Pharmacokinetics, pharmacodynamics and safety of the novel C-X-C chemokine receptor 3 antagonist ACT-777991: Results from the first-in-human study in healthy adults.

AIMS: The C-X-C chemokine receptor 3 (CXCR3) axis is highly upregulated in the tissue of patients with type 1 diabetes. Antagonizing CXCR3 may reduce the migration of CXCR3-expressing cells to the pancreas. The pharmacokinetics (PKs), target engagement (TE) (inhibition of CXCR3 internalization) and safety of single- and multiple-ascending doses (SADs and MADs) of ACT-777991, a novel orally available potent CXCR3 antagonist, were assessed in a double-blind, randomized, placebo-controlled phase 1 study. METHODS: Doses up to 100 mg (SAD part) and 40 mg twice daily (MAD part) were investigated in a total of 70 male and female healthy participants. Food effect was integrated as an SAD subpart. PK, TE, safety and tolerability data were collected up to 4 days after (last) dosing. RESULTS: In both SAD and MAD parts, ACT-777991 was rapidly absorbed with a time to reach maximum concentration between 0.5 and 1.5 h post dose, followed by a biphasic disposition with a terminal half-life between 9.7 and 10.3 h. Increase in exposure and maximum concentration of ACT-777991 were dose-proportional. Steady state was reached after 48 h with minimal accumulation. The rate but not the extent of absorption was modified by food intake. A dose-dependent TE was demonstrated in both SAD and MAD parts. ACT-777991 was well tolerated. Neither a treatment-related pattern nor a dose-response relationship was determined for adverse events or any safety variable. No QT prolongation liability of regulatory concern was detected. CONCLUSIONS: In this first-in-human study, ACT-777991 showed good tolerability for all doses tested and a PK and TE profile suitable for further clinical development.

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.

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.

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.

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.

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.

Interaction potential of the dual orexin receptor antagonist ACT-541468 with CYP3A4 and food: results from two interaction studies.

PURPOSE: ACT-541468 is a novel dual orexin receptor antagonist (DORA) under development for the treatment of insomnia. In vitro studies suggested a significant role of CYP3A4 in ACT-541468 metabolism and an impact on CYP3A4 activity. METHODS: Subsequently, two clinical cross-over studies investigated the victim (n = 14 healthy subjects) and perpetrator (n = 20) potential of 25 mg ACT-541468 with respect to CYP3A4. The effect of food intake on the pharmacokinetics of ACT-541468 was also investigated. RESULTS: Moderate CYP3A4 inhibition by diltiazem (240 mg/day) increased the Cmax and AUC0-∞ of ACT-541468 by 1.4-fold (90% confidence interval (CI): 1.2-1.6) and 2.4-fold (90% CI: 2.0-2.8), respectively, and prolonged t½ by 80% (90% CI: 60-90) without affecting tmax. Single- and multiple-dose administration of 25 mg ACT-541468 had no impact on the pharmacokinetics of the sensitive substrate midazolam and its main metabolite 1-hydroxy midazolam indicated by 90% CI of the geometric mean ratios of Cmax and AUC within bioequivalence criteria and by an unchanged tmax. After a high-fat high-calorie breakfast, the pharmacokinetic profile of 25 mg ACT-541468 showed a decrease of Cmax by 24% (90% CI: 17-31) and a delay of tmax by approximately 2 h (90% CI: 1.4-2.4), whereas t½ and AUC0-24 remained essentially unchanged. ACT-541468 given alone or in combination with diltiazem, midazolam, or food was safe and well tolerated. CONCLUSIONS: Overall, ACT-541468 has been determined as CYP3A4 substrate but without any perpetrator drug-drug interaction potential regarding CYP3A4 in humans. Food affected ACT-541468 absorption without modifying overall exposure.

Pineal clock gene oscillation is disturbed in Alzheimer's disease, due to functional disconnection from the "master clock".

The suprachiasmatic nucleus (SCN) is the "master clock" of the mammalian brain. It coordinates the peripheral clocks in the body, including the pineal clock that receives SCN input via a multisynaptic noradrenergic pathway. Rhythmic pineal melatonin production is disrupted in Alzheimer's disease (AD). Here we show that the clock genes hBmal1, hCry1, and hPer1 were rhythmically expressed in the pineal of controls (Braak 0). Moreover, hPer1 and hbeta1-adrenergic receptor (hbeta1-ADR) mRNA were positively correlated and showed a similar daily pattern. In contrast, in both preclinical (Braak I-II) and clinical AD patients (Braak V-VI), the rhythmic expression of clock genes was lost as well as the correlation between hPer1 and hbeta1-ADR mRNA. Intriguingly, hCry1 mRNA was increased in clinical AD. These changes are probably due to a disruption of the SCN control, as they were mirrored in the rat pineal deprived of SCN control. Indeed, a functional disruption of the SCN was observed from the earliest AD stages onward, as shown by decreased vasopressin mRNA, a clock-controlled major output of the SCN. Thus, a functional disconnection between the SCN and the pineal from the earliest AD stage onward could account for the pineal clock gene changes and underlie the circadian rhythm disturbances in AD.

Environmental control and adrenergic regulation of pineal activity in the diurnal tropical rodent, Arvicanthis ansorgei.

Like nocturnal rodents, the diurnal tropical rodent Arvicanthis ansorgei shows a daily rhythm in pineal melatonin content. Seasonal and photoperiodic variations in the biosynthetic activity of the pineal gland: arylalkylamine-N-acetyltransferase (AA-NAT), hydroxyindole-O-methyltransferase (HIOMT) activities and melatonin content were measured in male and female A. ansorgei captured near Samaya, Mali, and kept either under artificial laboratory photoperiods [light-dark (LD) cycles: LD 14:10, LD 12:12 or LD 10:14 or caught in the field in Mali and killed at four different times of the year (January, April, June and November). Under artificial photoperiod, the duration of the nocturnal peak of AA-NAT activity and melatonin content increased with the duration of the dark period while the amplitude did not significantly change. In the field, annual variations in the amplitude of the nocturnal melatonin peak were observed with a maximum in April (highest temperature, low humidity and no grass availability, only seeds) and a minimum in November (high humidity, maximum green grass availability). The variations in the amplitude of the melatonin peak were not correlated with changes in AA-NAT HIOMT activities, suggesting that seasonal variations in the amplitude of the melatonin peak are not driven by these enzymes. Daytime injections of the beta-adrenergic agonist, isoproterenol, stimulated melatonin synthesis in January, April and June, but not in November. The annual differences in the amplitude of the melatonin peak as well as the seasonal differences in the response to an adrenergic stimulation suggest that environmental factors other than photoperiod, such as temperature, humidity and consequent food availability, could be important in the regulation of the annual variations in the pineal biosynthetic activity in this species.