Phase I/Ib, open-label, multicenter, dose-escalation study of the anti-TGF-ß monoclonal antibody, NIS793, in combination with spartalizumab in adult patients with advanced tumors.

BACKGROUND: NIS793 is a human IgG2 monoclonal antibody that binds to transforming growth factor beta (TGF-ß). This first-in-human study investigated NIS793 plus spartalizumab treatment in patients with advanced solid tumors. METHODS: Patients received NIS793 (0.3-1 mg/kg every 3 weeks (Q3W)) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 plus spartalizumab (NIS793 0.3-30 mg/kg Q3W and spartalizumab 300 mg Q3W or NIS793 20-30 mg/kg every 2 weeks [Q2W] and spartalizumab 400 mg every 4 weeks (Q4W)). In dose expansion, patients with non-small cell lung cancer (NSCLC) resistant to prior anti-programmed death ligand 1 or patients with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE). RESULTS: Sixty patients were treated in dose escalation, 11 with NIS793 monotherapy and 49 with NIS793 plus spartalizumab, and 60 patients were treated in dose expansion (MSS-CRC: n=40; NSCLC: n=20). No dose-limiting toxicities were observed. The RDE was established as NIS793 30 mg/kg (2100 mg) and spartalizumab 300 mg Q3W. Overall 54 (49.5%) patients experienced ≥1 treatment-related adverse event, most commonly rash (n=16; 13.3%), pruritus (n=10; 8.3%), and fatigue (n=9; 7.5%). Three partial responses were reported: one in renal cell carcinoma (NIS793 30 mg/kg Q2W plus spartalizumab 400 mg Q4W), and two in the MSS-CRC expansion cohort. Biomarker data showed evidence of target engagement through increased TGF-ß/NIS793 complexes and depleted active TGF-ß in peripheral blood. Gene expression analyses in tumor biopsies demonstrated decreased TGF-ß target genes and signatures and increased immune signatures. CONCLUSIONS: In patients with advanced solid tumors, proof of mechanism of NIS793 is supported by evidence of target engagement and TGF-ß pathway inhibition. TRIAL REGISTRATION NUMBER: NCT02947165.

Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody.

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.

Lack of Effect of Cenerimod, a Selective S1P1 Receptor Modulator, on the Pharmacokinetics of a Combined Oral Contraceptive.

Cenerimod, a sphingosine-1-phosphate 1 receptor modulator, is in development for the treatment of systemic lupus erythematosus, a disease mainly affecting women of childbearing potential. The effect of cenerimod on the pharmacokinetics (PK) of a combined oral contraceptive (COC, 100 µg levonorgestrel and 20 µg ethinylestradiol (EE)) was investigated. A randomized, double-blind, parallel-group study was performed in 24 healthy male and female subjects. A single oral dose of COC was administered alone and after 35 days of once daily (o.d.) administration of cenerimod 0.5 (n = 10) or 4 (n = 14) mg. Exposure to EE alone or in combination with cenerimod was comparable as reflected by the geometric mean ratios and the respective 90% confidence intervals, while a slight increase in exposure (approximately 10-25%) to levonorgestrel was observed at clinically relevant concentrations of cenerimod. Overall, COC alone or in combination with cenerimod was safe and well tolerated. Two subjects reported one adverse event each (one headache after COC alone, and gastroenteritis in combination with cenerimod 4 mg). In conclusion, cenerimod does not affect the PK of levonorgestrel or EE to a clinically relevant extent. Therefore, COC can be selected as method of contraception during and after cenerimod therapy without the risk of interaction.

Insights from In Vitro and Clinical Data to Guide Transition from the Novel P2Y12 Antagonist Selatogrel to Clopidogrel, Prasugrel, and Ticagrelor.

Reduced pharmacodynamic (PD) effects of irreversible oral P2Y12 receptor antagonists have been reported when administered during cangrelor infusion. Therefore, the PD interaction liability of the novel P2Y12 receptor antagonist selatogrel with irreversible (i.e., clopidogrel, prasugrel) and reversible (i.e., ticagrelor) oral P2Y12 receptor antagonists was investigated in vitro and in healthy subjects. In vitro, selatogrel reduced the effects of clopidogrel and prasugrel in a concentration-dependent manner, while additive effects were observed for the combination of selatogrel and ticagrelor. Accordingly, a single-center, randomized, double-blind, two-way crossover study was conducted consisting of six groups. In each group (N = 12), an open-label loading dose of 300 or 600 mg clopidogrel, 60 mg prasugrel, or 180 mg ticagrelor was administered 30 minutes (i.e., at t max of selatogrel) or 12 hours after a single subcutaneous dose of 16 mg selatogrel or placebo. Inhibition of platelet aggregation (IPA) was assessed at various time points up to 48 hours. Reduced IPA was determined when clopidogrel or prasugrel was administered 30 minutes after selatogrel (∼40 and 70% lower IPA, respectively, at 24 hours postdosing). However, when administering prasugrel 12 hours after selatogrel, IPA was not impacted (>90% IPA) and in the case of clopidogrel reduced effects were partially mitigated. Similar IPA was determined for ticagrelor when administered 30 minutes after selatogrel or placebo. In conclusion, reduced IPA was observed for clopidogrel and prasugrel when administered after selatogrel, which can be mitigated by applying an appropriate time interval. No PD interaction with ticagrelor was observed.

PK/PD modeling of a clazosentan thorough QT study with hysteresis in concentration-QT and RR-QT.

Clazosentan's potential QT liability was investigated in a thorough QT study in which clazosentan was administered intravenously as a continuous infusion of 20 mg/h immediately followed by 60 mg/h. Clazosentan prolonged the placebo-corrected change-from-baseline QT interval corrected for RR with Fridericia's formula (ΔΔQTcF) with the maximum QT effect occurring 4 h after the maximum drug concentration, apparently associated with vomiting. The delayed effect precluded the standard linear modeling approach. This analysis aimed at characterizing the concentration-QT relationship in consideration of RR-QT hysteresis, concentration-ΔΔQTcF hysteresis, and the influence of vomiting. Nonlinear mixed-effects modeling was applied to characterize pharmacokinetics and pharmacodynamics, i.e., ΔΔQTcF. Simulations were used to predict ΔΔQTcF for expected therapeutic dose used in Phase 3 clinical development. Correction for RR-QT hysteresis did not influence ΔΔQTcF to a relevant extent. Pharmacokinetics of clazosentan were best described by a linear two-compartment model. The delayed QT prolongation was characterized by an indirect-response model with loglinear drug effect. Vomiting had no statistically significant influence on QT prolongation despite apparent differences between subjects vomiting and not vomiting, probably since vomiting occurred mostly after the main QT prolongation. Following a simulated 3-h infusion of 15 mg/h of clazosentan, the upper bound of the predicted 90% CI for mean ΔΔQTcF was expected to exceed the 10-ms regulatory threshold of concern with maximum effect 3.5 h after end of infusion. TRN: NCT03657446, 05 Sep 2018.

Pharmacokinetics and Pharmacodynamics of Cenerimod, A Selective S1P1 R Modulator, Are Not Affected by Ethnicity in Healthy Asian and White Subjects.

Cenerimod is a sphingosine-1-phosphate 1 receptor (S1P1 R) modulator in phase II development for treatment of systemic lupus erythematosus. Its pharmacokinetics (PKs), pharmacodynamics (PDs), as well as safety and tolerability were investigated in white and Asian subjects to allow for recruitment of Asian patients in future studies. A randomized, double-blind, placebo-controlled parallel-group study was performed in 20 healthy male subjects (n = 10 per ethnicity). A single, oral dose of 4 mg cenerimod or placebo (ratio 8:2) was administered under fasted conditions. The PKs of cenerimod were similar in white and Asian subjects indicated by geometric mean ratios (90% confidence interval) of 0.99 (0.80-1.21) for maximum plasma concentration, 0.96 (0.75-1.24) for area under the plasma concentration-time curve from 0 to infinity, and 1.04 (0.86-1.25) for terminal half-life. Accordingly, the extent and time course of reduction in lymphocyte count (as PD biomarker) were also similar in white and Asian subjects as compared with placebo. As observed for other S1PR modulators, a transient mean (SD) heart rate reduction in white (15.1 (14.8) bpm) and Asian (11.8 (6.16) bpm) subjects was observed following administration of cenerimod. The drug was safe and well-tolerated indicated by occurrence of a single adverse event of chemical conjunctivitis in a white subject that was not suspected as study drug related. In conclusion, the determined absence of any relevant PK or PD differences supports using the same doses of cenerimod in white and Asian patients in upcoming late-phase studies.

Association Between Vomiting and QT Hysteresis: Data from a TQT Study with the Endothelin A Receptor Antagonist Clazosentan.

This study investigated the potential QT liability of the selective endothelin-1 A receptor antagonist clazosentan at a therapeutic (20 mg/h) and supratherapeutic (60 mg/h) intravenous (i.v.) dose. A randomized, placebo- and moxifloxacin-controlled, double-blind, 3-period, crossover study was conducted in 36 healthy subjects receiving clazosentan (20 mg/h followed by 60 mg/h i.v. for 3 h each), placebo (i.v. for 6 h), and moxifloxacin (single oral dose of 400 mg concomitantly with placebo i.v. for 6 h). At least three replicate ECGs were extracted from Holter recordings at predefined time points from 1 h pre-dose to 24 h after end of infusion. Pharmacokinetic blood sampling was performed for concentration/QT analysis (primary endpoint). For moxifloxacin, the lower bound of the 90% confidence interval (CI) of baseline- and placebo-corrected QTcF (ΔΔQTcF) was > 5 ms at its maximum plasma concentration together with a positive slope of the concentration/QT regression line demonstrating assay sensitivity. For clazosentan, time of peak exposure preceded maximum ΔΔQTcF by 4 h indicating delayed QT-prolonging effects leading to invalidity of the concentration/QT analysis. The secondary by-time-point analysis revealed QT liability of clazosentan (i.e., upper bound of 90% CI ∆∆QTcF > 10 ms). Delayed QT prolongation (i.e., hysteresis) was predominantly observed in subjects with nausea and vomiting, potentially caused by vagal reaction and/or decreases in potassium concentration. By contrast, there was no association with other adverse events, food intake, or concomitant medication. In conclusion, clazosentan at therapeutic and supratherapeutic doses has QT liability with hysteresis effects being associated with nausea and vomiting.

Clinical Pharmacology of Clazosentan, a Selective Endothelin A Receptor Antagonist for the Prevention and Treatment of aSAH-Related Cerebral Vasospasm.

Aneurysmal subarachnoid hemorrhage (aSAH) may lead to cerebral vasospasm and is associated with significant morbidity and mortality. It represents a major unmet medical need due to few treatment options with limited efficacy. The role of endothelin-1 (ET-1) and its receptor ETA in the pathogenesis of aSAH-induced vasospasm suggests antagonism of this receptor as promising asset for pharmacological treatment. Clazosentan is a potent ETA receptor antagonist for intravenous use currently under development for the prevention of aSAH-induced cerebral vasospasm. The pharmacokinetics of clazosentan are characterized by an intermediate clearance, a volume of distribution similar to that of the extracellular fluid volume, dose-proportional exposure, an elimination independent of drug-metabolizing enzymes, and a disposition mainly dependent on the hepatic uptake transporter organic anion transport polypeptide 1B1/1B3. In healthy subjects, clazosentan leads to an increase in ET-1 concentration and prevents the cardiac and renal effects mediated by infusion of ET-1. In patients, it significantly reduced the incidence of moderate or severe vasospasm as well as post-aSAH vasospasm-related morbidity and mortality. Clazosentan is well tolerated up to the expected therapeutic dose of 15 mg/h and, in aSAH patients, lung complications, hypotension, and anemia were adverse events more commonly reported following clazosentan than placebo. In summary, clazosentan has a pharmacokinetic, pharmacodynamic, and safety profile suitable to become a valuable asset in the armamentarium of therapeutic modalities to prevent aSAH-induced cerebral vasospasm.

Modelling pharmacokinetics and pharmacodynamics of the selective S1P1 receptor modulator cenerimod in healthy subjects and systemic lupus erythematosus patients.

AIMS: Assessment of time to attain steady state as well as drug accumulation following long-term treatment with the selective sphingosine-1-phosphate 1 receptor modulator cenerimod and prediction of the incidence of low total lymphocyte (LY) counts. Differences in pharmacokinetics and pharmacodynamics based on demographic characteristics and between healthy subjects and systemic lupus erythematosus (SLE) patients were to be identified. METHODS: Data from 4 Phase I studies and 1 Phase II study were pooled to develop a population pharmacokinetic/pharmacodynamic model describing cenerimod concentration and its effect on LY count. Simulations addressed the objectives. RESULTS: Simulations of 365 days of treatment indicated a time to steady state of 49 days and changes in exposure of 15% beyond 35 days. For a dose of 2 mg, the predicted incidences of LY counts below 0.5 and 0.2 × 109 cells/L were 18.2 and 0.6% for healthy subjects and 25.9 and 1.0% for SLE patients, respectively. Incidence increased with higher dose and lower baseline LY counts. For body weights of 50 and 100 kg compared to 75 kg, exposure was predicted to change by +37% and -20%, respectively. CONCLUSION: Long-term cenerimod administration is not expected to result in exposure and LY count reduction substantially different from results of completed studies. Low LY counts are predicted to occur more frequently in SLE patients compared to healthy subjects. Dose individualization based on the model is not considered necessary. Model-based simulations enable benefit-risk evaluations, supporting planning of late-phase clinical studies and scientific exchange with health authorities.

First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study.

OBJECTIVE: To investigate the pharmacodynamics, pharmacokinetics and safety of cenerimod-a potent, oral, selective sphingosine 1-phosphate 1 receptor modulator-in patients with SLE. METHODS: This multicentre, double-blind, placebo-controlled study was conducted in two parts. In part A, patients with SLE were randomised 1:1:1:1 to receive oral cenerimod 0.5, 1 or 2 mg, or placebo once daily for 12 weeks. Following an interim safety review of part A, additional patients were randomised 3:1 for part B and received cenerimod 4 mg or placebo once daily for 12 weeks. Endpoints included changes in total lymphocyte count, SLE Disease Activity Index-2000 (SLEDAI-2K) score (modified (mSLEDAI-2K) to exclude leucopenia), biomarker anti-double-stranded DNA (anti-dsDNA) antibodies, pharmacokinetic assessments and treatment-emergent adverse events (TEAEs). RESULTS: Part A included 49 patients (1:1:1:1 receiving cenerimod 0.5, 1 or 2 mg, or placebo) and part B included 18 patients (13 cenerimod; 5 placebo). Cenerimod caused a statistically significant dose-dependent reduction in total lymphocyte count from baseline to end of treatment (EOT). Compared with placebo at EOT, cenerimod 4 mg had an estimated treatment effect on change from baseline in mSLEDAI-2K score of -2.420 (p=0.0306), and on anti-dsDNA antibodies of -64.55 U/mL (p=0.0082), suggesting clinical and biological improvement in these exploratory efficacy analyses. Trough plasma concentrations were dose proportional and reached steady-state conditions after 4 weeks of once daily dosing. All groups reported similar, non-dose-related frequencies of TEAEs (cenerimod 0.5 mg: 41.7%; 1 mg: 41.7%; 2 mg: 46.2%; 4 mg: 38.5% and placebo: 58.8%). A small, dose-related, non-clinically relevant decrease in heart rate was only observed in the first 6 hours after initiation. CONCLUSIONS: With an acceptable safety profile, the efficacy findings suggest that cenerimod has the potential to treat patients with SLE. Further investigation in larger patient populations with longer treatment duration is warranted.

Cardiodynamic Interactions between Two S1P1 Receptor Modulators in an Experimental Clinical Setting: Different Pharmacokinetic Properties as an Opportunity to Mitigate First-Dose Heart Rate Effects.

A decrease in heart rate (HR) is a well-established first-dose effect of sphingosine-1-phosphate subtype 1 receptor (S1P1R) modulators. For compounds with a short half-life (t1/2), this can be mitigated by gradual up-titration to therapeutic doses, whereas this is not required for compounds with a long t1/2 due to the less pronounced first-dose-related negative chronotropic effects. Based on this conceptual framework, this mechanistic study investigated whether first-dose HR effects of ponesimod (t1/2 ~32 h) can be mitigated by prior administration of cenerimod (t1/2 ~415 h). Healthy subjects (n = 12) were randomly assigned to active or placebo (2:1 ratio). Active treatment consisted of a single dose of 10 mg ponesimod on Day 1, 18, and 37 and multiple-dose administration of 2 mg once daily cenerimod (Day 9-36). Placebos of cenerimod and ponesimod were used as reference treatment. Cardiodynamic parameters were derived from 24 h Holter electrocardiogram (ECG) assessments on Day 1, 9, 10, 18, 36, and 37. Ponesimod (10 mg) alone triggered a transient mean decrease from baseline in hourly mean HR of 17 bpm. In contrast, decreases of 5.0 and 4.8 bpm were observed when ponesimod was given at near half steady-state (Day 18) or steady-state (Day 37) cenerimod, respectively. Hourly mean HR decreased after first administration of cenerimod and placebo was 7.4 and 4.0 bpm, respectively. Treatment with ponesimod and cenerimod alone or in combination was safe and tolerated. First-dose-related negative chronotropic effects of ponesimod were less pronounced when administered after initiation of cenerimod suggesting mitigation of this class-related liability.

Influence of Rifampin-Mediated Organic Anion-Transporting Polypeptide 1B1/1B3 Inhibition on the Pharmacokinetics of Clazosentan.

Clazosentan is a selective endothelin A receptor antagonist in development for the prevention and treatment of vasospasm postsubarachnoid hemorrhage. It is a substrate of organic anion-transporting polypeptide 1B1/1B3 based on preclinical data. This randomized, double-blind, two-period, cross-over study investigated the pharmacokinetics, safety, and tolerability of an intravenous infusion of clazosentan (15 mg/hour for 3 hours) after the intravenous administration of placebo or rifampin (600 mg/100 mL in 30 minutes). A total of 14 healthy male participants were enrolled resulting in 13 completers. Clazosentan exposure was three to four times higher after organic anion-transporting polypeptide 1B1/1B3 inhibition, as reflected by the geometric mean ratio (90% confidence interval) of area under the plasma concentration-time curve from zero to infinity: 3.88 (3.24-4.65). Clearance and volume of distribution decreased to a similar extent. Elimination half-life was not affected. A similar pattern but a higher incidence and frequency of adverse events were observed when clazosentan was given with rifampin than with placebo.

Clinical Pharmacology of the Reversible and Potent P2Y12 Receptor Antagonist ACT-246475 After Single Subcutaneous Administration in Healthy Male Subjects.

ACT-246475 is a selective and reversible P2Y12 receptor antagonist inducing inhibition of platelet aggregation (IPA). A randomized, double-blind, placebo-controlled, parallel-design study was performed to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating single subcutaneous doses of ACT-246475 (1, 2, 4, 8, 16, or 32 mg) in healthy male subjects (N = 8 per dose, 3:1 active:placebo ratio). Pharmacodynamic effects were assessed based on maximum platelet aggregation and P2Y12 reaction units using light transmission aggregometry and VerifyNow® assays, respectively. ACT-246475 was safe and well tolerated up to 32 mg based on adverse event data and absence of clinically relevant changes in hematology, biochemistry, vital signs, and electrocardiogram variables. Median time to reach maximum plasma concentration was 0.5-0.75 hours, and geometric mean terminal half-life ranged from 1.3 to 9.2 hours across the tested dose range. Exposure to ACT-246475 was dose proportional across all dose groups. The maximal %IPA was reached within 30 minutes after subcutaneous administration of ACT-246475. A dose-dependent duration and extent of effect were observed based on area under the effect curve and maximum effect data. Similar results were observed for maximum platelet aggregation and P2Y12 reaction units. The %IPA was ≥85% at doses ≥2 mg. This level of %IPA was extended to at least 12 hours in the 32-mg dose group. The safety and pharmacokinetic/pharmacokinetic profile with quick onset and adequate duration of IPA support further investigation in patients with coronary artery disease.

Pharmacological rescue of nociceptive hypersensitivity and oxytocin analgesia impairment in a rat model of neonatal maternal separation.

Oxytocin (OT), known for its neurohormonal effects around birth, has recently been suggested for being a critical determinant in neurodevelopmental disorders. This hypothalamic neuropeptide exerts a potent analgesic effect through an action on the nociceptive system. This endogenous control of pain has an important adaptive value but might be altered by early life stress, possibly contributing to its long-term consequences on pain responses and associated comorbidities. We tested this hypothesis using a rat model of neonatal maternal separation (NMS) known to induce long-term consequences on several brain functions including chronic stress, anxiety, altered social behavior, and visceral hypersensitivity. We found that adult rats with a history of NMS were hypersensitive to noxious mechanical/thermal hot stimuli and to inflammatory pain. We failed to observe OT receptor-mediated stress-induced analgesia and OT antihyperalgesia after carrageenan inflammation. These alterations were partially rescued if NMS pups were treated by intraperitoneal daily injection during NMS with OT or its downstream second messenger allopregnanolone. The involvement of epigenetic changes in these alterations was confirmed since neonatal treatment with the histone deacetylase inhibitor SAHA, not only normalized nociceptive sensitivities but also restored OT receptor-mediated stress-induced analgesia and the endogenous antihyperalgesia in inflamed NMS rats. There is growing evidence in the literature that early life stress might impair the nociceptive system ontogeny and function. This study suggests that these alterations might be restored while stimulating OT receptor signaling or histone deacetylase inhibitors, using molecules that are currently available or part of clinical trials for other pathologies.

Accelerated Development of the Dual Orexin Receptor Antagonist ACT-541468: Integration of a Microtracer in a First-in-Human Study.

The orexin system regulates sleep and arousal and is targeted by ACT-541468, a new dual orexin receptor antagonist (DORA). Healthy male subjects received a single oral dose of 5-200 mg to assess safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), mass balance, metabolism, and absolute bioavailability utilizing a 14 C-labeled, orally and intravenously (i.v.) administered microtracer. The drug was safe and well tolerated; the PK profile was characterized by quick absorption and elimination, with median time to reach maximum concentration (tmax ) of 0.8-2.8 h and geometric mean terminal half-life (t1/2 ) of 5.9-8.8 h. Clear dose-related effects on the central nervous system were observed at ≥25 mg, indicating a suitable PK-PD profile for a sleep-promoting drug, allowing for rapid onset and duration of action limited to the intended use. This comprehensive first-in-human study created a wealth of data, while saving resources in drug development.

Pharmacokinetics, Pharmacodynamics, Tolerability, and Food Effect of Cenerimod, a Selective S1P1 Receptor Modulator in Healthy Subjects.

The pharmacokinetics, pharmacodynamics, tolerability, and food effect of cenerimod, a potent sphingosine-1-phosphate subtype 1 receptor modulator, were investigated in three sub-studies. Two double-blind, placebo-controlled, randomised studies in healthy male subjects were performed. Cenerimod was administered either as single dose (1, 3, 10 or 25 mg; Study 1) or once daily for 35 days (0.5, 1, 2 or 4 mg; Study 2). A two-period cross-over, open-label study was performed to assess the food effect (1 mg, Study 3). The pharmacokinetic profile of cenerimod was characterised by a tmax of 5.0-6.2 h. Terminal half-life after single and multiple doses ranged from 170 to 199 h and 283 to 539 h, respectively. Food had no relevant effect on the pharmacokinetics of cenerimod. A dose-dependent decrease in lymphocyte count was observed after initiation of cenerimod and reached a plateau (maximum change from baseline: -64%) after 20-23 days of treatment. Lymphocyte counts returned to baseline values at end-of-study examination. One serious adverse event of circulatory collapse (25 mg dose group, maximum tolerated dose: 10 mg) and adverse events of mild-to-moderate intensity were reported. Treatment initiation was associated with transient decreases in heart rate and blood pressure at doses >1 and ≥10 mg, respectively.

A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects.

PURPOSE: In vitro data showed that selexipag and its active metabolite (ACT-333679) have an inductive effect on CYP3A4, CYP2B6, and CYP2C9 at concentrations approximately 100-fold higher than the maximum plasma concentration (C max) measured under steady-state conditions. In order to confirm in vivo the lack of induction at the enterocyte level, we assessed the effect of selexipag on midazolam, a substrate of hepatic and intestinal CYP3A4. METHODS: This study was conducted according to an open-label, randomized, two-way crossover design. A total of 20 subjects received a single oral dose of 7.5 mg midazolam alone (treatment A) or on top of steady-state selexipag (treatment B). Selexipag was administered twice daily using an up-titration scheme consisting of three steps: 400, 600, 1000, and 1600 µg with increments every fourth day. A 24-h pharmacokinetic profile was performed following midazolam administration, and bioequivalence criteria were investigated on an exploratory basis. RESULTS: The C max of midazolam and 1-hydroxymidazolam was decreased by approximately 20 and 14%, respectively, following treatment B compared to A. The time to reach C max for midazolam and 1-hydroxymidazolam was similar between treatments. The terminal half-life was reduced in treatment B compared to A for both midazolam (16%) and 1-hydroxymidazolam (20%). Exposure (area under the curve) to midazolam and 1-hydroxymidazolam was similar between treatments, and the 90% confidence intervals of geometric mean ratios were within the bioequivalence interval. Treatment with midazolam, selexipag, and the combination was safe and well tolerated. CONCLUSION: Exposure to midazolam and 1-hydroxymidazolam was not affected by treatment with selexipag.

Effects of multiple-dose ponesimod, a selective S1P1 receptor modulator, on lymphocyte subsets in healthy humans.

This study investigated the effects of ponesimod, a selective S1P1 receptor modulator, on T lymphocyte subsets in 16 healthy subjects. Lymphocyte subset proportions and absolute numbers were determined at baseline and on Day 10, after once-daily administration of ponesimod (10 mg, 20 mg, and 40 mg each consecutively for 3 days) or placebo (ratio 3:1). The overall change from baseline in lymphocyte count was -1,292±340×106 cells/L and 275±486×106 cells/L in ponesimod- and placebo-treated subjects, respectively. This included a decrease in both T and B lymphocytes following ponesimod treatment. A decrease in naïve CD4+ T cells (CD45RA+CCR7+) from baseline was observed only after ponesimod treatment (-113±98×106 cells/L, placebo: 0±18×106 cells/L). The number of T-cytotoxic (CD3+CD8+) and T-helper (CD3+CD4+) cells was significantly altered following ponesimod treatment compared with placebo. Furthermore, ponesimod treatment resulted in marked decreases in CD4+ T-central memory (CD45RA-CCR7+) cells (-437±164×106 cells/L) and CD4+ T-effector memory (CD45RA-CCR7-) cells (-131±57×106 cells/L). In addition, ponesimod treatment led to a decrease of -228±90×106 cells/L of gut-homing T cells (CLA-integrin ß7+). In contrast, when compared with placebo, CD8+ T-effector memory and natural killer (NK) cells were not significantly reduced following multiple-dose administration of ponesimod. In summary, ponesimod treatment led to a marked reduction in overall T and B cells. Further investigations revealed that the number of CD4+ cells was dramatically reduced, whereas CD8+ and NK cells were less affected, allowing the body to preserve critical viral-clearing functions.

Absolute Bioavailability of Ponesimod, a Selective S1P1 Receptor Modulator, in Healthy Male Subjects.

BACKGROUND AND OBJECTIVES: The pharmacokinetic profile of ponesimod, a sphingosine-1-phosphate receptor 1 modulator, is characterized by a rapid absorption [time to maximum concentration (t max) of 2-4 h] and a terminal half-life (t ½) of 32 h after single-dose administration. The aim of this study was to assess additional pharmacokinetic parameters [absolute bioavailability, total clearance (CL), and volume of distribution (V ss)] in healthy male subjects. METHODS: After ensuring in a pilot phase the full pharmacokinetic profile, safety, and tolerability of a 5-mg intravenous infusion of ponesimod over 3 h (treatment A), the study proceeded to the randomized, two-way crossover, single-dose (treatment A; treatment B: 10 mg oral) main phase. RESULTS: The absolute bioavailability of ponesimod was 83.8 % [90 % confidence interval (CI): 80.2-87.5]. CL and V ss (95 % CI) were 3.8 L/h (3.3-4.3) and 160 L (146.1-174.2), respectively. C max (95 % CI) was 48.5 ng/mL (43.9-53.6) and 61.4 ng/mL (55.3-68.3) after intravenous infusion and oral administration, respectively. The t ½ (95 % CI) following intravenous infusion was 32.9 h (28.5-38.1) and 31.7 h (27.9-36.0) following oral administration. Ponesimod administered by both routes of administration was well tolerated and resulted in transient decreases in lymphocyte count and heart rate. CONCLUSIONS: This study indicates high absolute bioavailability, low CL, and moderate V ss of ponesimod.