Crinetics Pharma’s Promising Study on CRN04894 for Cushing’s Syndrome: A Potential Game-Changer?

Posted on November 1, 2025 by MaryO

Crinetics Pharmaceuticals is conducting a study titled ‘A Phase 1b/2a Open-label Multiple-ascending Dose Exploratory Study of CRN04894 in ACTH-dependent Cushing’s Syndrome.’ This study aims to evaluate the safety, tolerability, and pharmacokinetics of CRN04894, an ACTH receptor antagonist, in treating Cushing’s Syndrome, a condition characterized by excessive cortisol production. The study’s significance lies in its potential to offer a new treatment avenue for patients with Cushing’s disease or Ectopic ACTH Syndrome.

The intervention being tested is a drug named atumelnant, which is an orally active agent designed to block the action of ACTH at its receptor. This intervention is administered in tablet form and is intended to manage the symptoms of ACTH-dependent Cushing’s Syndrome.

The study employs an interventional design with a sequential model, featuring multiple ascending doses over 10 to 14 days. It is open-label, meaning there is no masking, and its primary purpose is treatment-focused, aiming to assess the drug’s effects on participants.

The study began on March 27, 2023, and is currently recruiting participants. The last update was submitted on April 8, 2025. These dates are crucial as they indicate the study’s progress and ongoing nature, which is essential for stakeholders tracking its development.

This clinical update could influence Crinetics Pharma’s stock performance positively by showcasing their commitment to advancing treatment options for Cushing’s Syndrome. Investors may view this as a promising development, potentially enhancing market sentiment. The study’s progress should be monitored alongside competitors in the endocrinology space to gauge its broader industry impact.

https://www.tipranks.com/news/company-announcements/crinetics-pharmas-promising-study-on-crn04894-for-cushings-syndrome-a-potential-game-changer

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Cushing Syndrome Test Choice Should Fit Patient Factors & Disease Stage

Posted on October 20, 2025 by MaryO

Caused by excessive exposure to the hormone cortisol, endogenous Cushing syndrome (CS) is difficult to diagnose. Currently available biochemical tests that assess cortisol production have limited diagnostic specificity and sensitivity, and their performance can vary depending on the patient, according to a review article in Current Opinion in Endocrinology, Diabetes and Obesity.

“Whether performed on blood, urine, saliva, or hair, all biochemical tests for CS have advantages and disadvantages. It is therefore essential to select them based on the individual characteristics of the patient and the stage of the disease in order to improve their diagnostic performance,” wrote corresponding author Antoine Tabarin, MD, and coauthor Amandine Ferriere, MD, of the University Hospital of Bordeaux in Pessac, France.

The Endocrine Society recommends initial screening of patients with suspected CS using 24-hour urinary-free cortisol (UFC), late-night salivary cortisol (LNSC), or the overnight dexamethasone suppression test (ONDST). To avoid false negatives from variability in cortisol production, UFC and LNSC tests should be performed twice.

Among the three screening options, meta-analysis findings suggest comparable diagnostic performance, the authors reported.

“However, they also concluded that these investigations should not be used indiscriminately,” the review continued, “and should be selected according to various circumstances.”

ONDST results can be affected by medications, age, a history of bariatric surgery, and even individual differences in dexamethasone metabolism, according to the review. UFC requires patient education and a complete 24-hour urine collection. LNSC testing, which biochemically assesses the loss of circadian rhythmicity consistent in CS, may not be appropriate for people with highly variable sleep schedules, including shift workers.

For early detection of Cushing disease (CD) recurrence after pituitary surgery, LNSC is the recommended first-line procedure for biochemical follow-up. LNSC is also the tool of choice for monitoring patients with CS treated with medication, the article reported.

For patients with adrenocorticotropic hormone (ACTH)-dependent CS, UFC offers high accuracy for assessing the likelihood of CD and ectopic adrenocorticotropin. However, for the diagnosis of cyclical or intermittent CS, repeat UFC tests are “cumbersome and nearly impossible,” the authors wrote.

LNSC, on the other hand, allows for frequent daily assessment of cortisol secretion which is helpful for identifying cyclical CS. Similarly, measurements of cortisol and cortisone levels in the hair can assess mid- to long-term tissular exposure to cortisol and signal cyclical CS as well, the review explained.

References

Ferriere A, et al. Curr Opin Endocrinol Diabetes Obes. 2025;32(5):233-239. doi:10.1097/MED.0000000000000923

From https://www.physiciansweekly.com/post/cushing-syndrome-test-choice-should-fit-patient-factors-disease-stage

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Sleep Disturbances in Patients With Cushing Syndrome and Mild Autonomous Cortisol Secretion

Posted on October 16, 2025 by MaryO

The Journal of Clinical Endocrinology & Metabolism, dgaf553, https://doi.org/10.1210/clinem/dgaf553

Abstract

Context

The impact of active hypercortisolism on sleep is incompletely characterized. Studies report impaired sleep in patients with Cushing syndrome (CS). Patients with mild autonomous cortisol secretion (MACS) demonstrate mild nocturnal hypercortisolism that could impact sleep.

Objectives

To characterize sleep abnormalities in patients with CS and MACS using the Pittsburgh Sleep Quality Index (PSQI), identify factors associated with poor sleep, and compare sleep abnormalities in patients with MACS versus referent subjects.

Methods

We conducted a single-center cross-sectional study of adults with active CS and MACS. Clinical and biochemical severity scores for hypercortisolism were calculated. Parallelly, we enrolled referent subjects. Quality of life was assessed using 1) Short Form-36 in all participants, and 2) Cushing QoL in patients with active hypercortisolism. Sleep quality was assessed using PSQI.

Results

PSQI was assessed in 154 patients with CS (mean 12, SD ±4.5), 194 patients with MACS (mean 11, SD 4.6), and 89 referents (mean 5, SD ±3.4). Patients with MACS exhibited shorter sleep duration, longer sleep latency, more severe daytime dysfunction, lower sleep efficiency, and a higher sleep medication use compared to referent subjects (P = <0.001 for all). Age-, sex, and BMI adjusted analysis demonstrated no differences in PSQI or its subcomponents between patients with CS and MACS (P >0.05 for all). In a multivariable analysis of patients with MACS, younger age, female sex and higher clinical hypercortisolism severity score were associated with impaired sleep. In patients with CS, only younger age was associated with poor sleep.

Conclusions

Patients with MACS demonstrate sleep impairment that is similar to patients with CS. Younger women with higher clinical severity of MACS are more likely to have impaired sleep.

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The Impact of Adrenalectomy On Metabolic Outcomes of Patients Wwth Mild Autonomous Cortisol Secretion Defined by Low-Dose Dexamethasone Suppression Testing

Posted on October 12, 2025 by MaryO

Abstract

Background

Up to 50% of patients with adrenal incidentalomas have mild autonomous cortisol secretion, which may increase their cardiometabolic morbidity, compared with patients with nonfunctional adrenal tumors. Studies evaluating cardiometabolic outcomes of patients with mild autonomous cortisol secretion defined by 1-mg dexamethasone suppression testing (cortisol 1.8–5 μg/dL) have demonstrated mixed results. The aim of this study was to assess the metabolic outcomes of patients with mild autonomous cortisol secretion, defined by the 1-mg dexamethasone suppression testing criterion, compared with patients with nonfunctional adrenal tumors who underwent adrenalectomy.

Methods

We conducted a single-institution retrospective cohort study comparing adult patients who underwent unilateral adrenalectomy from November 30, 2011, to August 19, 2023, for mild autonomous cortisol secretion (1-mg dexamethasone suppression testing cortisol 1.8–5 μg/dL) or nonfunctional adrenal tumors (1-mg dexamethasone suppression testing cortisol <1.8 μg/dL). Preoperative prevalences and postoperative changes in diabetes mellitus, hypertension, dyslipidemia, and elevated body mass index (≥25) were assessed. Patients were followed from the time of surgery until their last outpatient visit. Multivariable logistic regression was pursued for outcomes that varied between cohorts.

Results

A total of 65 patients (53 mild autonomous cortisol secretion and 12 nonfunctional adrenal tumors) were analyzed. Patients with mild autonomous cortisol secretion were older and more likely to have diabetes mellitus than patients with nonfunctional adrenal tumors (odds ratio: 7.81, 95% confidence interval [0.94, 64.96], P = .04). Patients were followed for a median of 28.1 months [11.1, 55.3 months]. Patients with mild autonomous cortisol secretion were more likely to have postoperative weight improvement (odds ratio: 8.31, [0.97, 71.14], P = .03). After adjusting for clinically relevant variables, the 1-mg dexamethasone suppression testing cortisol was predictive of postoperative weight improvement (odds ratio: 1.88, [1.1, 3.65], P = .04).

Conclusion

Weight loss should be considered as a potential benefit of adrenalectomy in patients with mild autonomous cortisol secretion.

Introduction

Mild autonomous cortisol secretion (MACS) is the most common hormonal abnormality diagnosed in patients with adrenal incidentalomas, impacting 20%–50% of patients.1 Patients with MACS have biochemical evidence of adrenocorticotropic hormone (ACTH)-independent hypercortisolism but lack clinical stigmata commonly associated with overt hypercortisolism, such as facial plethora, abdominal adiposity, extremity weakness and wasting, and/or violaceous striae.2 Overt hypercortisolism is well recognized to cause cardiovascular, musculoskeletal, and metabolic disorders, which have variable resolution even after diagnosis and treatment.3 There is a growing body of evidence that patients with MACS also have increased cardiometabolic morbidity and mortality compared with patients with nonfunctional adrenal tumors,4 but this evidence is challenging to interpret given wide variability in diagnostic criteria that have historically been used.5, 6, 7
Recent guidelines have suggested that a diagnosis of MACS be applied to all patients with a morning (AM) serum cortisol of >1.8 μg/dL after low-dose (1-mg) dexamethasone suppression testing (DST) who lack overt features of hypercortisolism.8,9 However, prior studies comparing cardiometabolic outcomes between patients with MACS and nonfunctional adrenal tumors as well as between patients who underwent operative and nonoperative management have used a 1-mg DST AM serum cortisol of 1.8–5.0 μg/dL as a definition of mild (“subclinical”) hypercortisolism.10, 11, 12, 13, 14, 15, 16 Given that these studies have demonstrated mixed results,4 the primary aim of this study was to assess the metabolic outcomes of patients with MACS, as defined by a 1-mg DST AM cortisol of 1.8–5.0 μg/dL, compared with patients with nonfunctional adrenal tumors who underwent adrenalectomy.

Section snippets

Methods

This was a single-institution retrospective cohort study of patients aged ≥18 years who underwent initial unilateral adrenalectomy from November 30, 2011, to August 19, 2023. Patients were identified through a prospectively maintained database of all patients who underwent adrenalectomy at the study institution. Patients were excluded if they had a 1-mg DST AM serum cortisol of >5 μg/dL, ACTH-dependent hypercortisolism, primary aldosteronism, pheochromocytoma, primary bilateral macronodular

Results

Of the 460 patients who underwent adrenalectomy during the study period, 53 patients met criteria for MACS and 12 patients for nonfunctional adrenal tumors, yielding a cohort of 65 patients. Patients with MACS were older than those with nonfunctional adrenal tumors (MACS, median 60 years [IQR: 54, 68 years] vs nonfunctional adrenal tumors, 49 years [37, 57 years], P = .02) but were similar by sex, race, ethnicity, BMI, nodule size, laterality, and surgical approach (Table II). Among patients

Discussion

MACS is the most common hormonal abnormality diagnosed in patients with adrenal incidentalomas. Despite lacking clinical stigmata of overt hypercortisolism, patients with MACS appear to have increased cardiometabolic morbidity and mortality similar to patients with overt hypercortisolism. The optimal management of MACS is debated, and prior studies using a 1-mg DST AM serum cortisol of 1.8–5.0 μg/dL as a definition of mild hypercortisolism have demonstrated mixed results. Hence, this study

Funding/Support

This project is funded in part by the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin. This publication was supported by the National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through grant number UL1TR001436. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The grant supports the creation and maintenance of

CRediT authorship contribution statement

Alexa Lisevick Kumar: Writing – original draft, Visualization, Methodology, Formal analysis, Data curation, Conceptualization. Sophie Dream: Writing – review & editing, Validation, Supervision, Methodology, Investigation. Tahseen Shaik: Resources, Project administration, Investigation, Data curation. Kara Doffek: Resources, Project administration, Investigation, Data curation. Ryan Conrardy: Writing – review & editing, Methodology, Formal analysis. James W. Findling: Writing – review & editing,

Conflict of Interest/Disclosure

Dr Findling reports consulting for Corcept, Diurnal, Crinetics and serving as an investigator for Recordati. The rest of the authors reported no biomedical financial interests or potential conflicts of interest.

References (34)

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    Comorbidities in mild autonomous cortisol secretion and the effect of treatment: systematic review and meta-analysis

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  • X. Ren et al.

    Evaluating the efficacy of surgical and conservative approaches in mild autonomous cortisol secretion: a meta-analysis

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    (2024)
  • M.M. Khadembashiri et al.

    Comparison of adrenalectomy with conservative treatment on mild autonomous cortisol secretion: a systematic review and meta-analysis

    Front Endocrinol

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  • Y.S. Elhassan et al.

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A Preliminary Model to Tailor Osilodrostat In Patients With Adrenocorticotropic Hormone (ACTH)-Dependent Cushing’s syndrome

Posted on October 10, 2025 by MaryO

Abstract

Over the past 10 years, osilodrostat has become one of the most commonly used steroidogenesis inhibitors in patients with Cushing’s syndrome. The starting dose is usually determined based on the product characteristics, the prescriber’s experience, and cortisol levels. However, no study has attempted to determine whether there was a dose–response relationship between osilodrostat and cortisol reduction. In this study, we developed a preliminary kinetic–pharmacodynamic model to tailor osilodrostat in patients with Adrenocorticotropin hormone (ACTH)-dependent Cushing’s syndrome. We first analyzed the decrease in cortisol 48 hours after initiation or dose change of osilodrostat in 18 patients. Simulations were then performed for different doses of osilodrostat to evaluate the variation in cortisol concentrations. Our results report the first dose–response relationship between osilodrostat dose and cortisol levels, which should be helpful in identifying the optimal dosing regimen in patients with Cushing’s syndrome and in individualizing treatment to approximate a nychthemeral rhythm.

osilodrostat, Cushing’s syndrome, Cushing’s disease, cortisol, adrenal insufficiency
Issue Section:

Brief Report

Significance

The current preliminary study is a first step in trying to better understand the effect of osilodrostat on cortisol, which should help determine the optimal dose for each patient.

Introduction

Cushing’s syndrome is a rare condition in which increased cortisol levels lead to a wide range of comorbidities and increased mortality. Surgery is usually regarded as the first-line and most effective treatment.1 In some cases, cortisol-lowering drugs are necessary, mainly after failed surgery.2,3 Among several steroidogenesis inhibitors such as ketoconazole and metyrapone,4,5 osilodrostat, which acts through inhibition of 11β-hydroxylase, is now being considered an effective drug in controlling cortisol hypersecretion. Initially designed as a CYP11B2 inhibitor, the study by Ménard et al.6 involving both animal models and healthy human subjects showed that osilodrostat reduced cortisol levels from a dose of 1 mg/day, while lower doses exerted an anti-aldosterone effect. Since then, several clinical trials and retrospective studies emphasized its efficacy in all etiologies of Cushing’s syndrome.7-9 While the usual recommended starting dose is 2 mg twice a day, precise studies on the short-term effect of osilodrostat on plasma cortisol are lacking. These data could, however, be of interest to tailor the treatment. Moreover, baseline urinary free cortisol (UFC) level is not able to predict response to osilodrostat.10 Taking advantage of serial cortisol measurements performed in inpatient clinics in our center at the time osilodrostat became available, we developed a pharmacokinetic (PK)/pharmacodynamic model of plasma cortisol variation as a function of osilodrostat dose in patients with Adrenocorticotropin-hormone (ACTH)-dependent Cushing’s syndrome.

Patients and methods

Clinical data and hormonal measurements

We retrospectively included patients with ACTH-dependent Cushing’s syndrome, who had serial measurements of plasma cortisol (every 4 hours for 24 hours) before and after the first osilodrostat dose between 2019 and 2024. These measurements were part of our standard of care approach when osilodrostat became available in our tertiary expert center as a thorough evaluation of the efficacy and tolerance of a new drug. The initial dose ranged from 2 to 15 mg/day, depending on the severity of hypercortisolism. Subsequently, osilodrostat dose was gradually adjusted based on the successive cortisol measurements described above. Sex, age at diagnosis, and etiologies were recorded, as well as plasma cortisol measurements 48 hours after the initiation or any change in the osilodrostat dose and time elapsed since change of dose and last administration were recorded. All plasma cortisol measurements were performed with the same Elecsys II Cortisol, Cobas (Roche Diagnostics) assay in the hormonal laboratory of our center; cross-reactivity with 11-deoxycortisol is 4.9%. According to our institutional policy, this retrospective study did not require specific signed informed consent from patients as the data collected were anonymized. It was thus approved by the Ethics Committee of Assistance Publique—Hopitaux de Marseille (RGPD PADS reference RUXXX2). The current study complies with the Declaration of Helsinki.

Pharmacokinetics and statistical analysis

The pharmacodynamic parameters of osilodrostat on cortisol concentrations were analyzed using a kinetic–pharmacodynamic (PD) model in the software Nonlinear Mixed Effects Modeling version 7.4 (NONMEM Icon Development Solutions, Ellicott City, MD, United States). PK analysis from a previously published study6 was used to predict plasma concentration in our patients. The PK parameters were described in the article, and mean concentration values were obtained by digitizing the graph of osilodrostat vs time using the software WebPlotDigitizer version 4.2.11 With these data, a one-compartment population PK model was used to predict osilodrostat concentrations for different dosing regimens. Direct and indirect relationship between osilodrostat-predicted concentration and variation of cortisol concentrations were evaluated to consider a delay. The variation of cortisol concentrations was calculated with reference to a session without treatment. Several functions were tested to describe the relationship such as linear and sigmoidal. Model selection and evaluation were done by the likelihood ratio test (objective function), goodness-of-fit plots (observed vs predicted variation of cortisol concentrations, observed vs individual predictions, normalized prediction distribution errors vs time and variation of cortisol predictions), bootstrap, and visual predictive checks. Graphical analysis was performed with the R software version 4.4.012 using the ggplot2 package.13 Simulations were performed for different doses of osilodrostat to evaluate the variation on cortisol concentrations using the package rxode2.14

Results

Of the patients who were prescribed osilodrostat at least once between 2019 and 2024, 18 were presenting ACTH-dependent Cushing’s syndrome, 12 women (66.6%) and 6 men (33.3%). Mean age was 53.2 ± 15 years. The cause of Cushing’s syndrome was Cushing’s disease in 16 patients (88.9%), ectopic ACTH secretion in 1 patient (5.6%), and ACTH-dependent hypercortisolism of uncertain diagnosis in 1 patient (5.6%). Clinical characteristics are presented in Table 1. It should be noted that none of the patients included were Asian.

 

 

Table 1.

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Clinical characteristics of patients with all included patients and differentiated according to gender.

All patientsa Women Men
Age at diagnosis 53.2 ± 15 54 ± 17.2 51.5 ± 10.5
Weight 81.7 ± 13.7 79.5 ± 12.7 86.2 ± 15.6
% of CD 88.9 83.3 100
ULN of 24 hour UFC 4.4 ± 8.3 5.5 ± 10.3 2.5 ± 1.8
Osilodrostat starting dose 3.3 ± 2.2 3.7 ± 2.4 2.5 ± 1.4
Cortisol before osilodrostat intake 422.9 ± 159.2 414.7 ± 176.6 439.4 ± 130.7
Cortisol 4 hour after osilodrostat 404 ± 165.6 408.2 ± 200.1 395.5 ± 70.8

 

Abbreviations: CD, Cushing’s disease; ULN, upper limit range; UFC, urinary free cortisol.

aOf note, none of the included patients were Asian.

In their article, Ménard et al.6 showed that the dose–exposure relationship was not strictly proportional. A one-compartment model was enhanced by increasing the relative bioavailability with the dose and was estimated that the dose resulting in a 50% increase in bioavailability was 1.06 mg. The PK parameters derived from Ménard et al.6 were fixed and used to predict osilodrostat concentration in our patients. A direct relationship between the predicted osilodrostat concentrations and variation of cortisol concentrations (%) gave a better fit than an indirect model. The drug effect was modeled with the following sigmoidal function (Eq. 1);

(1)

where Imax is the maximal inhibition and IC50 is the apparent half-maximal inhibitory concentration.

The estimated PD parameters were IC50 and Imax. Their values as well as the relative standard errors (RSE%) and the corresponding bootstrap IC50 are shown in Table 2. Final parameters were used to simulate n = 500 profiles following a single dose of osilodrostat.

 

 

 

Table 2.

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Pharmacodynamic parameters of osilodrostat’s effects on the variation of cortisol concentrations.

Parameters Unit Estimation RSE% Bootstrap
0.025 0.975
KA (fixed)a 1/hour 4.03 — — —
CL/F (fixed)a L/hour 18.3 — — —
V/F (fixed)a L 125 — —
Imax % 44.5 18.7 12.51 90.9
IC50 mg/L 0.011 37.4 0.0001 0.10
Interindividual variability (ω)
 Imax 0.40 30.9 0.003 1.86
 IC50 3.78 41.0 0.003 9.22
Residual unexplained variability (σ)
 Additive % 23.8 12.2 18.2 29.9

 

Abbreviations: CL/F, apparent clearance; IC50, osilodrostat concentration associated with half the maximal inhibition of the cortisol variation; Imax, maximum inhibitory effect of osilodrostat on the variation of cortisol; KA, first-order absorption rate constant; RSE, relative standard error; V/F, apparent volume of distribution.

 

aAdapted from Ménard et al.6

The effects on plasma cortisol variation are depicted in Figure 1. Cortisol concentration declines during the first hour after taking osilodrostat, from 24% for a 1 mg dose to over 42% for a 20 mg dose. Thereafter, from the first hour onward, cortisol increases progressively, with loss of treatment efficacy occurring around the 10th-15th hour for 1 and 2 mg, while for doses above 5 mg, a moderate effect persists over the following hours. Figure 2 shows the variation in cortisol concentration for a 2 mg dose, with median decrease in cortisol variation of 31%, ranging from 0% to 67.5%, with, as mentioned above, a maximum effect 1 hour after osilodrostat intake, and a progressive increase in cortisol levels, mainly during the 12 hours following treatment. The same analysis for 10 mg revealed a median reduction in cortisol of 38%, ranging from 5% to 80%. Figure 3 describes the relationship between osilodrostat concentration and cortisol variation, showing that the maximum effect corresponds to the maximum concentration and that a decrease in osilodrostat concentration results in an increase in cortisol level.

Relationship between time since last administration of osilodrostat and cortisol concentrations.

Figure 1.

Relationship between time since last administration of osilodrostat and cortisol concentrations.

Open in new tabDownload slide

Visual predictive variation on cortisol concentrations following 2 or 10 mg osilodrostat administration.

Figure 2.

Visual predictive variation on cortisol concentrations following 2 or 10 mg osilodrostat administration.

Open in new tabDownload slide

Relation between osilodrostat concentration and cortisol variation.

Figure 3.

Relation between osilodrostat concentration and cortisol variation.

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Discussion

To the best of our knowledge, this is the first study that attempts to define a dose/efficacy relationship between osilodrostat dose and the variation of plasma cortisol. First, our results suggest that the effect of osilodrostat appears immediately after the peak of concentration, 1 hour after treatment intake, which highlights the parallel evolution of osilodrostat and cortisol concentrations. This is unusual, as typically effect peak takes few hours, following concentration peak.15 The relationship between osilodrostat concentration and the effect on cortisol is not linear but sigmoidal with a rapid increase in concentrations producing a rapid significant effect, leading to a maximal effect. Because elimination is a slower process than absorption, the effect’s decline will also be slower: this means that efficiency remains stable during the first 5 hours, with a further progressive increase of cortisol and a loss of efficiency around 10-15 hours after intake. This confirms the need for two intakes per day, with one early in the morning and the other 12 hours later in the evening. In addition, even if our simulation suggests a wide interindividual variability, we were able to determine the impact of different doses of osilodrostat on the percent decrease in plasma cortisol levels. For instance, 20 mg osilodrostat leads to an estimated 42% decrease in cortisol concentration. Interestingly, Ferrari et al.16 recently showed that patients controlled with two doses of osilodrostat for at least 1 month had the same efficacy with a single intake (combing both doses) at 4 or 7 Pm. This is quite surprising and will need to be evaluated in future studies: our preliminary model could give more precise information on this point.

Cushing’s syndrome is also characterized by a loss of circadian rhythm leading to increased comorbidities such as diabetes, hypertension, and cardiovascular disease.17,18 This is why 24 hour UFC can only be considered an imperfect marker of glucocorticoid overexposure even though it is an easy-to-use marker, as exemplified by its use in all the clinical trials performed on cortisol-lowering drugs.7,8,10,19 Predicting the efficacy of osilodrostat on plasma cortisol might be helpful to tailor the treatment as a titrating approach. Of note, some studies suggested that there might be an inpatient variability of cortisol secretion in Cushing’s syndrome,20 and this might account for a bias in our results. However, none of our patients had cyclical Cushing’s syndrome. Moreover, 12 patients in our cohort had at least two cortisol cycles (every 4 hours during the day) before starting treatment. A comparison of these two cycles using Student’s t-test showed no significant difference (P = .7), indicating no obvious spontaneous variability. Our preliminary report gives interesting insights into the maximal efficacy expected for a single dose of osilodrostat, thus defining the initial dosage needed to rapidly control hypercortisolism, as opposed to the dose currently recommended by the manufacturer (2 mg twice daily). Thus, our results could help define an optimal dose in the morning, but also in the evening, with the aim of re-establishing a circadian profile. This will, however, have to be confirmed on an interventional study focusing on comorbidities, quality of life and their potential improvements while using this PK model.

The main limitation of this proof-of-concept study is the large CI. This may be due to the relatively low number of patients and the fact that cortisol was measured every 4 hours instead of every hour, but also to the large variability in efficacy between subjects. Due to the number of patients included in the analysis, it was not possible to investigate further if a covariate, such as the gender, may explain these differences between individuals. It is important to highlight that although our model predicts cortisol levels 1 hour post intake as the most reliable predictor of future efficacy, cortisol measurements were taken every 4 hours. Thus, this finding should be confirmed in prospective studies with more frequent cortisol measurements, particularly 1 hour after osilodrostat administration. While the kinetic–pharmacodynamic approach used in this study can present with some inherent limitations, this type of approach is regularly used to define the modalities of use for a medication in a new indication. A nonlinear mixed-effects modeling allows the use of data from the routine clinical follow-up of patients. This method is thus effective and particularly well-suited for sparse data. Finally, a larger study could include closer measurements of cortisol. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) is the best method for avoiding cross-reactivity with steroid precursors and could be used for these measurements. However, we used the Elecsys Cortisol II Immunoassay, which shows <5% cross-reactivity with 11-deoxycortisol; thus, our results are credible.

In conclusion, we designed a kinetic–pharmacodynamic model to adapt osilodrostat in patients with ACTH-dependent Cushing’s syndrome. Our model shows that cortisol level 1 hour after treatment is the best indicator of future efficacy. Moreover, depending on the initial cortisol level and the goal to be achieved, different doses should be prescribed. Despite wide inter-patient variability, we believe our model provides insight into the minimal dose necessary to decrease cortisol levels and the maximal efficacy expected for a given dose. Thus, it should help physicians tailor the treatment to reach maximal efficacy in the shortest possible time. The next step will be to analyze whether this percent decrease remains stable on a long-term basis or becomes more important with time, as suggested by some clinical cases showing delayed adrenal insufficiency on stable doses of osilodrostat.21

Authors’ contributions

Cecilia Piazzola (Conceptualization [equal], Formal analysis [equal], Writing—original draft [equal]), Frederic Castinetti (Conceptualization [equal], Formal analysis [equal], Writing—review & editing [equal]), Katharina von Fabeck (Conceptualization [equal], Writing—review & editing [equal]), and Nicolas Simon (Conceptualization [equal], Methodology [equal], Supervision [equal], Validation [equal], Writing—original draft [equal], Writing—review & editing [equal])

Funding

This work received an unrestricted educational grant from Recordati Rare Diseases.

To see the references and the original article, please go here: https://academic.oup.com/ejendo/article/193/4/K11/8255719?login=false

 

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