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Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteers

Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing... This multiple ascending dose study of the selective aldosterone synthase inhibitor baxdrostat demonstrated a dose-dependent reduction in plasma aldosterone with no meaningful effect on plasma cortisol. There were no deaths or serious adverse events, and all treatment-emergent adverse events in subjects receiving baxdrostat were mild in severity. Chronically elevated aldosterone levels can lead to highly homologous enzyme responsible for cortisol synth- hypokalemia, sodium reabsorption, and fluid retention, esis 11β-hydroxylase (CYP11B1) [15]. In vivo, nonhuman resulting in increased blood pressure (BP). Furthermore, primate pharmacology characterization showed that bax- inflammation, end organ damage, fibrosis, cardiovascular drostat blunted aldosterone production while having no events (e.g., ventricular hypertrophy), and adverse renal effect on cortisol levels [15]. events (e.g., increased urinary albumin excretion, progres- In accordance with the in vitro and in vivo studies, sion of renal failure) can occur with increased aldosterone baxdrostat demonstrated selectivity for aldosterone synthase levels independently of BP [6]. The association between as shown by a dose-dependent reduction in plasma aldos- high plasma aldosterone and decreased long-term survival terone with no effect on ACTH-stimulated plasma cortisol has been demonstrated in patients with congestive heart levels following administration of single ascending doses in the first-in-human study [15]. Although baxdrostat is the failure [7–10], acute myocardial infarction (MI) [11], and coronary artery disease outside the setting of acute MI or parent compound, multiple metabolites are present at lower heart failure [12]. Thus, aldosterone synthase inhibition may concentrations. The active metabolites of baxdrostat also be a promising therapeutic strategy for BP control and exhibited a high degree of selectivity for aldosterone syn- mitigation of end organ damage [13]. thase over 11β-hydroxylase. The primary metabolite, CIN- Baxdrostat (CIN-107) is a highly potent, selective, and 107-M, is a chiral molecule. The 2 enantiomers of CIN-107- competitive small molecule inhibitor of aldosterone syn- M showed >20-fold greater selectivity for aldosterone thase, as demonstrated by preclinical and first-in-human synthase compared to 11β-hydroxylase; however, the more clinical studies [14, 15]. In vitro, baxdrostat exhibited a high potent R enantiomer of CIN-107-M appears to not be selectivity ratio for aldosterone synthase compared to the formed in humans. Given the lower concentrations of the 110 M. W. Freeman et al. metabolites, the parent compound is thought to be the pri- have a body mass index (BMI) ≥ 18 and ≤30 kg/m .In mary contributor to the pharmacologic effect (data on file). addition, they were required to have an appropriate response Baxdrostat had a favorable pharmacokinetic (PK) profile in to cortisol stimulation (cohorts 1 and 2) or a normal cortisol humans. Plasma exposures increased in a dose-proportional level during the inpatient run-in period (cohorts 3–5). manner over the expected therapeutic dose range with a Subjects were excluded if they had (1) a personal or family mean half-life of 29 h, a result that supports once-daily history of long QT syndrome, complex ventricular arrythmias, dosing. Side effects were mild and included headache, or family history of sudden death; (2) personal history of or nasopharyngitis, and diarrhea. current clinically significant arrhythmias; (3) prolonged QTcF The favorable preclinical and early-phase clinical profiles of (>450 ms); (4) seated BP > 150/90 mm Hg or <90/50 mm Hg; baxdrostat warranted assessment at steady state to confirm (5) resting heart rate >100 beats per minute (bpm) or <50 bpm, whether the effects are maintained following multiple doses sinus node dysfunction, or clinically significant heart block; (6) [15], as this has not been the case for 2 previously explored postural tachycardia or orthostatic hypotension; or (7) serum aldosterone synthase inhibitors. In multiple-dose studies, potassium greater than the upper limit of normal of the refer- LCI699 (Novartis Pharmaceuticals) was less selective for ence range and serum sodium less than the lower limit of aldosterone synthase than for 11β-hydroxylase. Significant normal of the reference range. increases in the aldosterone precursor 11-deoxycorticosterone; dose-dependent accumulation of 11-deoxycortisol; and Study design impairment of ACTH-stimulated cortisol synthesis indicated a latent inhibition of cortisol synthesis by LCI699 [16]. The Subjects were randomized in a 3:1 ratio to baxdrostat or potency of another aldosterone synthase inhibitor, LY3045697 placebo once daily for 10 days as follows: (Eli Lilly and Company), was found to decrease significantly with daily dosing. The authors suggest that the decrease in Cohort 1: 2.5 mg baxdrostat or matching placebo on a potency could not be explained by elevated aldosterone pre- low-salt diet, 9 subjects receiving baxdrostat and cursors, but rather likelybyanincrease in aldosterone synthase 3 subjects receiving placebo activity over time [17]. Cohort 2: 5.0 mg baxdrostat or matching placebo on a These results support the importance of the current low-salt diet, 9 subjects receiving baxdrostat and multiple ascending dose assessment to further the under- 3 subjects receiving placebo standing of baxdrostat attained with the prior single-dose Cohort 3: 1.5 mg baxdrostat or matching placebo on a study [15]. This randomized, double-blind, placebo- normal-salt diet, 9 subjects receiving baxdrostat and controlled phase 1 study evaluated the safety, PK, and 3 subjects receiving placebo pharmacodynamics (PD) of multiple ascending doses of Cohort 4: 2.5 mg baxdrostat or matching placebo on a baxdrostat in healthy volunteers. normal-salt diet, 6 subjects receiving baxdrostat and 2 subjects receiving placebo Cohort 5: 0.5 mg baxdrostat or matching placebo on a Methods normal-salt diet, 9 subjects receiving baxdrostat and 3 subjects receiving placebo. Study objectives Cohorts 1 and 2 were dosed concurrently with a minimum The primary objectives of this study were to assess safety, 5-day lag between the first dose for cohort 2 and the first dose tolerability, PK, and PD of baxdrostat following oral dosing for cohort 1. A data review committee met between cohorts 2 once daily for 10 days in subjects with a normal- or low-salt and 3 and determined that cohorts 3 through 5 could be dosed diet. The low-salt diet cohorts were included to stimulate concurrently. Each patient had a screening period of up to aldosterone production and to evaluate safety in potential 28 days, followed by a 5-day run-in period in which the patients who may be following a low-salt diet. subjects adhered to a controlled, standardized diet and underwent baseline PD assessments (Supplementary Fig. 1). Subjects This was followed by a 15-day inpatient treatment period in which the subjects received baxdrostat or placebo once daily Subjects were included in the study if they were between for 10 days while remaining on the controlled, standardized the ages of 18 and 55 years and in good health based on diet. Blood and urine sample collection for PK and PD medical and psychiatric history, physical examination, analysis continued for an additional 5 days and was pro- electrocardiogram (ECG), orthostatic vital signs, and rou- ceeded by a follow-up visit 3 ± 1 days after clinic discharge. tine laboratory tests (blood chemistry, hematology, coagu- The study drug was a 2 mg/mL baxdrostat oral solution lation, and urinalysis). Subjects had to be nonsmokers and and matching oral placebo solution. Subjects received a Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the. . . 111 single dose of oral solution of baxdrostat or placebo on the PK. Pharmacokinetic parameters were calculated by standard mornings of days 1 through 10 at 8:00 a.m. (± 2 h). On days noncompartmental methods using Phoenix WinNonlin™ 1 and 10, the dose was given following an overnight fast (of (Certara, Inc., Princeton, NJ) and verified with SAS (SAS at least 8 h), and subjects remained fasted for at least 4 h Institute, Inc., Cary, NC) software. Plasma PK parameters after dosing on these days. On all other days, subjects fasted included maximum observed plasma concentration on day 1 for a minimum of 2 h before and 2 h after dosing. (C )and day10(C ), time to C on day1(T ) max,D1 max,D10 max max,D1 For cohort 1, the controlled, standardized low-salt diet and day 10 (T ), and area under the plasma concentration- max,D10 + + consistedof50to60mEq Na /d and70 to100 mEqK /d time curve(AUC)fromtime0 to 24hpostdoseonday 1 from day −5 until day −1. Based on decreases in sodium (AUC ) or from time 0 to 24 h on day 10 (AUC ). 0-24 h 0-tau levels observed in some subjects during the run-in period prior Steady-state plasma PK parameters consisted of accumulation to any subjects receiving the study drug, the diet was modified ratio based on C (R ), accumulation ratio based on AUC max Cmax + + to 65 to 70 mEq Na /d and70to100 mEqK /d from day 1 (R ), apparent first-order terminal elimination rate constant AUC through the remainder of the study. Cohort 2 subjects were (λ ), terminal phase elimination half-life (t ), apparent plasma z 1/2 given a low-salt diet consisting of up to 65 to 70 mEq Na /d clearance (CL /F), and apparent volume of distribution (V /F). ss ss and70to 100 mEq K /d for the full run-in and treatment An exploratory dose proportionality analysis of baxdrostat, periods. Cohorts 3 through 5 were on a normal-salt diet of 100 C , and AUC (day 1) or C ,AUC ,and max,D1 0-24 h max,D10 0-tau + + to 104 mEq Na /d and70to100 mEq K /d for the full run-in AUC (day 10) was performed using a power model to esti- 0-t and treatment periods. mate the mean slope and 90% confidence interval (CI). TM Cohorts 1 and 2 also underwent an ACTH (Cortrosyn ) The cumulative amount of drug excreted in urine on day challenge at baseline (day −1), 1 h after the first dose of study 1(A ) and day 10 (A ), fraction of dose excreted e,D1 e,D10 drug on day 1, and 1 h after the final dose of study drug on day renally on day 1 (F ) and day 10 (F ), and renal e,D1 e,D10 10. This was done to increase aldosterone and cortisol levels to clearance on day 1 (CL ) and day 10 (CL ) composed R,D1 R,D10 more thoroughly evaluate the specificity of baxdrostat for tar- single-dose urine PK parameters. geting aldosterone synthase. The ACTH challenge consisted of TM an intravenous injection of 0.25 mg Cortrosyn administered Pharmacodynamic and safety analyses over 2 min after an overnight fast. Plasma PD measures included concentrations of aldoster- Analytical methods one, 18-hydroxycorticosterone, corticosterone, 11-deox- ycorticosterone, cortisol (free and total), 11-deoxycortisol, Plasma and urine samples were analyzed to measure con- ACTH, sodium, chloride, and potassium. AUCs were cal- centrations of baxdrostat and its primary metabolite (CIN-107- culated using a noncompartmental analysis and the linear M), aldosterone and its precursors, cortisol and its precursor, trapezoidal/linear interpolation method. Urine PD measures and ACTH using a validated liquid chromatography tandem included concentrations of aldosterone, cortisol (free and mass spectrometry method (LC-MS/MS). The quantifiable total), tetrahydroaldosterone, sodium, chloride, potassium, ranges for both baxdrostat and its metabolite CIN-107-M in creatinine, and phosphorus. Other PD measures were plasma and urine were 0.05 to 50 ng/mL (low range) and 5 to seated, orthostatic, and positional changes in vital signs, as 2500 ng/mL (high range), using baxdrostat-d and CIN-107- well as changes in body weight and BMI. Safety assess- M-d , respectively, as the internal standards. Plasma samples ments involved adverse events, physical examinations, were extracted by protein precipitation with methanol, fol- ECGs, orthostatic vital signs, and clinical laboratory lowed by analysis by LC-MS/MS with electrospray ionization evaluations. in positive mode and multiple reaction monitoring. All scheduled study-related laboratory tests were performed by Statistical analyses Medpace Reference Laboratories (Cincinnati, OH, USA), Medpace Bioanalytical Laboratories (Cincinnati, OH, USA), Subjects who received placebo were pooled into 2 treatment Mercy Health—West Hospital Laboratory (Cincinnati, groups: placebo with low-salt diet and placebo with normal- OH, USA), or Laboratory Corporation of America (Dublin, salt diet. Descriptive statistics were calculated for PK, PD, OH, USA). and safety measures. The effects of dose on plasma aldos- terone and cortisol (free and total) and their precursors were Pharmacokinetic analyses investigated using an analysis of variance model on change in AUC over 12 h from day −1 to day 1 and from day −1to Blood samples were collected prior to and after dosing on days day 10. Data are presented as change from baseline in least 1 and 10 for measurement of plasma baxdrostat and CIN-107- squares mean (90% CI) AUC of plasma aldosterone on 0-12h M concentrations to characterize single-dose and steady-state days 1 and 10. The results of the exploratory dose 112 M. W. Freeman et al. Table 1 Baseline demographics and clinical characteristics Demographic or Low-salt diet Normal-salt diet characteristic Pooled placebo 2.5 mg baxdrostat 5.0 mg baxdrostat Pooled placebo 0.5 mg baxdrostat 1.5 mg baxdrostat 2.5 mg baxdrostat (n = 6) (n = 9) (n = 9) (n = 8) (n = 9) (n = 9) (n = 6) Age (y), mean ± SD 43.8 ± 6.4 37.2 ± 8.7 39.3 ± 10.2 37.0 ± 8.7 37.9 ± 8.6 44.8 ± 8.6 39.0 ± 9.7 Race, n (%) White 2 (33.3) 4 (44.4) 5 (55.6) 5 (62.5) 3 (33.3) 3 (33.3) 4 (66.7) Black or African 4 (66.7) 5 (55.6) 3 (33.3) 3 (37.5) 6 (66.7) 5 (55.6) 2 (33.3) American Asian 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) Other 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Ethnicity, n (%) Hispanic or Latino 1 (16.7) 0 (0.0) 2 (22.2) 1 (12.5) 2 (22.2) 1 (11.1) 0 (0.0) Not Hispanic or Latino 5 (83.3) 9 (100.0) 7 (77.8) 7 (87.5) 7 (77.8) 8 (88.9) 6 (100.0) Sex, n (%) Female 1 (16.7) 4 (44.4) 3 (33.3) 1 (12.5) 4 (44.4) 1 (11.1) 3 (50.0) Male 5 (83.3) 5 (55.6) 6 (66.7) 7 (87.5) 5 (55.6) 8 (88.9) 3 (50.0) Height (cm), mean ± SD 175.3 ± 10.2 168.9 ± 10.7 170.1 ± 12.2 170.2 ± 8.6 171.5 ± 11.5 173.4 ± 9.7 171.7 ± 8.2 Body weight (kg), 78.3 ± 13.2 77.0 ± 11.0 75.8 ± 12.0 70.4 ± 11.0 79.5 ± 12.0 78.6 ± 11.3 74.9 ± 5.5 mean ± SD BMI (kg/m ), mean ± SD 25.3 ± 2.5 26.9 ± 1.4 26.0 ± 1.7 24.3 ± 3.2 26.9 ± 1.8 26.0 ± 2.5 25.5 ± 2.4 BMI body mass index proportionality power model were assessed using the Smith criteria (0.9031, 1.0969) [18] and the less stringent Hummel criteria (0.6990, 1.3010) [19]. Three subjects had negligible aldosterone concentrations on day −1 that increased to more expected levels on days 1 and 10. Including these subjects in the baseline analyses skewed the results and disrupted cross-treatment compar- isons; therefore, they were considered outliers and were not included in the data presented here. Results Subjects Demographics and baseline characteristics are presented in Table 1. Most study participants were male (70%), Black or African American (50%), and not Hispanic or Latino (88%). The average age was 40 years, and mean BMI ranged from 24 to 27 kg/m . The demographic and baseline character- istics were generally well matched in sex and race across treatment groups. Pharmacokinetics Single-dose and steady-state plasma PK parameters of bax- Fig. 1 Plasma Baxdrostat Concentration vs. Time on Days 1 and 10. drostat are presented in Supplementary Table 1. Baxdrostat Plasma baxdrostat concentration (ng/mL) by scheduled time point and was rapidly absorbed with a median T observed within max treatment. Data are mean ± standard deviation 4 h of dosing (Fig. 1). Baxdrostat concentrations declined from peak in an apparent biphasic manner with a mean t increased exposure with increasing dose. At steady state, 1/2 ranging from approximately 26 to 31 h. The plasma baxdrostat exposure was approximately 2- to 2.5-fold higher concentration-time profile of baxdrostat demonstrated than after a single dose. Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the. . . 113 Fig. 2 Baxdrostat Reduces Plasma Aldosterone Levels in a Dose- effect-time curve from time 0 to 12 h postdose on day 1 and day 10. dependent Manner. Estimated percentage change from baseline Data are least squares mean and 90% confidence intervals. AUC (day −1) in plasma aldosterone area under the pharmacodynamic indicates area under the curve An exploratory analysis to assess dose proportionality Pharmacodynamics demonstrated that with increasing doses of baxdrostat there was a proportional increase in both C and AUC on A dose-dependent reduction of plasma aldosterone (esti- max 0-24 h day 1 (according to the Hummel criteria). Similarly, pro- mated percentage change from baseline AUC ) occurred 0-12h portional increases in C , AUC , and AUC on day 10 with baxdrostat doses ≥1.5 mg, regardless of normal- or max 0-tau 0-t were also observed. low-salt diet. Decreases in plasma aldosterone were Although CIN-107-M is not believed to contribute observed starting on day 1 and were sustained, with levels substantially to the effects of baxdrostat, its prevalence reduced by ~51 to 73% on day 10 (Fig. 2). Corresponding warrants characterization. On average, CIN-107-M repre- dose-dependent decreases of aldosterone and tetra- sents 8 to 11% of the parent compound based on C hydroaldosterone urine excretion were also observed (data max,D10 and 10 to 22% of the parent compound based on AUC . not shown). 0-inf Based on plasma concentration data, CIN-107-M was Baxdrostat caused a modest increase in the aldosterone formed ~4 to 24 h after the initial dose of baxdrostat on precursor 11-deoxycorticosterone under both normal- and day 1 andwas typicallyobservedwithin4 hatsteadystate low-salt diet conditions. Additional aldosterone precursors (day 10). Plasma levels of CIN-107-M showed a dose- demonstrated stepwise changes indicative of the progressive proportional increase similar to the PK of the parent impact of aldosterone synthase inhibition on the pathway compound (data not shown). Approximately 7% (mean of aldosterone synthesis. 18-hydroxycorticosterone (the F ranged from 6.3 to 10.8% across treatment groups) immediate precursor to aldosterone) levels were generally e,D1 of the baxdrostat dose was recovered unchanged in the comparable or decreased compared to baseline, although to urine on day 1. At steady state (day 10), ~32% was a lesser extent than aldosterone. Corticosterone levels recovered unchanged (mean F ranged from 30.7 to increased in an apparent dose-dependent manner, likely due e,D10 33.6% across treatment groups). to 11β-hydroxylase activity (Supplementary Fig. 2). 114 M. W. Freeman et al. Fig. 3 Baxdrostat Does Not Have a Significant Effect on Plasma curve from time 0 to 12 h postdose on day 1 and day 10. Data are least Cortisol Levels. Estimated percentage change from baseline (day −1) squares mean and 90% confidence intervals. AUC indicates area under in plasma cortisol (total) area under the pharmacodynamic effect-time the curve Baxdrostat had no meaningful effect on plasma cortisol potassium). The sodium:potassium ratio was increased (total or free) or 11-deoxycortisol concentrations even in the (sodium loss in the urine was greater than the potassium presence of the ACTH challenge in the low-salt diet groups retention) on day 1 following the first dose of baxdrostat; (Fig. 3). Likewise, there was no meaningful effect on urine however, this effect was diminished by day 10. This appears free cortisol (Supplementary Fig. 3). Subjects on a low-salt to be mediated by a greater elimination of sodium on day 1 diet had increased plasma ACTH levels at baseline. The compared to day 10, as potassium did not substantially increases were somewhat more pronounced in subjects change over the course of the treatment period (Fig. 4). receiving baxdrostat compared to placebo. Under normal- Renal function was assessed by plasma blood urea salt conditions, however, baxdrostat resulted in a dose- nitrogen (BUN), creatinine, and glomerular filtration rate. dependent decrease in ACTH. There were mild increases in BUN, creatinine, and the There were no clinically significant changes or dose- BUN:creatinine ratio. A mild reduction in glomerular fil- related trends in seated heart rate or BP (Supplementary tration rate (<15%) was also observed. These results sug- Fig. 4). A slight trend toward mild, drug-induced decreases gests that baxdrostat has a mild diuretic effect. Mean body in orthostatic BP and moderate increases in orthostatic heart weight and BMI decreased slightly from baseline during the rate were observed, but there was no clear dose- treatment period in all treatment groups, including placebo; dependency. The most pronounced effects on heart rate however, the decrease was more pronounced in subjects occurred in the 5-mg baxdrostat treatment group. receiving baxdrostat. The values largely returned to baseline Baxdrostat administration resulted in mild dose- at the follow-up visit. dependent decreases in plasma sodium levels and increa- There were no deaths, serious adverse events, or dis- ses in potassium levels, as would be expected from the continuations due to treatment-emergent adverse events observed reduction in aldosterone (Supplementary Fig. 5). (TEAEs). Overall, 6 (14.3%) subjects receiving baxdrostat Urine sodium and potassium levels corresponded to the and 3 (21.4%) subjects receiving placebo experienced a changes observed in plasma (increased sodium, decreased TEAE that was considered related to the study drug. All Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the. . . 115 Fig. 4 Urinary Sodium and Potassium Concentrations Following interquartile range (box) and minimum-maximum (whiskers) for Baxdrostat Administration. Urine sodium and potassium concentra- sodium or potassium from 24 h urine collections tions at baseline (BL), day 1, and day 10. Box whiskers show TEAEs in subjects receiving baxdrostat were mild possibly increased mortality rates [21, 22]. Based on pre- (Table 2). There were no clinically meaningful changes in clinical studies, it was predicted that baxdrostat would physical examination findings, vital signs, electro- selectively inhibit aldosterone synthase [15]. Our results cardiograms (including no QT prolongation), or clinical demonstrate that at doses ≥1.5 mg, baxdrostat produces a laboratory results related to safety. dose-dependent decrease in aldosterone compared to base- line and placebo while having no meaningful impact on cortisol levels, supporting the selective nature of baxdrostat. Discussion Importantly, the aldosterone-lowering effect was sustained, suggesting no apparent compensatory mechanisms over the Consistent with the single ascending dose study results [15], duration of the study and thus differentiating baxdrostat oral dosing of baxdrostat resulted in dose-proportional from the previously studied aldosterone synthase inhibitors increases in plasma baxdrostat and its metabolite with a LCI699 and LY3045697. relatively long half-life of 26 to 31 h, resulting in support of Lack of specificity for aldosterone synthase has resulted once-daily dosing. in the discontinuation of LCI699, which was previously One of the challenges of aldosterone synthase inhibition being developed for the treatment of hypertension [16]. is to achieve high selectivity for the enzyme, which shares LCI699 was selective for aldosterone synthase after a single 93% homology to cortisol synthase [20]. Suppression of dose; however, after multiple-dose administration it showed cortisol could lead to compromised stress response, a time-dependent loss of selectivity [23]. LY3045697 lost impaired immune system, inadequate metabolism, and its aldosterone-reducing potency after multiple doses (half 116 M. W. Freeman et al. Table 2 Summary of adverse events Adverse events, n (%) Low-salt diet Normal-salt diet Pooled placebo 2.5 mg baxdrostat 5.0 mg baxdrostat Pooled placebo 0.5 mg baxdrostat 1.5 mg baxdrostat 2.5 mg baxdrostat (n = 6) (n = 9) (n = 9) (n = 8) (n = 9) (n = 9) (n = 6) Any AE 2 (33.3) 3 (33.3) 3 (33.3) 1 (12.5) 1 (11.1) 1 (11.1) 3 (50.0) Any TEAE 2 (33.3) 3 (33.3) 3 (33.3) 1 (12.5) 1 (11.1) 1 (11.1) 3 (50.0) Palpitations 0 (0.0) 0 (0.0) 0 (0.0) 1 (12.5) 0 (0.0) 0 (0.0) 0 (0.0) Ventricular 1 (16.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) tachycardia Eye irritation 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Abdominal pain 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Constipation 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) Nausea 1 (16.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Rhinitis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Viral infection 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Back pain 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Headache 0 (0.0) 1 (11.1) 1 (11.1) 0 (0.0) 1 (11.1) 0 (0.0) 1 (16.7) Dizziness postural 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (33.3) Dizziness 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Presyncope 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Anxiety 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Dry throat 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Dysphonia 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Any treatment- 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) emergent SAE Any drug-related 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) treatment-emergent SAE Any TEAE leading 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) to death Any TEAE leading to 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) discontinuation TEAEs are defined as any AE, regardless of relationship to the study drug, which began after the first dose was administered AE adverse event, SAE serious adverse event, TEAE treatment-emergent adverse event maximal inhibitory concentration was 47 times higher than moderate increases in orthostatic heart rate indicate that after single-dose administration) despite similar PK with baxdrostat represents a promising treatment for the negative both single- and multiple-dose administration [17]. health impact of elevated aldosterone. It is difficult to pre- Baxdrostat decreased plasma aldosterone levels under dict how the observed 51 to 73% reduction in plasma both low-salt and normal-salt diet conditions; the 2.5-mg aldosterone will translate to BP reduction in patients with baxdrostat dose used in both low- and normal-salt condi- primary aldosteronism or uncontrolled or treatment-resistant tions showed a similar effect on lowering plasma aldoster- hypertension; however, further studies in these patient one levels. The low-salt diet subjects of cohorts 1 and 2 also populations will help elucidate this relationship. underwent an ACTH challenge to further stimulate aldos- There are potential benefits of selective aldosterone terone and cortisol levels prior to receiving baxdrostat. synthase inhibition vs. MR antagonism. For example, due to Baxdrostat suppressed plasma aldosterone levels while the hypothalamic-pituitary axis feedback loop, blocking having no meaningful effect on cortisol, even in the pre- MRs activates the RAAS, leading to a compensatory sence of the ACTH challenge, further supporting the increase in aldosterone, which could overcome the blockade selectivity of baxdrostat to inhibit aldosterone synthase. by MR antagonists [25]. In addition, current MR antago- As expected, the inhibition of aldosterone synthase by nists (spironolactone and eplerenone) are accompanied by baxdrostat resulted in an increase in the aldosterone pre- adverse events, such as sexual dysfunction, gynecomastia in cursor 11-deoxycorticosterone under both normal- and low- men, and electrolyte imbalances [26]. Baxdrostat was well salt diet conditions. However, the magnitude of increase tolerated with a favorable safety profile. The most common was modest (~2- to 3-fold) compared to what has previously TEAEs in subjects receiving baxdrostat were headache, been observed for LCI699, where 11-deoxycorticosterone postural dizziness, and dizziness. levels increased up to 10-fold [24]. The relatively small sample size for each treatment group Although the study was conducted in healthy volunteers, is a limitation of the current study. Because it was con- the apparent diuretic effect, the slight trends toward mild ducted in healthy subjects, the clinical relevance of these baxdrostat-induced decreases in orthostatic BP, and the findings needs to be investigated in patients who have Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the. . . 117 uncontrolled or treatment-resistant hypertension or primary Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, aldosteronism. As expected, we were unable to detect BP adaptation, distribution and reproduction in any medium or format, as changes in our healthy subjects and therefore were not able long as you give appropriate credit to the original author(s) and the to definitively identify the efficacious dose range for source, provide a link to the Creative Commons license, and indicate if patients with hypertension or primary aldosteronism. changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless Moreover, the relationship between the magnitude of indicated otherwise in a credit line to the material. If material is not aldosterone lowering and BP lowering is not yet defined. included in the article’s Creative Commons license and your intended For these reasons, further study is needed to understand the use is not permitted by statutory regulation or exceeds the permitted dose-response for lowering BP in these patients, including use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. the possibility of additional higher doses. org/licenses/by/4.0/. References Conclusions 1. Whelton PK, Carey RM, Aronow WS, Casey DE Jr, Collins KJ, Oral administration of baxdrostat was safe and well toler- Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ ated in all subjects and resulted in dose-proportional ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High increases in plasma baxdrostat with a half-life that sup- Blood Pressure in Adults: A Report of the American College of ports once-daily dosing. The dose-dependent decrease in Cardiology/American Heart Association Task Force on Clinical plasma aldosterone at doses ≥1.5 mg and lack of effect on Practice Guidelines. J Am Coll Cardiol. 2018;71:e127–248. cortisol demonstrate the selective blockade of aldosterone 2. Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol. 2007;3:486–92. synthase and support continued study in ongoing phase 2 3. Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, clinical trials evaluating the efficacy and safety of baxdro- McInnes G, et al. Spironolactone versus placebo, bisoprolol, and stat for treatment-resistant or uncontrolled hypertension and doxazosin to determine the optimal treatment for drug-resistant primary aldosteronism. hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386:2059–68. 4. Kallistratos MS, Pittaras A, Theodoulidis I, Grassos C, Poulime- Acknowledgements This study was funded by CinCor Pharma, Inc. nos LE, Manolis AJ. Adverse effects of mineralocorticoid receptor Technical and editorial support for this paper was provided by antagonist administration. Curr Pharm Des. 2018;24:5537–41. MedLogix Communications, LLC, and funded by CinCor Pharma, Inc. 5. Fourkiotis V, Vonend O, Diederich S, Fischer E, Lang K, Endres S, et al. Effectiveness of eplerenone or spironolactone treatment in Author contributions All authors contributed to the conception or preserving renal function in primary aldosteronism. Eur J Endo- design of the work; acquisition, analysis, or interpretation of data; crinol. 2013;168:75–81. drafting the paper or revising it critically for important intellectual 6. Epstein M. Aldosterone as a determinant of cardiovascular and content; and final approval of the version to be published. renal dysfunction. J R Soc Med. 2001;94:378–83. 7. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones Funding This study was funded by CinCor Pharma, Inc. regulating cardiovascular function in patients with severe con- gestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation. 1990;82:1730–6. Compliance with ethical standards 8. Vantrimpont P, Rouleau JL, Ciampi A, Harel F, de Champlain J, Bichet D, et al. Two-year time course and significance of neuro- Conflict of interest MF is an employee of CinCor Pharma, Inc. and humoral activation in the Survival and Ventricular Enlargement receives stock-based compensation. JH is an employee of CinCor (SAVE) Study. Eur Heart J. 1998;19:1552–63. Pharma, Inc. and receives stock-based compensation. MB is an 9. Latini R, Masson S, Anand I, Salio M, Hester A, Judd D, et al. employee of and has equity in CinRx Pharma, LLC, which has an The comparative prognostic value of plasma neurohormones at equity stake in CinCor Pharma, Inc. BM is an employee of and has baseline in patients with heart failure enrolled in Val-HeFT. Eur equity in CinRx Pharma, LLC, which has an equity stake in CinCor Heart J. 2004;25:292–9. Pharma, Inc. JI is an employee of and has equity in CinRx Pharma, 10. Guder G, Bauersachs J, Frantz S, Weismann D, Allolio B, Ertl G, LLC, which has an equity stake in CinCor Pharma, Inc. et al. Complementary and incremental mortality risk prediction by cortisol and aldosterone in chronic heart failure. Circulation. Ethics approval The trial was conducted in accordance with the 2007;115:1754–61. principles of the Declaration of Helsinki and the Good Clinical Prac- 11. Beygui F, Collet JP, Benoliel JJ, Vignolles N, Dumaine R, Bar- tice guidelines of the International Council for Harmonization. The thelemy O, et al. High plasma aldosterone levels on admission are study was conducted at Medpace Clinical Pharmacology Unit (Cin- associated with death in patients presenting with acute ST- cinnati, OH), with approval from the institutional review board, and all elevation myocardial infarction. Circulation. 2006;114:2604–10. patients provided written informed consent before enrollment in 12. Ivanes F, Susen S, Mouquet F, Pigny P, Cuilleret F, Sautiere K, the trial. et al. Aldosterone, mortality, and acute ischaemic events in coronary artery disease patients outside the setting of acute Publisher’s note Springer Nature remains neutral with regard to myocardial infarction or heart failure. Eur Heart J. jurisdictional claims in published maps and institutional affiliations. 2012;33:191–202. 118 M. W. Freeman et al. 13. Marney AM, Brown NJ. Aldosterone and end-organ damage. Clin 19. Hummel J, McKendrick S, Brindley C, French R. Exploratory Sci. 2007;113:267–78. assessment of dose proportionality: review of current approaches 14. Martin RE, Aebi JD, Hornsperger B, Krebs HJ, Kuhn B, Kuglstatter and proposal for a practical criterion. Pharm Stat. 2009;8:38–49. A, et al. Discovery of 4-Aryl-5,6,7,8-tetrahydroisoquinolines as 20. Mornet E, Dupont J, Vitek A, White PC. Characterization of two potent, selective, and orally active aldosterone synthase (CYP11B2) genes encoding human steroid 11 beta-hydroxylase (P-450(11) inhibitors: in vivo evaluation in rodents and cynomolgus monkeys. J beta). J Biol Chem. 1989;264:20961–7. Med Chem. 2015;58:8054–65. 21. Oelkers W. Adrenal insufficiency. N Engl J Med. 1996;335:1206–12. 15. Bogman K, Schwab D, Delporte ML, Palermo G, Amrein K, 22. Wagner RL, White PF. Etomidate inhibits adrenocortical function Mohr S, et al. Preclinical and early clinical profile of a highly in surgical patients. Anesthesiology. 1984;61:647–51. selective and potent oral inhibitor of aldosterone synthase 23. Menard J, Rigel DF, Watson C, Jeng AY, Fu F, Beil M, et al. (CYP11B2). Hypertension. 2017;69:189–96. Aldosterone synthase inhibition: cardiorenal protection in animal 16. Amar L, Azizi M, Menard J, Peyrard S, Watson C, Plouin PF. disease models and translation of hormonal effects to human Aldosterone synthase inhibition with LCI699: a proof-of-concept subjects. J Transl Med. 2014;12:340. study in patients with primary aldosteronism. Hypertension. 24. Schumacher CD, Steele RE, Brunner HR. Aldosterone synthase 2010;56:831–8. inhibition for the treatment of hypertension and the derived 17. Sloan-Lancaster J, Raddad E, Flynt A, Jin Y, Voelker J, Miller mechanistic requirements for a new therapeutic strategy. J JW. LY3045697: Results from two randomized clinical trials of a Hypertens. 2013;31:2085–93. novel inhibitor of aldosterone synthase. J Renin Angiotensin 25. Deinum J, Riksen NP, Lenders JW. Pharmacological treatment of Aldosterone Syst. 2017;18:1470320317717883. aldosterone excess. Pharm Ther. 2015;154:120–33. 18. Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, 26. Hargovan M, Ferro A. Aldosterone synthase inhibitors in hyper- Callaghan JT, et al. Confidence interval criteria for assessment of tension: current status and future possibilities. JRSM Cardiovasc dose proportionality. Pharm Res. 2000;17:1278–83. Dis. 2014;3:2048004014522440. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Hypertension Research Springer Journals

Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the pharmacokinetics and demonstrating the safety and selectivity of the aldosterone synthase inhibitor baxdrostat in healthy volunteers

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10.1038/s41440-022-01070-4
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Abstract

This multiple ascending dose study of the selective aldosterone synthase inhibitor baxdrostat demonstrated a dose-dependent reduction in plasma aldosterone with no meaningful effect on plasma cortisol. There were no deaths or serious adverse events, and all treatment-emergent adverse events in subjects receiving baxdrostat were mild in severity. Chronically elevated aldosterone levels can lead to highly homologous enzyme responsible for cortisol synth- hypokalemia, sodium reabsorption, and fluid retention, esis 11β-hydroxylase (CYP11B1) [15]. In vivo, nonhuman resulting in increased blood pressure (BP). Furthermore, primate pharmacology characterization showed that bax- inflammation, end organ damage, fibrosis, cardiovascular drostat blunted aldosterone production while having no events (e.g., ventricular hypertrophy), and adverse renal effect on cortisol levels [15]. events (e.g., increased urinary albumin excretion, progres- In accordance with the in vitro and in vivo studies, sion of renal failure) can occur with increased aldosterone baxdrostat demonstrated selectivity for aldosterone synthase levels independently of BP [6]. The association between as shown by a dose-dependent reduction in plasma aldos- high plasma aldosterone and decreased long-term survival terone with no effect on ACTH-stimulated plasma cortisol has been demonstrated in patients with congestive heart levels following administration of single ascending doses in the first-in-human study [15]. Although baxdrostat is the failure [7–10], acute myocardial infarction (MI) [11], and coronary artery disease outside the setting of acute MI or parent compound, multiple metabolites are present at lower heart failure [12]. Thus, aldosterone synthase inhibition may concentrations. The active metabolites of baxdrostat also be a promising therapeutic strategy for BP control and exhibited a high degree of selectivity for aldosterone syn- mitigation of end organ damage [13]. thase over 11β-hydroxylase. The primary metabolite, CIN- Baxdrostat (CIN-107) is a highly potent, selective, and 107-M, is a chiral molecule. The 2 enantiomers of CIN-107- competitive small molecule inhibitor of aldosterone syn- M showed >20-fold greater selectivity for aldosterone thase, as demonstrated by preclinical and first-in-human synthase compared to 11β-hydroxylase; however, the more clinical studies [14, 15]. In vitro, baxdrostat exhibited a high potent R enantiomer of CIN-107-M appears to not be selectivity ratio for aldosterone synthase compared to the formed in humans. Given the lower concentrations of the 110 M. W. Freeman et al. metabolites, the parent compound is thought to be the pri- have a body mass index (BMI) ≥ 18 and ≤30 kg/m .In mary contributor to the pharmacologic effect (data on file). addition, they were required to have an appropriate response Baxdrostat had a favorable pharmacokinetic (PK) profile in to cortisol stimulation (cohorts 1 and 2) or a normal cortisol humans. Plasma exposures increased in a dose-proportional level during the inpatient run-in period (cohorts 3–5). manner over the expected therapeutic dose range with a Subjects were excluded if they had (1) a personal or family mean half-life of 29 h, a result that supports once-daily history of long QT syndrome, complex ventricular arrythmias, dosing. Side effects were mild and included headache, or family history of sudden death; (2) personal history of or nasopharyngitis, and diarrhea. current clinically significant arrhythmias; (3) prolonged QTcF The favorable preclinical and early-phase clinical profiles of (>450 ms); (4) seated BP > 150/90 mm Hg or <90/50 mm Hg; baxdrostat warranted assessment at steady state to confirm (5) resting heart rate >100 beats per minute (bpm) or <50 bpm, whether the effects are maintained following multiple doses sinus node dysfunction, or clinically significant heart block; (6) [15], as this has not been the case for 2 previously explored postural tachycardia or orthostatic hypotension; or (7) serum aldosterone synthase inhibitors. In multiple-dose studies, potassium greater than the upper limit of normal of the refer- LCI699 (Novartis Pharmaceuticals) was less selective for ence range and serum sodium less than the lower limit of aldosterone synthase than for 11β-hydroxylase. Significant normal of the reference range. increases in the aldosterone precursor 11-deoxycorticosterone; dose-dependent accumulation of 11-deoxycortisol; and Study design impairment of ACTH-stimulated cortisol synthesis indicated a latent inhibition of cortisol synthesis by LCI699 [16]. The Subjects were randomized in a 3:1 ratio to baxdrostat or potency of another aldosterone synthase inhibitor, LY3045697 placebo once daily for 10 days as follows: (Eli Lilly and Company), was found to decrease significantly with daily dosing. The authors suggest that the decrease in Cohort 1: 2.5 mg baxdrostat or matching placebo on a potency could not be explained by elevated aldosterone pre- low-salt diet, 9 subjects receiving baxdrostat and cursors, but rather likelybyanincrease in aldosterone synthase 3 subjects receiving placebo activity over time [17]. Cohort 2: 5.0 mg baxdrostat or matching placebo on a These results support the importance of the current low-salt diet, 9 subjects receiving baxdrostat and multiple ascending dose assessment to further the under- 3 subjects receiving placebo standing of baxdrostat attained with the prior single-dose Cohort 3: 1.5 mg baxdrostat or matching placebo on a study [15]. This randomized, double-blind, placebo- normal-salt diet, 9 subjects receiving baxdrostat and controlled phase 1 study evaluated the safety, PK, and 3 subjects receiving placebo pharmacodynamics (PD) of multiple ascending doses of Cohort 4: 2.5 mg baxdrostat or matching placebo on a baxdrostat in healthy volunteers. normal-salt diet, 6 subjects receiving baxdrostat and 2 subjects receiving placebo Cohort 5: 0.5 mg baxdrostat or matching placebo on a Methods normal-salt diet, 9 subjects receiving baxdrostat and 3 subjects receiving placebo. Study objectives Cohorts 1 and 2 were dosed concurrently with a minimum The primary objectives of this study were to assess safety, 5-day lag between the first dose for cohort 2 and the first dose tolerability, PK, and PD of baxdrostat following oral dosing for cohort 1. A data review committee met between cohorts 2 once daily for 10 days in subjects with a normal- or low-salt and 3 and determined that cohorts 3 through 5 could be dosed diet. The low-salt diet cohorts were included to stimulate concurrently. Each patient had a screening period of up to aldosterone production and to evaluate safety in potential 28 days, followed by a 5-day run-in period in which the patients who may be following a low-salt diet. subjects adhered to a controlled, standardized diet and underwent baseline PD assessments (Supplementary Fig. 1). Subjects This was followed by a 15-day inpatient treatment period in which the subjects received baxdrostat or placebo once daily Subjects were included in the study if they were between for 10 days while remaining on the controlled, standardized the ages of 18 and 55 years and in good health based on diet. Blood and urine sample collection for PK and PD medical and psychiatric history, physical examination, analysis continued for an additional 5 days and was pro- electrocardiogram (ECG), orthostatic vital signs, and rou- ceeded by a follow-up visit 3 ± 1 days after clinic discharge. tine laboratory tests (blood chemistry, hematology, coagu- The study drug was a 2 mg/mL baxdrostat oral solution lation, and urinalysis). Subjects had to be nonsmokers and and matching oral placebo solution. Subjects received a Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the. . . 111 single dose of oral solution of baxdrostat or placebo on the PK. Pharmacokinetic parameters were calculated by standard mornings of days 1 through 10 at 8:00 a.m. (± 2 h). On days noncompartmental methods using Phoenix WinNonlin™ 1 and 10, the dose was given following an overnight fast (of (Certara, Inc., Princeton, NJ) and verified with SAS (SAS at least 8 h), and subjects remained fasted for at least 4 h Institute, Inc., Cary, NC) software. Plasma PK parameters after dosing on these days. On all other days, subjects fasted included maximum observed plasma concentration on day 1 for a minimum of 2 h before and 2 h after dosing. (C )and day10(C ), time to C on day1(T ) max,D1 max,D10 max max,D1 For cohort 1, the controlled, standardized low-salt diet and day 10 (T ), and area under the plasma concentration- max,D10 + + consistedof50to60mEq Na /d and70 to100 mEqK /d time curve(AUC)fromtime0 to 24hpostdoseonday 1 from day −5 until day −1. Based on decreases in sodium (AUC ) or from time 0 to 24 h on day 10 (AUC ). 0-24 h 0-tau levels observed in some subjects during the run-in period prior Steady-state plasma PK parameters consisted of accumulation to any subjects receiving the study drug, the diet was modified ratio based on C (R ), accumulation ratio based on AUC max Cmax + + to 65 to 70 mEq Na /d and70to100 mEqK /d from day 1 (R ), apparent first-order terminal elimination rate constant AUC through the remainder of the study. Cohort 2 subjects were (λ ), terminal phase elimination half-life (t ), apparent plasma z 1/2 given a low-salt diet consisting of up to 65 to 70 mEq Na /d clearance (CL /F), and apparent volume of distribution (V /F). ss ss and70to 100 mEq K /d for the full run-in and treatment An exploratory dose proportionality analysis of baxdrostat, periods. Cohorts 3 through 5 were on a normal-salt diet of 100 C , and AUC (day 1) or C ,AUC ,and max,D1 0-24 h max,D10 0-tau + + to 104 mEq Na /d and70to100 mEq K /d for the full run-in AUC (day 10) was performed using a power model to esti- 0-t and treatment periods. mate the mean slope and 90% confidence interval (CI). TM Cohorts 1 and 2 also underwent an ACTH (Cortrosyn ) The cumulative amount of drug excreted in urine on day challenge at baseline (day −1), 1 h after the first dose of study 1(A ) and day 10 (A ), fraction of dose excreted e,D1 e,D10 drug on day 1, and 1 h after the final dose of study drug on day renally on day 1 (F ) and day 10 (F ), and renal e,D1 e,D10 10. This was done to increase aldosterone and cortisol levels to clearance on day 1 (CL ) and day 10 (CL ) composed R,D1 R,D10 more thoroughly evaluate the specificity of baxdrostat for tar- single-dose urine PK parameters. geting aldosterone synthase. The ACTH challenge consisted of TM an intravenous injection of 0.25 mg Cortrosyn administered Pharmacodynamic and safety analyses over 2 min after an overnight fast. Plasma PD measures included concentrations of aldoster- Analytical methods one, 18-hydroxycorticosterone, corticosterone, 11-deox- ycorticosterone, cortisol (free and total), 11-deoxycortisol, Plasma and urine samples were analyzed to measure con- ACTH, sodium, chloride, and potassium. AUCs were cal- centrations of baxdrostat and its primary metabolite (CIN-107- culated using a noncompartmental analysis and the linear M), aldosterone and its precursors, cortisol and its precursor, trapezoidal/linear interpolation method. Urine PD measures and ACTH using a validated liquid chromatography tandem included concentrations of aldosterone, cortisol (free and mass spectrometry method (LC-MS/MS). The quantifiable total), tetrahydroaldosterone, sodium, chloride, potassium, ranges for both baxdrostat and its metabolite CIN-107-M in creatinine, and phosphorus. Other PD measures were plasma and urine were 0.05 to 50 ng/mL (low range) and 5 to seated, orthostatic, and positional changes in vital signs, as 2500 ng/mL (high range), using baxdrostat-d and CIN-107- well as changes in body weight and BMI. Safety assess- M-d , respectively, as the internal standards. Plasma samples ments involved adverse events, physical examinations, were extracted by protein precipitation with methanol, fol- ECGs, orthostatic vital signs, and clinical laboratory lowed by analysis by LC-MS/MS with electrospray ionization evaluations. in positive mode and multiple reaction monitoring. All scheduled study-related laboratory tests were performed by Statistical analyses Medpace Reference Laboratories (Cincinnati, OH, USA), Medpace Bioanalytical Laboratories (Cincinnati, OH, USA), Subjects who received placebo were pooled into 2 treatment Mercy Health—West Hospital Laboratory (Cincinnati, groups: placebo with low-salt diet and placebo with normal- OH, USA), or Laboratory Corporation of America (Dublin, salt diet. Descriptive statistics were calculated for PK, PD, OH, USA). and safety measures. The effects of dose on plasma aldos- terone and cortisol (free and total) and their precursors were Pharmacokinetic analyses investigated using an analysis of variance model on change in AUC over 12 h from day −1 to day 1 and from day −1to Blood samples were collected prior to and after dosing on days day 10. Data are presented as change from baseline in least 1 and 10 for measurement of plasma baxdrostat and CIN-107- squares mean (90% CI) AUC of plasma aldosterone on 0-12h M concentrations to characterize single-dose and steady-state days 1 and 10. The results of the exploratory dose 112 M. W. Freeman et al. Table 1 Baseline demographics and clinical characteristics Demographic or Low-salt diet Normal-salt diet characteristic Pooled placebo 2.5 mg baxdrostat 5.0 mg baxdrostat Pooled placebo 0.5 mg baxdrostat 1.5 mg baxdrostat 2.5 mg baxdrostat (n = 6) (n = 9) (n = 9) (n = 8) (n = 9) (n = 9) (n = 6) Age (y), mean ± SD 43.8 ± 6.4 37.2 ± 8.7 39.3 ± 10.2 37.0 ± 8.7 37.9 ± 8.6 44.8 ± 8.6 39.0 ± 9.7 Race, n (%) White 2 (33.3) 4 (44.4) 5 (55.6) 5 (62.5) 3 (33.3) 3 (33.3) 4 (66.7) Black or African 4 (66.7) 5 (55.6) 3 (33.3) 3 (37.5) 6 (66.7) 5 (55.6) 2 (33.3) American Asian 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) Other 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Ethnicity, n (%) Hispanic or Latino 1 (16.7) 0 (0.0) 2 (22.2) 1 (12.5) 2 (22.2) 1 (11.1) 0 (0.0) Not Hispanic or Latino 5 (83.3) 9 (100.0) 7 (77.8) 7 (87.5) 7 (77.8) 8 (88.9) 6 (100.0) Sex, n (%) Female 1 (16.7) 4 (44.4) 3 (33.3) 1 (12.5) 4 (44.4) 1 (11.1) 3 (50.0) Male 5 (83.3) 5 (55.6) 6 (66.7) 7 (87.5) 5 (55.6) 8 (88.9) 3 (50.0) Height (cm), mean ± SD 175.3 ± 10.2 168.9 ± 10.7 170.1 ± 12.2 170.2 ± 8.6 171.5 ± 11.5 173.4 ± 9.7 171.7 ± 8.2 Body weight (kg), 78.3 ± 13.2 77.0 ± 11.0 75.8 ± 12.0 70.4 ± 11.0 79.5 ± 12.0 78.6 ± 11.3 74.9 ± 5.5 mean ± SD BMI (kg/m ), mean ± SD 25.3 ± 2.5 26.9 ± 1.4 26.0 ± 1.7 24.3 ± 3.2 26.9 ± 1.8 26.0 ± 2.5 25.5 ± 2.4 BMI body mass index proportionality power model were assessed using the Smith criteria (0.9031, 1.0969) [18] and the less stringent Hummel criteria (0.6990, 1.3010) [19]. Three subjects had negligible aldosterone concentrations on day −1 that increased to more expected levels on days 1 and 10. Including these subjects in the baseline analyses skewed the results and disrupted cross-treatment compar- isons; therefore, they were considered outliers and were not included in the data presented here. Results Subjects Demographics and baseline characteristics are presented in Table 1. Most study participants were male (70%), Black or African American (50%), and not Hispanic or Latino (88%). The average age was 40 years, and mean BMI ranged from 24 to 27 kg/m . The demographic and baseline character- istics were generally well matched in sex and race across treatment groups. Pharmacokinetics Single-dose and steady-state plasma PK parameters of bax- Fig. 1 Plasma Baxdrostat Concentration vs. Time on Days 1 and 10. drostat are presented in Supplementary Table 1. Baxdrostat Plasma baxdrostat concentration (ng/mL) by scheduled time point and was rapidly absorbed with a median T observed within max treatment. Data are mean ± standard deviation 4 h of dosing (Fig. 1). Baxdrostat concentrations declined from peak in an apparent biphasic manner with a mean t increased exposure with increasing dose. At steady state, 1/2 ranging from approximately 26 to 31 h. The plasma baxdrostat exposure was approximately 2- to 2.5-fold higher concentration-time profile of baxdrostat demonstrated than after a single dose. Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the. . . 113 Fig. 2 Baxdrostat Reduces Plasma Aldosterone Levels in a Dose- effect-time curve from time 0 to 12 h postdose on day 1 and day 10. dependent Manner. Estimated percentage change from baseline Data are least squares mean and 90% confidence intervals. AUC (day −1) in plasma aldosterone area under the pharmacodynamic indicates area under the curve An exploratory analysis to assess dose proportionality Pharmacodynamics demonstrated that with increasing doses of baxdrostat there was a proportional increase in both C and AUC on A dose-dependent reduction of plasma aldosterone (esti- max 0-24 h day 1 (according to the Hummel criteria). Similarly, pro- mated percentage change from baseline AUC ) occurred 0-12h portional increases in C , AUC , and AUC on day 10 with baxdrostat doses ≥1.5 mg, regardless of normal- or max 0-tau 0-t were also observed. low-salt diet. Decreases in plasma aldosterone were Although CIN-107-M is not believed to contribute observed starting on day 1 and were sustained, with levels substantially to the effects of baxdrostat, its prevalence reduced by ~51 to 73% on day 10 (Fig. 2). Corresponding warrants characterization. On average, CIN-107-M repre- dose-dependent decreases of aldosterone and tetra- sents 8 to 11% of the parent compound based on C hydroaldosterone urine excretion were also observed (data max,D10 and 10 to 22% of the parent compound based on AUC . not shown). 0-inf Based on plasma concentration data, CIN-107-M was Baxdrostat caused a modest increase in the aldosterone formed ~4 to 24 h after the initial dose of baxdrostat on precursor 11-deoxycorticosterone under both normal- and day 1 andwas typicallyobservedwithin4 hatsteadystate low-salt diet conditions. Additional aldosterone precursors (day 10). Plasma levels of CIN-107-M showed a dose- demonstrated stepwise changes indicative of the progressive proportional increase similar to the PK of the parent impact of aldosterone synthase inhibition on the pathway compound (data not shown). Approximately 7% (mean of aldosterone synthesis. 18-hydroxycorticosterone (the F ranged from 6.3 to 10.8% across treatment groups) immediate precursor to aldosterone) levels were generally e,D1 of the baxdrostat dose was recovered unchanged in the comparable or decreased compared to baseline, although to urine on day 1. At steady state (day 10), ~32% was a lesser extent than aldosterone. Corticosterone levels recovered unchanged (mean F ranged from 30.7 to increased in an apparent dose-dependent manner, likely due e,D10 33.6% across treatment groups). to 11β-hydroxylase activity (Supplementary Fig. 2). 114 M. W. Freeman et al. Fig. 3 Baxdrostat Does Not Have a Significant Effect on Plasma curve from time 0 to 12 h postdose on day 1 and day 10. Data are least Cortisol Levels. Estimated percentage change from baseline (day −1) squares mean and 90% confidence intervals. AUC indicates area under in plasma cortisol (total) area under the pharmacodynamic effect-time the curve Baxdrostat had no meaningful effect on plasma cortisol potassium). The sodium:potassium ratio was increased (total or free) or 11-deoxycortisol concentrations even in the (sodium loss in the urine was greater than the potassium presence of the ACTH challenge in the low-salt diet groups retention) on day 1 following the first dose of baxdrostat; (Fig. 3). Likewise, there was no meaningful effect on urine however, this effect was diminished by day 10. This appears free cortisol (Supplementary Fig. 3). Subjects on a low-salt to be mediated by a greater elimination of sodium on day 1 diet had increased plasma ACTH levels at baseline. The compared to day 10, as potassium did not substantially increases were somewhat more pronounced in subjects change over the course of the treatment period (Fig. 4). receiving baxdrostat compared to placebo. Under normal- Renal function was assessed by plasma blood urea salt conditions, however, baxdrostat resulted in a dose- nitrogen (BUN), creatinine, and glomerular filtration rate. dependent decrease in ACTH. There were mild increases in BUN, creatinine, and the There were no clinically significant changes or dose- BUN:creatinine ratio. A mild reduction in glomerular fil- related trends in seated heart rate or BP (Supplementary tration rate (<15%) was also observed. These results sug- Fig. 4). A slight trend toward mild, drug-induced decreases gests that baxdrostat has a mild diuretic effect. Mean body in orthostatic BP and moderate increases in orthostatic heart weight and BMI decreased slightly from baseline during the rate were observed, but there was no clear dose- treatment period in all treatment groups, including placebo; dependency. The most pronounced effects on heart rate however, the decrease was more pronounced in subjects occurred in the 5-mg baxdrostat treatment group. receiving baxdrostat. The values largely returned to baseline Baxdrostat administration resulted in mild dose- at the follow-up visit. dependent decreases in plasma sodium levels and increa- There were no deaths, serious adverse events, or dis- ses in potassium levels, as would be expected from the continuations due to treatment-emergent adverse events observed reduction in aldosterone (Supplementary Fig. 5). (TEAEs). Overall, 6 (14.3%) subjects receiving baxdrostat Urine sodium and potassium levels corresponded to the and 3 (21.4%) subjects receiving placebo experienced a changes observed in plasma (increased sodium, decreased TEAE that was considered related to the study drug. All Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the. . . 115 Fig. 4 Urinary Sodium and Potassium Concentrations Following interquartile range (box) and minimum-maximum (whiskers) for Baxdrostat Administration. Urine sodium and potassium concentra- sodium or potassium from 24 h urine collections tions at baseline (BL), day 1, and day 10. Box whiskers show TEAEs in subjects receiving baxdrostat were mild possibly increased mortality rates [21, 22]. Based on pre- (Table 2). There were no clinically meaningful changes in clinical studies, it was predicted that baxdrostat would physical examination findings, vital signs, electro- selectively inhibit aldosterone synthase [15]. Our results cardiograms (including no QT prolongation), or clinical demonstrate that at doses ≥1.5 mg, baxdrostat produces a laboratory results related to safety. dose-dependent decrease in aldosterone compared to base- line and placebo while having no meaningful impact on cortisol levels, supporting the selective nature of baxdrostat. Discussion Importantly, the aldosterone-lowering effect was sustained, suggesting no apparent compensatory mechanisms over the Consistent with the single ascending dose study results [15], duration of the study and thus differentiating baxdrostat oral dosing of baxdrostat resulted in dose-proportional from the previously studied aldosterone synthase inhibitors increases in plasma baxdrostat and its metabolite with a LCI699 and LY3045697. relatively long half-life of 26 to 31 h, resulting in support of Lack of specificity for aldosterone synthase has resulted once-daily dosing. in the discontinuation of LCI699, which was previously One of the challenges of aldosterone synthase inhibition being developed for the treatment of hypertension [16]. is to achieve high selectivity for the enzyme, which shares LCI699 was selective for aldosterone synthase after a single 93% homology to cortisol synthase [20]. Suppression of dose; however, after multiple-dose administration it showed cortisol could lead to compromised stress response, a time-dependent loss of selectivity [23]. LY3045697 lost impaired immune system, inadequate metabolism, and its aldosterone-reducing potency after multiple doses (half 116 M. W. Freeman et al. Table 2 Summary of adverse events Adverse events, n (%) Low-salt diet Normal-salt diet Pooled placebo 2.5 mg baxdrostat 5.0 mg baxdrostat Pooled placebo 0.5 mg baxdrostat 1.5 mg baxdrostat 2.5 mg baxdrostat (n = 6) (n = 9) (n = 9) (n = 8) (n = 9) (n = 9) (n = 6) Any AE 2 (33.3) 3 (33.3) 3 (33.3) 1 (12.5) 1 (11.1) 1 (11.1) 3 (50.0) Any TEAE 2 (33.3) 3 (33.3) 3 (33.3) 1 (12.5) 1 (11.1) 1 (11.1) 3 (50.0) Palpitations 0 (0.0) 0 (0.0) 0 (0.0) 1 (12.5) 0 (0.0) 0 (0.0) 0 (0.0) Ventricular 1 (16.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) tachycardia Eye irritation 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Abdominal pain 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Constipation 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) Nausea 1 (16.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Rhinitis 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Viral infection 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Back pain 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Headache 0 (0.0) 1 (11.1) 1 (11.1) 0 (0.0) 1 (11.1) 0 (0.0) 1 (16.7) Dizziness postural 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (33.3) Dizziness 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Presyncope 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Anxiety 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Dry throat 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (16.7) Dysphonia 0 (0.0) 0 (0.0) 1 (11.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Any treatment- 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) emergent SAE Any drug-related 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) treatment-emergent SAE Any TEAE leading 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) to death Any TEAE leading to 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) discontinuation TEAEs are defined as any AE, regardless of relationship to the study drug, which began after the first dose was administered AE adverse event, SAE serious adverse event, TEAE treatment-emergent adverse event maximal inhibitory concentration was 47 times higher than moderate increases in orthostatic heart rate indicate that after single-dose administration) despite similar PK with baxdrostat represents a promising treatment for the negative both single- and multiple-dose administration [17]. health impact of elevated aldosterone. It is difficult to pre- Baxdrostat decreased plasma aldosterone levels under dict how the observed 51 to 73% reduction in plasma both low-salt and normal-salt diet conditions; the 2.5-mg aldosterone will translate to BP reduction in patients with baxdrostat dose used in both low- and normal-salt condi- primary aldosteronism or uncontrolled or treatment-resistant tions showed a similar effect on lowering plasma aldoster- hypertension; however, further studies in these patient one levels. The low-salt diet subjects of cohorts 1 and 2 also populations will help elucidate this relationship. underwent an ACTH challenge to further stimulate aldos- There are potential benefits of selective aldosterone terone and cortisol levels prior to receiving baxdrostat. synthase inhibition vs. MR antagonism. For example, due to Baxdrostat suppressed plasma aldosterone levels while the hypothalamic-pituitary axis feedback loop, blocking having no meaningful effect on cortisol, even in the pre- MRs activates the RAAS, leading to a compensatory sence of the ACTH challenge, further supporting the increase in aldosterone, which could overcome the blockade selectivity of baxdrostat to inhibit aldosterone synthase. by MR antagonists [25]. In addition, current MR antago- As expected, the inhibition of aldosterone synthase by nists (spironolactone and eplerenone) are accompanied by baxdrostat resulted in an increase in the aldosterone pre- adverse events, such as sexual dysfunction, gynecomastia in cursor 11-deoxycorticosterone under both normal- and low- men, and electrolyte imbalances [26]. Baxdrostat was well salt diet conditions. However, the magnitude of increase tolerated with a favorable safety profile. The most common was modest (~2- to 3-fold) compared to what has previously TEAEs in subjects receiving baxdrostat were headache, been observed for LCI699, where 11-deoxycorticosterone postural dizziness, and dizziness. levels increased up to 10-fold [24]. The relatively small sample size for each treatment group Although the study was conducted in healthy volunteers, is a limitation of the current study. Because it was con- the apparent diuretic effect, the slight trends toward mild ducted in healthy subjects, the clinical relevance of these baxdrostat-induced decreases in orthostatic BP, and the findings needs to be investigated in patients who have Results from a phase 1, randomized, double-blind, multiple ascending dose study characterizing the. . . 117 uncontrolled or treatment-resistant hypertension or primary Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, aldosteronism. As expected, we were unable to detect BP adaptation, distribution and reproduction in any medium or format, as changes in our healthy subjects and therefore were not able long as you give appropriate credit to the original author(s) and the to definitively identify the efficacious dose range for source, provide a link to the Creative Commons license, and indicate if patients with hypertension or primary aldosteronism. changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless Moreover, the relationship between the magnitude of indicated otherwise in a credit line to the material. If material is not aldosterone lowering and BP lowering is not yet defined. included in the article’s Creative Commons license and your intended For these reasons, further study is needed to understand the use is not permitted by statutory regulation or exceeds the permitted dose-response for lowering BP in these patients, including use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. the possibility of additional higher doses. org/licenses/by/4.0/. References Conclusions 1. 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Journal

Hypertension ResearchSpringer Journals

Published: Jan 1, 2023

Keywords: Aldosterone synthase inhibitor; Aldosterone; CYP11B2; Hypertension; Primary aldosteronism

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