Multiple-ascending doses of ACT-1014-6470, an oral complement factor 5a receptor 1 (C5a1 receptor) antagonist: Tolerability, pharmacokinetics and target engagement.

AIMS: Targeting the complement factor 5a receptor 1 (C5a1 receptor) offers potential to treat various autoimmune diseases. The C5a1 receptor antagonist ACT-1014-6470 was well tolerated in a single-ascending dose study in healthy subjects. This double-blind, randomized, placebo-controlled study aimed to investigate the safety, tolerability, pharmacokinetics (PK) and target engagement of multiple-ascending doses of ACT-1014-6470. METHODS: Per dose level, 10 healthy male and female subjects of nonchildbearing potential (1:1 sex ratio) were enrolled to assess 30, 60 and 120 mg ACT-1014-6470 administered twice daily for 4.5 days under fed conditions. Adverse events, clinical laboratory data, vital signs, electrocardiogram and PK blood samples were collected up to 120 h post last dose and ex vivo stimulated matrix metalloproteinase 9 was quantified as target engagement biomarker. At the 60-mg dose level, PK samples were collected until 8 weeks post last dose. RESULTS: The total adverse event number was 57 and no treatment-related safety pattern was apparent. At steady state, ACT-1014-6470 reached maximum plasma concentrations after 2-3 h and the half-life estimated up to Day 10 was 115-146 h across dose levels. Exposure parameters increased dose-proportionally, steady state was attained between Day 3-5, and ACT-1014-6470 accumulated 2-fold. At the 60-mg dose level, ACT-1014-6470 was quantifiable until 8 weeks after the last dose. Matrix metalloproteinase 9 release was suppressed to endogenous background concentrations up to the last sampling time point, confirming sustained target engagement of ACT-1014-6470. CONCLUSION: The compound was generally safe and well tolerated at all dose levels, warranting further clinical investigations.

First-in-human study with ACT-1014-6470, a novel oral complement factor 5a receptor 1 (C5aR1) antagonist, supported by pharmacokinetic predictions from animals to patients.

Aberrantly controlled activation of the complement system contributes to inflammatory diseases. Safety, tolerability, and pharmacokinetics of single-ascending doses of ACT-1014-6470, a novel orally available complement factor 5a receptor 1 antagonist, were assessed in a randomized, double-blind, placebo-controlled Phase 1 study. Six ACT-1014-6470 doses (0.5-200 mg) were selected after predictions from a Complex Dedrick plot. In each group, ACT-1014-6470 or matching placebo was administered to six and two healthy male individuals under fed conditions, respectively, including a cross-over part with 10 mg administered also under fasted conditions. Pharmacokinetic blood sampling and safety assessments (adverse events, clinical laboratory, vital signs, 12-lead electrocardiogram, and QT telemetry) were performed. ACT-1014-6470 was absorbed with a time to maximum plasma concentration (tmax ) of 3 h across dose levels and eliminated with a terminal half-life of 30-46 h at doses ≥ 2.5 mg. Exposure increased approximately dose proportionally. Under fed compared to fasted conditions, ACT-1014-6470 exposure was 2.2-fold higher and tmax delayed by 1.5 h. Pharmacokinetic modelling predicted that twice-daily oral administration is warranted in a subsequent multiple-dose study. No clinically relevant findings were observed in safety assessments. ACT-1014-6470 was well tolerated at all doses and could provide a novel therapy with more patient-friendly administration route compared to biologicals.

Pharmacokinetic and pharmacodynamic interactions between daridorexant, a dual orexin receptor antagonist, and citalopram in healthy subjects.

Daridorexant (ACT-541468) is a new dual orexin receptor antagonist being evaluated for the treatment of insomnia, which is a common comorbidity of depression and anxiety. Therefore, daridorexant is likely to be administered concomitantly with agents (e.g., citalopram) used to treat these disorders. In this single-centre, single-blind, randomized, placebo-controlled, sequential design Phase 1 study with the inclusion of two double-blind crossover parts, the pharmacokinetic (PK; blood sampling at regular intervals) and pharmacodynamic (PD; battery of objective and subjective PD tests performed at regular intervals) interactions between daridorexant (50 mg) and citalopram (20 mg, single dose and at steady state) as well as the safety/tolerability in healthy subjects were investigated. There were no relevant effects of citalopram (single dose/steady state) on daridorexant exposure and vice versa. PD variables measured after morning administration of daridorexant alone showed effects consistent with a sleep-promoting compound. Only co-administration of daridorexant with citalopram at steady state led to relevant changes in objective (unstable tracking) and subjective (visual analogue scale alertness and Karolinska Sleepiness Scale) PD endpoints compared to daridorexant alone. No serious or severe adverse events were reported, while no clinically relevant treatment-emergent effects on ECG parameters, clinical laboratory, or vital signs were observed. In conclusion, the co-administration of daridorexant and citalopram lead to only minor changes in PK parameters, while performance of PD assessments following co-administration were mainly driven by the expected central nervous system effects of daridorexant. Doses up to 50 mg daridorexant can be safely co-administered with citalopram.

Multiple-dose clinical pharmacology of the selective orexin-1 receptor antagonist ACT-539313.

AIMS: Compounds that selectively target orexin-1 receptors may be beneficial for the treatment of various disorders. The role of selective orexin-1 receptor antagonists (1-SORAs) in addictive behavior and stress/anxiety-related disturbances has been demonstrated in animals. ACT-539313, an orally active, potent 1-SORA, has been assessed in a clinical single-ascending dose study and exhibited good safety and tolerability. In the two reported studies on ACT-539313, multiple-dose pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability were investigated and in a proof-of-mechanism study a CO2 challenge was applied as pharmacological model for induction of anxiety and panic symptoms (sequential inhalation of air, 7.5% CO2, and 35% CO2). METHODS: Two double-blind, placebo-controlled, randomized, multiple-dose studies included 58 healthy male and female subjects. In Study 1, multiple-ascending oral doses of 30, 100, and 200 mg twice daily (b.i.d.) ACT-539313 were investigated in 3 dose groups of 8 or 12 subjects (of whom 2 received placebo per dose group). Study 2 was conducted as a randomized two-way crossover design, enrolling 21 male and 9 female subjects who received 200 mg ACT-539313 or matching placebo b.i.d. for 2.5 days followed by a CO2 challenge, with a washout period in between. PK, PD (objective and subjective measures of sedation, alertness, effects on central nervous system (CNS), and anxiety/panic symptoms), safety, and tolerability were assessed. RESULTS: At steady state, ACT-539313 was rapidly absorbed with a median time to maximum plasma concentration of 1.8-2.3 h and eliminated with a mean half-life of 3.8-6.5 h. Overall exposure increased dose-proportionally. In Study 1, PD effects confirmed activity of ACT-539313 on the CNS, without consistent or marked effects of sedation, reduced alertness or visuo-motor impairment. In the CO2 challenge, cortisol concentrations were lower during initial air inhalation after treatment with ACT-539313 compared to placebo, while no difference was detected after CO2 inhalation. Trends for lower scores in subjective anxiety assessments were observed for ACT-539313. Besides reports of stress related to the challenge, the most frequently reported adverse events were somnolence and headache. No clinically relevant effects in other safety assessments were observed. CONCLUSIONS: Multiple-dose administration of ACT-539313 was safe and well tolerated up to multiple doses of 200 mg b.i.d. The drug's PK properties as well as the pattern of a decrease in stress-related symptoms after the CO2 challenge support further investigations of ACT-539313.

First-in-human study with ACT-539313, a novel selective orexin-1 receptor antagonist.

AIMS: The orexin system is involved in anxiety behaviour and corresponding physiological reactions and constitutes a target for treatment of anxiety disorders. ACT-539313 is a potent, selective orexin-1 receptor antagonist being developed for the treatment of anxiety disorders. This first-in-human study investigated its single-dose pharmacokinetics (PK) including food effect, pharmacodynamics (PD), safety and tolerability. METHODS: This double-blind, placebo-controlled, randomized study included 40 healthy male subjects. Ascending oral doses of 10-400 mg ACT-539313 were investigated in 5 dose groups of 8 subjects (of whom 2 received placebo per dose group). At 100 mg, subjects received ACT-539313 in fasted and fed conditions in a fixed sequential design. PK, PD (objective and subjective measures of sedation and effects on central nervous system), safety and tolerability were assessed. RESULTS: In fasted conditions, ACT-539313 was rapidly absorbed (median time to maximum plasma concentration [Cmax ] 0.7-3.5 h) and cleared from plasma with a mean terminal half-life of 3.3-5.7 h across dose levels. A 1.63-fold (90% confidence interval: 1.26-2.11) increase in Cmax and no change in area under the concentration-time curve extrapolated to infinity was observed under fed compared to fasted conditions. No relevant PD signals were detected except for a trend of reduced saccadic peak velocity around time to Cmax . The most commonly reported adverse events were somnolence and headache. All adverse events were transient and of mild or moderate intensity. No treatment-related effects on vital signs, clinical laboratory or 12-lead electrocardiogram were observed. CONCLUSIONS: ACT-539313 exhibits good safety and tolerability at single doses of up to and including 400 mg that warrant further investigations.

Multiple-Ascending Dose Study in Healthy Subjects to Assess the Pharmacokinetics, Tolerability, and CYP3A4 Interaction Potential of the T-Type Calcium Channel Blocker ACT-709478, A Potential New Antiepileptic Drug.

BACKGROUND: ACT-709478 is a selective, orally available T-type calcium channel blocker being studied as a potential new treatment in epilepsy. ACT-709478 had previously been investigated in a single-ascending dose study up to a dose of 400 mg. OBJECTIVES: The aim of this study was to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of ACT-709478. In addition, the drug-drug interaction potential of multiple doses of ACT-709478 with the cytochrome P450 3A4 substrate midazolam was investigated. METHODS: This double-blind, placebo-controlled, randomized study included 46 healthy male and female subjects. Ascending multiple oral doses of ACT-709478 were administered to 10 (cohorts 1-2) or 12 (cohorts 3-4) subjects (two taking placebo per cohort). In cohorts 1-2, 30 or 10 mg ACT-709478 was administered once daily for 12 days. An up-titration regimen was used in cohorts 3-4 with administration of 10, 30, and 60 mg for 7 days each in both cohorts and an additional dose level of 100 mg ACT-709478 once daily for 8 days in cohort 4. Single doses of midazolam were administered at baseline and concomitantly to 60 mg and 100 mg ACT-709478 in cohort 4. Blood sampling for pharmacokinetic evaluations and safety assessments (clinical laboratory, vital signs, adverse events, and electrocardiogram) were performed regularly. Holter electrocardiograms were recorded at baseline and for 24 h at steady state and central nervous system effects were assessed with pharmacodynamic tests at baseline and steady state. RESULTS: ACT-709478 was absorbed with a time to reach the maximum plasma concentration of 3.5-4.0 h and eliminated with a half-life of 45-53 h. Steady state was reached after 5-7 days of dosing and exposure increased dose-proportionally. An accumulation index of approximately three fold was observed in cohorts 1 and 2. Exposure to midazolam was lower upon concomitant administration of 60 and 100 mg ACT-709478 compared to midazolam alone while the half-life and time to reach the maximum plasma concentration of midazolam remained unchanged, suggesting a weak induction at the gastrointestinal but not hepatic level. Pharmacokinetic parameters of 1-hydroxymidazolam were not affected by ACT-709478 administration. The most frequent adverse events were dizziness, somnolence, and headache. A tolerability signal was detected in cohort 1 (30 mg once daily); therefore, the dose was decreased to 10 mg once daily in cohort 2. The subsequently established up-titration regimen, starting with 10 mg once daily, considerably improved tolerability. Multiple doses up to 100 mg once daily were well tolerated. No treatment-related effects were detected on vital signs, clinical laboratory tests, Holter electrocardiogram variables, or in the pharmacodynamic tests. CONCLUSIONS: ACT-709478 exhibits good tolerability up to 100 mg once daily using an up-titration regimen and pharmacokinetic properties that support further clinical investigations. A weak induction of gastrointestinal cytochrome P450 3A4 activity was observed, unlikely to be of clinical relevance. CLINICALTRIALS. GOV IDENTIFIER: NCT03165097.

Novel 1 L polyethylene glycol-based bowel preparation (NER1006): proof of concept assessment versus standard 2 L polyethylene glycol with ascorbate - a randomized, parallel group, phase 2, colonoscopist-blinded trial.

BACKGROUND: Colonoscopy requires colon cleansing. For this, many polyethylene glycol (PEG)-based preparations still require a high preparation-volume intake. Using an increased osmotic load with ascorbate (Asc), five new low-volume PEG-based bowel preparations (LVPEG) were tested for clinical proof of concept. METHODS: This two-part, open-label study examined preparation-volumes of 1-1.25 L and total required fluid volumes of 2-3 L. Part 1, in healthy volunteers, used mean cumulative 24-h stool weight (target > 2750 g) to identify a lead candidate. Part 2 was endoscopist-blinded: patients undergoing screening colonoscopy were randomized before treatment with the selected lead, one of two variants of it, or the control 2 L PEG + Asc. Two primary endpoints were used for proof of concept demonstration: mean 24-h stool weight and bowel cleansing success (Harefield Cleansing Scale). RESULTS: A total of 120 subjects (30 per group) were enrolled/randomized 1:1:1:1 (max 40:60 gender ratio) per completed Part. In Part 1, LVPEG-3 achieved the largest mean stool weight (3399 g: P < 0.0001 vs target) and was selected for Part 2. In Part 2, stool weights exceeded the target, notably for LVPEG-4 (3215 g: P < 0.001), which achieved 100% cleansing success after a total required fluid intake of 2 L. The control achieved 90% cleansing success. Adverse events were few, gastrointestinal in nature and similar between groups. CONCLUSIONS: LVPEG-4 achieved a clinically useful combination of cleansing, safety/tolerability and low consumption volume: 1 L preparation + 1 L required additional fluid. Named NER1006, LVPEG-4 demonstrated clinical proof of concept and warrants further investigation. TRIAL REGISTRATION: October 2012. Identifier: NCT01714466 . EudraCT: 2012-003052-37 The trial was prospectively registered.

First-in-man study of ACT-709478, a novel selective triple T-type calcium channel blocker.

OBJECTIVE: Increased activity of T-type Ca2+ channels is linked to idiopathic generalized epilepsies, thus blocking these channels may be a new treatment option. ACT-709478 is an orally available triple T-type Ca2+ channel blocker. The aim of this first-in-man study was to investigate the pharmacokinetics, pharmacodynamics, tolerability, and safety of single doses of ACT-709478 in healthy subjects. METHODS: This double-blind, placebo-controlled, randomized study included 65 healthy male subjects. Ascending single oral doses of 1-400 mg ACT-709478 or placebo were administered to sequential groups of eight subjects (6 on active, 2 on placebo). Effect of food was tested in a crossover part at 60 mg. Blood and saliva sampling for pharmacokinetic evaluations and safety assessments was performed regularly. Effects on the central nervous system were assessed with a battery of pharmacodynamic tests. RESULTS: The maximum plasma concentration (Cmax ) was reached within 3 to 4 hours (≤60 mg) and within 20 to 28 hours (>60 mg), and across all dose levels the terminal half-life (95% confidence interval) ranged from 36 (29-45) to 43 (22-86) hours. Multiple peaks were observed and Cmax and area under the plasma concentration-time curve (AUC)0-∞ increased in a less than dose-proportional manner. A 1.6-fold increase in Cmax and no change in AUC0-∞ was observed in fed compared to fasted conditions. A significant correlation (P < 0.0001) between plasma and saliva concentrations was established using linear regression. All adverse events were transient and of mild or moderate intensity. No treatment-related effects on vital signs, clinical laboratory, telemetry, or electrocardiography were detected. The results of pharmacodynamic tests did not show relevant mean changes compared to baseline or placebo. SIGNIFICANCE: ACT-709478 exhibits good tolerability and safety after single-dose administration and its pharmacokinetic and pharmacodynamic properties warrant further investigations.