Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects

AIMS BAF312 is the next generation selective sphingosine 1-phosphate receptor modulator (S1PR) that targets multiple sclerosis via effects on the immune system, and may have direct effects on S1PR-expressing cells in the central nervous system. Previous studies have shown transient decreases in heart rate (HR) following administration of S1PR modulators including BAF312. The objective of the current study is to determine whether dose titration of BAF312 reduces or eliminates these effects. METHODS 56 healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25–10 mg over 9–10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed. RESULTS Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable treatment difference on each of Days 1–12 vs. the non-titration regimen on Day 1 for HR effects (P < 0.0001). HRs in the non-titration regimen showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on Day 1 in either titration regimen. On Days 3–7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 bpm; P ≤ 0.0001). By Day 9, HRs in both titration regimens were comparable to placebo; this effect was maintained until end of treatment Day 12. CONCLUSION Both titration regimens effectively attenuated the initial bradyarrhythmia observed on Day 1 of treatment with BAF312 10 mg

Pharmacokinetic and pharmacodynamic interaction of siponimod (BAF312) and propranolol in healthy subjects

Objective: To evaluate the cardiac and pulmonary effects of siponimod (BAF312) and propranolol co-administration in healthy subjects. Methods: Healthy subjects (n = 76) were randomized in a doubleblind manner to receive propranolol at siponimod steady state (group A), siponimod at propranolol steady state (group B), placebo (group C) and propranolol (group D). Pharmacodynamic evaluations included maximum change from baseline in time-matched hourly average heart rate (Emax HR) and mean arterial blood pressure (Emax MABP) over 24 hours postdose, change from baseline in PR intervals, cardiac rhythm, and forced expiratory volume in 1 second (FEV1). Pharmacokinetic and safety parameters were also assessed. Results: Siponimod and propranolol when administered alone resulted in similar HR decrease at steady state. Compared to propranolol alone, the combination at steady state had an additional 6.21 bpm (95%CI: 2.32, 10.11) decrease of mean EmaxHR, a decrease of 5.04 bpm (0.52, 9.56) for group A and 7.39 bpm (2.87, 11.90) for group B. A minor decrease in MABP and a trend towards PR interval increase were noted with co-administration treatment vs. propranolol alone. There were no episodes of second-degree atrioventricular blocks or sinus pauses > 3 seconds. Baseline-corrected FEV1 was reduced by -0.07 L (95% CI: -0.17, 0.03) for group A and -0.05 L (-0.15, 0.05) for group B vs. propranolol alone. There were no cardiovascular adverse events during coadministration treatment. Conclusions: Coadministration of siponimod and propranolol was well tolerated. Bradyarrhythmic effects were less pronounced when propranolol was added to siponimod steady-state therapy compared with siponimod addition to propranolol

Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with severe renal impairment: A single-dose, open-label, parallel-group study

Objective To investigate the pharmacokinetics (PK), safety, and tolerability of siponimod and selected metabolites (M3 and M5) in subjects with varying degrees of renal impairment (RI) compared to demographically matched healthy subjects (HS). Methods The study enrolled subjects with severe RI (n=8) and matched HS (n=8). Subjects with moderate and mild RI were to be enrolled only if interim analysis showed ≥50% increase in maximum plasma concentration (Cmax) or area under the curve (AUC) of total and/or unbound siponimod in severe RI subjects versus HS. All subjects received single oral dose of siponimod 0.25 mg on Day 1; PK and safety were evaluated during the follow-up (~13 days). Results PK of siponimod was marginally affected in severe RI subjects versus HS: Cmax decreased by 8% and AUClast and AUCinf increased by 23% and 24%, respectively. Siponimod plasma unbound (u) fraction was 7% higher in the severe RI subjects versus HS. Cmax(u) was comparable while AUClast(u) and AUCinf(u) increased by 32% and 33%, respectively, compared to HS. M3 exposure was similar (Cmax decreased by 9%; AUClast and AUCinf increased by 11%) and M5 exposure was slightly lower (Cmax decreased by 26%; AUClast decreased by 16%) in subjects with severe renal impairment compared with matched HS. No adverse events were reported during this study. Conclusions Changes in the plasma exposure of total and unbound siponimod and metabolites M3 and M5 were not considered to be clinically relevant. Further investigation of PK in subjects with mild and moderate RI was not warranted

Pharmacokinetics, safety, and tolerability of siponimod (BAF312) in subjects with different levels of hepatic impairment: a single-dose, open-label, parallel-group study

This open-label, parallel-group study assessed the pharmacokinetics (PK), safety and tolerability of siponimod and its metabolites (M3 and M5) in subjects with mild, moderate and severe hepatic impairment (HI) compared to demographically-matched healthy subjects (HS). The study enrolled 40 subjects (each HI group, n=8; HS group, n=16). A staged design was employed starting with the enrollment of subjects with mild HI, followed by moderate and severe HI groups. All subjects received a single oral dose of 0.25 mg siponimod on Day 1; PK and safety data were collected during the 21-day follow-up. No significant differences were observed in the plasma exposure of siponimod in mild, moderate, and severe HI groups vs. HS: Cmax changed by 16%, -13%, and -16%; AUC by 5%, -13%, and 15%, respectively. The unbound siponimod PK parameters vs. HS were similar in mild HI, and increased in the moderate (Cmax, 15%; AUC, 17%) and severe HI groups (Cmax, 11%; AUC, 50%). Exposure of M3 and M5 also showed 2-5 fold increase particularly in the moderate and severe HI groups vs HS. There were no clinically relevant safety findings. These results do not warrant any dose adjustments of siponimod in subjects with HI

Cardiac Effects of Siponimod (BAF312) Re-initiation after Variable Periods of Drug Discontinuation in Healthy Subjects

Purpose The goal of this study was to investigate the effect of siponimod treatment re-initiation on the initial negative chronotropic effects and cardiac rhythm after variable drug discontinuation periods. Methods This partially double-blind, randomized, placebo-controlled study was conducted in healthy subjects. Siponimod doses (0.5-4.0 mg) and placebo were evaluated in combination with drug discontinuation periods ranging from 48 to 192 hours. Twelve-lead Holter ECGs were performed from 1.5 hours before until 24 hours after single-dose re-initiation. Atrioventricular blocks (AVBs) and sinus pauses (RR >2 seconds) were categorized according to dose level, discontinuation period, and resting and nonresting hours. Findings Of the enrolled 138 subjects, 117 were evaluated. Demographic and baseline characteristics were comparable between the treatment groups. Subjects rechallenged at the combination of 4 mg/192 hours (highest investigated dose and longest discontinuation period [7 missed doses]) exhibited the highest decrease in pooled, placebo-adjusted heart rate (HR) of 14.53 beats/min. The magnitude of the negative chronotropic effect of siponimod re-initiation was dependent on both dose and duration of treatment discontinuation. Regardless of the dose, the placebo-adjusted HR reduction at re-initiation of drug treatment after up to 96 hours of drug discontinuation remained <10 beats/min. Except for 1 outlier for HR decrease under the 96-hour/placebo combination, no outliers were observed for any combination up to and including the 96-hour discontinuation periods. Most of the AVBs and sinus pauses were observed during nocturnal hours concurrent with increased vagal tone. All detected AVBs and sinus pauses were asymptomatic and not considered clinically relevant. Implications Siponimod could be safely re-initiated without retitration after drug discontinuation periods up to 96 hours. Retitration is required if patients miss ≥4 consecutive doses

Effect of mavoglurant (AFQ056) on the pharmacokinetics of a combined oral contraceptive containing ethinyl estradiol and levonorgestrel in healthy women

Objective: To compare the pharmacokinetics (PKs) of a combination oral contraceptive (OC) when given alone or concomitantly with the selective metabotropic glutamate receptor 5 antagonist mavoglurant (AFQ056). Methods: This open-label, fixed-sequence, two-period study included 30 healthy female subjects aged 18–40 years. In Period 1, a single oral dose of an OC containing 30 μg ethinyl estradiol (EE)/150 μg levonorgestrel (LNG) was administered alone. In Period 2, OC was administered with a clinically relevant multiple-dose of 100 mg b.i.d. mavoglurant under-steady conditions. Plasma concentrations of EE and LNG were measured up to 72 hours post administration and PK parameters Cmax and AUClast were estimated using noncompartmental methods. Results: The geometric mean ratios of EE PK parameters Cmax and AUClast obtained with and without mavoglurant were 0.97 (90% confidence interval [CI]: 0.90-1.06) and 0.94 (90% CI: 0.86-1.03), respectively. The corresponding Cmax and AUClast for LNG were 0.81 (90% CI: 0.75-0.87) and 0.68 (90% CI: 0.63 0.73), respectively. Conclusions: In conclusion, the EE PK was unchanged, whereas Cmax and AUClast of LNG was approximately 19% and 32% lower, respectively, when given with mavoglurant. Further investigation regarding the impact on contraceptive efficacy is warranted

Distinct effects of orexin 2 receptor antagonism and dual orexin 1,2 receptor antagonism on sleep architecture in mice.

Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, SB-649868, suvorexant (MK-4305) and filorexant (MK-6096), have shown promise for the treatment of insomnias and sleep disorders. Whether antagonism of both OX1R and OX2R is necessary for sleep induction has been a matter of some debate. Experiments using knockout mice suggest that it may be sufficient to antagonize only OX2R. The recent identification of an orally bioavailable, brain penetrant OX2R selective antagonist 2-((1H-Indol-3-yl)methyl)-9-(4-methoxypyrimidin-2-yl)-2,9-diazaspiro[5.5]undecan-1-one (IPSU) has allowed us to directly test whether selective antagonism of OX2R may also be a viable strategy for induction of sleep. We have previously demonstrated that IPSU and suvorexant increase sleep when dosed during the mouse active phase (lights off); IPSU achieving this primarily by increasing NREM sleep, suvorexant primarily by increasing REM sleep. Here, we tested the effects of suvorexant and IPSU during the inactive phase (lights on), in order to determine their effects on sleep architecture during a phase when sleep is naturally more prevalent. At the doses tested, only suvorexant further decreased wake during the inactive period and only during the first hour after drug application. Whereas IPSU was devoid of effects on the time spent in NREM or REM, suvorexant substantially disturbed the sleep architecture by selectively increasing REM during the first 4 hours after dosing. Thus, OX2R selective antagonists may have a reduced tendency for perturbing NREM/REM architecture in comparison with DORAs. Whether this effect will prove to be a general feature of SORAs versus DORAs remains to be seen

Metabolism and Disposition of Siponimod, a Novel Selective S1P1/S1P5 Agonist, in Healthy Volunteers and In Vitro Identification of Human Cytochrome P450 Enzymes Involved in Its Oxidative Metabolism

Siponimod, a next generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism and excretion of a single oral dose of [14C]siponimod 10 mg in four healthy male subjects. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds. Unchanged siponimod accounted for 57% of the total plasma radioactivity (AUC), indicating substantial exposure to metabolites. Siponimod showed medium to slow absorption (median Tmax: 4 h) and moderate distribution (Vz/F: 291 L). Siponimod was mainly cleared through biotransformation predominantly by oxidative metabolism. The mean apparent elimination half-life of siponimod in plasma was 56.6 h. Siponimod was excreted mostly in feces in the form of oxidative metabolites. The excretion of radioactivity was close to complete after 13 days. Based on the metabolite patterns, a phase II metabolite (M3) formed by glucuronidation of hydroxylated siponimod was the main circulating metabolite in plasma. However, in subsequent mouse ADME and clinical PK studies, a long-lived non-polar metabolite (M17, cholesterol ester of siponimod) was identified as the most prominent systemic metabolite. Furthermore, we conducted in vitro experiments to investigate the enzymes responsible for the oxidative metabolism of siponimod. Selective inhibitors and recombinant enzyme results identified cytochrome P450 2C9 (CYP2C9) as the predominant contributor to the human liver microsomal biotransformation of siponimod, with minor contributions from CYP3A4 and other P450 enzymes