Recorlev (levoketoconazole) / Xeris Biopharma - LARVOL DELTA

Update and practical recommendations for the use of medical treatment of Cushing´s syndrome. (PubMed, Endocr Rev) - "Currently available medical treatments include adrenal steroidogenesis inhibitors that block cortisol secretion (ketoconazole, levoketoconazole, metyrapone, osilodrostat, mitotane, and etomidate), drugs that modulate pituitary ACTH secretion (pasireotide and cabergoline), and drugs that block peripheral glucocorticoid receptors (mifepristone). In this review, we summarize the main indications for medical treatment in CS, the mechanism of drug action, efficacy, recommended doses, and safety of the currently available drugs, as well as potential future treatments. We also discuss titration and block-and-replace approaches for control of hypercortisolism and provide recommendations for the use and monitoring of medical treatment in CS, including patients with endogenous hypercortisolism in special situations such as pregnancy, cyclic CS and mild autonomous cortisol secretion."

Journal • Cushing’s Disease • Endocrine Disorders

The effect of hypercortisolism treatment on dyslipidemia in Cushing syndrome: systematic review and meta-analysis. (PubMed, J Clin Endocrinol Metab) - "Our study demonstrate a significant improvement in serum lipid levels after treatment of CS. Since the cardiovascular complications of hypercortisolism depend on several factors, further studies are needed to determine whether this directly translates into an adequate reduction in the risk of major cardiovascular events."

Journal • Retrospective data • Cardiovascular • Cushing’s Disease • Dyslipidemia • Endocrine Disorders • Metabolic Disorders

Liver impairment and medical management of Cushing syndrome and MACS. (PubMed, Front Endocrinol (Lausanne)) - "Normocortisolemic subjects with liver steatosis/metabolic-associated steatohepatitis seem to have higher cortisol concentration than the healthy population...We present two CS cases with baseline liver impairment, which improved on the treatment with steroidogenesis inhibitors. The case reports are followed by literature review regarding liver dysfunction in endogenous hypercortisolemia, impact of hypothalamic-pituitary-adrenal axis on the liver, and liver safety profile of medical treatment used in endogenous hypercortisolemia."

Journal • Review • Cushing’s Disease • Endocrine Disorders • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure

Increased Weight Loss With the Combination of Levoketoconazole and Semaglutide in a Patient With Mild Hypercortisolism. (PubMed, AACE Endocrinol Diabetes) - "Medications included sertraline 100 mg daily and metformin 500 mg daily, which was increased; spironolactone was added, and Ozempic 0.25 mg subcutaneously weekly was started and titrated up to 1 mg subcutaneously weekly...A dexamethasone suppression test showed a non-suppressed adrenocorticotropic hormone 10 (reference: 7.2-63.3) and morning cortisol 6.7 ng/dL (reference: <1.8 ng/dL)...Our case shows that combined use of levoketoconazole and semaglutide resulted in significant weight loss and improvement of biochemical and psychological parameters. Hypercortisolism may mimic other diagnoses, and further exploration is needed about possible additive effects of levoketoconazole with semaglutide."

Journal • Acne Vulgaris • Adrenal Cortex Carcinoma • CNS Disorders • Cushing’s Disease • Depression • Endocrine Disorders • Genetic Disorders • Mood Disorders • Obesity • Oncology • Polycystic Ovary Syndrome • Psychiatry • Solid Tumor

Relapse of Cyclic Cushing Syndrome With a 19-Year Remission: Potential Involvement of COVID-19 in the Relapse. (PubMed, JCEM Case Rep) - "Cyclic Cushing syndrome (cyclic CS) is characterized by phases of hypercortisolemia and normocortisolemia or hypocortisolemia...The present case suggests that careful follow-up is essential for patients with uncured cyclic CS even if long-term remission is achieved. Additionally, a relapse of cyclic CS with a glucocorticoid-driven positive feedback mechanism could be induced by infection and treatment with glucocorticoids."

Journal • Carcinoid Tumor • Cushing’s Disease • Endocrine Disorders • Infectious Disease • Novel Coronavirus Disease • Oncology • Pituitary Gland Carcinoma • Solid Tumor • Thymus Cancer

Levoketoconazole Use Prior to Adrenalectomy (ENDO 2025) - "A one milligram overnight dexamethasone suppression test was abnormal at 2.0 µg/dL...Recorlev®, 150 mg daily was started in December 2023 with Trulicity and metformin discontinued.At a January 2024 follow-up, the Recorlev® dose was increased to 150 twice daily... This is the first documented case of pre-operative use of Recorlev® in a patient undergoing adrenalectomy. The tumor was found to secrete both cortisol and aldosterone. Pre-operative administration of Recorlev® successfully attenuated these hormones, facilitating a smooth surgical procedure and favorable postoperative outcome."

Adrenal Cortex Carcinoma • Asthma • Dyslipidemia • Endocrine Cancer • Genetic Disorders • Immunology • Metabolic Disorders • Obesity • Oncology • Respiratory Diseases • Solid Tumor

Pituitary Macroadenoma With Suprasellar Extension and Optic Chiasm Compression Causing Cushing's Disease: a Case Report (ENDO 2025) - "Ketoconazole was started as Levoketoconazole was not approved by insurance, and she was referred for surgery.Pituitary ACTH-dependent Cushing disease is rare, with high morbidity and mortality, peaking in the 3rd–4th decade (female:male 3:1)...Brain MRI and a high-dose dexamethasone test follow. If an adenoma >6 mm is found, surgery is performed. If <6 mm, bilateral inferior petrosal sinus sampling with CRH or desmopressin stimulation is needed."

Case report • Clinical • Cardiovascular • Cushing’s Disease • Endocrine Disorders • Genetic Disorders • Hypertension • Obesity • Ophthalmology • Pain • Pituitary Gland Carcinoma

Serum Inflammation based scores in prediction of liver fibrosis among Cushing syndrome and MACS patients: Data from ERCUSYN Krakow database. (ESPE-ESE 2025) - "There may be an association between FIB4 and SIBS in the following pattern: 1)positive with NLR in CS; 2)positive with NPR and negative with PLR in: CS, MACS and normocortisolemic population; 3)negative with SII in MACS and normocortisolemic population. Further studies are needed to estabilish SIBS role in LF prediction."

Clinical • Cushing’s Disease • Diabetes • Dyslipidemia • Endocrine Disorders • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders

Evaluation of the effect of hypercortisolemia treatment on bone metabolism and structure in patients with endogenous Cushing's syndrome- a single center experience (ESPE-ESE 2025) - "Our results confirmed that normocortisolemia improved calcium-phosphate metabolism. Further conclusions regarding changes in calcium-phosphate levels and bone turnover markers over time in normocortisolemic patients can be drawn when a larger study group has been enrolled."

Clinical • Cardiovascular • Cushing’s Disease • Diabetes • Endocrine Disorders • Hypertension • Metabolic Disorders • Orthopedics • Rare Diseases • DKK1

Xeris Biopharma Delivers Record Fourth Quarter and Full-Year 2024 Results; and Announces 2025 Guidance (Businesswire) - "Gvoke: Net revenue was $82.8 million for the year ended December 31, 2024 – an increase of approximately 24% compared to prior year...Recorlev: Net revenue was $64.3 million for the year ended December 31, 2024 – an increase of approximately 118% compared to prior year...Keveyis: Net revenue was $49.5 million for the year ended December 31, 2024 – a decrease of approximately 13% compared to prior year."

Commercial • CNS Disorders • Cushing’s Disease • Endocrine Disorders • Severe Hypoglycemia • Type 2 Diabetes Mellitus

New Trends in Treating Cushing's Disease. (PubMed, touchREV Endocrinol) - "At the pituitary level, pasireotide is an approved somatostatin receptor ligand, and compounds targeting cell cycle regulation, cell signalling and epigenetics are now under investigation. Levoketoconazole and osilodrostat are novel steroid inhibitors, and relacorilant overcomes the adverse effects of mifepristone. Adrenal ACTH receptor blockage and immunotherapy could also play a role."

Journal • Cushing’s Disease • Endocrine Disorders • Oncology • SSTR

Efficacy and Safety of Levoketoconazole in Managing Cushing's Syndrome: A Systematic Review. (PubMed, Indian J Endocrinol Metab) - "Levoketoconazole has good efficacy and safety in CS. Bigger and longer studies are warranted to establish its superiority over ketoconazole."

Journal • Review • Cushing’s Disease • Endocrine Disorders

Cushings Conundrum: Taming the Hormone Hurricane (ENDO 2024) - "Ketoconazole was initiated but discontinued later due to rising liver enzymes, Metyrapone and spironolactone were initiated and etomidate infusion titrated off...Dexamethasone was initiated given concern for relative adrenal insufficiency during this time and was later switched to hydrocortisone, and eventually discontinued with normalizing cortisol levels...Metyrapone and mitotane are alternatives but supply challenges exist. Osilodrostat, studied for short-term use, has limited data in ectopic ACTH syndromes... Managing ACTH-producing neuroendocrine tumors necessitates a multidisciplinary approach. In severe Cushing's syndrome, etomidate infusion quickly normalizes cortisol but requires intensive care due to sedation risks. Ketoconazole and levoketoconazole carry a hepatotoxicity risk."

Anesthesia • Cardiovascular • Critical care • Cushing’s Disease • Diabetes • Endocrine Cancer • Endocrine Disorders • Hematological Disorders • Hepatology • Hypertension • Metabolic Disorders • Musculoskeletal Diseases • Nephrology • Neuroendocrine Tumor • Oncology • Pancreatic Cancer • Pulmonary Disease • Rare Diseases • Renal Disease • Solid Tumor

Severe IGF-2 Mediated Hypoglycemia in a Patient With Adrenocortical Carcinoma: A Case Report (ENDO 2024) - "CT scan of his chest and abdomen at that time revealed a large left suprarenal mass and multiple lung and liver masses; a biopsy from the liver lesion confirmed the diagnosis of ACC and he was started on treatment with mitotane, levoketoconazole and hydrocortisone. Oncology attempted treatment with 3 cycles of cisplatin and etoposide, with no significant response; subsequently, treatment with Keytruda initially decreased tumor size, but ultimately his CT scan showed progression of disease and mitotane was stopped in August 2023.When brought to the hospital in September 2023 due to seizures and altered mental status, the patient's blood glucose (BG) was 25 mg/dL (70-110 mg/dL) on point of care testing, so he was started on IV 10% dextrose with improvement in BG and mental status... This case illustrates the importance of appropriate workup of IGF-2 mediated hypoglycemia, allowing for the best possible therapeutic approach. In our case, reducing tumor burden was not..."

Case report • Clinical • Adrenal Cortex Carcinoma • CNS Disorders • Critical care • Cushing’s Disease • Endocrine Disorders • Epilepsy • Genito-urinary Cancer • Hepatology • Hypoglycemia • Oncology • Solid Tumor • IGF1 • IGF2

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 (ENDO 2024) - "In this post-hoc analysis, lower mUFC at baseline predicted the likelihood of achieving mUFC normalization following 6 months of levoketoconazole Maintenance therapy and was associated withlower Maintenance dose requirements and lower rates of potentially clinically important liver-related AEs.Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference."

Clinical • Retrospective data • Cushing’s Disease • Endocrine Disorders

Treatment of Cushing's With Levoketoconazole: A Case Series (ENDO 2024) - "He achieved control with pasireotide but discontinued due to abnormal liver function tests. LKCZ is a new option for the treatment of CS in patients whose disease persists after TSS. These 3 patients had improvement of sxs and normalization of cortisol levels while on LKCZ, although one patient discontinued LKCZ due to a rash that was previously experienced with KCZ. The other two patients are being carefully monitored for liver function test elevation, QTc abnormalities and adrenal insufficiency with no issues to date."

Clinical • Cardiovascular • CNS Disorders • Cushing’s Disease • Endocrine Disorders • Fatigue • Hypertension • Insomnia • Nephrology • Oncology • Psychiatry • Renal Disease • Sleep Disorder

Xeris Biopharma Reports Third Quarter 2023 Financial Results (Businesswire) - "Xeris Biopharma Holdings, Inc...announced financial results for the third quarter and nine months ended September 30, 2023 and corporate highlights...Recorlev^®: Third quarter net revenue was $8.1 million – an increase of $5.6 million compared to the same period of 2022. The average number of patients on Recorlev increased over 203% from the same period in 2022."

Sales • Cushing’s Disease

High Prevalence of Venous Thrombotic Events in Cushing's Syndrome: Data From ERCUSYN (ENDO 2023) - "We report a high VTE rate in CS patients within ERCUSYN. Of note, to our knowledge this is the largest registry-based study to date looking at VTE in CS patients. Importantly, more than half of the VTE events were diagnosed in patients with normocortisolaemia.*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation."

Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Endocrine Disorders • Hypertension • Metabolic Disorders • Obesity • Oncology • Osteoporosis • Rheumatology • Venous Thromboembolism

OPTICS: Open-label Treatment in Cushing's Syndrome (clinicaltrials.gov) - P3 | N=51 | Completed | Sponsor: Cortendo AB | Active, not recruiting ➔ Completed | Trial completion date: Jun 2023 ➔ Dec 2022 | Trial primary completion date: Jun 2023 ➔ Dec 2022

Trial completion • Trial completion date • Trial primary completion date • Endocrine Disorders

An evaluation of pharmacological options for Cushing's disease: what are the state-of-the-art options? (PubMed, Expert Opin Pharmacother) - ": Since there is still no standardized pharmacological approach and the superiority of one drug over another has not been established yet due to the lack of comparative studies, each time clinicians' choices should be patient-tailored. Age, gender, tumor features, severity of hypercortisolism, comorbidities/complications, rapidity of action of each drug, side effects, drug-drug interactions, contraindications, availability, patients' preferences and costs should be all taken into account."

Journal • Endocrine Disorders • Oncology • Palliative care

Management of Ectopic ACTH Syndrome with Liver Metastases – A Case Series (AACE 2023) - "The cortisol did not suppress with 1-mg or 8-mg dexamethasone...A PET scan (64Cu-DOTATATE in patient A, F18-FDG in patient B, and 68Ga DOTATATE in patient C) revealed hepatic metastases in all patients. Patient A was started on levoketoconazole and metyrapone, underwent trans-arterial radio-embolization (TARE) of the liver metastases, after which levoketoconazole was stopped...While surgical excision of the primary tumor is curative, patients might present with symptomatic hypercortisolism and unknown primary tumor or metastatic disease. Utilizing steroidogenic inhibitors to alleviate hypercortisolism and using TAE/TARE for patients with liver metastases to reduce disease burden, when appropriate, will improve quality of life and preserve adrenal function as compared to bilateral adrenalectomy."

Clinical • Cardiovascular • Diabetes • Endocrine Cancer • Endocrine Disorders • Gastrointestinal Cancer • Hepatocellular Cancer • Hypertension • Infectious Disease • Neuroendocrine Tumor • Oncology • Pneumonia • Respiratory Diseases • Solid Tumor

Common Adverse Events During Levoketoconazole Titration: An Integrated Analysis of Data from Two Prospective Cushing’s Syndrome (CS) Clinical Trials (AACE 2023) - "Detailed characterization of common AEs from an integrated dataset of 2 clinical studies populations during titration with levoketoconazole provides new knowledge relevant to levoketoconazole clinical use as chronic medical treatment in adult patients with CS."

Adverse events • Clinical • Atrial Fibrillation • Cardiovascular • Endocrine Disorders • Fatigue • Hypertension • Infectious Disease • Musculoskeletal Pain • Pain • Respiratory Diseases

"$XERS Xeris Biopharma Announces FDA Grants Orphan-drug Exclusivity for Recorlev® https://t.co/jujkEb1Dbe" (@stock_titan)

FDA event • Orphan drug

How best to monitor the specific side effects of medical treatments of Cushing's disease. (PubMed, Best Pract Res Clin Endocrinol Metab) - "The efficacy of these drugs will not be detailed in this review, nor their roles in the therapeutic algorithm of Cushing's disease. This review will rather focus specifically on adverse events associated with these drugs (ketoconazole, levoketoconazole, metyrapone, osilodrostat, pasireotide, cabergoline and mifepristone), and the way in which to monitor and treat them, based on retrospective studies and the most recently published prospective studies."

Adverse events • Journal • Review • Endocrine Disorders • SSTR

A Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushing's Syndrome. (clinicaltrials.gov) - P3 | N=84 | Completed | Sponsor: Cortendo AB | N=44 ➔ 84

Enrollment change • Adrenal Cortex Carcinoma • Endocrine Disorders • Solid Tumor