Ectopic Adrenocorticotropic Hormone Production in a Stage IV Neuroendocrine Tumor: A Rare Presentation of Cushing’s Syndrome

Posted on April 25, 2025 by MaryO

Abstract

Neuroendocrine tumors (NETs) are heterogeneous neoplasms that arise from neuroendocrine cells, resulting in endocrine imbalances that impact quality of life and prognosis. Ectopic adrenocorticotropic hormone (ACTH) production by NETs is a rare cause of ACTH-dependent Cushing’s syndrome. While the majority of these cases are associated with intrathoracic tumors, recent reports have indicated an increasing incidence of cases originating from diverse anatomical sites. Furthermore, despite comprehensive imaging efforts, a substantial proportion of cases remain challenging to localize.

In this case, we describe a 54-year-old man with a stage IV NET with metastatic liver and pancreatic lesions, who presented with Cushing’s syndrome due to ectopic ACTH production. The patient exhibited symptoms of severe hypercortisolism, including weight gain, proximal muscle weakness, acute-onset heart failure, and hypertension. Imaging revealed bilateral adrenal hypertrophy. Laboratory tests revealed hypokalemia and hyperglycemia and confirmed elevated cortisol levels and a lack of suppression after dexamethasone administration, consistent with ectopic rather than pituitary ACTH production. The patient was treated with metyrapone because ketoconazole was contraindicated because of liver metastasis and recent upper gastrointestinal bleeding requiring proton pump inhibitor use. This case highlights the rare occurrence of ACTH-producing NETs and emphasizes the importance of considering this diagnosis in cases with similar presentations. Furthermore, medical management of this patient without surgical intervention, owing to multiple contraindications, offers an important perspective for treating complex cases.

Introduction

Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms that can secrete various hormones; however, ectopic adrenocorticotropic hormone (ACTH) production is rare, occurring in only 5-10% of all Cushing’s syndrome cases [1]. Liddle et al. described the first case in 1962 [2]. A recent case series that examined the clinical and diagnostic treatment of ectopic ACTH in a tertiary center included information on only 12 cases collected over a 17-year period [3]. The most common site for ectopic ACTH from malignancy is the intrathoracic region, primarily in small-cell lung carcinomas. Unfortunately, obtaining a single diagnostic image that can detect tumor-producing ACTH remains challenging. According to the literature, ectopic ACTH resulting in Cushing’s syndrome can remain undetected [3,4].

In the present case, a patient with a stage IV NET presented with the classic features of Cushing’s syndrome, leading to the diagnosis of ectopic ACTH production. The complexity of this case, owing to the patient’s metastatic disease, the contraindications for certain therapies, and the requirement for atypical medical management, highlights the challenges of treating advanced NETs, especially metastatic lesions with hormonal overproduction. This report aimed to underscore the importance of early recognition and the effectiveness of metyrapone as a treatment for hypercortisolism in metastatic NET.

Case Presentation

A 54-year-old man with a known history of a World Health Organization (WHO) grade 3, stage IV NET with metastatic lesions in the liver and pancreas presented to the hospital with new-onset acute heart failure. His medical history consisted of papillary thyroid cancer diagnosed in January 2023, for which he underwent total thyroidectomy and left neck dissection. Three months later, the patient was found to have a new liver lesion that was biopsied and was consistent with a WHO grade 3 NET (Figure 1). He was started on capecitabine and temozolomide chemotherapy regimen, which was switched to folinic acid, fluorouracil, and oxaliplatin due to disease progression. He had undergone positron emission tomography (PET)/computed tomography (CT) as part of the follow-up for NET, and the findings were consistent with hypermetabolic pancreatic and liver lesions. However, no uptake was observed in the lungs and/or adrenal glands (Figure 2).

Liver-tissue-section-showing-positive-synaptophysin-immunohistochemical-staining-in-neoplastic-cells,-consistent-with-a-neuroendocrine-neoplasm.
Figure 1: Liver tissue section showing positive synaptophysin immunohistochemical staining in neoplastic cells, consistent with a neuroendocrine neoplasm.
FDG-PET/CT-scan-of-the-whole-body-showing-hypermetabolic-pancreatic-tail-mass-which-measures-up-to-6.5-cm-and-multifocal-liver-hypermetabolic-metastases.-
Figure 2: FDG PET/CT scan of the whole body showing hypermetabolic pancreatic tail mass which measures up to 6.5 cm and multifocal liver hypermetabolic metastases.

FDG: fluorodeoxyglucose; PET: positron emission tomography; CT: computed tomography

The patient was admitted first with gastrointestinal (GI) bleeding secondary to duodenal ulcers that were managed with a proton pump inhibitor (PPI), pantoprazole 40 mg, oral, BID (Figure 3). Ten days later, he presented with worsening dyspnea and shortness of breath, and clinical examination was consistent with volume overload and 4+ pitting edema in the lower extremities. Additionally, he was found to have a significantly low potassium level (2.6 mmol/L) and worsening serum blood glucose (341 mg/dL). The constellation of symptoms in the patient, including significant weight gain, obesity, easy bruising, proximal muscle weakness, acute-onset heart failure, hypertension, hypokalemia, and worsening hyperglycemia with new insulin requirements, raised concerns about hypercortisolism and prompted testing. The serum ACTH levels were markedly elevated (488 pg/mL; reference range: 10-60 pg/mL). CT of the abdomen and pelvis revealed bilateral adrenal gland hypertrophy (Figure 4).

Upper-endoscopy-images-showing-four-cratered,-non-bleeding-duodenal-ulcers-with-a-clean-ulcer-base-(Forrest-Class-III).
Figure 3: Upper endoscopy images showing four cratered, non-bleeding duodenal ulcers with a clean ulcer base (Forrest Class III).
CT-of-the-abdomen-and-pelvis-demonstrating-bilateral-adrenal-gland-hypertrophy.
Figure 4: CT of the abdomen and pelvis demonstrating bilateral adrenal gland hypertrophy.

CT: computed tomography

Morning cortisol levels were significantly increased (42.2 µg/dL), and the 8-mg dexamethasone suppression test showed no suppression, with a post-dexamethasone cortisol level of 44.2 µg/dL. The 24-hour urinary-free cortisol level was elevated (2259 µg/24 hour; reference range: 3.5-45 µg/24 hour). At this time, the differential diagnoses included but were not limited to Cushing’s disease or ectopic ACTH production secondary to metastatic NET. However, given that the patient had bilateral adrenal gland hypertrophy that was noted on imaging and his cortisol did not suppress with a high-dose dexamethasone suppression test, these findings support ectopic ACTH secretion secondary to metastatic NET over Cushing’s disease from a pituitary source. 

After confirming the diagnosis, the patient was started on metyrapone 500 mg, administered two times per day; his serum cortisol began to decrease (from 42 to 38 µg/dL) and continued to decline until it reached the lowest level (8.9 µg/dL) with metyrapone 500 mg, administered four times per day. Unfortunately, because of cost-related issues, the patient was switched to octreotide; however, subsequently, his serum cortisol level increased (from 8.9 to 49 µg/dL). Ketoconazole was not a viable option because of drug-drug interactions with PPI. Alternative suppressive medications were considered and included osilodrostat and mifepristone. However, given the patient’s QTc prolongation and previous history of arrhythmia, it was felt that the use of these medications was too high risk for fatal arrhythmia. Given the limited medical options, the patient was evaluated for surgery, and, given the multiple comorbidities as well as metastatic disease without an apparent culprit lesion, he was not initially deemed to be a suitable surgical candidate. Therefore, metyrapone was reinitiated to control hypercortisolemia while the patient was admitted, and it effectively lowered his total serum cortisol levels. However, given that metyrapone was not a long-term option and medical management had failed (octreotide was ineffective in controlling serum cortisol levels, and ketoconazole could not be used due to drug-to-drug interactions with PPI), surgery was considered as an option. Despite the high risk associated with the procedures owing to the patient’s condition, bilateral adrenalectomy was performed, considering the lack of medical options and the patient’s goals of care. The patient was discharged home on oral hydrocortisone, 15 mg in the morning and 10 mg in the evening, in addition to fludrocortisone 0.1 mg daily. The patient’s body surface area is 2.5 m². The pathology of his adrenal glands was consistent with that of a metastatic NET (Figure 5). The patient was seen in the endocrinology clinic after bilateral adrenalectomy for a follow-up almost one month after the procedure. He reported feeling tired and falling asleep quite often. He used to be able to walk; however, now, he could only make it a quarter of the way due to muscle weakness. Unfortunately, further follow-up and outcome could not be evaluated as the patient died three months after his bilateral adrenalectomy surgery, and the cause of death was unknown.

Adrenal-tissue-section-showing-positive-synaptophysin-immunohistochemical-staining-in-neoplastic-cells,-consistent-with-a-neuroendocrine-neoplasm.
Figure 5: Adrenal tissue section showing positive synaptophysin immunohistochemical staining in neoplastic cells, consistent with a neuroendocrine neoplasm.

Discussion

This case of a stage IV NET with ectopic ACTH production leading to Cushing’s syndrome is notable because of its rarity and complexity. Although NETs are known for their diverse hormonal secretions, only a small subset of them are associated with ACTH production, making this case an important addition to the limited literature.

NETs causing ectopic Cushing’s syndrome are most frequently found in the intrathoracic region (40-60%), including bronchial tumors, small-cell lung carcinoma, and thymic carcinomas. Additional sites where these tumors may occur include the pancreas and thyroid gland (particularly medullary thyroid carcinoma). Less common locations include the prostate, rectum, ovaries, and bladder [5].

Our patient’s PET/CT findings were consistent with those of hypermetabolic lesions in the liver and pancreas. However, there was no uptake in the lungs, which is the most common site reported in the literature [5]. Additionally, there was no uptake in the adrenal glands, and the pathology was later found to be consistent with NETs. This posed a challenge to the diagnosis and identification of the culprit lesion. Reportedly, high-resolution cross-sectional CT imaging has a sensitivity of 50-67% in identifying the source of ectopic ACTH production, and when the findings are negative, a variety of nuclear medicine functional imaging techniques (Octreoscan, fluorine-18 fluorodeoxyglucose PET/CT, and gallium-68 somatostatin receptor-targeted PET/CT) can be used [6]. However, despite advances in imaging modalities, up to 20% of ectopic ACTH syndrome cases remain occult after initial imaging [4,7]. 

ACTH-producing pancreatic neuroendocrine (pNE) tumors are rare malignancies characterized by their aggressive nature [8]. Individuals diagnosed with this condition have less favorable outcomes compared with those with insulinoma, gastrinoma, or nonfunctional ACTH-producing pNE tumors [9]. The underlying reasons for the aggressiveness of the tumor and the resulting poor patient outcomes remain elusive. One study proposed that decreased methylation of the proopiomelanocortin promoter may enhance the ability of the tumors to secrete ACTH [10].

A similar presentation was reported by Al-Toubah et al. in a 2023 case series on ACTH-secreting pNE neoplasms. That study highlighted the rarity of ACTH production in these tumors and emphasized that such cases often present with severe hypercortisolemia and Cushing’s syndrome. However, most patients in their series were treated with ketoconazole, which was not an option for our patient because of liver metastasis and recent upper GI bleeding requiring PPI treatment [11].

A systematic review published in February 2021 by Wu et al. investigated ACTH-producing pNE tumors. That study analyzed 210 publications, including data from 336 patients diagnosed with this condition. The results indicated a higher prevalence among female individuals (66.4%), at an average age of 44.7 years. The review reported the following frequencies of clinical symptoms: 69.3% experienced hypokalemia, 63.2% developed diabetes, 60.1% suffered from weakness, 56.4% had hypertension, 41.1% displayed moon face, and 37.4% presented with edema [12].

In the present case, the patient presented with decompensated heart failure, which is consistent with various case reports describing acute decompensated heart failure as the first presentation. Sugihara et al. reported three cases of Cushing’s syndrome characterized by left ventricular failure as the predominant feature associated with gross left ventricular hypertrophy [13]. Similarly, Petramala et al. reported a case of a 28-year-old woman with Cushing’s syndrome secondary to an adrenal adenoma who exhibited congestive heart failure as an initial symptom [14]. In this regard, some studies have examined the relationship between cardiac dysfunction and hypercortisolism and found that cardiac remodeling is independent of hypertension and is probably related to the direct action of cortisol on myocardial tissue via glucocorticoid receptors [15,16]. These cardiac impairments may be reversible with the appropriate treatment of the underlying hypercortisolism, such as the surgical resection of the adrenal adenoma or pituitary adenoma, and the medical management of heart failure [14].

Our patient received metyrapone and could not be treated using ketoconazole because of liver metastasis and drug-drug interactions with PPI, as previously mentioned. In 2022, Landry et al. studied the management of ACTH-secreting NETs [17]. Their study, including 76 patients, found that most patients had metastatic disease at the time of ectopic Cushing’s syndrome diagnosis, similar to our case. Furthermore, they found that de novo hyperglycemia predicted worse survival outcomes. Therefore, controlling the hypercortisolic phase is crucial. Unfortunately, most patients present with metastatic disease, which makes surgical management, that is, removing the ACTH-producing tumor, not always an option. Additionally, they found that patients with medically resistant ectopic Cushing’s syndrome, subsequently controlled with bilateral adrenalectomy, had significantly better disease-specific survival following ectopic Cushing’s syndrome diagnosis than did patients who did not undergo bilateral adrenalectomy.

In our case, there were limited treatment options given the metastatic burden and limitations in using some of the medications to control hypercortisolism. In their article, Landry et al. stated “We have learned this over time as, unfortunately, most patients in our cohort who were diagnosed with resistant ectopic Cushing syndrome only used one type of suppression therapy by the end of the study” [17]. One medication, peptide receptor radionuclide therapy, was reported in multiple studies [5,18,19]. However, the Food and Drug Administration did not approve this therapy until 2018, and it has not been examined for ectopic Cushing’s disease, especially in the metastatic NET setting.

As surgical resection remains the recommended first-line treatment for the majority of patients with Cushing’s syndrome [20], medical therapy plays a critical role when surgery is not feasible; many studies reviewed the use of agents such as mifepristone [21], levoketoconazole [22], and pasireotide [23,24]. Additionally, a recent review study that focused on the clinical consideration for osilodrostat in the management of patients with ectopic ACTH found that quality of life improved during the use of long-term osilodrostat as a treatment for ectopic Cushing’s syndrome raised from a pNE tumor [25].

Conclusions

This case highlights the complexities involved in the diagnosis and management of ectopic ACTH-producing NETs. Due to the rarity of such presentations, clinicians must maintain a high index of suspicion for ectopic ACTH production in patients with unexplained hypercortisolism, particularly when signs of Cushing’s syndrome are present. Additionally, the management of preoperative hypercortisolism may be challenging, as in our patient. The treatment approach in this case was unconventional, given the patient’s ineligibility for surgery due to difficulties in localizing the exact lesion and the metastatic disease. Medical management with metyrapone was chosen. However, as it was cost-prohibitive, alternative therapy with octreotide was attempted, but it failed to achieve adequate control. Ketoconazole was not an option given the recent GI bleeding, and eventually, our patient underwent bilateral adrenalectomy. Therefore, future studies are required to develop predictive markers to determine which patients will benefit from bilateral adrenalectomy versus long-term pharmacotherapy. An extensive study on perioperative management in cases with ectopic ACTH would have proven to be useful in ensuring the survival of our patient.

References

  1. Lacroix A, Feelders RA, Stratakis CA, Nieman LK: Cushing’s syndrome. Lancet. 2015, 386:913-27. 10.1016/S0140-6736(14)61375-1
  2. Liddle GW, Island DP, Ney RL, Nicholson WE, Shimizu N: Nonpituitary neoplasms and Cushing’s syndrome. Ectopic “adrenocorticotropin” produced by nonpituitary neoplasms as a cause of Cushing’s syndrome. Arch Intern Med. 1963, 111:471-5. 10.1001/archinte.1963.03620280071011
  3. González Fernández L, Maricel Rivas Montenegro A, Brox Torrecilla N, et al.: Ectopic Cushing’s syndrome: clinical, diagnostic, treatment and follow-up outcomes of 12 cases of lung ectopic ACTH. Endocrinol Diabetes Metab Case Rep. 2023, 2023:22-0378. 10.1530/EDM-22-0378
  4. Varlamov E, Hinojosa-Amaya JM, Stack M, Fleseriu M: Diagnostic utility of gallium-68-somatostatin receptor PET/CT in ectopic ACTH-secreting tumors: a systematic literature review and single-center clinical experience. Pituitary. 2019, 22:445-55. 10.1007/s11102-019-00972-w
  5. Davi’ MV, Cosaro E, Piacentini S, et al.: Prognostic factors in ectopic Cushing’s syndrome due to neuroendocrine tumors: a multicenter study. Eur J Endocrinol. 2017, 176:453-61. 10.1530/EJE-16-0809
  6. Frete C, Corcuff JB, Kuhn E, et al.: Non-invasive diagnostic strategy in ACTH-dependent Cushing’s syndrome. J Clin Endocrinol Metab. 2020, 105:3273-84. 10.1210/clinem/dgaa409
  7. Zisser L, Kulterer OC, Itariu B, et al.: Diagnostic role of PET/CT tracers in the detection and localization of tumours responsible for ectopic Cushing’s syndrome. Anticancer Res. 2021, 41:2477-84. 10.21873/anticanres.15024
  8. Falconi M, Eriksson B, Kaltsas G, et al.: ENETS consensus guidelines update for the management of patients with functional pancreatic neuroendocrine tumors and non-functional pancreatic neuroendocrine tumors. Neuroendocrinology. 2016, 103:153-71. 10.1159/000443171
  9. Maragliano R, Vanoli A, Albarello L, et al.: ACTH-secreting pancreatic neoplasms associated with Cushing syndrome: clinicopathologic study of 11 cases and review of the literature. Am J Surg Pathol. 2015, 39:374-82. 10.1097/PAS.0000000000000340
  10. Zhang C, Jin J, Xie J, et al.: The clinical features and molecular mechanisms of ACTH-secreting pancreatic neuroendocrine tumors. J Clin Endocrinol Metab. 2020, 105:3449-58. 10.1210/clinem/dgaa507
  11. Al-Toubah T, Pelle E, Hallanger-Johnson J, Haider M, Strosberg J: ACTH-secreting pancreatic neuroendocrine neoplasms: a case-series. J Neuroendocrinol. 2023, 35:e13336. 10.1111/jne.13336
  12. Wu Y, Xiong G, Zhang H, Wang M, Zhu F, Qin R: Adrenocorticotropic hormone-producing pancreatic neuroendocrine neoplasms: a systematic review. Endocr Pract. 2021, 27:152-7. 10.1016/j.eprac.2020.10.012
  13. Sugihara N, Shimizu M, Shimizu K, Ino H, Miyamori I, Nakabayashi H, Takeda R: Disproportionate hypertrophy of the interventricular septum and its regression in Cushing’s syndrome. Report of three cases. Intern Med. 1992, 31:407-13. 10.2169/internalmedicine.31.407
  14. Petramala L, Battisti P, Lauri G, et al.: Cushing’s syndrome patient who exhibited congestive heart failure. J Endocrinol Invest. 2007, 30:525-8. 10.1007/BF03346339
  15. Fallo F, Budano S, Sonino N, Muiesan ML, Agabiti-Rosei E, Boscaro M: Left ventricular structural characteristics in Cushing’s syndrome. J Hum Hypertens. 1994, 8:509-13.
  16. Yiu KH, Marsan NA, Delgado V, et al.: Increased myocardial fibrosis and left ventricular dysfunction in Cushing’s syndrome. Eur J Endocrinol. 2012, 166:27-34. 10.1530/EJE-11-0601
  17. Landry JP, Clemente-Gutierrez U, Pieterman CR, et al.: Management of adrenocorticotropic hormone-secreting neuroendocrine tumors and the role of bilateral adrenalectomy in ectopic Cushing syndrome. Surgery. 2022, 172:559-66. 10.1016/j.surg.2022.03.014
  18. Cheung NW, Boyages SC: Failure of somatostatin analogue to control Cushing’s syndrome in two cases of ACTH-producing carcinoid tumours. Clin Endocrinol (Oxf). 1992, 36:361-7. 10.1111/j.1365-2265.1992.tb01461.x
  19. De Rosa G, Testa A, Liberale I, Pirronti T, Granone P, Picciocchi A: Successful treatment of ectopic Cushing’s syndrome with the long-acting somatostatin analog octreotide. Exp Clin Endocrinol. 1993, 101:319-25. 10.1055/s-0029-1211252
  20. Gadelha M, Gatto F, Wildemberg LE, Fleseriu M: Cushing’s syndrome. Lancet. 2023, 402:2237-52. 10.1016/S0140-6736(23)01961-X
  21. Fleseriu M, Molitch ME, Gross C, Schteingart DE, Vaughan TB 3rd, Biller BM: A new therapeutic approach in the medical treatment of Cushing’s syndrome: glucocorticoid receptor blockade with mifepristone. Endocr Pract. 2013, 19:313-26. 10.4158/EP12149.RA
  22. Fleseriu M, Auchus RJ, Pivonello R, Salvatori R, Zacharieva S, Biller BM: Levoketoconazole: a novel treatment for endogenous Cushing’s syndrome. Expert Rev Endocrinol Metab. 2021, 16:159-74. 10.1080/17446651.2021.1945440
  23. Colao A, De Block C, Gaztambide MS, Kumar S, Seufert J, Casanueva FF: Managing hyperglycemia in patients with Cushing’s disease treated with pasireotide: medical expert recommendations. Pituitary. 2014, 17:180-6. 10.1007/s11102-013-0483-3
  24. Trementino L, Cardinaletti M, Concettoni C, Marcelli G, Boscaro M, Arnaldi G: Up-to 5-year efficacy of pasireotide in a patient with Cushing’s disease and pre-existing diabetes: literature review and clinical practice considerations. Pituitary. 2015, 18:359-65. 10.1007/s11102-014-0582-9
  25. Fleseriu M, Auchus RJ, Bancos I, Biller BM: Osilodrostat treatment for adrenal and ectopic Cushing syndrome: integration of clinical studies with case presentations. J Endocr Soc. 2025, 9:bvaf027. 10.1210/jendso/bvaf027

https://www.cureus.com/articles/351968-ectopic-adrenocorticotropic-hormone-production-in-a-stage-iv-neuroendocrine-tumor-a-rare-presentation-of-cushings-syndrome?score_article=true#!/

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Xeris Presents New Post Hoc Analysis on Effects of Levoketoconazole (Recorlev®) in Cushing’s Syndrome Patients at ENDO 2024

Posted on June 6, 2024 by MaryO

In patients with Cushing’s syndrome maintained on Recorlev, a lower baseline mUFC was associated with higher cortisol normalization rate.

Lower mUFC at baseline was also associated with lower maintenance dose requirements and lower rates of potentially clinically important liver-related adverse events and liver test abnormalities.

The SONICS study previously showed that Recorlev treatment was effective at normalizing cortisol across the spectrum of Cushing’s syndrome severity.

Xeris Biopharma Holdings, Inc. (Nasdaq: XERS), a growth-oriented biopharmaceutical company committed to improving patients’ lives by developing and commercializing innovative products across a range of therapies, today announced it presented a post-hoc analysis from its previously published SONICS study on the effects of levoketoconazole (Recorlev®) in adults with Cushing’s syndrome at ENDO 2024 in Boston, June 1-4, 2024.

“The results of this analysis suggest that patients with Cushing’s syndrome/disease with lower mUFC(s) normalize at a higher rate than those with more severe disease and may require lower doses of Recorlev and experience lower rates of liver-related adverse events. This exploratory analysis brings further perspective to the importance of individualizing and tailoring medical management,” said James Meyer, PharmD, Xeris’ Senior Director, Publications and Medical Communications.

Title: Effects of Levoketoconazole on 24-hour Mean UFC (mUFC) in the SONICS Study: Relation to Baseline mUFC in Adults with Cushing’s Syndrome: A Post-hoc Analysis (SAT-085)

This post-hoc exploration included all enrolled patients in SONICS who were treated and had a post-baseline mUFC, aiming to further elucidate relationships between baseline biochemical disease severity, drug dose, and intermediate-term mUFC response. For the current analyses, 92 patients treated with levoketoconazole and with baseline mUFC measurement (modified ITT) were stratified into 3 baseline mUFC subgroups: Group 1 (≤ 2.5x upper limit of normal (ULN)); Group 2 (>2.5x to ≤ 5x ULN); or Group 3 (>5x ULN) and analyzed in respect to mUFC response, average daily dose, and adverse events following 6 months of maintenance therapy. Groups 1 and 2 were similar in baseline characteristics; whereas Group 3 differed with younger age, fewer female participants, more recently diagnosed, and more frequently on prior therapy.

Group 2 (Baseline mUFC 267.9 nmol/D) had the highest apparent mUFC response rate (12/33 [36.4%]), 95% CI 0.20, 0.54) as compared with Group 1 (Baseline mUFC 498.7 nmol/D) (12/38 [31.6%], 95% CI 0.16, 0.47) or Group 3 (Baseline mUFC 1672.8 nmol/D) (5/21 [23.8%]; 95% CI 0.01, 0.55); Group 3 having a notably lower response.

Daily doses of levoketoconazole were related to baseline mUFC. Thus, Group 3 used a nominally higher average daily dose (631 mg and 741 mg) during maintenance therapy and at the last dose in the 6-month maintenance phase (regardless of completion status) than Group 1 (475 mg and 545 mg) or Group 2 (548 mg and 611 mg).

Group 3 had more liver-related AEs of special interest than Group 1 or 2 (14% vs 7.9% or 3.0%) and more AEs leading to discontinuation (24% vs 12% or 16%). Group 3 had a higher incidence of liver test (ALT, AST, GGT) abnormalities compared to Group 1 and Group 2.

This post hoc analysis demonstrated:

  • Normalization of mUFC with levoketoconazole in Cushing’s syndrome patients maintained on levoketoconazole in the SONICS study for up to 6 months appeared to vary inversely with baseline mUFC.
  • Lower mUFC at baseline was also associated with lower maintenance dose requirements and lower rates of potentially clinically important liver-related AEs and liver test abnormalities.
  • Whether observed baseline characteristic differences between the highest tertile of baseline mUFC and the 2 lower tertiles were simply coincidental to or confounders or mediators of the described relationships with mUFC remains to be explored.

About Cushing’s Syndrome

Endogenous Cushing’s syndrome is a rare, serious, and potentially fatal endocrine disease caused by chronic elevated cortisol exposure–often the result of a benign tumor of the pituitary gland. This benign tumor tells the body to overproduce high levels of cortisol for a sustained period of time, which often results in characteristic physical signs and symptoms that are distressing to patients. The disease is most common among adults between the ages of 30–50, and it affects women three times more often than men. Women with Cushing’s syndrome may experience a variety of health issues including menstrual problems, difficulty becoming pregnant, excess male hormones (androgens), primarily testosterone, which can cause hirsutism (growth of coarse body hair in a male pattern), oily skin, and acne.3

Additionally, the multisystem complications of the disease are potentially life threatening. These include metabolic changes such as high blood sugar or diabetes, high blood pressure, high cholesterol, fragility of various tissues including blood vessels, skin, muscle, and bone, and psychological disturbances such as depression, anxiety, and insomnia.3 Untreated, the five-year survival rate is only approximately 50%.4

About Recorlev®

Recorlev® (levoketoconazole) is a cortisol synthesis inhibitor for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.1 Endogenous Cushing’s syndrome is a rare but serious and potentially lethal endocrine disease caused by chronic elevated cortisol exposure.2 Recorlev is the pure 2S,4R enantiomer of ketoconazole, a steroidogenesis inhibitor.1 Recorlev has demonstrated in two successful Phase 3 studies to significantly reduce mean urine free cortisol.1

The Phase 3 program for Recorlev included SONICS and LOGICS, two multinational studies designed to evaluate the safety and efficacy of Recorlev when used to treat endogenous Cushing’s syndrome. The SONICS study met its primary and secondary endpoints, significantly reducing and normalizing mean urinary free cortisol concentrations without a dose increase.1,2 The LOGICS study, which met its primary endpoint and key secondary endpoint, was a double-blind, placebo-controlled randomized-withdrawal study of Recorlev that was designed to supplement the efficacy and safety information provided by SONICS.1 The ongoing open-label OPTICS study will gather further useful information related to the long-term use of Recorlev.

Recorlev was approved by the US FDA in December 2021 and received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing’s syndrome.

Indication & Important Safety Information for Recorlev®

BOXED WARNING: HEPATOTOXICITY AND QT PROLONGATION
HEPATOTOXICITY

Cases of hepatotoxicity with fatal outcome or requiring liver transplantation have been reported with oral ketoconazole. Some patients had no obvious risk factors for liver disease. Recorlev is associated with serious hepatotoxicity. Evaluate liver enzymes prior to and during treatment.

QT PROLONGATION

Recorlev is associated with dose-related QT interval prolongation. QT interval prolongation may result in life-threatening ventricular dysrhythmias such as torsades de pointes. Perform ECG and correct hypokalemia and hypomagnesemia prior to and during treatment.

INDICATION

Recorlev is a cortisol synthesis inhibitor indicated for the treatment of endogenous hypercortisolemia in adult patients with Cushing’s syndrome for whom surgery is not an option or has not been curative.

Limitations of Use

Recorlev is not approved for the treatment of fungal infections.

CONTRAINDICATIONS

  • Cirrhosis, acute liver disease or poorly controlled chronic liver disease, baseline AST or ALT > 3 times the upper limit of normal, recurrent symptomatic cholelithiasis, a prior history of drug induced liver injury due to ketoconazole or any azole antifungal therapy that required discontinuation of treatment, or extensive metastatic liver disease.
  • Taking drugs that cause QT prolongation associated with ventricular arrythmias, including torsades de pointes.
  • Prolonged QTcF interval > 470 msec at baseline, history of torsades de pointes, ventricular tachycardia, ventricular fibrillation, or prolonged QT syndrome.
  • Known hypersensitivity to levoketoconazole, ketoconazole or any excipient in Recorlev.
  • Taking certain drugs that are sensitive substrates of CYP3A4 or CYP3A4 and P-gp.

WARNINGS AND PRECAUTIONS

Hepatotoxicity

Serious hepatotoxicity has been reported in patients receiving Recorlev, irrespective of the dosages used or the treatment duration. Drug-induced liver injury (peak ALT or AST greater than 3 times upper limit of normal) occurred in patients using Recorlev. Avoid concomitant use of Recorlev with hepatotoxic drugs. Advise patient to avoid excessive alcohol consumption while on treatment with Recorlev. Routinely monitor liver enzymes and bilirubin during treatment.

QT Prolongation

Use Recorlev with caution in patients with other risk factors for QT prolongation, such as congestive heart failure, bradyarrythmias, and uncorrected electrolyte abnormalities, with more frequent ECG monitoring considered. Routinely monitor ECG and blood potassium and magnesium levels during treatment.

Hypocortisolism

Recorlev lowers cortisol levels and may lead to hypocortisolism with a potential for life-threatening adrenal insufficiency. Lowering of cortisol levels can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol levels may result in adrenal insufficiency that can be manifested by hypotension, abnormal electrolyte levels, and hypoglycemia. Routinely monitor 24-hour urine free cortisol, morning serum or plasma cortisol, and patient’s signs and symptoms for hypocortisolism during treatment.

Hypersensitivity Reactions

Hypersensitivity to Recorlev has been reported. Anaphylaxis and other hypersensitivity reactions including urticaria have been reported with oral ketoconazole.

Risks Related to Decreased Testosterone

Recorlev may lower serum testosterone in men and women. Potential clinical manifestations of decreased testosterone concentrations in men may include gynecomastia, impotence and oligospermia. Potential clinical manifestations of decreased testosterone concentrations in women include decreased libido and mood changes.

ADVERSE REACTIONS

Most common adverse reactions (incidence > 20%) are nausea/vomiting, hypokalemia, hemorrhage/contusion, systemic hypertension, headache, hepatic injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory infection, myalgia, arrhythmia, back pain, insomnia/sleep disturbances, and peripheral edema.

DRUG INTERACTIONS

  • Consult approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE prior to initiating Recorlev.
  • Sensitive CYP3A4 or CYP3A4 and P-gp Substrates: Concomitant use of Recorlev with these substrates is contraindicated or not recommended.
  • Atorvastatin: Use lowest atorvastatin dose possible and monitor for adverse reactions for dosages exceeding 20 mg daily.
  • Metformin: Monitor glycemia, kidney function, and vitamin B12 and adjust metformin dosage as needed.
  • Strong CYP3A4 Inhibitors or Inducers: Avoid use of these drugs 2 weeks before and during Recorlev treatment.
  • Gastric Acid Modulators: See Full Prescribing Information for recommendations regarding concomitant use with Recorlev.

USE IN SPECIFIC POPULATIONS

Lactation: Advise not to breastfeed during treatment and for one day after final dose.

To report SUSPECTED ADVERSE REACTIONS, contact Xeris Pharmaceuticals, Inc. at 1-877-937-4737 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see Full Prescribing Information including Boxed Warning.

About Xeris

Xeris (Nasdaq: XERS) is a growth-oriented biopharmaceutical company committed to improving patient lives by developing and commercializing innovative products across a range of therapies. Xeris has three commercially available products; Gvoke®, a ready-to-use liquid glucagon for the treatment of severe hypoglycemia, Keveyis®, a proven therapy for primary periodic paralysis, and Recorlev® for the treatment of endogenous Cushing’s syndrome. Xeris also has a robust pipeline of development programs to extend the current marketed products into important new indications and uses and bring new products forward using its proprietary formulation technology platforms, XeriSol™ and XeriJect®, supporting long-term product development and commercial success.

Xeris Biopharma Holdings is headquartered in Chicago, IL. For more information, visit www.xerispharma.com, or follow us on X, LinkedIn, or Instagram.

Forward-looking Statement

Any statements in this press release other than statements of historical fact are forward-looking statements. Forward-looking statements include, but are not limited to, statements about future expectations, plans and prospects for Xeris Biopharma Holdings, Inc. including statements regarding expectations for the release of clinical data, post hoc analyses or results from clinical trials, including the SONICS study, the market and therapeutic potential of its products and product candidates, including the levoketoconazole (Recorlev®), the potential utility of its formulation platforms and other statements containing the words “will,” “would,” “continue,” “expect,” “should,” “anticipate” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. These forward-looking statements are based on numerous assumptions and assessments made in light of Xeris’ experience and perception of historical trends, current conditions, business strategies, operating environment, future developments, geopolitical factors, and other factors it believes appropriate. By their nature, forward-looking statements involve known and unknown risks and uncertainties because they relate to events and depend on circumstances that will occur in the future. The various factors that could cause Xeris’ actual results, performance or achievements, industry results and developments to differ materially from those expressed in or implied by such forward-looking statements, include, but are not limited to, its financial position and need for financing, including to fund its product development programs or commercialization efforts, whether its products will achieve and maintain market acceptance in a competitive business environment, its reliance on third-party suppliers, including single-source suppliers, its reliance on third parties to conduct clinical trials, the ability of its product candidates to compete successfully with existing and new drugs, and its and collaborators’ ability to protect its intellectual property and proprietary technology. No assurance can be given that such expectations will be realized and persons reading this communication are, therefore, cautioned not to place undue reliance on these forward-looking statements. Additional risks and information about potential impacts of financial, operational, economic, competitive, regulatory, governmental, technological, and other factors that may affect Xeris can be found in Xeris’ filings, including its most recently filed Annual Report on Form 10-K filed with the Securities and Exchange Commission, the contents of which are not incorporated by reference into, nor do they form part of, this communication. Forward-looking statements in this communication are based on information available to us, as of the date of this communication and, while we believe our assumptions are reasonable, actual results may differ materially. Subject to any obligations under applicable law, we do not undertake any obligation to update any forward-looking statement whether as a result of new information, future developments or otherwise, or to conform any forward-looking statement to actual results, future events, or to changes in expectations.

1. Recorlev [prescribing information]. Chicago, IL: Xeris Pharmaceuticals, Inc.; 2021. 2. Fleseriu M, et al. Lancet Diabetes Endocrinol. 2019;7(11):855-865. 3. Pivonello R et al. Lancet Diabetes Endocrinol. 2016; 4: 611-29. 4. Plotz CM, et al. Am J Med. 1952 November;13(5):597-614.

Recorlev®, Xeris Pharmaceuticals®, Xeris CareConnectionTM, Keveyis®, Gvoke®, and Ogluo® are trademarks owned by or licensed to Xeris Pharmaceuticals, Inc. PANTHERx Rare Pharmacy is a service mark of PANTHERx Rare, LLC. All other trademarks referenced herein are the property of their respective owners. All rights reserved. US-PR-22-00001 1/22

From https://www.morningstar.com/news/business-wire/20240603311134/xeris-presents-new-post-hoc-analysis-on-effects-of-levoketoconazole-recorlev-in-cushings-syndrome-patients-at-endo-2024

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ENDO 2021 Roundup: COVID-19 Risk With Adrenal Insufficiency, Cushing’s Death Risk, Jatenzo Liver Data, and More

Posted on March 29, 2021 by MaryO

Some of the latest research advancements in the field of endocrinology presented at the Endocrine Society’s virtual ENDO 2021 meeting included quantifying diabetic ketoacidosis readmission rates, hyperglycemia as a severe COVID-19 predictor, and semaglutide as a weight loss therapy. Below are a few more research highlights:

More Safety Data on Jatenzo

In a study of 81 men with hypogonadism — defined as a serum testosterone level below 300 ng/dL — oral testosterone replacement therapy (Jatenzo) was both safe and effective in a manufacturer-sponsored study.

After 24 months of oral therapy, testosterone concentration increased from an average baseline of 208.3 ng/dL to 470.1 ng/dL, with 84% of patients achieving a number in the eugonadal range.

And importantly, the treatment also demonstrated liver safety, as there were no significant changes in liver function tests throughout the 2-year study — including alanine aminotransferase (28.0 ± 12.3 to 26.6 ± 12.8 U/L), aspartate transaminase (21.8 ± 6.8 to 22.0 ± 8.2 U/L), and bilirubin levels (0.58 ± 0.22 to 0.52 ± 0.19 mg/dL).

Throughout the trial, only one participant had elevation of liver function tests.

“Our study finds testosterone undecanoate is an effective oral therapy for men with low testosterone levels and has a safety profile consistent with other approved testosterone products, without the drawbacks of non-oral modes of administration,” said lead study author Ronald Swerdloff, MD, of the Lundquist Research Institute in Torrance, California, in a statement.

In addition, for many men with hypogonadism, “an oral option is preferred to avoid issues associated with other modes of administration, such as injection site pain or transference to partners and children,” he said. “Before [testosterone undecanoate] was approved, the only orally approved testosterone supplemental therapy in the United States was methyltestosterone, which was known to be associated with significant chemical-driven liver damage.”

Oral testosterone undecanoate received FDA approval in March 2019 following a rocky review history.

COVID-19 Risk With Adrenal Insufficiency

Alarming new data suggested that children with adrenal insufficiency were more than 23 times more likely to die from COVID-19 than kids without this condition (relative risk 23.68, P<0.0001). This equated to 11 deaths out of 1,328 children with adrenal insufficiency compared with 215 deaths out of 609,788 children without this condition (0.828% vs 0.035%).

These young patients with adrenal insufficiency also saw a much higher rate of sepsis (RR 21.68, P<0.0001) and endotracheal intubation with COVID-19 infection (RR 25.45, P<0.00001).

Data for the analysis were drawn from the international TriNetX database, which included patient records of children ages 18 and younger diagnosed with COVID-19 from 60 healthcare organizations in 31 different countries.

“It’s really important that you take your hydrocortisone medications and start stress dosing as soon as you’re sick,” study author Manish Raisingani, MD, of the University of Arkansas for Medical Sciences and Arkansas Children’s in Little Rock, explained during a press conference. “This will help prevent significant complications due to COVID-19 or any other infections. A lot of the complications that we see in kids with adrenal insufficiency are due to inadequate stress dosing of steroids.”

And with kids starting to return back to in-person schooling, “parents should also be reeducated about using the emergency injections of hydrocortisone,” Raisingani added. He noted that the COVID-19 complication rates were likely so high in this patient population because many had secondary adrenal insufficiency due to being on long-term, chronic steroids. Many also had comorbid respiratory illnesses, as well.

Cushing’s Death Risk

In a systematic review and meta-analysis of 87 studies — including data on 17,276 patients with endogenous Cushing’s syndrome — researchers found that these patients face a much higher death rate than those without this condition.

Overall, patients with endogenous Cushing’s syndrome faced a nearly three times higher mortality ratio (standardized mortality ratio 2.91, 95% CI 2.41-3.68, I2=40.3%), with those with Cushing’s disease found to have an even higher mortality risk (SMR 3.27, 95% CI 2.33-4.21, I2=55.6%).

And those with adrenal Cushing’s syndrome also saw an elevated death risk, although not as high as patients with the disease (SMR 1.62, 95% CI 0.08-3.16, I2=0.0%).

The most common causes of mortality among these patients included cardiac conditions (25%), infection (14%), and cerebrovascular disease (9%).

“The causes of death highlight the need for aggressive management of cardiovascular risk, prevention of thromboembolism, and good infection control, and emphasize the need to achieve disease remission, normalizing cortisol levels,” said lead study author Padiporn Limumpornpetch, MD, of the University of Leeds in England, in a statement.

From https://www.medpagetoday.com/meetingcoverage/endo/91808

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Etomidate Found Effective in Severe Cushing’s Syndrome

Posted on May 18, 2018 by MaryO

Etomidate — a steroid synthesis blocker — is an effective treatment for patients with severe Cushing’s syndrome who do not respond to ketoconazole, according to a new case report from Mexico.

The report, “Etomidate in the control of severe Cushing’s syndrome by neuroendocrine carcinoma,” appeared in the journal Clinical Case Reports.

The investigators reported the case of a 51-year-old woman with ectopic Cushing’s syndrome caused by a pancreatic tumor. Ectopic Cushing’s refers to cases of excess secretion of adrenocorticotropin hormone (ACTH) outside the pituitary or adrenal glands.

The patient underwent distal pancreatectomy — the surgical removal of the bottom half of the pancreas — in 2015 due to an ACTH-secreting tumor. Although she had a good initial response, liver metastasis was evident by 2016.

Compared to measurements in 2016, morning blood cortisol, 24-hour urinary-free cortisol, and ACTH levels significantly increased in 2017. The patient also showed low levels of the luteinizing and follicle-stimulating hormones, which the scientists attributed to her severe hypercortisolism (excess cortisol levels).

The woman was being treated with ketoconazole to lower her cortisol values and later received chemoembolization — a method to reduce blood supply and deliver chemotherapy directly to a tumor — for her liver metastasis.

Although ketoconazole is generally the treatment of choice for the control of hormone production in the adrenal glands, its effectiveness is often limited and is associated with side effects, clinicians noted.

In April 2017, the patient arrived at the emergency room with sepsis — a potentially life-threatening complication of an infection — that originated in the gut.

Because ketoconazole had failed to lower cortisol levels, the patient started receiving infused etomidate, an inhibitor of the enzyme 11‐beta‐hydroxylase that prevents cortisol synthesis.

This treatment was stopped one day before the bilateral removal of the adrenal glands as a definitive treatment for the elevated production of cortisol.

While the patient experienced decreased levels of potassium, calcium, and magnesium with an initial dose of 0.04 mg per kg body weight an hour of etomidate, a gradual decrease of etomidate — depending on her cortisol levels — corrected these alterations.

After surgery, the patient showed a significant improvement in her general health, including control of her sepsis. She is currently taking hydrocortisone and fludrocortisone, with treatment for liver metastasis pending.

“Etomidate is a very effective drug in severe Cushing’s syndrome that is refractory to ketoconazole,” the researchers wrote.

“Control of the serum cortisol levels in ectopic Cushing’s syndrome can be obtained with infusion rates much lower than those used in anesthesia, without respiratory side effects,” they added.

The authors recommend an initial dose of etomidate of 0.04 mg/kg per hour, daily monitoring of 24-hour urinary cortisol and cortisol levels, and a gradual decrease of the etomidate dose according to daily measurements of metabolites.

From https://cushingsdiseasenews.com/2018/05/17/severe-cushings-syndrome-case-study-finds-etomidate-effective-therapy/

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Clinical Trial for Cortendo

Posted on March 13, 2015 by MaryO

Cortendo Clinical Trial

 

About the Study

OBJECTIVE:

The purpose of this study is to test the effects of different doses of COR-003 on people with endogenous Cushing’s syndrome, primarily by measuring the cortisol levels in urine and secondarily by measuring other health parameters such as blood pressure, weight, liver function, etc. This study is also being conducted to find out if COR-003 is safe to use. This study is open-label, which means both the health providers and the participants in the study are aware of the drug or treatment being given.

STUDY DESIGN:

  • The study will begin with a screening period to make sure subjects are eligible to participate in the study.
  • After the screening period, subjects who are eligible for participation will each be given several different doses of COR-003, to be taken by mouth in tablet form.
  • After an individualized dose has been selected, participants will take COR-003 for 6 months.
  • Finally, participants will continue in the study for an additional 6 months at doses to be determined by the study doctor.
  • Throughout the study, participants will meet regularly with a study doctor and will take part in a variety of medical tests to make sure they are doing well and to see if COR-003 is working.
  • Participants in the study should be sure they have the time to participate. Participants will generally be followed for over a year.

See if you may be eligible for this clinical study. By providing your contact information, you will receive more information about the study and your eligibility.

About Cortendo

Cortendo is the sponsor of this study. This means Cortendo planned and organized this study. Cortendo will also collect and analyze the data from the study.

Cortendo is a global pharmaceutical company primarily focused on researching and providing treatments for rare diseases in endocrinology, such as Cushing’s syndrome. The company was founded in Sweden and its worldwide headquarters is located just outside of Philadelphia.

Fill out this form for more information: https://www.cushingssyndromestudy.com/registration.aspx

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