Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study

Abstract

Introduction/Purpose
Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS).

Materials and Methods
A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%).

Results
35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred.

Conclusions
The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.

Full text

Relacorilant, a Selective
Glucocorticoid Receptor Modulator,
Induces Clinical Improvements in
Patients With Cushing Syndrome:
Results From A Prospective,
Open-Label Phase 2 Study
Rosario Pivonello
1
, Irina Bancos
2
, Richard A. Feelders
3
, Atil Y. Kargi
4
, Janice M. Kerr
5
,
Murray B. Gordon
6
, Cary N. Mariash
7
, Massimo Terzolo
8
, Noel Ellison
9
and Andreas G. Moraitis
10
*
1
Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy,
2
Department of Internal Medicine, Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester,
MN, United States,
3
Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, Rotterdam,
Netherlands,
4
Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Miami, Miami, FL,
United States,
5
Department of Endocrinology, Division of Endocrinology, Metabolism and Diabetes, University of Colorado
Denver, Aurora, CO, United States,
6
Allegheny Neuroendocrinology Center, Allegheny General Hospital, Pittsburgh, PA,
United States,
7
Methodist Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States,
8
Department of Clinical and Biological Sciences, Internal Medicine 1 –San Luigi Gonzaga Hospital, University of Turin,
Orbassano, Italy,
9
Biostatistics, Trialwise, Inc, Houston, TX, United States,
10
Drug Research and Development, Corcept
Therapeutics, Menlo Park, CA, United States
Introduction/Purpose: Relacorilant is a selective glucocorticoid receptor modulator
(SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of
relacorilant in patients with endogenous Cushing syndrome (CS).
Materials and Methods: A single-arm, open-label, phase 2, dose-finding study with 2
dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was
conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d;
n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18)
for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures
included proportion of patients with clinically meaningful changes in hypertension and/or
hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical
response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood
pressure, measured by a standardized and validated 24-h ABPM. For patients with
hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c,
normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose
tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%).
Results: 35 adults with CS and hypertension and/or hyperglycemia (impaired glucose
tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men)
received treatment and had postbaseline data. In the low-dose group, 5/12 patients
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6628651
Edited by:
Corin Badiu,
Carol Davila University of Medicine
and Pharmacy, Romania
Reviewed by:
Annamaria Anita Livia Colao,
University of Naples Federico II, Italy
George Mastorakos,
National and Kapodistrian University
of Athens, Greece
*Correspondence:
Andreas G. Moraitis
amoraitis@corcept.com
This article was submitted to
Pituitary Endocrinology,
a section of the journal
Frontiers in Endocrinology
Specialty section:
Received: 01 February 2021
Accepted: 25 June 2021
Published: 14 July 2021
Citation:
Pivonello R, Bancos I, Feelders RA,
Kargi AY, Kerr JM, Gordon MB,
Mariash CN, Terzolo M, Ellison N
and Moraitis AG (2021) Relacorilant, a
Selective Glucocorticoid Receptor
Modulator, Induces Clinical
Improvements in Patients
With Cushing Syndrome:
Results From A Prospective,
Open-Label Phase 2 Study.
Front. Endocrinol. 12:662865.
doi: 10.3389/fendo.2021.662865
CLINICAL TRIAL
published: 14 July 2021
doi: 10.3389/fendo.2021.662865

(41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved
response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12
patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events
included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea,
and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred.
Conclusions: The SGRM relacorilant provided clinical benefit to patients with CS without
undesirable antiprogesterone effects or drug-induced hypokalemia.
Keywords: clinical trial, cortisol, Cushing syndrome, glucocorticoid, hypercortisolism, hyperglycemia,
hypertension, relacorilant
INTRODUCTION
Endogenous hypercortisolism (Cushing syndrome [CS]) is a
complex, multisystem endocrine disorder characterized by
cortisol excess and is frequently associated with hypertension
and hyperglycemia (including impaired glucose tolerance/type 2
diabetes mellitus [IGT/T2DM]) (1,2). CS, especially if untreated,
is associated with increased cardiovascular-related mortality and
multiple morbidities beyond hypertension and hyperglycemia,
including visceral obesity, dyslipidemia, liver steatosis,
osteoporosis, hypercoagulopathy, susceptibility to infection,
neuropsychiatric disorders, and reproductive and sexual
disturbances (2–11).
Medical therapies, including pituitary-targeting agents,
steroid synthesis inhibitors, and glucocorticoid receptor [GR]
antagonists, are a treatment option for patients who are not
candidates for surgery, and for patients with persistent or
recurrent hypercortisolism after surgery who are unsuitable
for, or unwilling to undergo, additional surgical procedures
(12–15).
The competitive GR and progesterone antagonist mifepristone
was approved by the Food and Drug Administration in 2012 to
control hyperglycemia in patients with endogenous CS who have
IGT or T2DM. The clinical benefit of mifepristone in patients with
CS was shown in an open-label, phase 3 trial, SEISMIC (Study of
the Efficacy and Safety of Mifepristone in the Treatment of
Endogenous Cushing Syndrome) (16). Serum cortisol and
ACTH levels may rise in response to GR antagonism with
mifepristone (15,17,18). In patients with CS, further increases
in cortisol in turn can lead to stimulation of the mineralocorticoid
receptor, resulting in adverse events such as hypertension and
hypokalemia (15,18,19). Because of its mechanism of action,
clinical and metabolic parameters, rather than cortisol levels, must
be monitored in patients during mifepristone treatment for
assessment of efficacy (18).
Relacorilant (CORT125134, Corcept Therapeutics, Menlo
Park, CA) is an investigational, highly selective GR modulator
that competitively antagonizes cortisol activity (20). Unlike
mifepristone, relacorilant does not bind to the progesterone
receptor (20). Given its binding affinity profile, it was
hypothesized that relacorilant would provide patients with
endogenous CS the treatment benefits of cortisol modulation,
but without the unwanted effects of progesterone receptor
antagonism (e.g., induction of abortion, progesterone receptor
modulator-associated endometrial changes and irregular vaginal
bleeding in women).
This dose-finding study was designed to assess the efficacy
and safety of relacorilant in patients with endogenous
hypercortisolism due to either excess ACTH secretion (from a
pituitary or other ectopic tumor) or autonomous adrenal cortisol
secretion, as well as to inform phase 3 study design. Because GR
antagonism lowers cortisol activity, but not cortisol levels (16),
an improvement in clinical manifestations of hypercortisolism
were evaluated as assessments of efficacy with relacorilant. This
study assessed the impact of reduced cortisol activity on blood
pressure and parameters of blood glucose control following
treatment with relacorilant in patients with CS. Additional
secondary and exploratory outcome measures were also assessed.
MATERIALS AND METHODS
Study Design
This phase 2, multicenter, single-arm, open-label, dose-finding
study (NCT02804750) assessed the efficacy and safety of
relacorilant using 2 dose groups: a low-dose group and a high-
dose group. The dose in each group was increased by 50 mg every
4 weeks (Figure 1). The low-dose group received a starting
relacorilant dose of 100 mg/d, followed by 150 mg/d and then
200 mg/d. The high-dose group began with a starting relacorilant
dose of 250 mg/d, followed by 300 mg/d, 350 mg/d, and 400 mg/
d. Dose reductions were permitted at the discretion of the
investigator for safety/tolerability. Enrolment in the high-dose
Abbreviations: ABPM, ambulatory blood pressure monitoring; ACTH,
adrenocorticotropic hormone; ALT, alanine aminotransferase; aPTT, activated
partial thromboplastin time; AST, aspartate aminotransferase; AUC, area under
the curve; BDI-II, Beck Depression Inventory; BMI, body mass index; CD,
Cushing disease; CI, confidence interval; CS, Cushing syndrome; DBP, diastolic
blood pressure; DST, dexamethasone suppression test; ET, early termination; GR,
glucocorticoid receptor; HbA1c, glycated hemoglobin; HOMA-IR, homeostatic
model assessment of insulin resistance; IGT, impaired glucose tolerance; LNSC,
late-night salivary cortisol; NAFLD, nonalcoholic fatty liver disease; oGTT, oral
glucose tolerance test; QoL, quality of life; SBP, systolic blood pressure; SD,
standard deviation; SGRM, selective glucocorticoid receptor modulator; TEAE,
treatment-emergent adverse event; T2DM, type 2 diabetes mellitus; UFC, urinary
free cortisol; ULN, upper limit of normal.
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6628652

group began after completion of enrollment of the low-
dose group.
The study was approved by the institutional review board at
each study center and conducted in accordance with the World
Medical Association Declaration of Helsinki and the
International Council on Harmonisation Good Clinical
Practice guidelines. All patients provided written informed
consent. The study was conducted at 19 centers in the United
States, Italy, United Kingdom, Hungary, and The Netherlands
between February 2017 and September 2018.
Patients
Adult patients aged 18 to 80 years with a diagnosis of
endogenous CS and requiring medical treatment (i.e., those for
whom surgery or radiation is contraindicated or has been
refused) were eligible for the study. These patients must have
met at least 2 of the following biochemical criteria based on the
Endocrine Society Guidelines (Nieman 2008): (1) a 24-h urinary
free cortisol (UFC) above the upper limit of normal (ULN) (50
µg/24 h [138 nmol/d]) on at least 2 collections, (2) a late-night
salivary cortisol (LNSC) value above ULN (10-11 PM normal
range, ≤0.09 µg/dL [2.5 nmol/L]) on at least 2 collections, or (3) a
lack of cortisol suppression (>1.8 µg/dL serum cortisol [49.7
nmol/L]) on either the overnight 1-mg or 48-h 2-mg
dexamethasone suppression test (DST) (1,21). In addition,
patients were also required to have at least 2 clinical signs or
symptoms of hypercortisolism: a Cushingoid appearance (moon
facies, dorsocervical fat pad, and/or facial plethora), increased
body weight or central obesity, proximal muscle weakness, low
bone mass (dual energy X-ray absorptiometry T < -1.0),
psychiatric symptoms (including depression or psychosis), easy
bruising, or skin changes (hirsutism, violaceous striae, and/or
acne) (1).
Patients with adrenal adenomas were also eligible if they met
the following criteria for autonomous cortisol secretion based on
the European Society of Endocrinology/European Network for
the Study of Adrenal Tumors Guidelines (Fassnacht 2016):
unilateral or bilateral adrenal disease, lack of cortisol
suppression (>5 µg/dL [>138 nmol/L] serum cortisol) on either
1-mg or 48-h 2-mg DST, low or suppressed ACTH (<10 pg/mL
[<2.2 pmol/L]), and presence of at least 2 comorbidities
potentially related to cortisol excess (e.g., T2DM, hypertension,
obesity, osteoporosis) (21).
Because changes in blood pressure and glucose tolerance
served as key efficacy endpoints, patients included in the
study were required to have uncontrolled hypertension
(hypertension cohort), and/or IGT or T2DM (hyperglycemia
cohort). Uncontrolled hypertension was defined as a mean
systolic blood pressure (SBP) of ≥130 mmHg and/or mean
diastolic blood pressure (DBP) of ≥85 mmHg using 24-h
ambulatory blood pressure monitoring (ABPM) based on the
European Society of Hypertension Position Paper (O’Brien 2013)
(22). IGT was defined as a 2-h oral glucose tolerance test (oGTT)
plasma glucose value of 140-199 mg/dL (7.8-11.0 mmol/L) after
75 g of glucose, while T2DM was defined as a fasting plasma
glucose >126 mg/dL (7.0 mmol/L) or a 2-h plasma glucose ≥200
mg/dL (11.1 mmol/L) after a 75-g oGTT (23). Patients on
antidiabetic or antihypertensive medications were allowed in
FIGURE 1 | Study design: dose escalation in the low- and high-dose groups. ABPM, ambulatory blood pressure monitoring; oGTT, oral glucose tolerance test.
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6628653

the study if their doses were stable and had not been changed for
at least 1 month before the baseline assessment. Patients
receiving medications for CS underwent an appropriate
washout duration before baseline assessments were performed
(e.g., 1 month for adrenostatic medications such as metyrapone
and ketoconazole; 2 months for long-acting somatostatin analogs
and dopamine agonists; 1 month for short-acting somatostatin
analogs; and 6 weeks for mifepristone).
Patients with SBP >170 or DBP >110 mmHg, glycated
hemoglobin (HbA1c) >12%, uncontrolled hypothyroidism or
hyperthyroidism, or uncorrected hypokalemia (<3.5 mEq/L)
were excluded. Concurrent use of other medications for CS
was not allowed in the study. Patients who had undergone
radiation therapy for CS within 1 year of screening were
also excluded.
Assessments
Patients With Hypertension
Assessment of hypertension was performed using standardized,
validated 24-h ABPM to allow for an accurate measurement (22,
24). A clinically significant response was defined as a decrease of
≥5 mmHg in either mean 24-h SBP or DBP from baseline
without an increase in dosage of concurrent antihypertensive
medication or initiation of additional antihypertensive
medication during the treatment period.
Patients With Hyperglycemia
To assess glucose tolerance, a 2-h oGTT was administered and
HbA1c was evaluated in all patients with hyperglycemia.
Clinically meaningful response was defined ad-hoc as one of
the following: a decrease in HbA1c of ≥0.5% from baseline,
normalization of the 2-h plasma glucose value on the oGTT
(<140 mg/dL [<7.8 mmol/L]) or a decrease in the 2-h plasma
glucose value on the oGTT by ≥50 mg/dL (≥2.8 mmol/L) from
baseline, or a decrease in the total daily insulin dose by ≥25% or a
decrease in the daily sulfonylurea dose by ≥50% from baseline.
Based on the criterion used in the pivotal study of mifepristone,
SEISMIC (16), the hyperglycemia response was initially defined
as a decrease of ≥25% from baseline in the area under the
concentration-time curve for glucose (AUC
glucose
), without an
increase in dosage of concurrent antidiabetes medication or
additional antidiabetes medication during the treatment
period. However, unlike SEISMIC, a substantial portion of the
patients enrolled in the hyperglycemia group in the current study
had IGT rather than overt diabetes, and the patients with
diabetes had much better glycemic control (mean HbA1c was
6.6%, compared with 7.4% in SEISMIC) (16). Thus, a ≥25%
decrease in the total AUC
glucose
from baseline would not be
suitable to detect clinically meaningful improvements in
these patients.
Secondary and Exploratory Endpoints
Considering the numerous additional comorbidities and clinical
complications associated with CS, including obesity, impaired
glucose metabolism and insulin resistance, liver steatosis,
osteoporosis, immune disorders, thrombosis, and neuropsychiatric
diseases (2,3,5,10,11,25), the effect of relacorilant on several
secondary and exploratory endpoints was also assessed. These
included changes in body weight; serum fructosamine an
indicator of glucose metabolism control (26); homeostatic model
assessment of insulin resistance (HOMA-IR); liver function tests;
serum osteocalcin, a marker of bone metabolism (25); eosinophils;
activated partial thromboplastin time (aPTT), Factor VIII, and
platelet count for assessment of coagulation; quality of life (QoL)
as assessed using the Cushing QoL Questionnaire (27); depressive
symptoms as assessed using the Beck Depression Inventory (BDI-II)
(28); and cognitive function evaluated using the Trail Making Test
(Parts A and B) (29). Hormone changes were assessed using plasma
ACTH, and cortisol (24-h UFC, LNSC, and serum cortisol).
Treatment-emergent AEs (TEAEs) were assessed at every visit for
safety. Potassium levels were monitored, particularly for the
emergence of hypokalemia.
Blood, urine, and saliva samples were collected and analyzed
centrally (by Q
2
Solutions Laboratories, Valencia, CA; Quest
Diagnostics Nichol Institute, San Juan Capistrano, CA was used
for hormonal testing only). AUC
glucose
was calculated based on
results of the 2-h oGTTs. Plasma glucose and insulin values from
the baseline oGTT assessment (pre-glucose drink) were used to
calculate HOMA-IR (30). Urinary cortisol (normal range, 4-50
µg/24h [11-138 nmol/d]) was measured by tandem mass
spectrometry (MS/MS). Serum cortisol (8-10 AM normal
range, 4.6-20.6 µg/dL [127-567 nmol/L]) levels and LNSC
levels (10-11 PM normal range, ≤0.09 µg/dL [≤2.5 nmol/L]),
were measured by liquid chromatography LC-MS/MS. Plasma
ACTH (7-10 AM normal range, 6-50 pg/mL [1.3-11.1 pmol/L])
was measured with an immunochemiluminescent assay.
Statistical Analysis
No formal sample size calculation was performed. A sample size
of 30 patients (15 per dose group) was deemed sufficient for a
preliminary evaluation of the efficacy and safety of relacorilant
and to establish estimates of efficacy for future evaluation of the
study drug. All patients who received at least one dose of study
medication were included in the safety analysis. All patients who
received at least one dose of study medication and had
postbaseline data were included in the efficacy population.
Because of the small population in the clinical responder
analyses, additional exclusions for major protocol violations
were applied to specific visits or outcomes for patients in the
hypertension and hyperglycemia groups, rather than excluding
the patient entirely.
The key efficacy endpoints (hypertension and hyperglycemia
responders) were analyzed by dose group at Week 12 or early
termination (ET) for the low-dose group and Week 16 or ET for
the high-dose group, and summarized as last observed. The
number and percentage of patients considered responders was
presented along with the 95% exact binomial two-sided
confidence intervals (Clopper-Pearson). Because there was no
comparator group, statistical significance was determined if the
lower limit of the 95% exact binomial CIs for the responder rate
was >20%. This threshold for response was selected based on the
similar threshold used in the previously reported SEISMIC study
(16). SAS statistical software version 9.4 or higher (SAS Institute,
Cary, NC) was used.
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6628654

Descriptive statistics were used to summarize changes from
baseline in secondary and exploratory outcomes, including
weight, fructosamine, HOMA-IR, liver function tests, serum
osteocalcin, absolute eosinophils, aPTT, Factor VIII, platelet
count, QoL, depressive symptoms, cognitive function, and
TEAEs. Means or medians and Wilcoxon signed-rank p-values
were calculated to assess change from baseline for exploratory
outcomes (fructosamine, HOMA-IR, osteocalcin, absolute
eosinophils, coagulation parameters, QoL, depressive
symptoms, cognitive function, plasma ACTH, 24-h UFC,
LNSC, and serum cortisol changes).
RESULTS
Patients
Thirty-five patients meeting the inclusion criteria were enrolled.
All 35 received at least 1 treatment dose and were included in the
safety population. Seventeen patients were enrolled in the low-
dose group and 18 patients were enrolled in the high-dose group.
One patient did not have any postbaseline data and was excluded
from the efficacy population (n = 34) (Figure 2).
Baseline characteristics of the efficacy population (70.6%
female [12/24 premenopausal], mean ± SD age of 48.2 ± 13.33
years) are shown in Tables 1 and 2. Twenty-seven patients
(79.4%) were diagnosed with ACTH-dependent CS, and 7
(20.6%) were diagnosed with ACTH-independent CS (adrenal
adenoma). Of the patients with ACTH-dependent CS, 4 were
diagnosed with ectopic ACTH secretion. Among the total 34
patients, 47.1% (n = 16; 8 low-dose/8 high-dose group) were
diagnosed with both hyperglycemia and hypertension, 32.4%
(n = 11; 5 low-dose/6 high-dose group) were diagnosed with
hyperglycemia only, and 20.6% (n = 7; 4 low-dose/3 high-dose
group) were diagnosed with hypertension only. Among patients
in the hypertension analysis group (n = 23), mean 24-h blood
pressure (SBP/DBP) at baseline was 138.3/87.0 mmHg. Mean
HbA1c at baseline among patients in the hyperglycemia analysis
group (n = 27) was 6.6%. Among patients in the hyperglycemia
analysis group, 37.0% (10/27) had IGT and 63.0% (17/27)
had T2DM.
Key Efficacy Analyses
Among patients in the hypertension analysis population (n =
23), 5 of 12 patients (41.7%, 95% CI 15.17, 72.33) in the low-dose
FIGURE 2 | Patient disposition.
a
One patient in the high-dose group did not have any postbaseline data and was excluded from the efficacy population.
b
Two patients in
the high-dose hyperglycemia group did not have any postbaseline efficacy data while on study drug and were excluded from the hyperglycemia population.
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6628655

group and 7 of 11 patients (63.6%, 95% CI 30.79, 89.07) in the
high-dose group were responders at their last observed blood
pressure measurement (Table 3).
Among patients in the hyperglycemia analysis population
(n = 25), 2 of the 13 patients (15.4%, 95% CI 1.92%, 45.45) in the
low-dose group and 6 of the 12 patients (50.0%, CI 21.09%,
78.91%) in the high-dose group met the ad-hoc hyperglycemia
response at the last observed visit (Table 3). Additionally, when
both the low-dose and high-dose groups were combined, plasma
glucose levels during oGTT decreased (Figure 3), leading to a
statistically significant decrease in mean AUC
glucose
from
baseline to the last observed visit (-2.48 h•mmol/L, p< 0.01).
Secondary and Exploratory
Efficacy Analyses
Changes in Weight
In the efficacy population, the median weight at baseline was
similar among patients in the low-dose (85.5 kg) and high-dose
(91.1 kg) group. During the study, 7 of 17 patients (41.2%) in the
low-dose group and 10 of 16 patients (62.5%) in the high-dose
group lost weight. Among the patients who lost weight during
the study, the median (min, max) changes from baseline to last
observed visit were -2.0 kg (-2.5, -0.4) and -3.0 kg (-15.1, -1.1) for
the low-dose and high-dose groups, respectively. Among all
patients, the median weight change was 0.50 kg in the low-
dose group and -1.75 kg in the high-dose group.
Additional Exploratory Endpoints
Statistically significant improvements from baseline were
observed in various exploratory endpoints related to cortisol
excess in the efficacy population (Table 4). These included
improvements in fructosamine (mean change -13.92 µmol/L,
p= 0.002) among all patients with hyperglycemia. Decreases in
the liver function parameters alanine aminotransferase (mean
change -10.62 U/L, p< 0.001) and aspartate aminotransferase
(mean change -4.94 U/L, p= 0.001), and increases in serum
osteocalcin (mean change 3.00 µg/L, p < 0.01) and eosinophil
count (mean change 0.05•10
9
/L, p= 0.006) were observed in the
overall patient population. The aPTT increased significantly
(mean change 1.45 sec, p= 0.046) and was accompanied by
significant decreases in factor VIII (mean change -18.94%, p=
0.022) and platelet counts (mean change -68.82•10
9
/L, p< 0.001).
Statistically significant improvements from baseline to last
observed visit were observed in BDI-II Total score (mean
change -3.48, p= 0.004), Cushing QoL score (mean change
7.13, p= 0.002), and Trail Making Test Part A and Part B
(mean changes -4.13 sec, p= 0.003 and -24.69 sec, p<
0.001, respectively).
Hormone Changes
Among all patients with ACTH-dependent CS (n = 26 with
values at last visit), the median (min, max) change from baseline
to last observed visit was 3.7 (-15.6, 20.0) pmol/L [16.8 (-70.9,
90.9) pg/mL] (p= 0.003) for plasma ACTH; 4.0 (-1650.5, 1404.8)
nmol/d (1.4 [-598.0, 509.0] µg/24 h) (p= 0.873) for 24-h UFC;
-0.33 (-30.6, 47.7) nmol/L (-0.01 [-1.1, 1.7] µg/dL) (p= 0.815) for
TABLE 1 | Demographic and clinical characteristics at baseline (efficacy
population, n = 34).
Overall population
(n = 34)
Age, years (mean ± SD) 48.2 ± 13.33
Female sex, n (%) 24 (70.6)
White race, n (%) 34 (100)
Ethnicity, n (%)
Hispanic or Latino 3 (8.8)
Not Hispanic or Latino 31 (91.2)
Weight, kg (mean ± SD) 97.8 ± 27.41
BMI, kg/m
2
(mean ± SD) 35.6 ± 9.75
Etiology of CS, n (%)
ACTH-dependent: CD or ectopic, n (%) 27 (79.4)
ACTH, pmol/L (median [min, max]) 14.0 (6.0, 28)
24-h UFC, nmol/d (median [min, max]) 357.4 (83.4, 2823.8)
Adrenal adenoma (unilateral), n (%) 7 (20.6)
ACTH, pmol/L (median [min, max]) 1.0 (1.0, 1.6)
24-h UFC, nmol/d (median [min, max])
a
156.1 (56.9, 2341.0)
Osteocalcin, µg/L, (mean ± SD)
b
11.0 ± 7.55
Analysis cohorts
Hypertension, n (%) 23 (67.6)
24-h SBP, mmHg (mean ± SD) 138.3 ± 8.59
24-h DBP, mmHg (mean ± SD) 87.0 ± 5.65
Hyperglycemia, n (%) 27 (79.4)
IGT, n (%) 10 (37.0)
T2DM, n (%) 17 (63.0)
Fructosamine, µmol/L (mean ± SD) 225.3 ± 29.50
Fasting plasma glucose, mmol/L (mean ± SD) 6.6 ± 1.89
2-h oGTT plasma glucose, mmol/L (mean ± SD) 12.7 ± 4.08
AUC
glucose
,h•mmol/L (mean ± SD) 26.2 ± 8.05
HbA1c, % (mean ± SD) 6.6 ± 1.26
To convert values of glucose to mg/dL, divide by 0.0555; UFC to µg/24 h, divide by 2.76.
a
Includes one patient with an adrenal adenoma who had a baseline 24-h UFC of 2,341
nmol/d (848.2 µg/d).
b
Osteocalcin n = 33.
ACTH, adrenocorticotropic hormone; AUC, area under the curve; BMI, body mass index;
CD, Cushing disease; CS, Cushing syndrome; DBP, diastolic blood pressure; HbA1c,
glycated hemoglobin; IGT, impaired glucose tolerance; oGTT, oral glucose tolerance test;
SBP, systolic blood pressure; SD, standard deviation; T2DM, type 2 diabetes mellitus;
UFC, urinary free cortisol.
TABLE 2 | Median biochemistry at baseline (efficacy population, n = 34).
Low-dose group (n = 17) High-dose group (n = 17) Overall population (n = 34)
ACTH, pmol/L (min, max) 9.8 (1.0, 25.3) 14.0 (1.0, 28) 10.8 (1.0, 28.0)
24-h UFC, nmol/d (min, max) 357.4 (122.0, 2823.8) 251.6 (56.9, 2341.0) 357.0 (56.9, 2823.8)
LNSC, nmol/L (min, max) 7.2 (1.2, 36.5) 5.4 (2.1, 32.7) 6.6 (1.2, 36.5)
Serum cortisol, nmol/L (min, max) 483.0 (141.0, 748.0) 431.0 (235.0, 1352.0) 459.5 (141.0, 1352.0)
To convert values of ACTH to pg/mL, divide by 0.22; UFC to µg/24 h, divide by 2.76; LNSC and serum cortisol to µg/dL, divide by 27.6.
ACTH, adrenocorticotropic hormone; LNSC, late-night salivary cortisol; SD, standard deviation; UFC, urinary free cortisol.
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6628656

LNSC; and 22.0 (-127.0, 339.0) nmol/L (0.8 [-4.6, 12.3] µg/dL)
(p= 0.239) for serum cortisol.
In the adrenal subgroup (n = 7), median (min, max) change
from baseline to last observed visit was 0.2 (0, 1.4) pmol/L (0.9 [0,
6.4] pg/mL) for plasma ACTH; 7.0 (-1662.9, 42.8) nmol/d (2.6
[-602.5, 15.5] µg/24 h) for 24-h UFC; -0.7 (-6.8, 11.8) nmol/L
(-0.03 [-0.2, 0.4] µg/dL) for LNSC; and -3.9 (-179.0, 130.0) nmol/
L (-0.1 [-6.5, 4.7] µg/dL) for serum cortisol. There were too few
patients in the adrenal subgroup to adequately perform
statistical testing.
Safety
Overall, TEAEs were reported in 94.3% of patients (33/35)
during treatment with relacorilant, including 88.2% (15/17) in
the low-dose group and 100% (18/18) in the high-dose group
(Table 5). The most commonly reported TEAEs (≥20%) in both
the low-dose and high-dose groups combined were back pain
(31.4% [11/35]), headache (25.7% [9/35]), peripheral edema
(25.7% [9/35]), nausea (22.9% [8/35]), pain at extremities
(22.9% [8/35]), diarrhea (20.0% [7/35]), and dizziness (20.0%
[7/35]) (Table 5). In the high-dose group, the highest incidence
of TEAEs was observed with the initial starting dose of 250 mg
(100%, 18/18), when compared with incidences of TEAEs at
higher doses later (64.3% [9/14], 76.9% [10/13], and 25.0% [2/8]
at 300, 350, and 400 mg, respectively). For musculoskeletal and
gastrointestinal TEAEs specifically, the highest incidences also
occurred at the 250-mg starting dose (61.1% [11/18] and 38.9%
[7/18], respectively).
TEAEs leading to discontinuation were reported in 1 patient
(5.9%) in the low-dose group and 8 patients (44.4%) in the high-
dose group. TEAEs leading to discontinuation in more than one
patient were musculoskeletal in nature (e.g., myopathy,
back pain).
Five serious TEAEs were reported in 4 patients (pilonidal cyst,
myopathy, polyneuropathy, hypertension, and myocardial
infarction). All serious TEAEs occurred in the high-dose
group. In 3 patients, the serious TEAEs led to discontinuation
(myopathy, polyneuropathy, and myocardial infarction). For the
patient who developed a serious TEAE of myopathy, a cerebral
spinal fluid analysis revealed findings consistent with Guillain-
Barre syndrome based on the low cell count and moderately
elevated protein. The serious TEAE of polyneuropathy occurred
TABLE 3 | Summary of responder analysis in patients with hypertension (n = 23) and hyperglycemia (n = 25) at last observation.
Low-dose group High-dose group
Responder, n/N (%) 95% CI Responder, n/N (%) 95% CI
Hypertension
a
5/12 (41.7) 15.17, 72.33 7/11 (63.6) 30.79, 89.07
Hyperglycemia
b
2/13 (15.4) 1.92, 45.45 6/12 (50.0) 21.09, 78.91
CIs: 95% binomial exact two-sided confidence interval (Clopper-Pearson).
Two patients in the hyperglycemia responder analysis were excluded because they had no postbaseline efficacy data collected while on study drug.
a
Response defined as a ≥5 mmHg decrease in mean systolic or diastolic BP from baseline without the use of additional antihypertensive medication or an increase in dosage of a
concurrent antihypertensive medication.
b
Achieving any of the ad-hoc hyperglycemia response criteria with no increase in HbA1c. Patients who achieve the response criteria but whose HbA1c increases cannot be considered
overall responders. Ad-hoc response criteria: a ≥0.5% decrease in HbA1c, normalization (<140 mg/dL [<7.8 mmol/L]) or ≥50-mg/dL (2.8 mmol/L) decrease in 2-h glucose value on oGTT,
or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%).
CI, confidence interval.
FIGURE 3 | Results of oGTT tests at baseline and at last observation in the hyperglycemia group. p-value from Wilcoxon signed-rank. AUC, area under the curve;
oGTT, oral glucose tolerance test; SE, standard error.
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6628657

in a patient with underlying uncontrolled diabetes; nerve
conduction studies revealed parasympathetic autonomic
neuropathy and moderate sensory hypesthesia consistent with
diabetic neuropathy. The myocardial infarction (non-ST
segment elevation) event occurred in a patient with a history
of coronary artery disease, thromboembolism, pulmonary
embolism, and myocardial infarction. Cardiac catheterization
showed unchanged coronary lesions compared to previous
catheterization studies. During the study, no drug-induced
vaginal bleeding or hypokalemia was reported. No patients had
a platelet count <100,000/µL during the study, nor were there
any bleeding events related to a reduction in platelets.
No clinically significant changes in potassium levels were
observed in the study. Mean potassium levels changed from 4.33
mmol/L at baseline to 4.21 mmol/L at week 12 in the low-dose
group, and from 4.34 mmol/L at baseline to 4.33 mmol/L at week
16 in the high-dose group (Figure 4). Mean changes in
potassium levels from baseline to last observed visit across
each dose level ranged from -0.12 to 0.02 mmol/L in the low-
dose group and from -0.31 to 0.08 mmol/L in the high-
dose group.
DISCUSSION
Relacorilant is a selective glucocorticoid receptor modulator with
no affinity for the progesterone receptor (20). In this multicenter,
two-step, dose-finding study of patients with endogenous CS and
hypertension and/or hyperglycemia, relacorilant improved both
clinical hypertension and hyperglycemia parameters in the
respective patient groups. Although not formally assessed,
differences in response rates between dose groups suggested a
dose response. In addition, a number of exploratory endpoints
related to cortisol excess were significantly improved.
For patients in the hypertension subgroup, 41.7% (5/12) of
the low-dose group and 63.6% (7/11) of the high-dose group met
criteria for a clinically meaningful blood pressure response,
defined as patients with a decrease of ≥5 mmHg in either
mean 24-h SBP or DBP from baseline, and without an increase
of concurrent antihypertensive medication or additional
antihypertensive medication during the treatment period. In
the 24-week SEISMIC study, 38.1% (8/21) of patients met the
criteria for hypertension response, which for that trial was
defined as a ≥5 mmHg reduction from baseline in DBP
TABLE 4 | Mean change from baseline to last observation in exploratory secondary endpoints (efficacy population, n = 34).
Parameter Mean change from baseline to last observation p-value
Fructosamine (mmol/L) -13.92 0.002
HOMA-IR
a
-1.58 0.064
ALT (U/L) -10.62 < 0.001
AST (U/L) -4.94 0.001
Serum osteocalcin (mg/L) 3.00 < 0.01
Absolute eosinophils (10
9
/L) 0.05 0.006
aPTT (sec) 1.45 0.046
Factor VIII (%) -18.94 0.022
Platelet count (10
9
/L) -68.82 < 0.001
BDI-II Total score -3.48 0.004
Cushing QoL score 7.13 0.002
Trail Making Test Part A –Total time to complete test (sec) -4.13 0.003
Trail Making Test Part B –Total time to complete test (sec) -24.69 < 0.001
p-values for the mean change from baseline to last observation are from the Wilcoxon signed-rank test.
a
A significant difference was observed in the high-dose treatment group (mean change -3.2, p = 0.033).
ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; AUC, area under the curve; BDI, Beck Depression Inventory; HOMA-IR,
homeostatic model assessment for insulin resistance; QoL, quality of life.
TABLE 5 | TEAEs by preferred term in the safety population.
TEAE, n (%) Low-dose group (n = 17) High-dose group (n = 18) Overall population (n = 35)
Patients reporting ≥1 TEAE 15 (88.2) 18 (100.0) 33 (94.3)
TEAE occurring in ≥20% of either the low-dose or high-dose group
Back pain 4 (23.5) 7 (38.9) 11 (31.4)
Headache 4 (23.5) 5 (27.8) 9 (25.7)
Peripheral edema 4 (23.5) 5 (27.8) 9 (25.7)
Nausea 3 (17.7) 5 (27.8) 8 (22.9)
Pain in extremity 4 (23.5) 4 (22.2) 8 (22.9)
Diarrhea 4 (23.5) 3 (16.7) 7 (20.0)
Dizziness 3 (17.7) 4 (22.2) 7 (20.0)
Arthralgia 2 (11.8) 4 (22.2) 6 (17.1)
Dyspepsia 1 (5.9) 4 (22.2) 5 (14.3)
Myalgia 1 (5.9) 4 (22.2) 5 (14.3)
Abdominal pain 0 4 (22.2) 4 (11.4)
TEAE, treatment-emergent adverse event.
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6628658

assessed as the mean of 2 sequential clinic readings. The response
achieved with relacorilant is noteworthy considering that ABPM
provides a more accurate representation of blood pressure over a
24-h time period for patients (22,24). Although the response
criteria threshold (≥5 mmHg) appears similar between the
studies, they are not equivalent. Average clinic assessments by
trained staff are 10/5 mmHg (SBP/DBP) higher than 24-h ABPM
(31), and treatment-associated mean 24-h AMBP reductions are
disproportionately less than office blood pressure reductions (22,
32). Thus, these phase 2 data suggest a potential benefit for
relacorilant in improving hypertension in patients with CS.
For patients in the hyperglycemia subgroup, 15.4% (2/13) of
the low-dose group and 50.0% (6/12) the high-dose group met
the ad-hoc criteria for a clinically meaningful hyperglycemia
response, defined as either a decrease in HbA1c of ≥0.5% from
baseline or a normalization or improvement by ≥50 mg/dL (≥2.8
mmol/L) of the 2-h glucose value on the oGTT or a decrease in
antidiabetic medication. These criteria were selected because
each of them have been used in previous studies to
demonstrate a clinically meaningful improvement in the
hyperglycemia status of a patient (33–37). Initially, responder
criteria were selected for the hyperglycemia population,
modelled after the SEISMIC trial. In the SEISMIC trial
population, the mean baseline HbA1c (7.4%), 2-h postprandial
glucose (296.2 mg/dL [16.4 mmol/L]; data on file), and fasting
glucose (149.0 mg/dL [8.3 mmol/L]) were considerably higher
than in this trial population (mean baseline HbA1c 6.6%, mean
2-h postprandial glucose 229.4 mg/dL [12.7 mmol/L], mean
fasting glucose 119.3 mg/dL [6.6 mmol/L]). In SEISMIC, to
qualify as a responder, a ≥25% decrease in AUC
glucose
on the
oGTT without increase or addition of new antidiabetic
medication was required. Although the AUC standard would
have set an unsafely low glycemic goal in some individual cases
in the less severely hyperglycemic population of this study, 12%
(3/25) of the pooled hyperglycemia population achieved a ≥25%
decrease in AUC
glucose
from baseline, and more importantly, a
significant decrease in AUC
glucose
from baseline was observed
overall. Fructosamine is another biomarker for glucose control
and has been shown to correlate closely with HbA1c and glucose
levels in clinical trials (26). In an exploratory analysis, significant
improvement in serum fructosamine levels was observed in the
combined hyperglycemia population, further corroborating the
clinical improvements in hyperglycemia with relacorilant noted
when applying the ad-hoc responder criteria.
Significant improvement in several additional exploratory
endpoints were noted in the pooled patient population. Serum
osteocalcin, a marker of bone formation, has been shown to
negatively correlate with serum cortisol (25). In this study,
relacorilant was associated with a significant increase in serum
osteocalcin levels during treatment, indicating increased bone
turnover. Nonalcoholic fatty liver disease (NAFLD) is frequently
observed in patients with endogenous hypercortisolism (5). In a
previous case report, mifepristone treatment was associated with
improvement of NAFLD based on a marked reduction in liver
enzymes in a patient with hypercortisolism due to an adrenal
adenoma (38). Although formal assessments of hepatic steatosis
were not performed in this study, relacorilant was associated with
significant decreases in both alanine aminotransferase and aspartate
aminotransferase values. Significant improvement was also noted in
several coagulation parameters (Factor VIII, aPTT, and platelets),
cognition, depression, and QoL. These parameters are being further
examined in larger, randomized, placebo-controlled phase 3 studies
(clinicaltrials.gov NCT03697109, NCT04308590).
The most commonly associated TEAEs with relacorilant were
primarily musculoskeletal, gastrointestinal, or nervous system-
related in nature. Relacorilant was generally better tolerated
when patients were started at 100 mg in the low-dose group.
In the high-dose group, with a starting dose of 250 mg, a higher
rate of TEAEs and premature discontinuations were observed,
with the highest incidence of TEAEs observed early on in the trial
at the starting dose of 250 mg, followed by lower incidences on
continued treatment at the higher dose levels. This was
particularly apparent for musculoskeletal and gastrointestinal
TEAEs, suggesting that the higher starting dose prompted
symptoms consistent with rapid withdrawal from excess
cortisol. Symptoms of cortisol withdrawal (e.g., nausea, fatigue,
A
B
FIGURE 4 | Potassium levels by visit in the (A) low-dose group and (B) high-dose group.
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 6628659

arthralgia, headache) have also been observed in patients treated
with mifepristone (16,19) and have been shown to last for
several weeks (19).
During treatment with the GR antagonist mifepristone,
substantial increases in ACTH and cortisol were noted (16,
17). In SEISMIC, UFC levels increased 7.7-fold, and 63% of all
patients had at least a 2-fold increase in ACTH. In the present
study, the respective median changes from baseline in UFC and
ACTH were 4.0 nmol/d (1.4 µg/24 h) and 3.7 pmol/L (16.8 pg/
mL) in the ACTH-dependent CS group and 7.0 nmol/d (2.6 µg/
24 h) and 0.2 pmol/L (0.9 pg/mL) in the adrenal group. The
lower increases in ACTH and cortisol levels observed with
relacorilant from this study were consistent with findings from
studies conducted in healthy volunteers (39). Administration of
relacorilant to healthy subjects was shown to reverse the effects of
high-dose prednisone (25 mg) (39) and was not associated with
increases in ACTH (data on file). This may reflect differences in
the degree of GR antagonism in different tissues at the assessed
dosages. Although relacorilant is a potent antagonist of the GR
receptor (39), its effects in different tissues (e.g., pituitary) (40)
appear to differ from mifepristone (16). Two patients with
Cushing disease due to a macroadenoma were enrolled in the
phase 2 study and received de novo treatment with relacorilant
for 12 weeks as preoperative management (40). During
treatment, their ACTH levels remained consistent with
baseline. Two weeks after their last dose of relacorilant,
presurgical imaging revealed a reduction in the size of their
tumors (40). In vitro studies of relacorilant are underway to
further investigate these findings. Compared with patients
treated with mifepristone, the noticeably lower increases in
UFC and ACTH levels may also explain the absence of drug-
induced hypokalemia with relacorilant, and the greater benefitin
patients with hypertension (16). Elevated cortisol in CS is
associated with activation of the mineralocorticoid receptors
upon saturation of the 11b-hydroxysteroid type 2 enzyme
receptors, leading to hypokalemia and hypertension (41–43).
GR antagonism with mifepristone, leading to a further increase
in cortisol levels, can exacerbate these symptoms (19). In fact,
hypokalemia occurred in 44% of patients treated with
mifepristone in the 24-week clinical trial of 50 adults with
endogenous CS (16). Also, unlike mifepristone, there was no
drug-induced vaginal bleeding in the study due to the lack of
activity at the progesterone receptor.
This study has a number of limitations. First, it is an open-
label, phase 2 dose-finding study with a relatively small sample
size (no sample size calculation) and short treatment duration,
and there was potential heterogeneity in the dose escalation
scheme based on the investigators’clinical judgment. As part of
the study design, the low- and high-dose treatment groups were
different durations and were performed sequentially, not in
parallel, limiting the conclusions regarding a dose response.
Also, because of the small sample size, select data from
patients with major protocol deviations were included in the
analyses of clinical response. Finally, an ad-hoc analysis of
hyperglycemia response had to be conducted based on the
patient population enrolled; many of the outcome assessments
were exploratory in nature; and no adjustments for multiple
comparisons were performed. Nonetheless, these phase 2 results
provide the first clinical evidence to suggest that relacorilant may
offer the clinical benefitofpotentandhighlyspecific
glucocorticoid modulation in patients with endogenous CS
without the undesirable effects mediated by mifepristone’s
activity at the progesterone receptor or its frequent
mineralocorticoid activation via its marked elevation of cortisol
levels. Increases in ACTH and cortisol with relacorilant were
substantially less than with mifepristone, which may greatly
benefit patients.
Two larger phase 3 studies to further investigate the clinical
efficacy and safety of relacorilant in patients with endogenous CS
and hypertension or IGT/T2DM and in patients with CS caused
by a cortisol-producing adrenal adenoma or bilateral hyperplasia
are in progress. The safety data from this phase 2 study suggest
that patients should begin relacorilant treatment at a relatively
low dose. Because the starting dose of 100 mg in the low-dose
group was well tolerated, it was chosen as the starting dose in the
phase 3 trials of relacorilant. In those trials, patients begin
treatment at 100 mg/d for 2 weeks and the dose is gradually
escalated, enhancing tolerability and treatment persistence.
Further examination of the tissue specificity of relacorilant is
also underway, including the effect of relacorilant on pituitary
size in the phase 3 study. In vitro studies of relacorilant are being
conducted to further investigate the different effects of
relacorilant and mifepristone on cortisol and somatostatin
receptor expression.
DATA AVAILABILITY STATEMENT
The datasets presented in this study can be found in online
repositories. The names of the repository/repositories and
accession number(s) can be found below: Grouped datasets
analyzed during the current study are available here. Additional
individual datasets generated during and/or analyzed are not
publicly available but are available from the corresponding
author on reasonable request.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by the institutional review board at each study center.
The patients/participants provided their written informed
consent to participate in this study.
AUTHOR CONTRIBUTIONS
Study concept and design: AM. Study investigators who provided
study materials and/or patients: RP, IB, RF, AK, JK, MG, CM,
and MT. Statistical analysis: NE. Analyzed and interpreted
clinical data: All authors. Wrote manuscript or critically
revised it for content: All authors. All authors contributed to
the article and approved the submitted version.
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 66286510

FUNDING
This study was funded by Corcept Therapeutics. Open Access
publication fees were paid by Corcept Therapeutics.
ACKNOWLEDGMENTS
The authors thank the patients who participated in the study, as
well as the investigators and clinical research staff from the study
centers. The authors also thank Dat Nguyen, PharmD, of
Corcept Therapeutics and Nicole Cooper, MS, and Sarah
Mizne, PharmD, of MedVal Scientific Information Services,
LLC for medical writing and editorial assistance, which was
funded by Corcept Therapeutics. This manuscript was prepared
according to the International Society for Medical Publication
Professionals’“Good Publication Practice for Communicating
Company-Sponsored Medical Research: GPP3.”Data from this
paper were presented at the American Association of Clinical
Endocrinologists Annual Congress, May 16-20, 2018, Boston,
MA. Abstract 1219.
REFERENCES
1. Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM,
et al. The Diagnosis of Cushing’s Syndrome: An Endocrine Society Clinical
Practice Guideline. J Clin Endocrinol Metab (2008) 93:1526–40. doi: 10.1210/
jc.2008-0125
2. Ferrau F, Korbonits M. Metabolic Syndrome in Cushing’s Syndrome Patients.
Front Horm Res (2018) 49:85–103. doi: 10.1159/000486002
3. van der Pas R, Leebeek FW, Hofland LJ, de Herder WW, Feelders RA.
Hypercoagulability in Cushing’s Syndrome: Prevalence, Pathogenesis and
Treatment. Clin Endocrinol (Oxf) (2013) 78:481–8. doi: 10.1111/cen.12094
4. Minetto M, Reimondo G, Osella G, Ventura M, Angeli A, Terzolo M. Bone
Loss Is More Severe in Primary Adrenal Than in Pituitary-Dependent
Cushing’s Syndrome. Osteoporos Int (2004) 15:855–61. doi: 10.1007/
s00198-004-1616-3
5. Rockall AG, Sohaib SA, Evans D, Kaltsas G, Isidori AM, Monson JP, et al.
Hepatic Steatosis in Cushing’s Syndrome: A Radiological Assessment Using
Computed Tomography. Eur J Endocrinol (2003) 149:543–8. doi: 10.1530/
eje.0.1490543
6. Debono M, Bradburn M, Bull M, Harrison B, Ross RJ, Newell-Price J. Cortisol
as a Marker for Increased Mortality in Patients With Incidental
Adrenocortical Adenomas. J Clin Endocrinol Metab (2014) 99:4462–70.
doi: 10.1210/jc.2014-3007
7. Di Dalmazi G, Vicennati V, Garelli S, Casadio E, Rinaldi E, Giampalma E,
et al. Cardiovascular Events and Mortality in Patients With Adrenal
Incidentalomas That Are Either non-Secreting or Associated With
Intermediate Phenotype or Subclinical Cushing’s Syndrome: A 15-Year
Retrospective Study. Lancet Diabetes Endocrinol (2014) 2:396–405.
doi: 10.1016/s2213-8587(13)70211-0
8. Dekkers OM, Horváth-Puhó E, Jorgensen JO, Cannegieter SC, Ehrenstein V,
Vandenbroucke JP, et al. Multisystem Morbidity and Mortality in Cushing’s
Syndrome: A Cohort Study. J Clin Endocrinol Metab (2013) 98:2277–84.
doi: 10.1210/jc.2012-3582
9. Geer EB, Shafiq I, Gordon MB, Bonert V, Ayala A, Swerdloff RS, et al.
Biochemical Control During Long-Term Follow-Up of 230 Adult Patients
With Cushing Disease: A Multicenter Retrospective Study. Endocr Pract
(2017) 23:962–70. doi: 10.4158/ep171787.Or
10. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s Syndrome.
Lancet (2015) 386:913–27. doi: 10.1016/s0140-6736(14)61375-1
11. Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A.
Complications of Cushing’s Syndrome: State of the Art. Lancet Diabetes
Endocrinol (2016) 4:611–29. doi: 10.1016/s2213-8587(16)00086-3
12. Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO,
et al. Treatment of Cushing’s Syndrome: An Endocrine Society Clinical
Practice Guideline. J Clin Endocrinol Metab (2015) 100:2807–31.
doi: 10.1210/jc.2015-1818
13. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing’s
Disease. Endocr Rev (2015) 36:385–486. doi: 10.1210/er.2013-1048
14. Feelders RA, Newell-Price J, Pivonello R, Nieman LK, Hofland LJ, Lacroix A.
Advances in the Medical Treatment of Cushing’s Syndrome. Lancet Diabetes
Endocrinol (2019) 7:300–12. doi: 10.1016/s2213-8587(18)30155-4
15. Pivonello R, Ferrigno R, De Martino MC, Simeoli C, Di Paola N, Pivonello C,
et al. Medical Treatment of Cushing’s Disease: An Overview of the Current
and Recent Clinical Trials. Front Endocrinol (Lausanne) (2020) 11:648.
doi: 10.3389/fendo.2020.00648
16. Fleseriu M, Biller BM, Findling JW, Molitch ME, Schteingart DE, Gross C.
Mifepristone, a Glucocorticoid Receptor Antagonist, Produces Clinical and
Metabolic Benefits in Patients With Cushing’s Syndrome. J Clin Endocrinol
Metab (2012) 97:2039–49. doi: 10.1210/jc.2011-3350
17. Fleseriu M, Findling JW, Koch CA, Schlaffer S-M, Buchfelder M, Gross C.
Changes in Plasma ACTH Levels and Corticotroph Tumor Size in Patients
With Cushing’s Disease During Long-Term Treatment With the
Glucocorticoid Receptor Antagonist Mifepristone. J Clin Endocrinol Metab
(2014) 99:3718–27. doi: 10.1210/jc.2014-1843
18. Brown DR, East HE, Eilerman BS, Gordon MB, King EE, Knecht LA, et al.
Clinical Management of Patients With Cushing Syndrome Treated With
Mifepristone: Consensus Recommendations. Clin Diabetes Endocrinol (2020)
6:18. doi: 10.1186/s40842-020-00105-4
19. Yuen KC, Williams G, Kushner H, Nguyen D. Association Between
Mifepristone Dose, Efficacy, and Tolerability in Patients With Cushing
Syndrome. Endocr Pract (2015) 21:1087–92. doi: 10.4158/ep15760.Or
20. Hunt HJ, Belanoff JK, Walters I, Gourdet B, Thomas J, Barton N, et al.
Identification of the Clinical Candidate (R)-(1-(4-Fluorophenyl)-6-((1-
Methyl-1H-Pyrazol-4-Yl)Sulfonyl)-4,4a,5,6,7,8-Hexahydro-1H-Pyrazolo[3,4-
G]Isoquinolin-4a-Yl)(4-(Trifluoromethyl)Pyridin-2-Yl)Methanone
(CORT125134): A Selective Glucocorticoid Receptor (GR) Antagonist. J Med
Chem (2017) 60:3405–21. doi: 10.1021/acs.jmedchem.7b00162
21. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al.
Management of Adrenal Incidentalomas: European Society of Endocrinology
Clinical Practice Guideline in Collaboration With the European Network for
the Study of Adrenal Tumors. Eur J Endocrinol (2016) 175:G1–34.
doi: 10.1530/eje-16-0467
22. O’Brien E, Parati G, Stergiou G, Asmar R, Beilin L, Bilo G, et al. European
Society of Hypertension Position Paper on Ambulatory Blood Pressure
Monitoring. J Hypertens (2013) 31:1731–68. doi: 10.1097/HJH.0b013e
328363e964
23. Grant RW, Donner TW, Fradkin JE, Hayes C, Herman WH, Hsu WC, et al.
Standards of Medical Care in Diabetes—2015. Diabetes Care (2015) 38:S1–93.
doi: 10.2337/dc15-S003
24. UngerT,BorghiC,CharcharF,KhanNA,PoulterNR,PrabhakaranD,etal.2020
International Society of Hypertension Global Hypertension Practice Guidelines.
Hypertension (2020) 75:1334–57. doi: 10.1161/hypertensionaha.120.15026
25. Tóth M, Grossman A. Glucocorticoid-Induced Osteoporosis: Lessons From
Cushing’s Syndrome. Clin Endocrinol (Oxf) (2013) 79:1–11. doi: 10.1111/
cen.12189
26. Malmström H, Walldius G, Grill V, Jungner I, Gudbjörnsdottir S, Hammar N.
Fructosamine Is a Useful Indicator of Hyperglycaemia and Glucose Control in
Clinical and Epidemiological Studies–Cross-Sectional and Longitudinal
Experience From the AMORIS Cohort. PLoS One (2014) 9:e111463.
doi: 10.1371/journal.pone.0111463
27. Webb SM, Badia X, Barahona MJ, Colao A, Strasburger CJ, Tabarin A, et al.
Evaluation of Health-Related Quality of Life in Patients With Cushing’s
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
Frontiers in Endocrinology | www.frontiersin.org July 2021 | Volume 12 | Article 66286511

Syndrome With a New Questionnaire. Eur J Endocrinol (2008) 158:623–30.
doi: 10.1530/eje-07-0762
28. Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory-Ii.
San Antonio, TX: Psychological Corporation (1996).
29. Tombaugh TN. Trail Making Test A and B: Normative Data Stratified by Age
and Education. Arch Clin Neuropsychol (2004) 19:203–14. doi: 10.1016/s0887-
6177(03)00039-8
30. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC.
Homeostasis Model Assessment: Insulin Resistance and Beta-Cell Function
From Fasting Plasma Glucose and Insulin Concentrations in Man.
Diabetologia (1985) 28:412–9. doi: 10.1007/bf00280883
31. Head GA, Mihailidou AS, Duggan KA, Beilin LJ, Berry N, Brown MA, et al.
Definition of Ambulatory Blood Pressure Targets for Diagnosis and
Treatment of Hypertension in Relation to Clinic Blood Pressure:
Prospective Cohort Study. BMJ (2010) 340:c1104. doi: 10.1136/bmj.c1104
32. Schmieder RE, Schmidt ST, Riemer T, Dechend R, Hagedorn I, Senges J, et al.
Disproportional Decrease in Office Blood Pressure Compared With 24-Hour
Ambulatory Blood Pressure With Antihypertensive Treatment: Dependency
on Pretreatment Blood Pressure Levels. Hypertension (2014) 64:1067–72.
doi: 10.1161/hypertensionaha.113.03140
33. Gerich J. Pathogenesis and Management of Postprandial Hyperglycemia: Role
of Incretin-Based Therapies. Int J Gen Med (2013) 6:877–95. doi: 10.2147/
ijgm.S51665
34. Esposito K, Giugliano D, Nappo F, Marfella R. Campanian Postprandial
Hyperglycemia Study Group. Regression of Carotid Atherosclerosis by
Control of Postprandial Hyperglycemia in Type 2 Diabetes Mellitus.
Circulation (2004) 110:214–9. doi: 10.1161/01.Cir.0000134501.57864.66
35. Castinetti F, Guignat L, Giraud P, Muller M, Kamenicky P, Drui D, et al.
Ketoconazole in Cushing’s Disease: Is it Worth a Try? J Clin Endocrinol Metab
(2014) 99:1623–30. doi: 10.1210/jc.2013-3628
36. GoldbergRB, Einhorn D, Lucas CP, Rendell MS, Damsbo P, Huang WC, et al. A
Randomized Placebo-Controlled Trial of Repaglinide in the Treatment of Type
2Diabetes.Diabetes Care (1998) 21:1897–903. doi: 10.2337/diacare.21.11.1897
37. Marre M, VanGaal L, Usadel KH, BallM, Whatmough I, Guitard C. Nateglinide
Improves Glycaemic Control When Added to Metformin Monotherapy: Results
of a Randomized Trial With Type 2 Diabetes Patients. Diabetes Obes Metab
(2002) 4:177–86. doi: 10.1046/j.1463-1326.2002.00196.x
38. Ragucci E, Nguyen D, Lamerson M, Moraitis AG. Effects of Mifepristone on
Nonalcoholic Fatty Liver Disease in a Patient With a Cortisol-Secreting
Adrenal Adenoma. Case Rep Endocrinol (2017) 2017:6161348. doi: 10.1155/
2017/6161348
39. Hunt H, Donaldson K, Strem M, Zann V, Leung P, Sweet S, et al. Assessment
of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally
Administered CORT125134: An Adaptive, Double-Blind, Randomized,
Placebo-Controlled Phase 1 Clinical Study. Clin Pharmacol Drug Dev
(2018) 7:408–21. doi: 10.1002/cpdd.389
40. Terzolo M, Iacuaniello D, Pia A, Adriano P, Moraitis A, Pivonello R. Tumor
Shrinkage With Preoperative Relacorilant Therapy in Two Patients With
Cushing Disease Due to Pituitary Macroadenomas [Abstract]. J Endocr Soc
(2019) 3(suppl 1):SUN–463. doi: 10.1210/js.2019-SUN-463
41. Torpy DJ, Mullen N, Ilias I, Nieman LK. Association of Hypertension and
Hypokalemia With Cushing’s Syndrome Caused by Ectopic ACTH Secretion:
A Series of 58 Cases. Ann N Y Acad Sci (2002) 970:134–44. doi: 10.1111/
j.1749-6632.2002.tb04419.x
42. Howlett TA, Drury PL, Perry L, Doniach I, Rees LH, Besser GM. Diagnosis
and Management of ACTH-Dependent Cushing’s Syndrome: Comparison of
the Features in Ectopic and Pituitary ACTH Production. Clin Endocrinol
(Oxf) (1986) 24:699–713. doi: 10.1111/j.1365-2265.1986.tb01667.x
43. Isidori AM, Graziadio C, Paragliola RM, Cozzolino A, Ambrogio AG, Colao
A, et al. The Hypertension of Cushing’s Syndrome: Controversies in the
Pathophysiology and Focus on Cardiovascular Complications. J Hypertens
(2015) 33:44–60. doi: 10.1097/hjh.0000000000000415
Conflict of Interest: The authors declare that this study received funding from
Corcept Therapeutics (Menlo Park, CA, USA). The funder had a role in study
design, data collection and analysis, and AM, as an author of the manuscript and
employee of Corcept Therapeutics, had a role in the study design, the decision to
publish, the interpretation of clinical data, the revision of the manuscript, and
approval of the final manuscript to submit. Open Access publication fees were
paid by Corcept Therapeutics. RP: Consultant: Ferring, Ipsen, Novartis, Pfizer,
ViroPharma-Shire; Speaker: Novartis, ViroPharma-Shire; Research support:
Corcept Therapeutics, Novartis, ViroPharma-Shire; Grant support: IBSA,
Novartis, Pfizer, ViroPharma-Shire. IB: Consultant: HRA Pharma, Sparrow
Pharmaceutics, Strongbridge; Data and Safety Monitoring Panel, Adrenas. RF:
Consultant: Corcept Therapeutics; Speaker: HRA Pharma. AK: Consultant:
Strongbridge; Research support: Corcept Therapeutics. MG: Research support:
Corcept Therapeutics, Crinetics, Ionis, Ipsen, Novartis, Novo Nordisk, Opko,
Strongbridge, Teva. CM: Consultant: Horizon Therapeutics; Research support:
Corcept Therapeutics, Eli Lilly, Medtronic. MT: Consultant: HRA Pharma;
Research support: Corcept Therapeutics. NE: Consultant: Corcept Therapeutics,
Pentara, Trialwise. AM: Employee: Corcept Therapeutics.
The remaining author (JK) declares that the research was conducted in the absence
of any commercial or financial relationships that could be construed as a potential
conflict of interest.
The reviewer AALC declared a shared affiliation with one of the authors, RP, to the
handling editor at time of review.
Author NE was employed by company Trialwise.
Copyright © 2021 Pivonello, Bancos, Feelders, Kargi, Kerr, Gordon, Mariash, Terzolo,
Ellison and Moraitis. This is an open-access article distributed under the terms of the
Creative Commons Attribution License (CC BY). The use, distribution or
reproduction in other forums is permitted, provided the original author(s) and the
copyright owner(s) are credited and that the original publication in this journal is
cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
Pivonello et al. Relacorilant in Endogenous Hypercortisolism
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