Endocrine profile of the kisspeptin receptor agonist MVT-602 in healthy premenopausal women with and without ovarian stimulation: results from 2 randomized, placebo-controlled clinical tricals.

BACKGROUND: Kisspeptin is an essential regulator of hypothalamic gonadotropin-releasing hormone release and is required for physiological ovulation. Native kisspeptin-54 can induce oocyte maturation during in vitro fertilization treatment, including in women who are at high risk of ovarian hyperstimulation syndrome. MVT-602 is a potent kisspeptin receptor agonist with prospective utility to treat anovulatory disorders by triggering oocyte maturation and ovulation during medically assisted reproduction (MAR). Currently, the endocrine profile of MVT-602 during ovarian stimulation is unreported. OBJECTIVE: To determine the endocrine profile of MVT-602 in the follicular phase of healthy premenopausal women (phase-1 trial), and after minimal ovarian stimulation to more closely reflect the endocrine milieu encountered during MAR (phase-2a trial). DESIGN: Two randomized, placebo-controlled, parallel-group, dose-finding trials. SETTING: Clinical trials unit. PATIENTS: Healthy women aged 18-35 years, either without (phase-1; n = 24), or with ovarian stimulation (phase-2a; n = 75). INTERVENTIONS: Phase-1: single subcutaneous dose of MVT-602 (0.3, 1.0, or 3.0 µg) or placebo, (n = 6 per dose). Phase-2a: single subcutaneous dose of MVT-602 (0.1, 0.3, 1.0, or 3.0 µg; n = 16-17 per dose), triptorelin 0.2 mg (n = 5; active comparator), or placebo (n = 5). MAIN OUTCOME MEASURES: Phase-1: safety/tolerability; pharmacokinetics; and pharmacodynamics (luteinizing hormone [LH] and other reproductive hormones). Phase-2a: safety/tolerability; pharmacokinetics; pharmacodynamics (LH and other reproductive hormones); and time to ovulation assessed by transvaginal ultrasound. RESULTS: In both the trials, MVT-602 was safe and well tolerated across the entire dose range. It was rapidly absorbed and eliminated, with a mean elimination half-life of 1.3-2.2 hours. In the phase-2a trial, LH concentrations increased dose dependently; mean maximum change from baseline of 82.4 IU/L at 24.8 hours was observed after administration of 3 µg MVT-602 and remained >15 IU/L for 33 hours. Time to ovulation after drug administration was 3.3-3.9 days (MVT-602), 3.4 days (triptorelin), and 5.5 days (placebo). Ovulation occurred within 5 days of administration in 100% (3 µg), 88% (1 µg), 82% (0.3 µg), and 75% (0.1 µg), of women after MVT-602, 100% after triptorelin and 60% after placebo. CONCLUSIONS: MVT-602 induces LH concentrations of similar amplitude and duration as the physiological midcycle LH surge with potential utility for induction of oocyte maturation and ovulation during MAR. CLINICAL TRIAL REGISTRATION NUMBER: EUDRA-CT: 2017-003812-38, 2018-001379-20.

Assessment of the effect of the dual orexin receptor antagonist daridorexant on various indices of disease severity in patients with mild to moderate obstructive sleep apnea.

BACKGROUND: The dual orexin receptor antagonist daridorexant did not impact nighttime respiratory function as assessed by the apnea/hypopnea index (AHI) and nocturnal oxygen saturation (SpO2) and improved sleep in patients with mild to moderate obstructive sleep apnea (OSA). These analyses were supplemented with further evaluations of various indices of OSA severity and sleep variables. METHODS: In this randomized, double-blind, placebo-controlled, two-period, crossover study, 50 mg daridorexant or placebo was administered every evening for 5 days to 28 patients with mild to moderate OSA. Treatment differences (daridorexant - placebo) were explored for indices of OSA severity including the number and duration of apneas and hypopneas, mean and lowest nocturnal SpO2, sleep duration during each hour of polysomnography recording, and the number and mean and longest duration of awakenings. RESULTS: After repeated-dose daridorexant, more respiratory events were observed compared to placebo, ie., treatment difference of 16.4 events (90% confidence interval: -0.4, 33.2) which is explained by a longer total sleep time. However, no treatment difference was detected for the longest duration of apneas and hypopneas (1.5 s [-8.3, 11.2] and 8.2 s [-6.6, 23.0], respectively), and lowest SpO2 (0.9% [-0.3, 2.1]). The number of awakenings was similar between daridorexant and placebo while daridorexant shortened the longest duration by 16.2 min (8.5, 23.8). Overall, results were similar after single and repeated dosing for both respiratory and sleep aspects. CONCLUSION: These results suggest safe use of daridorexant in patients with mild to moderate OSA. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/NCT03765294.

Abuse potential assessment of the new dual orexin receptor antagonist daridorexant in recreational sedative drug users as compared to suvorexant and zolpidem.

STUDY OBJECTIVES: Abuse potential properties have been reported for the dual orexin receptor antagonists (DORAs) suvorexant and lemborexant. Daridorexant is a new DORA currently in late-stage clinical development. This randomized, double-blind, double-dummy, placebo- and active-controlled six-period crossover study assessed its abuse potential in healthy recreational sedative drug users (n = 63). METHODS: In each study period, a single, oral, morning dose of either daridorexant (50, 100, and 150 mg), placebo, or active control, i.e. suvorexant (150 mg) or zolpidem (30 mg), was administered. Primary pharmacodynamic (PD) endpoint was the Emax of the drug-liking visual analog scale (VAS) assessed over 24 h. Several secondary subjective and objective PD endpoints were also assessed. RESULTS: Study validity was confirmed based on drug-liking of suvorexant and zolpidem greater than placebo applying a predefined 15-point validity margin (p < 0.0001). Drug-liking VAS Emax (mean; 95% confidence interval) of daridorexant at 50 mg (73.2; 69.0-77.5) was significantly lower compared to suvorexant (80.7; 77.0-84.5) and zolpidem (79.9; 76.2-83.5) (p < 0.001), but similar at 100 mg (79.1; 75.0-83.3) and 150 mg (81.3; 77.7, 84.8). Such dose-related patterns were also observed for most secondary endpoints. At each daridorexant dose, Drug-liking VAS scores were greater than placebo. Both control drugs and daridorexant were safe and the pharmacokinetics of daridorexant was consistent with earlier trials indicating quick absorption and elimination. CONCLUSIONS: In this large, valid human abuse potential study, daridorexant showed dose-related drug-liking among recreational sedative drug users with lower effects at the highest phase-3 dose, and similar effects at higher doses compared to supratherapeutic doses of suvorexant and zolpidem. CLINICAL TRIAL REGISTRATION: Study to Evaluate the Abuse Potential of ACT-541468 in Healthy Recreational Drug Users, https://www.clinicaltrials.gov/ct2/show/NCT03657355?term=ACT-541468&draw=3&rank=18, NCT03657355.

Transition from Syringe to Autoinjector Based on Bridging Pharmacokinetics and Pharmacodynamics of the P2Y12 Receptor Antagonist Selatogrel in Healthy Subjects.

BACKGROUND AND OBJECTIVES: Selatogrel is a potent, reversible, and selective antagonist of the platelet P2Y12 receptor currently developed for the treatment of acute myocardial infarction (AMI). In the completed Phase I/II studies, selatogrel was subcutaneously (s.c.) administered as a lyophilizate-based formulation by syringe by a healthcare professional. In the Phase III study, selatogrel will be self-administered s.c. as a liquid formulation with an autoinjector at the onset of AMI symptoms to shorten treatment delay. This clinical bridging study compared the pharmacokinetics (PK) of selatogrel between the different formulations. METHODS: This was a single-center, randomized, open-label, three-period, cross-over Phase I study in 24 healthy subjects. In each period, a single subcutaneous dose of 16 mg selatogrel was administered as (1) a Phase III liquid formulation by autoinjector (Treatment A), (2) a Phase III liquid formulation by prefilled syringe (Treatment B), or (3) a Phase I/II reconstituted lyophilizate-based formulation by syringe (Treatment C). PK parameters including area under the plasma concentration-time curve from zero to infinity (AUC0-∞), maximum plasma concentration (Cmax), time to reach Cmax(tmax), and terminal half-life (t1/2) were determined using noncompartmental analysis. Pharmacodynamic (PD) parameters were estimated using PK/PD modeling, including the time of first occurrence of inhibition of platelet aggregation (IPA) ≥ 80% (tonset), duration of IPA above 80% (tduration), and responder rate defined as the percentage of subjects with tonset ≤ 30 min and tduration ≥ 3 h. Safety and tolerability were also assessed. RESULTS: Comparing Treatment A to Treatment C, the exposure (AUC0-∞) was bioequivalent with a geometric mean ratio (GMR) (90% confidence interval) of 0.95 (0.92-0.97) within the bioequivalence range (0.80-1.25). Absorption following Treatment A was slightly slower with a tmax occurring approximately 30 min later and a 20% lower Cmax. The autoinjector itself had no impact on the PK of selatogrel, as similar values of Cmax and AUC0-∞ were determined after administration as a Phase III liquid formulation by autoinjector or by prefilled syringe (i.e., GMR [90% confidence interval] of 1.06 [0.97-1.15] and 0.99 [0.96-1.03] for Cmax and AUC0-∞, respectively). PK/PD modeling predicted that the median tonset will occur slightly later for Treatment A (7.2 min) compared to Treatment C (4.2  min), while no relevant differences in tduration and responder rate were estimated between the two treatments. Selatogrel was safe and well tolerated following all three treatments. CONCLUSIONS: PK and simulated PD effects of selatogrel were similar across treatments. CLINICAL TRIAL REGISTRATION: NCT04557280.

Impact of Daridorexant, a Dual Orexin Receptor Antagonist, on Cardiac Repolarization Following Bedtime Dosing: Results from a Thorough QT Study Using Concentration-QT Analysis.

BACKGROUND AND OBJECTIVE: Daridorexant is a new dual orexin receptor antagonist currently in late-stage clinical development for the treatment of insomnia. This randomized, double-blind, placebo-controlled, four-period crossover study investigated the effect of daridorexant at a therapeutic and supratherapeutic dose on QT interval duration. METHODS: Thirty-six healthy subjects received single oral doses of daridorexant (50 mg; 200 mg), moxifloxacin (400 mg; open label), and placebo. All treatments were administered at bedtime to mimic therapeutic practice. The primary analysis was based on linear mixed-effects concentration-QT modelling. Triplicate ECG data were extracted from Holter recordings at baseline and until 24 h post dosing at time points matching those for pharmacokinetic sampling. Plasma concentrations of daridorexant were determined over 24 h. RESULTS: Assay sensitivity was demonstrated based on mean baseline- and placebo-corrected QT interval using Fridericia's formula (ΔΔQTcF) > 5 ms following moxifloxacin administration (p < 0.01). Following daridorexant administration, mean (90% confidence interval, CI) ΔΔQTcF was 1.40 ms (0.48; 2.32 ms) and 1.84 ms (-0.12; 3.79 ms) at the Cmax of 747 ng/mL (50 mg dose) and 1809 ng/mL (200 mg dose), respectively, i.e., the upper bounds of the CIs were < 10 ms defined as threshold of regulatory concern. Lack of relevant QT prolongation was confirmed by secondary by-time point analysis and absence of relevant findings in the categorical outlier analysis. Daridorexant was safe and well tolerated and its pharmacokinetics were consistent with previous data. CONCLUSION: Daridorexant does not impair cardiac repolarization evidenced by absence of relevant QT prolongation at therapeutic and supratherapeutic doses. Clinical Trials Registration ID: NCT04250506.

Effect of the novel dual orexin receptor antagonist daridorexant on night-time respiratory function and sleep in patients with moderate chronic obstructive pulmonary disease.

In patients with chronic obstructive pulmonary disease (COPD), sleep is often fragmented while, conversely, the use of sleep medications is of concern in these patients due to potential impairment of nocturnal breathing. This randomised, double-blind, placebo-controlled, two-period crossover study was conducted to evaluate the effect of the new dual orexin receptor antagonist daridorexant on night-time respiratory function and sleep in patients with moderate COPD. In each period, the highest Phase-III dose of 50 mg daridorexant or placebo was administered once daily in the evening for 5 consecutive days. The primary endpoint was peripheral oxygen saturation (SpO2 ) during total sleep time (TST) after last dosing. Night-time respiratory function and sleep were further evaluated based on the apnea-hypopnea index (AHI), sleep duration, and objective sleep parameters. Pharmacokinetics, safety, and tolerability were also assessed. Primary endpoint analysis revealed no significant mean treatment difference (i.e. daridorexant - placebo) for SpO2 during TST as it was 0.18% (90% confidence interval: -0.21 to 0.57). There was also no difference from placebo for SpO2 during non-rapid eye movement (REM) and REM sleep at Night 5 and after first dosing. The AHI was slightly increased compared to placebo, but not to a clinically meaningful extent. In addition, daridorexant improved objective sleep parameters (i.e. prolonged TST, increased sleep efficiency, and decreased wake after sleep onset), reached expected plasma concentrations, and was safe and well tolerated. In conclusion, single and multiple doses of 50 mg daridorexant do not impair night-time respiratory function and improves sleep in patients with moderate COPD.

A Multipurpose First-in-Human Study With the Novel CXCR7 Antagonist ACT-1004-1239 Using CXCL12 Plasma Concentrations as Target Engagement Biomarker.

The C-X-C chemokine receptor 7 (CXCR7) has evolved as a promising, druggable target mainly in the immunology and oncology fields modulating plasma concentrations of its ligands CXCL11 and CXCL12 through receptor-mediated internalization. This "scavenging" activity creates concentration gradients of these ligands between blood vessels and tissues that drive directional cell migration. This randomized, double-blind, placebo-controlled first-in-human study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of ACT-1004-1239, a first-in-class drug candidate small-molecule CXCR7 antagonist. Food effect and absolute bioavailability assessments were also integrated in this multipurpose study. Healthy male subjects received single ascending oral doses of ACT-1004-1239 (n = 36) or placebo (n = 12). At each of six dose levels (1-200 mg), repeated blood sampling was done over 144 hours for pharmacokinetic/pharmacodynamic assessments using CXCL11 and CXCL12 as biomarkers of target engagement. ACT-1004-1239 was safe and well tolerated up to the highest tested dose of 200 mg. CXCL12 plasma concentrations dose-dependently increased and more than doubled compared with baseline, indicating target engagement, whereas CXCL11 concentrations remained unchanged. An indirect-response pharmacokinetic/pharmacodynamic model well described the relationship between ACT-1004-1239 and CXCL12 concentrations across the full dose range, supporting once-daily dosing for future clinical studies. At doses ≥ 10 mg, time to reach maximum plasma concentration ranged from 1.3 to 3.0 hours and terminal elimination half-life from 17.8 to 23.6 hours. The exposure increase across the dose range was essentially dose-proportional and no relevant food effect on pharmacokinetics was determined. The absolute bioavailability was 53.0% based on radioactivity data after oral vs. intravenous 14 C-radiolabeled microtracer administration of ACT-1004-1239. Overall, these comprehensive data support further clinical development of ACT-1004-1239.

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.

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.

Effect of the new dual orexin receptor antagonist daridorexant on nighttime respiratory function and sleep in patients with mild and moderate obstructive sleep apnea.

In this randomized, double-blind, placebo-controlled, two-period crossover study, the effect of the dual orexin receptor antagonist daridorexant was evaluated on nighttime respiratory function and sleep in 28 patients with mild and moderate obstructive sleep apnea (OSA). In each period, 50 mg daridorexant or placebo was administered every evening for 5 days. The primary endpoint was apnea/hypopnea index (AHI) during total sleep time (TST) after the last dosing. Other endpoints included peripheral oxygen saturation (SpO2), sleep duration, latency to persistent sleep (LPS), wake after sleep onset (WASO), and sleep efficiency index (SEI). Pharmacokinetics, safety, and tolerability were also assessed. The mean treatment difference for AHI during TST (i.e. daridorexant - placebo) after the last dosing was 0.74 events/hour (90% confidence interval [CI]: -1.43, 2.92). The corresponding treatment difference for SpO2 during TST was 0.16% [90% CI: -0.21, 0.53]. Overall, there was no clinically relevant effect of daridorexant on AHI or SpO2-related data after single and repeated dosing irrespective of sleep phase (i.e. rapid eye movement [REM] vs non-REM). Moreover, after single and repeated dosing, daridorexant prolonged TST by 39.6 minutes (90% CI: 16.9, 62.3) and 38.8 minutes (19.7, 57.9), respectively, compared with placebo and favorably modulated other sleep-related endpoints (i.e. increased SEI, decreased WASO, and shortened LPS). It attained expected plasma concentrations and was well tolerated in patients with mild and moderate OSA. These results indicate that single and repeated doses of 50 mg daridorexant do not impair nighttime respiratory function and improve sleep in patients with mild and moderate OSA. Clinical Trial Registration: ClinicalTrials.gov NCT03765294. A study to investigate the effects of ACT-541468 on nighttime respiratory function in patients with mild to moderate obstructive sleep apnea. https://clinicaltrials.gov/ct2/show/ NCT03765294.

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.

A Pooled Analysis of Three Randomized Phase I/IIa Clinical Trials Confirms Absence of a Clinically Relevant Effect on the QTc Interval by Umibecestat.

Umibecestat, an orally active ß-secretase inhibitor, reduces the production of amyloid beta-peptide that accumulates in the brain of patients with Alzheimer's disease. The echocardiogram effects of umibecestat, on QTcF (Fridericia-corrected QT), on PR and QRS and heart rate (HR), were estimated by concentration-effect modeling. Three phase I/II studies with durations up to 3 months, with 372 healthy subjects over a wide age range, including both sexes and 2 ethnicities, were pooled, providing a large data set with good statistical power. No clinically relevant effect on QTcF, PR interval, QRS duration, or HR were observed up to supratherapeutic doses. The upper bound of 90% confidence intervals of the ∆QTcF was below the 10 ms threshold of regulatory concern for all concentrations measured. Prespecified sensitivity analysis confirmed the results in both sexes, in those over and below 60 years, and in Japanese subjects. All conclusions were endorsed by the US Food and Drug Administration (FDA).

Subcutaneous Selatogrel Inhibits Platelet Aggregation in Patients With Acute Myocardial Infarction.

BACKGROUND: Oral P2Y12 receptor antagonists exhibit delayed onset of platelet inhibition in patients with acute myocardial infarction (AMI). Selatogrel is a potent, highly selective, and reversible P2Y12 receptor antagonist with a rapid onset and short duration of action. OBJECTIVES: This study sought to assess inhibition of platelet aggregation following subcutaneous administration of selatogrel in patients with AMI. METHODS: Patients with AMI were randomized to a single subcutaneous dose of selatogrel of 8 or 16 mg. The primary endpoint was response to treatment (P2Y12 reaction units <100; measured by VerifyNow) at 30 min post-dose. Safety was assessed up to 48 h post-injection. RESULTS: Forty-seven patients received selatogrel 8 mg (n = 24) or 16 mg (n = 23) followed by ticagrelor (n = 43) or clopidogrel (n = 1). The proportion of responders 30 min post-dose was 91% (one-sided 97.5% confidence interval [CI]: 80% to 100%) and 96% (97.5% CI: 87% to 100%) with 8 and 16 mg, respectively (p values for responders >85% target; p = 0.142 and p = 0.009, respectively). Response rates were independent from type of AMI presentation, age, or sex. A similar response rate was observed at 15 min (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 91% [97.5% CI: 80% to 100%]), which was sustained at 60 min post-dose (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 96% [97.5% CI: 87% to 100%]). At 15 min, median P2Y12 reaction units was 51 (range: 4 to 208) for 8 mg and 9 (range: 2 to 175) for 16 mg. Selatogrel was well tolerated, without major bleeding complications. CONCLUSIONS: Single-dose subcutaneous administration of selatogrel in patients with AMI was safe and induced a profound, rapid, and dose-related antiplatelet response. (A Medical Research Study to Evaluate the Effects of ACT-246475 in Adults With Heart Attack; NCT03487445, 2018-000765-36 [EudraCT]).

Effect of Rifampin-Mediated OATP1B1 and OATP1B3 Transporter Inhibition on the Pharmacokinetics of the P2Y12 Receptor Antagonist Selatogrel.

In vitro studies have indicated that the P2Y12 receptor antagonist selatogrel is a substrate of organic anion-transporting-polypeptide (OATP)1B1 and OATP1B3 that are known to mediate hepatic uptake. Selatogrel is primarily eliminated via the biliary route. Therefore, the study aim was to investigate the effect of rifampin-mediated OATP1B1 and OATP1B3 inhibition on the pharmacokinetics (PK) of selatogrel. This was a randomized, double-blind, placebo-controlled, two-period, crossover study in 14 healthy subjects. In each period, a single subcutaneous dose of 4 mg selatogrel was administered, either immediately after a single intravenous 30 minutes infusion of 600 mg rifampin or after placebo. Plasma samples were collected for 36 hours and analyzed using a validated liquid chromatography-tandem mass spectrometry method. PK parameters of selatogrel were calculated using noncompartmental analysis. The effect of rifampin was explored based on geometric mean peak plasma concentration (Cmax ) and area under the concentration curve from zero to infinity (AUC0-∞ ) ratios and for time of maximum plasma concentration (Tmax ) by Wilcoxon signed rank test. In addition, the safety and tolerability of the study treatments were evaluated. The geometric mean ratios of Cmax and AUC0-∞ were 1.19 (90% confidence interval (CI) 1.11-1.28) and 1.43 (90% CI 1.36-1.51), respectively, indicating a minor selatogrel exposure increase when administered after an infusion of rifampin compared with placebo. Rifampin administration did not affect terminal half-life (t½ ) or Tmax of selatogrel. All study treatments were safe and well-tolerated. A single dose of 600 mg rifampin, a potent OATP1B1/1B3 inhibitor, did not impact the PK of selatogrel to a clinically relevant extent suggesting that OATP1B1 and OATP1B3 transporters do not play a major role in the elimination of selatogrel.

Absorption, distribution, metabolism, and excretion of cenerimod, a selective S1P1 receptor modulator in healthy subjects.

Cenerimod is a sphingosine-1-phosphate 1 receptor modulator under development for treatment of systemic lupus erythematosus.This single-centre, open-label, single-dose study investigated the mass balance and excretion routes and aimed at identifying and quantifying cenerimod metabolites in plasma, urine, and faeces after oral administration of 2 mg/100 µCi (3.7 MBq) of 14C-cenerimod.Total mean cumulative recovery was 84% of the administered dose (58-100% in faeces and 4.6-12% in urine). In a 0-504 h cross-subject area under the curve plasma pool, cenerimod and two metabolites were detected accounting for 78, 6.0, and 4.9% of total radioactivity, respectively, i.e. no major metabolite was identified in plasma. Cenerimod was only detected in faeces and accounted for 17% of the radioactivity excreted in this matrix. The metabolite M32 was detected in both urine and faeces and represented 23% and 66% of radioactivity excreted in these matrices, respectively. Other metabolites of unknown structure were detected in small amounts. Overall, M32 and cenerimod accounted for 52% and 13%, respectively, of the total radioactivity recovered.Among the excreted metabolites, only the non-enzymatically formed M32 represented more than 25% of total drug-related material. Therefore, no pharmacokinetic drug-drug interaction studies are foreseen.

Pharmacokinetics and Pharmacodynamics of Approved and Investigational P2Y12 Receptor Antagonists.

Coronary artery disease remains the major cause of mortality worldwide. Antiplatelet drugs such as acetylsalicylic acid and P2Y12 receptor antagonists are cornerstone treatments for the prevention of thrombotic events in patients with coronary artery disease. Clopidogrel has long been the gold standard but has major pharmacological limitations such as a slow onset and long duration of effect, as well as weak platelet inhibition with high inter-individual pharmacokinetic and pharmacodynamic variability. There has been a strong need to develop potent P2Y12 receptor antagonists with more favorable pharmacological properties. Prasugrel and ticagrelor are more potent and have a faster onset of action; however, they have shown an increased bleeding risk compared with clopidogrel. Cangrelor is highly potent and has a very rapid onset and offset of effect; however, its indication is limited to P2Y12 antagonist-naïve patients undergoing percutaneous coronary intervention. Two novel P2Y12 receptor antagonists are currently in clinical development, namely vicagrel and selatogrel. Vicagrel is an analog of clopidogrel with enhanced and more efficient formation of its active metabolite. Selatogrel is characterized by a rapid onset of action following subcutaneous administration and developed for early treatment of a suspected acute myocardial infarction. This review article describes the clinical pharmacology profile of marketed P2Y12 receptor antagonists and those under development focusing on pharmacokinetic, pharmacodynamic, and drug-drug interaction liability.

Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes.

AIMS: To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). METHODS AND RESULTS: In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4-11%). CONCLUSIONS: Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.

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.

Absorption, distribution, metabolism and excretion of the P2Y12 receptor antagonist selatogrel after subcutaneous administration in healthy subjects.

The P2Y12 receptor antagonist selatogrel which exhibits rapid inhibition of platelet aggregation following subcutaneous administration is in development for the treatment of acute myocardial infarction.This human ADME study was performed in six healthy male subjects to determine the routes of elimination and to identify/quantify the metabolites of selatogrel at a therapeutically relevant dose of 16 mg [14C]-radiolabelled selatogrel.The median tmax and t1/2 of selatogrel was 0.75 h and 4.7 h, respectively. It was safe and well tolerated based on adverse event, ECG, vital sign and laboratory data.Geometric mean total recovery of [14C]-radioactivity was 94.9% of which 92.5% was recovered in faeces and 2.4% in urine.Selatogrel was the most abundant entity in each matrix. In plasma, no major metabolite was identified. In excreta, the glucuronide M21 (14.7% of radioactivity) and the mono-oxidized A1 (6.2%) were the most abundant metabolites in urine and faeces, respectively.Overall, none of the metabolic pathways contributed to a relevant extent to the overall elimination of selatogrel, i.e. by more than 25% as defined per regulatory guidance. Hence, no pharmacokinetic interaction studies with inhibitors or inducers of drug-metabolizing enzymes are warranted for clinical development of selatogrel.

Impact of the organic cation transporter 2 inhibitor cimetidine on the single-dose pharmacokinetics of the glucosylceramide synthase inhibitor lucerastat in healthy subjects.

PURPOSE: Lucerastat is an orally available glucosylceramide synthase inhibitor with a potential to provide substrate reduction therapy for Fabry patients independent of their α-galactosidase A genotype. In humans, lucerastat is mainly eliminated as unchanged parent compound through renal excretion both by active secretion and passive filtration. In vitro studies indicated that lucerastat is a substrate of human organic cation transporter 2 (OCT2) mainly expressed in the kidney. METHODS: Therefore, this clinical study, conducted in 14 healthy male subjects, investigated the effect of 800 mg twice-daily oral administration of the OCT2 inhibitor cimetidine at steady state on the single-dose pharmacokinetics (PK) of 500 mg lucerastat. The safety and tolerability of lucerastat administered alone and concomitantly with cimetidine were also evaluated. RESULTS: Exposure to lucerastat was slightly higher upon co-administration of cimetidine indicated by geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0-∞) ratio of 1.22 (90% confidence interval [CI] 1.16-1.28). Cimetidine delayed the time to reach maximum lucerastat concentrations (tmax) by 1 h but did not affect its elimination half-life (t½) or maximum plasma concentration (Cmax) as geometric mean ratios were 1.00 (0.91-1.10) and 1.04 (0.92-1.17), respectively, at cimetidine steady state. Lucerastat was safe and well tolerated when given alone and in combination with cimetidine. CONCLUSION: These results indicate that the single-dose PK of lucerastat are not changed to a clinically relevant extent by cimetidine-mediated OCT2 inhibition, allowing the concomitant use of OCT2 inhibitors with lucerastat without any need for dose adjustment. TRIAL REGISTRATION: EudraCT: 2017-003725-14; ClinicalTrials.gov: NCT03380455.