combination, there was clear synergy [RC(2] between ozanimod and DMF when analyzing End Clinical Scores (Vehicle = 3.2 ± 0.25, Combination = 1.5 ± 0.23, p< 0.0001), Mean Maximal Score (Vehicle = 3.5 ± 0.16, ozanimod = 3.2 ± 0.09, DMF = 3.5 ± 0.14, Combination = 2.8 ± 0.17, p=0.001) and in assessments of demyelination within the spinal cord. Furthermore, we determined that the benefits of combining ozanimod with DMF were still observed when DMF was reduced from BID to QD dosing.
Conclusions: These data suggest there may be clinical benefit of combination therapy for ozanimod with DMF in RMS. This combination may also allow for reduced dosing frequency of DMF, which may overcome some of its tolerability and compliance issues.
Disclosure: FL Scott and K Taylor are employees of Celgene Corp and have no conflict of interest.
RJ Peach is a consultant to Celgene Corp and has no conflict of interest.