Contributions
Abstract: EP1618
Type: Poster Sessions
Abstract Category: Therapy - Neuroprotection and Repair
Background: Siponimod is a selective sphingosine 1-phosphate (S1P1,5) receptor modulator under development for the treatment of multiple sclerosis (MS). It significantly reduces disability progression in secondary progressive MS patients. Exploration of its central mode of action requires long-term studies in preclinical models of progressing chronic demyelination. However, as long-term studies are often impacted by stress responses inherent to repeated treatments by daily oral gavage, alternative administration methods are warranted.
Objective: To compare dose-related siponimod blood concentrations and pharmacological efficacy achieved in mice after administration via drinking water or drug-loaded diet.
Methods: C57BL/6J mice (6-10 weeks-old, females, n=3-6/group) were either treated for 2 weeks with siponimod dosed in drinking water to achieve 0.3, 1.5 or 3 mg/kg bodyweight or were fed over 2 weeks with siponimod-loaded pellets at 0.03, 0.01, 0.003 or 0.001%. Blood samples were collected in short intervals and at termination to assess the siponimod concentrations in blood and the lymphocyte counts (using Vet ABC or ADVIA haematology analysers).
Results: Administration of siponimod via drinking water resulted in dose-dependent siponimod blood concentrations of 0.6, 0.4 and 0.1 µM with doses of 3, 1.5 and 0.3 mg/kg body weight, respectively. However, a large time-dependency was observed and a small reduction in blood lymphocyte counts (20%) was observed in the 3 mg/kg group alone. After administration via siponimod-loaded pellets at 0.03, 0.01, 0.003 and 0.001%, siponimod blood concentrations were within the 12.5, 5.1, 1.4 and 0.5 µM range, while circulating lymphocyte counts were reduced by 81%, 56%, 50% and 39%, respectively. Conclusions: These results suggest the use of siponimod-loaded diet as a robust alternative to daily oral gavage to achieve efficacious siponimod blood exposures in long-term mouse disease models. These, the first results in an experimental autoimmune encephalomyelitis model, confirm efficacy for siponimod-loaded diet at ≥0.003%.
Disclosure: *Michael Dietrich, Christina Hecker, Marc Bigaud, Philipp Albrecht are equally contributing first/senior authors. This study was funded by Novartis Institutes for Biomedical Research, Basel, Switzerland. Christian Beerli, Claire Moebs, Pamela Ramseier, Catherine Afatsawo, Marc Bigaud are employees of Novartis Institutes for Biomedical Research, Basel, Switzerland. Michael Dietrich reports personal fees and non-financial support from Novartis and non-financial support from Biogen. Christina Hecker: nothing to disclose. Philipp Albrecht reports personal fees, grants and non-financial support from Biogen; grants, personal fees and non-financial support from Allergan; personal fees and non-financial support from Bayer; personal fees and non-financial support from Merck; grants, personal fees and non-financial support from Merz Pharmaceuticals; grants, personal fees and non-financial support from Novartis; grants, personal fees and non-financial support from Roche; grants, personal fees and non-financial support from Teva; grants, personal fees and non-financial support from Ipsen.
Abstract: EP1618
Type: Poster Sessions
Abstract Category: Therapy - Neuroprotection and Repair
Background: Siponimod is a selective sphingosine 1-phosphate (S1P1,5) receptor modulator under development for the treatment of multiple sclerosis (MS). It significantly reduces disability progression in secondary progressive MS patients. Exploration of its central mode of action requires long-term studies in preclinical models of progressing chronic demyelination. However, as long-term studies are often impacted by stress responses inherent to repeated treatments by daily oral gavage, alternative administration methods are warranted.
Objective: To compare dose-related siponimod blood concentrations and pharmacological efficacy achieved in mice after administration via drinking water or drug-loaded diet.
Methods: C57BL/6J mice (6-10 weeks-old, females, n=3-6/group) were either treated for 2 weeks with siponimod dosed in drinking water to achieve 0.3, 1.5 or 3 mg/kg bodyweight or were fed over 2 weeks with siponimod-loaded pellets at 0.03, 0.01, 0.003 or 0.001%. Blood samples were collected in short intervals and at termination to assess the siponimod concentrations in blood and the lymphocyte counts (using Vet ABC or ADVIA haematology analysers).
Results: Administration of siponimod via drinking water resulted in dose-dependent siponimod blood concentrations of 0.6, 0.4 and 0.1 µM with doses of 3, 1.5 and 0.3 mg/kg body weight, respectively. However, a large time-dependency was observed and a small reduction in blood lymphocyte counts (20%) was observed in the 3 mg/kg group alone. After administration via siponimod-loaded pellets at 0.03, 0.01, 0.003 and 0.001%, siponimod blood concentrations were within the 12.5, 5.1, 1.4 and 0.5 µM range, while circulating lymphocyte counts were reduced by 81%, 56%, 50% and 39%, respectively. Conclusions: These results suggest the use of siponimod-loaded diet as a robust alternative to daily oral gavage to achieve efficacious siponimod blood exposures in long-term mouse disease models. These, the first results in an experimental autoimmune encephalomyelitis model, confirm efficacy for siponimod-loaded diet at ≥0.003%.
Disclosure: *Michael Dietrich, Christina Hecker, Marc Bigaud, Philipp Albrecht are equally contributing first/senior authors. This study was funded by Novartis Institutes for Biomedical Research, Basel, Switzerland. Christian Beerli, Claire Moebs, Pamela Ramseier, Catherine Afatsawo, Marc Bigaud are employees of Novartis Institutes for Biomedical Research, Basel, Switzerland. Michael Dietrich reports personal fees and non-financial support from Novartis and non-financial support from Biogen. Christina Hecker: nothing to disclose. Philipp Albrecht reports personal fees, grants and non-financial support from Biogen; grants, personal fees and non-financial support from Allergan; personal fees and non-financial support from Bayer; personal fees and non-financial support from Merck; grants, personal fees and non-financial support from Merz Pharmaceuticals; grants, personal fees and non-financial support from Novartis; grants, personal fees and non-financial support from Roche; grants, personal fees and non-financial support from Teva; grants, personal fees and non-financial support from Ipsen.