Results from a Phase 1 Study Assessing the Pharmacokinetics of the Aldosterone Synthase Inhibitor Baxdrostat in Participants with Varying Degrees of Renal Function

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 (formerly CIN-107) is a highly potent and selective inhibitor of aldosterone synthase with the potential to treat hypertension, primary aldosteronism, and chronic kidney disease (CKD). 1,2Aldosterone is the principal mineralocorticoid in humans and a key mediator of fluid and electrolyte homeostasis in the renin-angiotensin-aldosterone-system (RAAS).It is synthesized in the zona glomerulosa in response to angiotensin II, high extracellular potassium concentration, and adrenocorticotropic hormone.The ratelimiting factor in the synthesis of aldosterone is the enzyme aldosterone synthase (also known as CYP11B2).The best characterized actions of aldosterone occur via activation of mineralocorticoid receptors (MRs) that result in increased water and sodium absorption by the kidneys.Previous attempts at developing a selective aldosterone synthase inhibitor for the treatment of hypertension have not been successful (LCI699 [No-vartis Pharmaceuticals] and LY3045697 [Eli Lilly and Company]). 3,4rimary aldosteronism is characterized by chronically elevated aldosterone levels, which can lead to inflammation and fibrosis that contribute to long-term cardiovascular and renal damage (eg, progression of renal failure independently from increased blood pressure [BP]). 5BP control, however, remains a central feature of the care of patients with primary aldosteronism and provides a significant renal benefit. 5ypertension and CKD are common comorbidities that can be exacerbated by elevated aldosterone levels. 6Drugs that inhibit the RAAS (angiotensinconverting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]) are the recommended agents for treating hypertension in patients with CKD; however, combination therapy of ACE inhibitors and ARBs is not advised due to significant adverse events. 6,7n addition, drugs that target the RAAS may increase potassium and the risk of hyperkalemia in patients with CKD. 7 Current guidelines recommend against using steroidal mineralocorticoid receptor antagonists (eg, spironolactone, eplerenone) for the treatment of advanced CKD due to their unfavorable safety profiles. 8][18][19] Preclinical and clinical studies have been performed to assess the pharmacokinetics (PK), pharmacodynamics, and safety of baxdrostat. 1,19,20In single and multiple ascending dose studies of baxdrostat, there was a dose-proportional increase in plasma baxdrostat levels, and the drug was rapidly absorbed with a C max typically observed within 2-3 hours of dosing. 1,19Plasma concentrations declined in an apparent biphasic manner with a mean half-life of 26-31 hours. 1,19Consistent with its mechanism of action of inhibiting aldosterone synthase, baxdrostat reduced plasma aldosterone levels in a dose-dependent manner while having no significant effect on cortisol levels, demonstrating high selectivity for aldosterone synthase (CYP11B2) inhibition over that of 11β-hydroxylase (CYP11B1), the enzyme that synthesizes cortisol. 1,19tabolism was predominantly mediated by oxidations and hydrolysis followed by phase 2 metabolism (data on file).The primary circulating metabolite (CIN-107-M) is also selective for aldosterone synthase inhibition; however, given that it is found in much lower concentrations, baxdrostat is likely the main contributor to the pharmacologic effect. 19Although renal clearance appears not to be a major factor in the elimination of baxdrostat, given the high prevalence of renal impairment in patients with hypertension and primary aldosteronism, it is important to understand whether dose adjustment might be required due to PK differences (eg, renal clearance, systemic exposure) in patients with impaired renal function.This study assessed the PK and safety of a single oral dose of baxdrostat administered to participants with varying degrees of renal function.

Study Design
This phase 1, open-label, single-dose, parallel-group study was designed using standard methods to assess the influence of impaired renal function on PK.The trial was conducted in accordance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonization.The study was conducted at Medpace, Inc. (Cincinnati, OH, USA), with approval from the Advarra Institutional Review Board (Columbia, MD, USA), and all participants provided written informed consent before enrollment in the trial.Inclusion and exclusion criteria are described in the Supplemental Information.Consistent with the FDA guidance for the assessment of PK in patients with impaired renal function, participants were enrolled into 3 renal function groups defined based on estimated glomerular filtration rate (eGFR) calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation 21 and further individualized based on calculated body surface area expressed in mL/min as follows: • control (normal renal function or mild renal impairment: eGFR ≥60 mL/min) • moderate to severe renal impairment (eGFR 15-59 mL/min) • kidney failure (eGFR <15 mL/min, including participants on dialysis).
All participants received a single 10-mg dose of baxdrostat in an open-label manner.Data from previously completed clinical trials suggest that therapeutic doses of baxdrostat ≤10 mg are appropriate for use in patients with hypertension, primary aldosteronism, or CKD. 1,15Single doses of baxdrostat as high as 360 mg have been previously administered in healthy subjects without any clinically significant safety findings. 1A single-dose study was considered appropriate because no time-dependent changes in the PK of baxdrostat have been detected.
Each subject had a screening period of up to 28 days, followed by admission to the clinical site (day −1) and baxdrostat administration (day 1).All participants were required to fast for a minimum of 10 hours prior to baxdrostat administration.They were then dosed at 8:00 AM (±2 hours) with two 5-mg tablets administered with approximately 240 mL of water.Participants continued fasting for a minimum of 4 hours after dosing.No other medications were permitted within 2 hours prior to dosing and for 2 hours after dosing with baxdrostat.Participants on dialysis received the study drug on a nondialysis day.Blood and urine sample collection for PK analysis continued for 7 days and was proceeded by a follow-up phone call 3 ± 1 days after clinic discharge (Figure 1).

Analytical Methods
Plasma and urine samples were analyzed to measure concentrations of baxdrostat and its primary metabolite (CIN-107-M) using liquid chromatography tandem mass spectrometry (LC-MS/MS).All PK samples were analyzed by Medpace Bioanalytical Laboratories (Cincinnati, OH, USA).
Plasma and urine samples were analyzed by LC-MS/MS with electrospray ionization in positive mode and multiple reaction monitoring following extraction by protein precipitation with methanol.Baxdrostat and its metabolite CIN-107-M in plasma and urine were quantified within 0.05-50 ng/mL (low range) and 5.00-2500 ng/mL (high range) using baxdrostat-d 5 and CIN-107-M-d 3 , respectively, as the internal standards.We used reversed-phase chromatographic separation on a C18 Fortis or HyperClone analytical column with a mobile phase (mobile phase A [0.1% formic acid in water] and mobile phase B [0.1% formic acid in methanol]) gradient of 20%-90% at a flow rate of 0.4 mL/min for a total run time of approximately 5 minutes.The transition from precursors to product for baxdrostat and its internal standard were 364.2-291.2and 369.2-291.2,respectively.The transitions for CIN-107-M and its internal standard were 309.2-291.2and 313.2-295.2,respectively.Between-day precision (% coefficient of variation) values for baxdrostat and CIN-107-M in plasma were within 2.2%-7.1% and 1.8%-7.8%,respectively.

PK Analyses
Blood and urine samples were collected prior to and after dosing for measurement of plasma and urine baxdrostat and CIN-107-M concentrations to characterize maximum observed plasma concentration (C max ), time to C max (T max ), area under the plasma concentrationtime curve (AUC) from time 0 to time of last quantifiable plasma concentrations (AUC 0-last ), and AUC from time 0 to infinity (AUC 0-inf ) for baxdrostat and CIN-107-M.The terminal phase elimination half-life, apparent plasma clearance, and apparent volume of distribution were calculated for plasma baxdrostat only.Urine PK parameters included the cumulative amount of baxdrostat and CIN-107-M excreted in urine (A e ), renal clearance (CL R ) of baxdrostat and CIN-107-M, and fraction of dose excreted renally (F e ) for baxdrostat.To understand the relationship between selected PK parameters and eGFR as a continuous variable, we analyzed C max , AUC 0-last , and AUC 0-inf versus baseline eGFR for each subject.Given the low plasma protein binding of baxdrostat in healthy human subjects (74% [data on file]), PK analyses were limited to total concentrations of baxdrostat and CIN-107-M.

Safety Analyses
Safety was assessed throughout the study based on adverse events, physical examinations, ECGs, seated and orthostatic vital signs, weight measurements, and clinical laboratory evaluations.

Statistical Analyses
From previous studies under the fasted state, the coefficients of variation for CIN-107 AUC (0-last) , AUC (0-inf) , and apparent plasma clearance (CL/F) ranged from 0.24 to 0.26.Approximately 10 subjects per group provide 80% power such that the 2-sided 95% confidence intervals lie entirely within a boundary of 0.6-1.4,while assuming the mean ratio of subjects with renal impairment and the control group is 1 for both AUC and CL/F.Categorical data were summarized with counts and percentages of participants.Descriptive statistics were  Baseline was defined as the last measurement prior to the dose of baxdrostat.Baseline eGFR value is presented as a continuous variable.AUC 0-inf , area under the curve from time 0 to infinity; AUC 0-last , area under the curve from 0 to the time of last quantifiable plasma concentration; CL/F, apparent plasma clearance; C max , maximum plasma concentration; eGFR, estimated glomerular filtration rate; t 1/2 , half-life.calculated for PK and safety measures, and geometric least squares mean and 95% confidence intervals were calculated for pairwise comparisons of PK parameters and renal function category.PK parameters were calculated with Phoenix WinNonlin (Certara USA, Inc., Princeton, NJ, USA) version 8.0 or higher and verified with SAS Version 9.4 or higher.

Participants
Baseline demographics and clinical characteristics were generally well matched among the renal function groups and are presented in Table 1.Participants were predominantly White (60.6%)males (75.8%) with an average age of 62 years and a mean BMI of 30 kg/m 2 .The continuum of eGFR values was well represented by all participants.All participants in the kidney failure group were on hemodialysis.

Pharmacokinetics
The structure of baxdrostat is shown in Figure 2. Plasma PK parameters of baxdrostat are presented in Table 2.The absorption of baxdrostat was similar among renal function groups.It was rapidly absorbed with a median T max observed within 1.5 hours of dosing for all groups (Figure 3) and an average half-life ranging from 30-42 hours.Pairwise comparisons of moderate to severe renal impairment versus control and kidney failure versus control showed that renal impairment had no noteworthy effect on C max , AUC (0-last) , AUC (0-inf) , half-life, apparent plasma clearance, or renal clearance.There was no indication of a strong linear or nonlinear relationship in the analysis of C max , AUC 0-last , AUC 0-inf , t 1/2 , or CL/F versus baseline eGFR for each subject (Figure 4).
The plasma CIN-107-M concentration-time curves for the moderate to severe renal impairment and kidney failure groups were qualitatively similar to the control group (Figure 5).The T max for CIN-107-M was observed approximately 22 hours after dosing for all renal function groups.
Urine PK parameters are also presented in Table 2. Approximately 12% of baxdrostat was recovered unchanged in the urine for the control and moderate to severe renal impairment groups.Inadequate urine production in the kidney failure group resulted in minimal renal excretion of baxdrostat in these participants, as expected (Figure 6).

Safety
There were no deaths, and 1 drug-related treatmentemergent adverse event (TEAE; diarrhea) occurred, which was mild in nature (Table S1).One subject in the kidney failure group discontinued from the study after experiencing 2 TEAEs of tremor and metabolic encephalopathy on study day 3 that were determined to be unrelated to the study drug.The metabolic encephalopathy was considered severe and secondary to the concomitant medications gabapentin, primidone, and baclofen.By study day 11, the metabolic encephalopathy resolved, and the patient was considered to be recovered.There were no clinically meaningful changes in vital signs, physical examinations, ECGs, or laboratory values, including sodium or potassium (data not shown).

Discussion
Baxdrostat is currently in clinical development as a new treatment for disorders associated with inappropriately elevated aldosterone levels, including hypertension, primary aldosteronism, and CKD.Hyperactivity of the RAAS contributes to the progression of CKD, 22 and patients with CKD have elevated levels of plasma aldosterone. 23Reducing aldosterone activity in these patients may therefore delay the progression of CKD by reducing BP and preventing renal fibrosis. 22pironolactone and eplerenone, older MR antagonists, have been shown to induce changes in biomarkers associated with an improvement in the progression of CKD, presumably due to their anti-inflammatory and antifibrotic effects; however, they are not approved for the treatment of CKD and use is not recommended in advanced CKD. 8 Finererone, a newer nonsteroidal MR antagonist, is approved for use in patients with diabetic kidney disease, but had a modest effect on BP, 10 whereas a phase 2 study of baxdrostat in patients with resistant hypertension demonstrated a significant reduction in systolic BP. 15 Thus, exploring the utility of baxdrostat in individuals with CKD as both an antihypertensive agent and a potential therapy for the slowing of renal disease progression is warranted.Evaluation of baxdrostat in patients with uncontrolled hypertension and CKD is currently underway (NCT05432167). 18ince renal disease can alter drug clearance, resulting in increased exposure and potentially greater drug effects or toxicity, it is common for dose adjustment to be necessary in patients with impaired kidney function. 24herefore, before conducting studies of baxdrostat in patients with impaired renal function, it was important to first determine if dose adjustment may be warranted due to alterations in the PK disposition of the drug.The results presented in this report indicate that neither moderate to severe renal impairment nor kidney failure had a noteworthy effect on overall baxdrostat exposure as assessed by C max and AUC, and no meaningful change in T max or t 1/2 as compared to the control group.These findings are not unexpected given that renal mechanisms are not a major contrib-utor to the clearance of baxdrostat, which is primarily metabolized by the liver, as indicated by the low abundance of unchanged baxdrostat in excreta.Plasma concentration-time curves and the systemic exposures to baxdrostat were as expected based on prior studies in healthy subjects. 1The half-life of baxdrostat was also comparable to previous studies. 1In addition, there were no trends in the PK parameters across the continuum of renal impairment.
As this study was only meant to evaluate PK in renally impaired participants, and not the impact of the drug on sodium or potassium handling or safety with multiple doses, additional longer-term studies are needed to fully evaluate the safety and efficacy of baxdrostat in patients with CKD.

Conclusions
Our results demonstrate that renal impairment did not significantly impact systemic exposure or clearance of a single 10-mg dose of baxdrostat.These findings suggest that dose adjustment of baxdrostat due to altered PK properties in patients with impaired renal function is not necessary, even in patients with end-stage renal disease.

Figure 3 .
Figure 3. Plasma baxdrostat concentration versus time.Mean plasma baxdrostat concentration (ng/mL) by renal function group from 0 to 24 hours (A) and 0 to 168 hours (B).eGFR, estimated glomerular filtration rate.

Figure 4 .
Figure 4. Plasma baxdrostat PK parameters versus baseline eGFR.Plasma baxdrostat C max (A), AUC 0-last (B), AUC 0-inf (C), t 1/2 (D), and CL/F (E) versus baseline eGFR.Baseline was defined as the last measurement prior to the dose of baxdrostat.Baseline eGFR value is presented as a continuous variable.AUC 0-inf , area under the curve from time 0 to infinity; AUC 0-last , area under the curve from 0 to the time of last quantifiable plasma concentration; CL/F, apparent plasma clearance; C max , maximum plasma concentration; eGFR, estimated glomerular filtration rate; t 1/2 , half-life.

Figure 5 .
Figure 5. Plasma CIN-107-M concentration versus time.Mean plasma concentration (ng/mL) by renal function group from 0 to 24 hours (A) and 0 to 168 hours (B).eGFR, estimated glomerular filtration rate.

Figure 6 .
Figure 6.Cumulative amount of baxdrostat excreted in urine.Cumulative concentration (μg) of baxdrostat by renal function group from 0 to 168 hours.Data are mean ± standard deviation.eGFR, estimated glomerular filtration rate.

Table 1 .
Baseline Demographics and Clinical Characteristics a BMI, body mass index; eGFR, estimated glomerular filtration rate; N/A, not available; SD, standard deviation.a All participants were on hemodialysis.

Table 2 .
Summary of Plasma and Urine PK Parameters of Baxdrostat and CIN-107-M AUC 0-last , area under the plasma concentration-time curve from time 0 to time of last quantifiable plasma concentration; AUC 0-inf , area under the plasma concentration-time curve from time 0 to infinity; CI, confidence interval; CL/F, apparent plasma clearance; C max , maximum observed plasma concentration; %CV, % coefficient of variation; F e , fraction of the dose excreted renally; GLSM, geometric least squares mean; PK, pharmacokinetic; SD, standard deviation; t 1/2 , terminal phase elimination half-life; T max , time to maximum observed plasma concentration.a n = 8.