CIN-102 is a deuterated form of domperidone in development for the treatment of acute, recurrent gastroparesis. This thorough QT study assessed the effects of CIN-102 on cardiac repolarization in 62 healthy volunteers. In this 4-period randomized crossover study, participants were administered single doses of 30-mg CIN-102 (representing therapeutic exposures), 100-mg CIN-102 (representing supratherapeutic exposures), placebo, and moxifloxacin (positive control). Continuous 12-lead electrocardiograms (ECGs) and time-matched blood samples were collected to determine plasma levels of deuterated domperidone and its major metabolites. The primary endpoint was placebo-corrected change-from-baseline QTc corrected by Fridericia's formula (ΔΔQTcF). By-time-point and concentration-QTc analyses excluded an effect on ΔΔQTcF exceeding 10 ms for both doses of CIN-102 at all time points up to deuterated domperidone plasma concentrations of ≈92  ng/mL (≈6 times the therapeutic steady-state concentration). There were no clinically relevant effects of CIN-102 on heart rate or cardiac conduction, and no deaths or serious adverse events occurred. This thorough QT study demonstrated that at doses producing therapeutic and supratherapeutic exposures, CIN-102 does not have a clinically meaningful effect on ECG parameters, including QT interval. This modified formulation of domperidone provides a potential gastroparesis treatment while decreasing the risk of QT prolongation associated with the traditional formulation of domperidone.

Baxdrostat is a selective small-molecule aldosterone synthase inhibitor in development for treatment of hypertension and chronic kidney disease. This phase 1, open-label, parallel-group study assessed the safety and pharmacokinetics (PK) of baxdrostat in participants with varying degrees of renal function. Participants were enrolled into control (estimated glomerular filtration rate [eGFR] ≥60 mL/min), moderate to severe renal impairment (eGFR 15-59 mL/min), or kidney failure (eGFR <15 mL/min) groups and received a single 10-mg baxdrostat dose followed by 7 days of inpatient PK blood and urine sampling. Safety was assessed by adverse events, clinical laboratory evaluations, vital signs, physical examinations, and electrocardiograms (ECGs). Thirty-2 participants completed the study. There were no deaths and only 1 mild drug-related adverse event (diarrhea). No clinically meaningful changes in laboratory values, vital signs, physical examinations, or ECGs occurred. Plasma concentration-time curves of baxdrostat were similar among all groups. Urine PK parameters were similar (approximately 12% excreted) in the moderate to severe renal impairment and control groups. Inadequate urine production in the kidney failure group resulted in minimal urinary baxdrostat excretion. Renal impairment had no significant impact on systemic exposure or clearance of baxdrostat, suggesting that dose adjustment due to PK differences in patients with kidney disease is unnecessary.

Baxdrostat is a selective small-molecule aldosterone synthase inhibitor in development for treatment of hypertension and chronic kidney disease. This phase 1, open-label, parallel-group study assessed the safety and pharmacokinetics (PK) of baxdrostat in participants with varying degrees of renal function. Participants were enrolled into control (estimated glomerular filtration rate [eGFR] >= 60 mL/min), moderate to severe renal impairment (eGFR 15-59 mL/min), or kidney failure (eGFR <15 mL/min) groups and received a single 10-mg baxdrostat dose followed by 7 days of inpatient PK blood and urine sampling. Safety was assessed by adverse events, clinical laboratory evaluations, vital signs, physical examinations, and electrocardiograms (ECGs). Thirty-2 participants completed the study. There were no deaths and only 1 mild drug-related adverse event (diarrhea). No clinically meaningful changes in laboratory values, vital signs, physical examinations, or ECGs occurred. Plasma concentration-time curves of baxdrostat were similar among all groups. Urine PK parameters were similar (approximately 12% excreted) in the moderate to severe renal impairment and control groups. Inadequate urine production in the kidney failure group resulted in minimal urinary baxdrostat excretion. Renal impairment had no significant impact on systemic exposure or clearance of baxdrostat, suggesting that dose adjustment due to PK differences in patients with kidney disease is unnecessary.

Due to the high comorbidity of diabetes and hypertension, co-administration of metformin with anti-hypertensive drugs is likely. Baxdrostat is an aldosterone synthase inhibitor in development for the potential treatment of hypertension. In vitro data indicated that baxdrostat inhibits the multidrug and toxin extrusion 1 (MATE1) and MATE2-K renal transporters. Metformin is a MATE substrate, so this study assessed potential effects of baxdrostat on the pharmacokinetics of metformin.Twenty-seven healthy volunteers received 1000 mg metformin alone and 1000 mg metformin in the presence of 10 mg baxdrostat in a randomized, crossover manner. Each treatment was separated by 10 or more days. Blood and urine samples were collected over a 3-day period after each treatment to measure plasma and urine concentrations of metformin. Safety was assessed by adverse events (AEs), physical examinations, electrocardiograms, vital signs, and clinical laboratory evaluations.There were no deaths, serious AEs, discontinuations due to treatment-emergent AEs, or noteworthy increases in AEs with either treatment, indicating that metformin and baxdrostat were well-tolerated when co-administered. Baxdrostat did not significantly affect plasma concentrations or renal clearance of metformin.The results of this study suggest that diabetic patients with hypertension receiving both metformin and baxdrostat are unlikely to require dose adjustment.ClinicalTrials.gov identifier no. NCT05526690.

Objective: To evaluate the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of the highly potent, selective small-molecule inhibitor of aldosterone synthase (CIN-107) in a randomized, double-blind, placebo-controlled phase 1 study in healthy volunteers. Design and methods: Subjects were randomized into 5 cohorts to receive CIN-107 or placebo once daily for 10 days. Cohorts 1 and 2 were placed on a low salt diet to stimulate aldosterone production and were administered 2.5 or 5.0 mg oral CIN-107, respectively. They also underwent an adrenocorticotropic hormone challenge to increase aldosterone and cortisol levels to evaluate the specificity of CIN-107 for aldosterone synthase. Cohorts 3, 4, and 5 were placed on a normal salt diet and were administered 1.5, 2.5, or 0.5 mg oral CIN-107, respectively. Blood samples were collected prior to and after dosing on days 1 and 10 for measurement of plasma CIN-107 concentrations to characterize single-dose and steady-state pharmacokinetics. Pharmacodynamic measurements included aldosterone, cortisol, and electrolytes. Safety assessments included physical examination, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations, including renal function. Results: Fifty-four subjects completed the study. There were no deaths, serious adverse events, or discontinuations due to treatment-emergent adverse events (TEAEs). All TEAEs in subjects receiving CIN-107 were mild in severity. Plasma concentrations of CIN-107 increased proportionally with ascending doses. CIN-107 was rapidly absorbed, with peak concentrations observed within 4 hours after dosing. Mean half-life was 26–31 hours. A dose-dependent reduction of plasma aldosterone occurred with CIN-107 doses ≧1.5 mg, regardless of normal or low salt diet. Decreases in plasma aldosterone started on Day 1 and were sustained, with levels reduced by approximately 51–73% on Day 10 (Figure 1). CIN-107 had no meaningful impact on plasma cortisol levels. The urine sodium:potassium ratio increased on Day 1 and diminished by Day 10, an effect mediated by greater elimination of sodium on Day 1 compared to Day 10. A mild increase in the blood urea nitrogen:creatinine ratio and a mild reduction in the glomerular filtration rate (<15%) suggest that CIN-107 produced a mild diuretic effect. Conclusions: CIN-107 was safe and well tolerated and resulted in dose-dependent increases in plasma CIN-107 with a half-life that supports once-daily dosing. The dose-dependent decrease in plasma aldosterone, transient increase in sodium excretion, and mild diuretic effect support continued study in ongoing phase 2 clinical trials evaluating the efficacy and safety of CIN-107 for treatment-resistant or uncontrolled hypertension and primary aldosteronism.

Baxdrostat is a selective inhibitor of aldosterone synthase designed for the treatment of disorders associated with elevated aldosterone. This study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of baxdrostat in healthy volunteers. Subjects were randomized to receive oral baxdrostat (0.5, 1.5, 2.5, or 5.0 mg) or placebo once daily for 10 days and were placed on either a low-salt or normal-salt diet for the duration of the study. Blood samples were collected before and after dosing on days 1 and 10 to characterize pharmacokinetics and pharmacodynamics. Safety was assessed by adverse events, physical examinations, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations. Fifty-four subjects completed the study. There were no deaths or serious adverse events, and all treatment-emergent adverse events in subjects receiving baxdrostat were mild in severity. Plasma levels of baxdrostat increased proportionally with ascending doses, with peak concentrations observed within 4 h after dosing and a mean half-life of 26 to 31 h. A dose-dependent reduction of plasma aldosterone occurred with baxdrostat doses ≥1.5 mg, regardless of diet. Decreases in plasma aldosterone were sustained, with levels reduced by approximately 51 to 73% on day 10. Baxdrostat had no meaningful impact on plasma cortisol levels and resulted in mild dose-dependent decreases in plasma sodium levels and increases in potassium levels. Baxdrostat was safe and well tolerated with a half-life that supports once-daily dosing. The dose-dependent reduction in plasma aldosterone and lack of effect on cortisol demonstrate the selective blockade of aldosterone synthase.

Abstract Background CIN-107 is a highly potent, selective, and competitive small molecule inhibitor of aldosterone synthase that is a potential treatment for disorders associated with elevated aldosterone levels, including hypertension and primary aldosteronism. This randomized, double-blind, placebo-controlled phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of multiple ascending doses of CIN-107 in healthy volunteers. Methods Subjects were randomized into 5 cohorts to receive CIN-107 or placebo once daily for 10 days. Cohorts 1 and 2 were placed on a low salt diet to stimulate aldosterone production and were administered 2.5 or 5.0 mg oral CIN-107, respectively. Cohorts 1 and 2 also underwent an adrenocorticotropic hormone (ACTH) challenge to increase aldosterone and cortisol levels to evaluate the specificity of CIN-107 for targeting aldosterone synthase. Cohorts 3, 4, and 5 were placed on a normal salt diet and were administered 1.5, 2.5, or 0.5 mg oral CIN-107, respectively. Blood samples were collected prior to and after dosing on days 1 and 10 for measurement of plasma CIN-107 concentrations to characterize single-dose and steady-state pharmacokinetics. Pharmacodynamic measurements included plasma aldosterone, cortisol, and electrolytes. Safety assessments included physical examination, electrocardiograms, orthostatic vital signs, and clinical laboratory evaluations. Results 54 subjects completed the study. There were no deaths, serious adverse events, or discontinuations due to treatment-emergent adverse events (TEAEs). All TEAEs in subjects receiving CIN-107 were mild in severity (Table 1). Plasma concentrations of CIN-107 increased proportionally with ascending doses. CIN-107 was rapidly absorbed, with peak concentrations observed within 4 hours after dosing. The concentration of plasma CIN-107 declined in an apparent biphasic manner with a half-life of 26 to 31 hours. A dose-dependent reduction of plasma aldosterone was observed with CIN-107 doses ≥1.5 mg, regardless of normal or low salt diet. Decreases in plasma aldosterone were observed starting on Day 1 and were sustained, with levels reduced by approximately 51–73% on Day 10 (Figure 1). The inhibition of aldosterone synthase by CIN-107 had no impact on plasma cortisol. CIN-107 resulted in mild dose-dependent decreases in plasma sodium levels and increases in potassium levels, as would be expected from the observed reduction in aldosterone. Conclusions Oral administration of CIN-107 was safe and well tolerated in all subjects and resulted in dose-dependent increases in plasma CIN-107 with a half-life that supports once-daily dosing. The dose-dependent decrease in plasma aldosterone and lack of effect on cortisol demonstrate the selective blockade of aldosterone synthase and support continued study in ongoing phase 2 clinical trials evaluating the efficacy and safety of CIN-107 for treatment-resistant or uncontrolled hypertension and primary aldosteronism. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): CinCor Pharma Inc