Nejmoa 2213169

The n e w e ng l a n d j o u r na l of m e dic i n e
Original Article
Phase 2 Trial of Baxdrostat for Treatment-

Resistant Hypertension
Mason W. Freeman, M.D., Yuan‑Di Halvorsen, Ph.D., William Marshall, M.D.,
Mackenzie Pater, Ph.D., Jon Isaacsohn, M.D., Catherine Pearce, D.H.Sc.,
Brian Murphy, M.D., M.P.H., Nicholas Alp, M.D., Ajay Srivastava, M.D.,
Deepak L. Bhatt, M.D., M.P.H., and Morris J. Brown, M.D.,
for the BrigHTN Investigators*
A BS T R AC T
BACKGROUND
Aldosterone synthase controls the synthesis of aldosterone and has been a phar- From CinCor Pharma (M.W.F., Y.-D.H.,
macologic target for the treatment of hypertension for several decades. Selective W.M., C.P.) and Brigham and Women’s
Hospital, Harvard Medical School
inhibition of aldosterone synthase is essential but difficult to achieve because (D.L.B.) — both in Boston; CinRx Phar-
cortisol synthesis is catalyzed by another enzyme that shares 93% sequence simi- ma (M.P., J.I., B.M.) and Medpace (N.A.,
larity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had A.S.) — both in Cincinnati; and the De-
partment of Clinical Pharmacology, Wil-
100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels re- liam Harvey Research Institute, Queen
duced plasma aldosterone levels but not cortisol levels. Mary University of London, London
(M.J.B.). Dr. Brown can be contacted at
METHODS morris.brown@qmul.ac.uk or at Queen
Mary University of London, Charter-
In this multicenter, placebo-controlled trial, we randomly assigned patients who house Sq., London EC1M 6BQ, United
had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or Kingdom.
higher, and who were receiving stable doses of at least three antihypertensive *The BrigHTN Investigators are listed in
agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once the Supplementary Appendix, available
daily for 12 weeks or placebo. The primary end point was the change in systolic at NEJM.org.
blood pressure from baseline to week 12 in each baxdrostat group as compared This article was published on November
with the placebo group. 7, 2022, and updated on January 6, 2023,
at NEJM.org.
RESULTS DOI: 10.1056/NEJMoa2213169
A total of 248 patients completed the trial. Dose-dependent changes in systolic Copyright © 2022 Massachusetts Medical Society.
blood pressure of −20.3 mm Hg, −17.5 mm Hg, −12.1 mm Hg, and −9.4 mm Hg
were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The
difference in the change in systolic blood pressure between the 2-mg group and
the placebo group was −11.0 mm Hg (95% confidence interval [CI], −16.4 to −5.5;
P<0.001), and the difference in this change between the 1-mg group and the pla-
cebo group was −8.1 mm Hg (95% CI, −13.5 to −2.8; P = 0.003). No deaths occurred
during the trial, no serious adverse events were attributed by the investigators to
baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdro-
stat-related increases in the potassium level to 6.0 mmol per liter or greater oc-
curred in 2 patients, but these increases did not recur after withdrawal and re-
initiation of the drug.
CONCLUSIONS
Patients with treatment-resistant hypertension who received baxdrostat had dose-
related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN Clinical
Trials.gov number, NCT04519658.)
n engl j med nejm.org 1

The New England Journal of Medicine
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E
levated blood pressure, the lead- Key exclusion criteria were a mean seated
ing global risk factor for cardiovascular systolic blood pressure of at least 180 mm Hg or
disease, stroke, disability, and death, af- a diastolic blood pressure of at least 110 mm Hg,
fects an estimated 1.4 billion persons world- an estimated glomerular filtration rate (GFR) of
wide.1 In the United States, approximately 10% less than 45 ml per minute per 1.73 m2 of body-
of persons with hypertension (10 to 12 million surface area, and uncontrolled diabetes. To be
persons) have treatment-resistant hypertension, eligible for the trial, patients who had been re-
which is defined as elevated blood pressure de- ceiving a mineralocorticoid receptor antagonist
spite concurrent use of at least three antihyper- or a potassium-sparing diuretic were required to
tensive drugs of different classes, including a discontinue these agents for a total of 4 weeks
diuretic.2 Persons with treatment-resistant hyper- before randomization. Complete inclusion and
tension have a substantially increased risk of exclusion criteria are provided in the Supplemen-
cardiovascular and renal adverse events.3,4 tary Methods section in the Supplementary Ap-
Patients with treatment-resistant hypertension pendix, available with the full text of this article
are often prescribed at least four antihyperten- at NEJM.org.
sive agents,5 with a goal (in the United States) of The trial registration was submitted to Clini-
an in-office systolic blood pressure of less than calTrials.gov on August 17, 2020. Although the
130 mm Hg and diastolic blood pressure of first patient in our trial underwent screening
80 mm Hg or less.2,6,7 Current guidelines recom- before that date, no patients were enrolled before
mend the addition of spironolactone, a mineralo- the trial registration was submitted or accepted.
corticoid receptor antagonist, as a fourth-line After a screening period of up to 8 weeks, eligible
agent despite common, dose-limiting adverse patients entered a 2-week, single-blind run-in
effects.6 A total of 40 to 50% of patients with period to determine whether medication adher-
hypertension remain inadequately treated,8 and ence was a factor in not attaining their blood-
yet no new class of antihypertensive medication pressure goal. Patients with at least 70% adher-
has been approved since 2007.9 ence (determined on the basis of pill counts) to
Aldosterone synthase inhibitors target a like- each antihypertensive medication and placebo dur-
ly cause of treatment resistance by suppress- ing the run-in period and a seated blood pres-
ing hormone synthesis rather than by blocking sure of at least 130/80 mm Hg were randomly
the mineralocorticoid receptor. Preclinical and assigned to receive either 0.5 mg, 1 mg, or 2 mg
phase 1 studies have shown that baxdrostat has of baxdrostat or matching placebo. The doses of
high selectivity (selectivity ratio, 100:1) for aldo- baxdrostat were selected on the basis of decreases
sterone synthase as compared with the enzyme in aldosterone levels that had been measured in
required for cortisol synthesis, 11β-hydroxylase, our previous multiple-ascending-dose study.11
which shares 93% sequence similarity with aldo- After randomization, clinical visits were con-
sterone synthase.10 In the current trial, we exam- ducted on days 3, 8, 15, 22, 43, 64, and 85 (the
ined the efficacy and safety of baxdrostat in last day of the treatment period), and a follow-up
patients with treatment-resistant hypertension. telephone call occurred 1 week after the last
dose (Fig. S1 in the Supplementary Appendix).
Additional details regarding the trial design are
Me thods
provided in the Supplementary Appendix.
Trial Design and Population BrigHTN was conducted primarily at commu-
BrigHTN, a multicenter, randomized, double- nity-based practices in the United States, as well
blind, placebo-controlled, parallel-group, dose- as at a small number of academic hospital–based
ranging trial, had an adaptive design. The trial practices. The trial was designed by CinCor
enrolled men and women who were 18 years of Pharma, CinRx Pharma, and external scientific
age or older, were receiving stable doses of at advisers and funded by CinCor Pharma. Data
least three antihypertensive medications (one of were collected and analyzed by authors em-
which was a diuretic), and had a mean blood ployed by Medpace and CinCor Pharma, who
pressure of at least 130/80 mm Hg while seated. vouch for the accuracy and completeness of the
Blood pressure was determined as the average of data and for the fidelity of the trial to the proto-
three measurements obtained with the use of an col, available at NEJM.org. The first draft of the
automated in-office blood-pressure monitor. manuscript was written by the first and last au-
2 n engl j med nejm.org

Baxdrostat for Treatment-Resistant Hypertension
thors. A professional writer paid by the sponsor renin activity. Details are provided in the Supple-
assisted the authors in the preparation of the mentary Appendix.
manuscript. All the authors made the decision to
submit the manuscript for publication. Statistical Analysis
The trial was conducted in accordance with We estimated that a sample of 77 patients in
the principles of the Declaration of Helsinki and each group would provide the trial with at least
the Good Clinical Practice guidelines of the In- 80% power to detect a difference in the mean
ternational Council for Harmonisation. All the (±SD) seated systolic blood pressure of 5±11 mm
clinical sites that participated in the trial ob- Hg after the 12-week treatment period between
tained approval from an institutional review each of the three baxdrostat groups and the
board at the site that was authorized to approve placebo group at a two-sided significance level
studies involving humans, and all patients pro- of 0.05. This estimate was based on the assump-
vided written informed consent before enroll- tion of a 13% early withdrawal rate, and an ini-
ment in the trial. An independent data monitor- tial enrollment of 348 patients (87 per trial
ing committee performed a formal unblinded group) was planned. To prevent imbalance be-
interim analysis when approximately 200 pa- tween the trial groups, patients were stratified
tients had completed the 12-week treatment according to their baseline systolic blood pres-
period. Details regarding the interim analysis sure (<145 mm Hg or ≥145 mm Hg) and their
are provided in the Supplementary Appendix. baseline estimated GFR (<60 ml per minute per
1.73 m2 or ≥60 ml per minute per 1.73 m2).
End Points The primary efficacy analysis compared the
The primary efficacy end point was the change change in the mean seated systolic blood pres-
in the mean seated systolic blood pressure from sure from baseline to the end of the treatment
baseline to the end of the 12-week treatment period between each baxdrostat group and the
period in each baxdrostat group as compared placebo group in the modified intention-to-treat
with the placebo group. The secondary end population (patients who received at least one
points were the change from baseline in the dose of baxdrostat or placebo and had a baseline
mean seated diastolic blood pressure and the value for the systolic blood-pressure assess-
percentage of patients with a seated blood pres- ment). We used linear regression for a repeated-
sure of less than 130/80 mm Hg at the end of the measures model and an unstructured covariance
12-week treatment period. No adjustments were matrix, and we assumed that missing blood-
made for multiplicity in the analysis of the sec- pressure values were missing at random. The
ondary outcomes; hence, the confidence inter- model used change from baseline as the depen-
vals should not be used in place of hypothesis dent variable and included fixed effects for treat-
tests. ment, visit, and treatment-by-visit interaction,
The safety end points included adverse events, including covariates of the baseline systolic
vital signs, and the results of laboratory tests, blood pressure and estimated GFR. Restricted
electrocardiography, and physical examinations. maximum likelihood estimation was used with
Prespecified adverse events of special interest an unstructured covariance matrix and the Ken-
were hyperkalemia, hyponatremia, and hypoten- ward–Roger approximation for degrees of free-
sion warranting clinical intervention. Patients dom. To preserve the overall alpha level for the
with potassium levels between 5.5 and 5.9 mmol primary end point, a fixed-sequence testing
per liter were contacted and asked to return for procedure was performed with the highest-dose
a repeat electrolyte measurement as soon as fea- group comparison tested first.
sible, but they continued to receive baxdrostat The secondary efficacy end point of change
or placebo. In contrast, patients with potassium from baseline in diastolic blood pressure was
levels between 6.0 and 6.4 mmol per liter were analyzed with the use of linear regression for a
directed to discontinue baxdrostat or placebo repeated-measures model like that used in the
and return for reevaluation as soon as feasible. primary efficacy analysis. A sensitivity analysis
Exploratory pharmacokinetic and pharmaco- was performed for missing data for the primary
dynamic analyses were performed to assess the end point, with the use of a control-based pat-
levels of plasma baxdrostat, serum and urinary tern imputation model and the assumption that
aldosterone, and serum cortisol as well as plasma the data were not missing at random.

779 Patients were assessed for eligibility
419 Did not meet inclusion criteria

or met exclusion criteria
360 Entered single-blind run-in period
85 Did not meet run-in criteria
275 Underwent randomization
1 Assigned to receive baxdrostat, 1 mg,

did not receive baxdrostat or placebo
69 Were assigned to and 69 Were assigned to and 67 Were assigned to and 69 Were assigned to and
received baxdrostat, 0.5 mg received baxdrostat, 1 mg received baxdrostat, 2 mg received placebo
4 Withdrew 9 Withdrew 11 Withdrew 2 Withdrew

3 Were lost to follow-up 1 Was lost to follow-up 3 Were lost to follow-up 1 Was lost to follow-up
1 Was withdrawn by 3 Withdrew consent 4 Withdrew consent 1 Had other reason
physician 1 Was withdrawn by 3 Were withdrawn by
physician physician
1 Had adverse event 1 Had adverse event
2 Had protocol deviation
1 Had other reason
69 Were included in the 69 Were included in the 67 Were included in the 69 Were included in the
safety and efficacy analyses safety and efficacy analyses safety and efficacy analyses safety and efficacy analyses
Figure 1. Screening, Randomization, and Follow-up.

Patients who received at least one dose of baxdrostat or placebo and who had a baseline systolic blood-pressure
measurement were included in the modified intention-to-treat population. The efficacy analyses were based on the
intention-to-treat approach. The primary reasons for trial discontinuation were withdrawal of consent and loss to
follow-up. A total of 248 patients completed the 12-week treatment period.
R e sult s were similar with respect to demographic and

clinical characteristics at baseline. The trial popu-
Patient Characteristics lation was predominantly White (70%). Black
A total of 779 patients underwent screening, and patients constituted a higher percentage of pa-
360 were included in the placebo run-in period. tients in the trial (28%) than their proportionate
A total of 275 patients were randomly assigned to representation in the U.S. population (Table S1).
receive once-daily baxdrostat at a dose of 0.5 mg The trial included a sizable percentage of pa-
(69 patients), 1 mg (70 patients), or 2 mg (67 tients who identified as Hispanic (43%) and a
patients), or placebo (69 patients). One patient small percentage who identified as Asian (2%)
who was randomly assigned to receive baxdro- (Table 1).
stat in the 1-mg group never received the drug, The first patient underwent screening on July
so the modified intention-to-treat population 30, 2020, and the last patient visit occurred on
included 274 patients (Fig. 1). The trial groups June 14, 2022. A total of 248 patients (90%) com-

Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.*
Baxdrostat, Baxdrostat, Baxdrostat,

Placebo 0.5 mg 1 mg 2 mg
Characteristic (N = 69) (N = 69) (N = 70) (N = 67)
Age
Mean — yr 63.8±10.8 61.5±10.3 62.7±10.1 61.2±10.8
<65 yr — no. (%) 32 (46) 39 (56) 39 (56) 41 (61)
≥65 yr — no. (%) 37 (54) 30 (43) 31 (44) 26 (39)
Male sex — no. (%) 42 (61) 36 (52) 37 (53) 38 (57)
Race or ethnic group — no. (%)†
White 51 (74) 45 (65) 48 (69) 47 (70)
Black 16 (23) 22 (32) 20 (29) 19 (28)
Asian 2 (3) 1 (1) 2 (3) 1 (1)
American Indian or Alaska Native 0 1 (1) 0 0
Hispanic or Latinx 30 (43) 33 (48) 23 (33) 32 (48)
Body-mass index‡ 32.1±5.3 33.2±5.3 31.9±5.2 33.3±5.1
Seated blood pressure — mm Hg
Systolic 148.9±12.4 147.6±12.5 147.7±13.1 147.3±11.8
Diastolic 88.2±6.1 87.6±7.7 87.7±6.0 88.2±7.1
Estimated glomerular filtration rate
Mean — ml/min/1.73 m2 85.5±17.5 81.0±20.4 83.2±20.6 85.2±19.4
<60 ml/min/1.73 m — no. (%)
2
6 (9) 14 (20) 11 (16) 8 (12)
≥60 ml/min/1.73 m2 — no. (%) 63 (91) 55 (80) 59 (84) 59 (88)
Diabetes — no. (%)
Yes 28 (41) 26 (38) 20 (29) 31 (46)
No 41 (59) 43 (62) 50 (71) 36 (54)
Sodium level — mmol/liter 139±3 139±2 138±3 140±2
Potassium level — mmol/liter 4.2±0.5 4.3±0.4 4.0±0.4 4.1±0.4
Creatinine level — mg/dl 0.9±0.2 1.0±0.3 0.9±0.3 0.9±0.3
Background antihypertensive drug — no. (%)
Diuretic 69 (100) 69 (100) 70 (100) 67 (100)
Beta-blocker 47 (68) 44 (64) 41 (59) 35 (52)
Calcium-channel blocker 47 (68) 44 (64) 49 (70) 47 (70)
ACE inhibitor or ARB 63 (91) 64 (93) 65 (93) 64 (96)
General antihypertensive drug 9 (13) 8 (12) 11 (16) 8 (12)
* Plus–minus values are means ±SD. Baseline characteristics are shown for the intention-to-treat population (all the patients who underwent
randomization). Percentages may not total 100 because of rounding. To convert the values for sodium to milligrams, multiply by 23, to con-
vert the values for potassium to milligrams, multiply by 39, and to convert the values for creatinine to micromoles per liter, multiply by 88.4.
ACE denotes angiotensin-converting enzyme, and ARB angiotensin-receptor blocker.
† Race or ethnic group was reported by the patient.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
pleted the 12-week treatment period (Fig. 1). The events, adverse events initially occurred at a
most common reasons for trial discontinuation higher frequency in the 1-mg and 2-mg dose
were withdrawal of consent (7 patients) and loss groups than in the 0.5-mg and placebo groups
to follow-up (8 patients). Although discontinua- (Tables S2 and S3). Fewer losses to follow-up
tions were not shown to be related to adverse occurred in the latter half of the trial, potentially

A Change from Baseline in Systolic Blood Pressure B Change from Baseline in Diastolic Blood Pressure
0 0
−5
−5
−10
LSM Change
LSM Change
(mm Hg)
(mm Hg)
−15 −9.4 −10
−12.1 −8.6
−9.2
−20
−17.5 −15 −11.8
−25 P=0.003 −20.3
−14.3
P<0.001
−30 −20
Placebo 0.5 mg 1 mg 2 mg Placebo 0.5 mg 1 mg 2 mg
Baxdrostat Baxdrostat
C Change in Systolic Blood Pressure over Time D Change in Diastolic Blood Pressure over Time
Placebo Baxdrostat, Baxdrostat, Baxdrostat, Placebo Baxdrostat, Baxdrostat, Baxdrostat,
0.5 mg 1 mg 2 mg 0.5 mg 1 mg 2 mg
0 0
−5
−5
−10
LSM Change
LSM Change
(mm Hg)
(mm Hg)
−15 −10
−20
−15
−25
−30 −20
0 20 40 60 80 100 0 20 40 60 80 100
Trial Day Trial Day
Figure 2. Dose-Dependent Decreases in Blood Pressure in Patients with Treatment-Resistant Hypertension Who Received Baxdrostat.
Shown are the changes from baseline in the least-squares mean (LSM) seated systolic blood pressure (Panel A) and diastolic blood
pressure (Panel B) according to the dose of baxdrostat. The changes in systolic blood pressure (Panel C) and diastolic blood pressure
(Panel D) according to the trial day are also shown. The baseline measurement was the measurement at randomization. Restricted max-
imum likelihood estimation was used with an unstructured covariance matrix and the Kenward–Roger approximation for degrees of free-
dom (Panels C and D). P values are shown for significant changes in blood pressure between the baxdrostat and placebo groups. I bars
indicate 95% confidence intervals.
because of improved coronavirus disease 2019 had met the criteria for overwhelming efficacy.
protocols and immunization, and these losses At week 12, baxdrostat was associated with dose-
were evenly distributed among the trial groups.12-15
dependent changes in the least-squares mean
The use of background medication was simi- (±SE) systolic blood pressure of −20.3±2.1 mm Hg,
lar among the trial groups. All the patients −17.5±2.0 mm Hg, and −12.1±1.9 mm Hg at the
received a diuretic, 91 to 96% received an angio- 2-mg, 1-mg, and 0.5-mg doses, respectively
tensin-converting–enzyme inhibitor or angioten- (Fig. 2). As compared with the change in sys-
sin-receptor blocker, and 64 to 70% received a tolic blood pressure of −9.4 mm Hg in the pla-
calcium-channel blocker (Table 1 and Table S4). cebo group, there were significantly greater de-
creases in systolic blood pressure in the 2-mg
Primary End Point baxdrostat group (difference between the 2-mg
After the prespecified interim analysis, the trial group and the placebo group, −11.0 mm Hg; 95%
was stopped early because the independent data confidence interval [CI], −16.4 to −5.5; P<0.001)
monitoring committee concluded that the trial and in the 1-mg baxdrostat group (difference

between the 1-mg group and the placebo group, hour (95% CI, 9.6 to 17.9) in the 2-mg baxdrostat
−8.1 mm Hg; 95% CI, −13.5 to −2.8; P = 0.003), group than in the placebo group (Fig. 3). Serum
but these decreases were not significantly great- cortisol levels were not reduced in any of the
er with the 0.5-mg dose. The results of the per- baxdrostat groups throughout the trial, and
protocol analysis are presented in Table S5, and there were no significant differences between
the results of the sensitivity analysis for missing the baxdrostat groups and the placebo group in
data are shown in Table S6. the least-squares mean change in these levels at
week 12. At the highest dose level of baxdrostat,
Secondary End Points the least-squares mean change in the serum
At the 2-mg dose, baxdrostat reduced diastolic cortisol level from baseline to the end of the
blood pressure by 14.3±1.31 mm Hg. The differ- trial was 1.91 μg per deciliter (95% CI, 0.70 to
ence in the change in diastolic blood pressure 3.12) (52.7 nmol per liter; 95% CI, 19.3 to 86.1)
between the baxdrostat 2-mg group and the (Fig. 3).
placebo group was −5.2 mm Hg (95% CI, −8.7 to
−1.6) (Fig. 2). Safety
No deaths occurred during the trial, and baxdro-
Exploratory End Points stat had an acceptable side-effect profile overall.
Pharmacokinetic Measures A total of 232 adverse events occurred during the
Plasma levels of baxdrostat increased propor- treatment period in 120 patients (44%) (Table 2).
tionately with increasing doses and reached a A higher percentage of patients in the 1-mg
maximum plasma level in less than 4 hours. group (52%) and 2-mg group (48%) had adverse
Details of this analysis are presented in Figure events than those in the 0.5-mg group (35%) or
S2 and Table S7. the placebo group (41%). Adverse events that oc-
curred in 5% or more patients in any of the trial
Pharmacodynamic Measures groups were urinary tract infections, hyperkale-
The use of baxdrostat led to a sustained dose- mia, headache, and fatigue. Most adverse events
dependent decrease in serum aldosterone levels (62%) were mild, and 89% were deemed by the
(Fig. 3). The least-squares mean differences in investigators to be unrelated to baxdrostat or
changes in aldosterone levels at the end of the placebo. A total of 18 serious adverse events oc-
trial between the baxdrostat groups and the curred in 10 patients; 6 occurred in a patient
placebo group ranged from −3.0 ng per deciliter with urosepsis. None of the serious adverse
(95% CI, −4.3 to −1.7) (−83.2 pmol per liter; 95% events were deemed by the investigators to be
CI, −119.3 to −47.2) at the 0.5-mg dose to −4.9 ng related to baxdrostat or placebo. There were no
per deciliter (95% CI, −6.3 to −3.5) (−135.9 pmol instances of adrenocortical insufficiency.
per liter; 95% CI, −174.8 to −97.1) at the 2-mg A total of 10 adverse events of special interest
dose. The 24-hour urinary aldosterone levels occurred in eight patients. These events, which
decreased with all three dose levels of baxdrostat were prespecified as adverse events of special
(Fig. 3); the changes in the urinary aldosterone interest because they warranted clinical inter-
level (normalized for urinary creatinine excre- vention, included one case of hypotension, three
tion) from baseline to the end of the trial were cases of hyponatremia, and six cases of hyperka-
−187 ng of aldosterone (95% CI, −254 to −119) lemia. Three of the cases of hyperkalemia,
per gram of creatinine with the 0.5-mg dose, which occurred in three patients, led to potas-
−180 ng of aldosterone (95% CI, −250 to −110) sium levels ranging from 6.0 to 6.3 mmol per
per gram of creatinine with the 1-mg dose, and liter. At a potassium level of 6.0 mmol per liter,
−273 ng of aldosterone (95% CI, −342 to −204) the protocol mandated temporary discontinua-
per gram of creatinine with the 2-mg dose. In tion of baxdrostat or placebo. One of these pa-
patients in the placebo group, the urinary aldo- tients was the patient with urosepsis who dis-
sterone level increased by 6 ng of aldosterone continued the trial because of multiple serious
(95% CI, −55 to 67) per gram of creatinine. adverse events that were deemed by the investi-
The least-squares mean change in plasma gators before unblinding of the trial-group as-
renin activity from baseline to the end of the signments to be unrelated to baxdrostat or pla-
trial was higher by 13.8 ng per milliliter per cebo. The other two patients resumed baxdrostat

A 24-Hr Urinary Aldosterone Normalized for Creatinine

100
Change in Urinary Aldosterone

Excretion (ng/g of creatinine)
0
Mean (±SD) Baseline
−100 24-Hr Urinary
Aldosterone Level
−200 ng/g
Placebo 364±228
−300 Baxdrostat, 0.5 mg 437±264
Baxdrostat, 1 mg 398±233
Baxdrostat, 2 mg 431±399
−400
Baxdrostat
B Serum Aldosterone
2
Change in Aldosterone Level
0 Placebo
Mean (±SD)
−2 Baseline Serum
(ng/dl)
Baxdrostat, 0.5 mg Aldosterone Level

−4 Baxdrostat, 1 mg ng/dl
Baxdrostat, 2 mg Placebo 6.7±4.8
−6 Baxdrostat, 0.5 mg 6.9±4.2
Baxdrostat, 1 mg 7.9±5.8
−8
0 20 40 60 80 100
Trial Day
C Plasma Renin Activity

20
Change in Plasma Renin Activity
15
Baxdrostat, 2 mg
Mean (±SD)
(ng/ml/hr)
10 Baseline Plasma
Renin Activity
5 Baxdrostat, 1 mg ng/ml/hr
Baxdrostat, 0.5 mg Placebo 4.5±6.7
0 Baxdrostat, 0.5 mg 3.1±5.2
Placebo Baxdrostat, 1 mg 5.2±10.8
−5
0 20 40 60 80 100
Trial Day
D Serum Total Cortisol

6
Change in Cortisol Level
4
Mean (±SD)
Baseline Serum
(µg/dl)
2 Baxdrostat, 2 mg Total Cortisol Level

Baxdrostat, 1 mg µg/dl
Baxdrostat, 0.5 mg
Placebo Placebo 8.9±3.6
0 Baxdrostat, 0.5 mg 9.6±4.0
−2
0 20 40 60 80 100
Trial Day

Figure 3 (facing page). Effects of Baxdrostat on Pharma- while receiving baxdrostat. The third patient in
codynamic Measures. this group did not resume baxdrostat. Hyperka-
Shown are the changes from baseline in the LSM values lemia was not correlated with the estimated GFR
for urinary aldosterone normalized for urinary creati- at screening. As shown in Table S8, which pro-
nine excretion (Panel A), serum aldosterone (Panel B), vides data on additional vital signs, no meaning-
plasma renin activity (Panel C), and serum total corti-
ful change in body weight occurred in any of the
sol (Panel D). The baseline measurement was the mea-
surement at randomization. Reported urinary aldoste- trial groups. Results of additional safety analy-
rone levels that were below the assay lower limit of ses are presented in Table S9.
quantification (<3 ng per deciliter) were imputed to be
one half this lower limit (1.5 ng per deciliter). Reported
serum aldosterone levels that were below the assay low- Discussion
er limit of quantification (<1 ng per deciliter) were im-
puted to be one half this lower limit (0.5 ng per deciliter). Our trial showed substantial decreases in blood
Values censored owing to dilution error and other miss- pressure when patients with treatment-resistant
ing values were excluded. To convert the values for cor- hypertension who were receiving stable doses of
tisol to nanomoles per liter, multiply by 27.6. To convert at least three antihypertensive medications also
the values for aldosterone to picomoles per liter, multi-
received the selective aldosterone synthase in-
ply by 27.74. I bars indicate 95% confidence intervals.
hibitor baxdrostat. The reduction in blood pres-
sure was associated with a decrease in the
2 days and 6 days after it was discontinued and plasma aldosterone level and a compensatory
completed the trial with normal potassium lev- increase in plasma renin activity, without a re-
els. The other three patients with hyperkalemia duction in the cortisol level. Baxdrostat gener-
had potassium levels between 5.5 and 5.9 mmol ally had an acceptable side-effect profile, and
per liter on at least two consecutive occasions, none of the patients discontinued the trial be-
and baxdrostat was discontinued. Two of these cause of hyperkalemia.
three patients resumed baxdrostat and also com- Treatment-resistant hypertension is associat-
pleted the trial with normal potassium levels ed with high cardiovascular risk,16 but this clas-
Table 2. Adverse Events That Occurred during the Treatment Period.
Baxdrostat, Baxdrostat, Baxdrostat,

Event (N = 69) (N = 69) (N = 69) (N = 67)
No. of No. of No. of No. of

Patients with No. of Patients with No. of Patients with No. of Patients with No. of
Event (%) Events Event (%) Events Event (%) Events Event (%) Events
Any serious adverse event* 2 (3) 3 0 0 2 (3) 3 6 (9) 12
Any adverse event 28 (41) 50 24 (35) 38 36 (52) 77 32 (48) 67
Adverse event of special 0 0 1 (1) 1 5 (7) 6 2 (3) 3
interest†
Hyponatremia 0 0 0 0 2 (3) 2 1 (2) 1
Hypotension 0 0 0 0 1 (1) 1 0 0
Potassium level 0 0 0 0 2 (3) 2 1 (2) 1
≥6.0 mmol/liter
Potassium level between 0 0 1 (1) 1 2 (3) 2 1 (2) 1
5.5 and 5.9 mmol/liter
on at least two con-
secutive occasions‡
* No serious adverse events were deemed by the investigators to be related to baxdrostat.
† Elevated potassium levels were adverse events of special interest if they warranted clinical intervention.
‡ One patient had a potassium level between 5.5 and 5.9 mmol per liter as well as a potassium level of 6.0 mmol per liter or higher, and these
measurements were counted as the same event; thus, a total of six patients with hyperkalemia had an adverse event of special interest.

sification provokes skepticism regarding the stat), was associated with off-target inhibition of
frequency with which poor medication adher- cortisol synthesis and was ultimately repurposed
ence accounts for the condition.17,18 Although to treat excess cortisol states rather than hyper-
nonadherence may be a contributor, there is tension.25 The selective action of baxdrostat may
mounting evidence that in adherent patients, avert the risk of inducing adrenal insufficiency
treatment-resistant hypertension is a subtype of and the loss of blood-pressure–lowering efficacy
hypertension that has a poor response to con- that can result from the accumulation of miner-
ventional drugs because of its pathogenesis. The alocorticoid receptor–activating steroid precur-
results of the Prevention and Treatment of sors seen with first-generation aldosterone syn-
Hypertension with Algorithm-based Therapy–2 thase inhibitors.25,26 These advantages will need
(PATHWAY-2) trial, combined with inferences to be confirmed in phase 3 trials involving more
from its three mechanistic substudies, provide patients over a longer period.
support for the hypothesis that treatment-resis- Similar caution applies to our findings re-
tant hypertension is associated with autono- garding potassium. Mild hyperkalemia is com-
mous aldosterone production, which could ac- mon in patients taking approved renin–angio-
count for the finding in that trial that a tensin–aldosterone system inhibitors.26 In our
mineralocorticoid receptor antagonist (spirono- trial, few patients who received baxdrostat had
lactone) had superior efficacy in reducing blood recurrent hyperkalemia, and the cases of elevated
pressure as compared with multiple other anti- potassium levels resolved quickly, without dose
hypertensive agents.19,20 Our trial, which adds to modification or intervention other than routine
the evidence that aldosterone appears to be a dietary advice.
driver of treatment resistance, showed dose- The limitations of the present phase 2 dose-
related reductions in both blood pressure and ranging trial include the fact that it was not de-
indexes of aldosterone secretion. We did not signed to test the benefits and risks of aldoste-
compare baxdrostat with alternative drugs. A rone synthase inhibition beyond 12 weeks, nor
meta-analysis involving 11,000 participants from to compare aldosterone synthase inhibition with
42 trials showed that in patients who received alternative antihypertensive agents. The selec-
currently licensed drugs (angiotensin-convert- tion of patients with an estimated GFR greater
ing–enzyme inhibitors, calcium-channel blockers, than 45 ml per minute reduced the likelihood of
or diuretics) in addition to previous therapy, sys- hyperkalemia, and planned longer-term studies
tolic blood pressure was a mean of 7 to 8 mm Hg may determine whether the incidences of hyper-
lower than that in those who received placebo.21 kalemia and other adverse events differ from
The main limitations of spironolactone with those reported for currently licensed drugs. The
respect to side effects — gynecomastia in men inclusion of patients with at least 70% adherence
and menstrual irregularities and postmenopaus- (assessed on the basis of pill counts) was based
al bleeding in women — are due to the off-target on the PATHWAY-2 trial, in which high adher-
blockade of multiple steroid hormone receptors ence was confirmed in a subgroup of patients by
by spironolactone. In addition, the risk of induc- means of urinary drug analysis.20 Excluded pa-
ing hyperkalemia with spironolactone, as shown tients might have had a lower response to bax-
in a large epidemiologic study involving patients drostat.
with heart failure, has contributed to a decrease In our trial, aldosterone synthase inhibition
in its use for other medical conditions.22 with baxdrostat led to substantial reductions in
An alternative strategy to mineralocorticoid systolic and diastolic blood pressure in patients
receptor blockade is to lower aldosterone levels with treatment-resistant hypertension.
through inhibition of aldosterone synthase. How-
ever, the development of such a drug has been Supported by CinCor Pharma.
Disclosure forms provided by the authors are available with
thwarted by the 93% sequence similarity be- the full text of this article at NEJM.org.
tween aldosterone synthase and the final enzyme A data sharing statement provided by the authors is available
required for cortisol synthesis, 11β-hydroxy with the full text of this article at NEJM.org.
We thank Jennifer Ayala, Ph.D., of MedLogix Communica-
lase.23,24 The first aldosterone synthase inhibitor tions, for professional writing and editorial support with an
to enter clinical development, LCI-699 (osilodro- earlier version of the manuscript.

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The n e w e ng l a n d j o u r na l of m e dic i n e

Phase 2 Trial of Baxdrostat for Treatment-

n engl j med﻿﻿ nejm.org﻿ 1

2 n engl j med﻿﻿ nejm.org﻿

The New England Journal of Medicine

n engl j med﻿﻿ nejm.org﻿ 3

779 Patients were assessed for eligibility

419 Did not meet inclusion criteria

360 Entered single-blind run-in period

85 Did not meet run-in criteria

275 Underwent randomization

1 Assigned to receive baxdrostat, 1 mg,

4 Withdrew 9 Withdrew 11 Withdrew 2 Withdrew

Figure 1. Screening, Randomization, and Follow-up.

R e sult s were similar with respect to demographic and

4 n engl j med﻿﻿ nejm.org﻿

The New England Journal of Medicine

Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.*

Baxdrostat, Baxdrostat, Baxdrostat,

n engl j med﻿﻿ nejm.org﻿ 5

6 n engl j med﻿﻿ nejm.org﻿

The New England Journal of Medicine

n engl j med﻿﻿ nejm.org﻿ 7

A 24-Hr Urinary Aldosterone Normalized for Creatinine

Change in Urinary Aldosterone

Baxdrostat, 0.5 mg Aldosterone Level

C Plasma Renin Activity

D Serum Total Cortisol

2 Baxdrostat, 2 mg Total Cortisol Level

8 n engl j med﻿﻿ nejm.org﻿

The New England Journal of Medicine

Table 2. Adverse Events That Occurred during the Treatment Period.

Baxdrostat, Baxdrostat, Baxdrostat,

No. of No. of No. of No. of

n engl j med﻿﻿ nejm.org﻿ 9

10 n engl j med﻿﻿ nejm.org﻿

The New England Journal of Medicine

n engl j med﻿﻿ nejm.org﻿ 11

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