A Study to Evaluate ACT-132577 in Healthy Subjects and in People With Severe Kidney Disease

• ACT-132577 (Drug), also known as Aprocitentan: Capsule

Primary outcomes

• Maximum plasma concentration (Cmax) of ACT-132577 [From baseline to up to 16 days]: Cmax of ACT-132577 will be derived by non-compartmental analysis of the plasma concentration-time profiles
• Area under the plasma concentration-time curves during a dosing interval [AUC(0-t)] of ACT-132577 [From baseline to up to 16 days]: AUC(0-T) of ACT-132577 will be derived by non-compartmental analysis of the plasma concentration-time profiles
• Area under the plasma concentration-time curves from time 0 to inf [AUC(0-inf)] [From baseline to up to 16 days]: AUC(0-inf) of ACT-132577 will be derived by non-compartmental analysis of the plasma concentration-time profiles

Secondary outcomes

• Time to reach Cmax (tmax) of ACT-132577 [From baseline to up to 16 days]: tmax of ACT-132577 will be derived by non-compartmental analysis of the plasma concentration-time profiles
• Terminal half-life [t(1/2)] [From baseline to up to 16 days]: t1/2 of ACT-132577 will be derived by non-compartmental analysis of the plasma concentration-time profiles
• Incidence of treatment-emergent adverse events [From baseline to up to 16 days]: The percentage of subjects with treatment-emergent adverse events will be reported
• Incidence of adverse events leading to premature discontinuation of study treatment [From baseline to up to 16 days]: The number of subjects who prematurely discontinued the study treatment due to an adverse event will be reported
• Incidence of any clinical relevant findings in ECG variables [From baseline to up to 16 days]: The number of subjects with any treatment-emergent electrocardiogram (ECG) abnormalities will be reported

Sex: All, ages: 18 Years to 65 Years, accepts healthy volunteers

Inclusion Criteria:

ALL SUBJECTS:

* Signed informed consent in the local language prior to any study-mandated procedure;
* Male/female aged 18 to 65 years (inclusive) at screening;
* Body mass index of 18.0 to 32.0 kg/m2 (inclusive) at screening. Body weight at least 50 kg;
* Women of childbearing potential must have a negative serum pregnancy test and use reliable birth controls up to 30 days after the end of study treatment.

HEALTHY SUBJECTS:

* Normal renal function confirmed by the estimated glomerular filtration rate (eGFR) determined at screening;
* Healthy on the basis of physical examination, cardiovascular assessments and laboratory tests.

SEVERE RENAL FUNCTION IMPAIRMENT SUBJECTS:

\- Severe renal function impairment is defined by eGFR estimated at screening between 15 mL/min/1.73 m2 and 29 mL/min/1.73 m2 (inclusive).

Exclusion Criteria:

ALL SUBJECTS:

* Pregnant or lactating women;
* Known hypersensitivity to ACT-132577 or drugs of the same class, or any of their excipients;
* Known hypersensitivity or allergy to natural rubber latex;
* Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol.

SEVERE RENAL FUNCTION IMPAIRMENT SUBJECTS:

* End-stage renal disease that requires dialysis;
* Hemoglobin concentration < 9 g/dL;
* History of severe renal stenosis;
* Serum potassium concentration > 5.5 mmol/L;
* Presence of severe cardiac disease;
* History of clinically relevant bleeding disorder;
* Presence of any organ disorder, with the exception of renal function impairment, or use of any medication which might interfere with the pharmacokinetics of ACT-132577;
* Known life-threatening disease with a life expectancy of less than 1 year;
* Presence of unstable diabetes mellitus.

• Sidharta PN, Ulc I, Dingemanse J. Single-Dose Pharmacokinetics and Tolerability of Aprocitentan, a Dual Endothelin Receptor Antagonist, in Subjects with Severe Renal Function Impairment. Clin Drug Investig. 2019 Nov;39(11):1117-1123. doi: 10.1007/s40261-019-00837-x. PMID 31435905

• Clinical Trials, Study director, Idorsia Pharmaceuticals Ltd.

NIH grants: 2016