Contributions
Abstract: EP1734
Type: ePoster
Abstract Category: Therapy - disease modifying - 29 Risk management for disease modifying treatments
Background: Ozanimod (RPC1063) is an oral, selective sphingosine 1-phosphate (S1P) 1 and 5 receptor modulator in clinical development for the treatment of relapsing multiple sclerosis and inflammatory bowel disease (Cohen, 2016; Sandborn, 2016). Initiation of S1P receptor modulators causes transient decreases in heart rate (HR) that decreases with repeat dosing (Kovarik, 2004). The primary objective of this study was to compare the cardiac effects of ozanimod initiation in combination with steady-state propranolol or diltiazem to that of ozanimod alone.
Methods: In a double-blind, placebo-controlled, 3-period crossover study, 2 separate groups (propranolol and diltiazem groups) of 18 healthy subjects each received 3 treatment arms (separated by 7-10 days) per randomly assigned sequence: 1) placebo for 5 days and a single dose of ozanimod 0.25 mg on Day 5; 2) propranolol 80 mg or diltiazem 240 mg once daily for 5 days and placebo on Day 5; and 3) propranolol or diltiazem for 5 days plus a single dose of ozanimod on Day 5. HR nadir (0-12 hours postdose) and maximum increase (over a 24-hour postdose) from baseline PR interval were evaluated using least squares mean (LSM) differences (ΔHR or ΔPR) from a linear mixed model, with fixed effects for sequence, treatment, period, baseline as continuous covariate and subject (sequence) as a random effect. The pharmacokinetics (PK) of individual drugs were evaluated.
Results: Administration of ozanimod alone in the propranolol group and diltiazem group resulted in mean (SD) HR reduction from 75.7 (8.12) and 73.8 (11.41) bpm at baseline to 62.7 (7.48) and 63.6 (7.95) bpm at nadir, respectively. Propranolol+ozanimod arm and diltiazem+ozanimod arm resulted in mean (SD) HR reduction from 65.6 (6.61) and 73.9 (9.68) bpm at baseline to 55.2 (5.80) and 61.6 (7.63) bpm at nadir, respectively. Compared to ozanimod alone, a small and not clinically meaningful ΔHR (95% confidence interval [CI]) of 0.57 bpm (-1.95 to 3.10) for propranolol+ozanimod or -1.31 bpm (-3.14 to 0.52) for diltiazem+ozanimod was observed. Small, non-clinically meaningful ΔPR (95% CI) for (propranolol+ozanimod vs propranolol) and (diltiazem+ozanimod vs diltiazem) were 1.65 ms (-2.98 to 6.27) and 4.53 ms (-5.26 to 14.3), respectively. The PK of individual drugs were not affected during co-administration.
Conclusion: Co-administration of ozanimod and propranolol or diltiazem did not result in further clinically meaningful changes in HR or PR interval.
Disclosure:
JL Boyd, Shareholder, Celgene;
S Walker, Consultancy, Celgene;
P McCloskey, Shareholder, Celgene;
M Syto, Shareholder, Celgene;
JQ Tran, Shareholder, Celgene;
B. Darpo, Shareholder, iCardiac Technologies.
Abstract: EP1734
Type: ePoster
Abstract Category: Therapy - disease modifying - 29 Risk management for disease modifying treatments
Background: Ozanimod (RPC1063) is an oral, selective sphingosine 1-phosphate (S1P) 1 and 5 receptor modulator in clinical development for the treatment of relapsing multiple sclerosis and inflammatory bowel disease (Cohen, 2016; Sandborn, 2016). Initiation of S1P receptor modulators causes transient decreases in heart rate (HR) that decreases with repeat dosing (Kovarik, 2004). The primary objective of this study was to compare the cardiac effects of ozanimod initiation in combination with steady-state propranolol or diltiazem to that of ozanimod alone.
Methods: In a double-blind, placebo-controlled, 3-period crossover study, 2 separate groups (propranolol and diltiazem groups) of 18 healthy subjects each received 3 treatment arms (separated by 7-10 days) per randomly assigned sequence: 1) placebo for 5 days and a single dose of ozanimod 0.25 mg on Day 5; 2) propranolol 80 mg or diltiazem 240 mg once daily for 5 days and placebo on Day 5; and 3) propranolol or diltiazem for 5 days plus a single dose of ozanimod on Day 5. HR nadir (0-12 hours postdose) and maximum increase (over a 24-hour postdose) from baseline PR interval were evaluated using least squares mean (LSM) differences (ΔHR or ΔPR) from a linear mixed model, with fixed effects for sequence, treatment, period, baseline as continuous covariate and subject (sequence) as a random effect. The pharmacokinetics (PK) of individual drugs were evaluated.
Results: Administration of ozanimod alone in the propranolol group and diltiazem group resulted in mean (SD) HR reduction from 75.7 (8.12) and 73.8 (11.41) bpm at baseline to 62.7 (7.48) and 63.6 (7.95) bpm at nadir, respectively. Propranolol+ozanimod arm and diltiazem+ozanimod arm resulted in mean (SD) HR reduction from 65.6 (6.61) and 73.9 (9.68) bpm at baseline to 55.2 (5.80) and 61.6 (7.63) bpm at nadir, respectively. Compared to ozanimod alone, a small and not clinically meaningful ΔHR (95% confidence interval [CI]) of 0.57 bpm (-1.95 to 3.10) for propranolol+ozanimod or -1.31 bpm (-3.14 to 0.52) for diltiazem+ozanimod was observed. Small, non-clinically meaningful ΔPR (95% CI) for (propranolol+ozanimod vs propranolol) and (diltiazem+ozanimod vs diltiazem) were 1.65 ms (-2.98 to 6.27) and 4.53 ms (-5.26 to 14.3), respectively. The PK of individual drugs were not affected during co-administration.
Conclusion: Co-administration of ozanimod and propranolol or diltiazem did not result in further clinically meaningful changes in HR or PR interval.
Disclosure:
JL Boyd, Shareholder, Celgene;
S Walker, Consultancy, Celgene;
P McCloskey, Shareholder, Celgene;
M Syto, Shareholder, Celgene;
JQ Tran, Shareholder, Celgene;
B. Darpo, Shareholder, iCardiac Technologies.