Publications and Posters Related to Investigational Agent RECORLEV™ (levoketoconazole)

Publications and Posters

* Investigational product candidates. The safety and efficacy of RECORLEV (levoketoconazole) and veldoreotide have not been established.

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Posters and Publications — Related to Investigational Agent RECORLEV (levoketoconazole)*

*Please note RECORLEV is the brand name for levoketoconazole (also known as 2S,4R ketoconazole, COR-003 or DIO-902 and lvedexketoconazole).

About Cushing’s Syndrome

  • Cushing’s disease. F. Castinetti, I. Morange, B. Conte-Devolx, T. Brue. Orphanet Journal of Rare Diseases. Volume 7. Page 41. 2012.
    • Abstract: Cushing’s disease, or pituitary ACTH dependent Cushing’s syndrome, is a rare disease responsible for increased morbidity and mortality. Signs and symptoms of hypercortisolism are usually non specific: obesity, signs of protein wasting, increased blood pressure, variable levels of hirsutism. Diagnosis is frequently difficult, and requires a strict algorithm. First-line treatment is based on transsphenoidal surgery, which cures 80% of ACTH-secreting microadenomas. The rate of remission is lower in macroadenomas. Other therapeutic modalities including anticortisolic drugs, radiation techniques or bilateral adrenalectomy will thus be necessary to avoid long-term risks (metabolic syndrome, osteoporosis, cardiovascular disease) of hypercortisolism. This review summarizes potential pathophysiological mechanisms, diagnostic approaches, and therapies... To read more, click here.
  • Incidence and late prognosis of Cushing’s syndrome: a population-based study. J. Lindholm, S. Juul, J. O. L. Jørgensen, J. Astrup, P. Bjerre, U. Feldt-Rasmussen, C. Hagen, J. Jørgensen, M. Kosteljanetz, L. Ø. Kristensen, P. Laurberg, K. Schmidt, J. Weeke. The Journal of Clinical Endocrinology & Metabolism. Volume 86. Number 1. Pages 117-23. 2001.
    • Abstract: The main purpose was to assess the incidence and late outcome of Cushing's syndrome, particularly in Cushing's disease. Information for all patients diagnosed with Cushing's syndrome during an 11-yr period in Denmark was retrieved. The incidence was 1.2-1.7/million.yr (Cushing's disease), 0.6/million.yr (adrenal adenoma) and 0.2/million.yr (adrenal carcinoma). Other types of Cushing's syndrome were rare. In 139 patients with nonmalignant disease, 11.1% had died during follow-up (median, 8.1 yr; range, 3.1-14.0), yielding a standard mortality ratio (SMR) of 3.68 [95% confidence interval (CI), 2.34-5.33]. The SMR was partly attributable to an increased mortality within the first year after diagnosis. Eight patients died before treatment could be undertaken. The prognosis in patients with malignant disease was very poor. Patients in whom more than 5 yr had elapsed since initial surgery were studied separately, including a questionnaire on their perceived quality of health. In 45 patients with Cushing's disease who had been cured through transsphenoidal neurosurgery, only 1 had died (SMR, 0.31; CI, 0.01-1.72) compared with 6 of 20 patients with persistent hypercortisolism after initial neurosurgery (SMR, 5.06; CI, 1.86-11.0). In patients with adrenal adenoma, SMR was 3.95 (CI, 0.81-11.5). The perceived quality of health was significantly impaired only in patients with Cushing's disease and appeared independent of disease control or presence of hypopituitarism. It is concluded that 1) Cushing's syndrome is rare and is associated with increased mortality, in patients with no concurrent malignancy also; 2) the excess mortality was mainly observed during the first year of disease; and 3) the impaired quality of health in long-term survivors of Cushing's disease is not fully explained... To read more, click here.
  • Cushing’s syndrome: from physiological principles to diagnosis and clinical care. H. Raff, T. Carroll. The Journal of Physiology. Volume 593. Number 3. Pages 493-506. 2015.
    • Abstract: The physiological control of cortisol synthesis in the adrenal cortex involves stimulation of adrenocorticotrophic hormone (ACTH) by hypothalamic corticotrophin-releasing hormone (CRH) and then stimulation of the adrenal by ACTH. The control loop of the hypothalamic–pituitary–adrenal (HPA) axis is closed by negative feedback of cortisol on the hypothalamus and pituitary. Understanding this system is required to master the diagnosis, differential diagnosis and treatment of endogenous hypercortisolism–Cushing’s syndrome. Endogenous Cushing’s syndrome is caused either by excess ACTH secretion or by autonomous cortisol release from the adrenal cortex. Diagnosis of cortisol excess exploits three physiological principles: failure to achieve the normal nadir in the cortisol diurnal rhythm, loss of sensitivity of ACTH-secreting tumours to cortisol negative feedback, and increased excretion of free cortisol in the urine. Differentiating a pituitary source of excess ACTH (Cushing’s disease) from an ectopic source is accomplished by imaging the pituitary and sampling for ACTH in the venous drainage of the pituitary. With surgical removal of ACTH or cortisol-secreting tumours, secondary adrenal insufficiency ensues because of the prior suppression of the HPA axis by glucocorticoid negative feedback. Medical therapy is targeted to the anatomical location of the dysregulated component of the HPA axis. Future research will focus on new diagnostics and treatments of Cushing’s syndrome. These are elegant examples of translational research: understanding basic physiology informs the development of new approaches to diagnosis and treatment. Appreciating pathophysiology generates new areas for inquiry of basic physiological and biochemical mechanisms... To read more, click here.
  • Epidemiology of Cushing's syndrome. C. Steffensen, A. M. Bak, K. Zoylner Rubeck, J. O. L. Jørgensen. Neuroendocrinology. Volume 92. Suppl 1. Pages 1-5. 2010.
    • Abstract: Overt Cushing's syndrome is a rare disorder with an annual incidence of 2-3/million of which benign adrenal adenomas account for 0.6/million. The female:male ratio is 3:1. Preliminary data indicate a high proportion of subclinical Cushing's syndrome in certain risk populations such as patients with type 2 diabetes or osteoporosis. The clinical implications of these observations are presently unclear. Surgery remains first line treatment for overt disease and initial cure or remission is obtained in 65-85% of patients with Cushing's disease. Late recurrences, however, occur in up to 20% and the risk does not seem to plateau even after 20 years of follow-up. A 2- to 3-fold increase in mortality is observed in most studies, and this excess mortality seems confined to patients in whom initial cure was not obtained. Cushing's syndrome continues to pose diagnostic and therapeutic challenges and life-long follow-up is mandatory... To read more, click here.

Current Management of Cushing’s Syndrome

  • Biochemical control in Cushing disease. Geer EB, Shafiq I, Gordon MB, Bonert V, Ayala A, Swedloff RS, Katznelson L, Lalazar Y, Manuyloa E, Pulaski-Liebert KJ, Carmichael JD, Hannoush Z, Surampudi V, Boder MS, Cherepanov D, Eagan M, Lee J, Said Q, Neary MP, Biller BMK. Biochemical control during long-term follow-up of 230 adult patients with Cushing disease: a multicenter retrospective study. Endocrin Pract. 2017;23:962.970.
    • Abstract: Background: Cushing disease (CD) results from excessive exposure to glucocorticoids caused by an adrenocorticotropic hormone-secreting pituitary tumor. Inadequately treated CD is associated with significant morbidity and elevated mortality. Multicenter data on CD patients treated in routine clinical practice are needed to assess treatment outcomes in this rare disorder. The study purpose was to describe the burden of illness and treatment outcomes for CD patients… To read more, click here. (A subscription to this site/publication is required to access the full article)
  • Hepatic safety of ketoconazole in Cushing’s syndrome: results of a compassionate use programme in France. J. Young, J. Bertherat, M. C. Vantyghem, O. Chabre, S. Senoussi, R. Chadarevian, F. Castinetti. European Journal of Endocrinology. 2018 Feb 22 (online ahead of print). pii: EJE-17-0886. doi: 10.1530/EJE-17-0886.
    • Abstract: Objective: Ketoconazole (KTZ) is one of few available treatments for Cushing’s syndrome (CS). Although KTZ has been associated with severe hepatotoxicity, little information is available about hepatic safety in CS. The aim of this study was to document changes in liver function in patients with CS treated with KTZ. Design: An observational prospective French cohort study (compassionate use programme). Methods: Enrolled patients were stratified into a KTZ-naïve cohort and a cohort already treated by another formulation of ketoconazole (KTZ-switch cohort). Liver function markers (aspartate transaminase (AST), alkaline phosphatase, γ glutamyltransferase and bilirubin) were monitored at regular intervals. Patients with ALT >3×ULN (Upper Limit of Normal), total bilirubin >2×ULN or both ALP>2×ULN and ALT>ULN were considered to have liver injury. Results: Overall, 108 patients were analysed (47 KTZ-naïve; 61 KTZ-switch). The median KTZ dose was 600 mg/day. Most abnormalities observed were asymptomatic mild increases of liver enzymes. ... To read more, click here.
  • Ketoconazole in Cushing’s disease: is it worth a try? F. Castinetti, L. Guignat, P. Giraud, M. Muller, P. Kamenicky, D. Drui, P. Caron, F. Luca, B. Donadille, M.C. Vantyghem, H. Bihan, B. Delemer, G. Raverot, E. Motte, M. Philippon, I. Morange, B. Conte-Devolx, L. Quinquis, M. Martinie, D. Vezzosi, M. Le Bras, C. Baudry, S. Christin-Maitre, B. Goichot, P. Chanson, J. Young, O. Chabre, A. Tabarin, J. Bertherat, T. Brue. The Journal of Clinical Endocrinology & Metabolism. Volume 99. Number 5. Pages 1623-30. 2014.
    • Abstract: Background: The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate... To read more, click here.
  • Update on medical treatment for Cushing’s disease. D. Cuevas-Ramos, D. Shao Ting Lim, M. Fleseriu. Clinical Diabetes and Endocrinology. Volume 2. Number 16. 2016.
    • Abstract: Cushing’s disease (CD) is the most common cause of endogenous Cushing’s syndrome (CS). The goal of treatment is to rapidly control cortisol excess and achieve long-term remission, to reverse the clinical features and reduce long-term complications associated with increased mortality. While pituitary surgery remains first line therapy, pituitary radiotherapy and bilateral adrenalectomy have traditionally been seen as second-line therapies for persistent hypercortisolism. Medical therapy is now recognized to play a key role in the control of cortisol excess. In this review, all currently available medical therapies are summarized, and novel medical therapies in phase 3 clinical trials, such as osilodrostat and levoketoconazole are discussed, with an emphasis on indications, efficacy and safety. Emerging data suggests increased efficacy and better tolerability with these novel therapies and combination treatment strategies, and potentially increases the therapeutic options for treatment of CD. New insights into the pathophysiology of CD are highlighted, along with potential therapeutic applications. Future treatments on the horizon such as R-roscovitine, retinoic acid, epidermal growth factor receptor inhibitors and somatostatin-dopamine chimeric compounds are also described, with a focus on potential clinical utility... To read more, click here.
  • Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies. M. Fleseriu, F. Castinetti. Pituitary: The Official Journal of the Pituitary Society. Volume 19. Number 6. Pages 643-53. 2016.
    • Abstract: Purpose: Endogenous Cushing’s syndrome (CS) is a rare disease that results from exposure to high levels of cortisol; Cushing’s disease (CD) is the most frequent form of CS. Patients with CS suffer from a variety of comorbidities that increase the risk of mortality. Surgical resection of the disease-causing lesion is generally the first-line treatment of CS. However, some patients may not be eligible for surgery due to comorbidities, and approximately 25% of patients, especially those with CD, have recurrent disease. For these patients, adrenal steroidogenesis inhibitors may control cortisol elevation and subsequent symptomatology. CS is rare overall, and clinical studies of adrenal steroidogenesis inhibitors are often small and, in many cases, data are limited regarding the efficacy and safety of these treatments. Our aim was to better characterize the profiles of efficacy and safety of currently available adrenal steroidogenesis inhibitors, including drugs currently in development... To read more, click here.
  • Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. L. K. Nieman, B. M. K. Biller, J. W. Findling, M. H. Murad, J. Newell-Price, M. O. Savage, A. Tabarin. The Journal of Clinical Endocrinology & Metabolism. Volume 100. Number 8. Pages 2807-31. 2015.
    • Abstract: Objective: The objective is to formulate clinical practice guidelines for treating Cushing's syndrome. Participants: Participants include an Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer. The European Society for Endocrinology co-sponsored the guideline. Evidence: The Task Force used the Grading of Recommendations, Assessment, Development, and Evaluation system to describe the strength of recommendations and the quality of evidence. The Task Force commissioned three systematic reviews and used the best available evidence from other published systematic reviews and individual studies... To read more, click here.

Health and Economic Burden From Cushing’s Syndrome

  • Incremental healthcare resource utilization and costs in US patients with Cushing’s disease compared with diabetes mellitus and population controls. M.S. Broder, M. P. Neary, E. Chang, W. H. Ludlam. Pituitary: The Official Journal of the Pituitary Society. Volume 18. Number 6. Pages 796-802. 2015.
    • Abstract: Purpose: Resource utilization and costs in Cushing’s disease (CD) patients have not been studied extensively. We compared CD patients with diabetes mellitus (DM) patients and population-based controls to characterize differences in utilization and costs... To read more, click here. (Subscription or purchase required.)
  • Algorithm development and the clinical and economic burden of Cushing’s disease in a large US health plan database. T. Burton, E. Le Nestour, M. Neary, W. H. Ludlam. Pituitary: The Official Journal of the Pituitary Society. Volume 19. Number 2. Pages 167-74. 2016.
    • Abstract: Purpose: This study aimed to develop an algorithm to identify patients with CD, and quantify the clinical and economic burden that patients with CD face compared to CD-free controls. Method: A retrospective cohort study of CD patients was conducted in a large US commercial health plan database between 1/1/2007 and 12/31/2011. A control group with no evidence of CD during the same time was matched 1:3 based on demographics. Comorbidity rates were compared using Poisson and health care costs were compared using robust variance estimation... To read more, click here.
  • Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. O. M. Dekkers, E. Horváth-Puhó, J. O. L. Jørgensen, S. C. Cannegieter. V. Ehrenstein, J. P. Vandenbroucke, A. M. Pereira, H. T. Sørensen. The Journal of Clinical Endocrinology & Metabolism. Volume 98. Number 6. Pages 2277-84. 2013.
    • Abstract: Context: Cushing’s syndrome (CS) is associated with hypercoagulability, insulin resistance, hypertension, bone loss, and immunosuppression. To date, no adequately large cohort study has been performed to assess the multisystem effects of CS. Objective: We aimed to examine the risks for mortality, cardiovascular disease, fractures, peptic ulcers, and infections in CS patients before and after treatment... To read more, click here.
  • The burden of Cushing’s disease: clinical and health-related quality of life aspects. R. A. Feelders, S. J. Pulgar, A. Kempel, A. M. Pereira. European Journal of Endocrinology. Volume 167. Number 3. Pages 311-26. 2012.
    • Abstract: Objective: Cushing’s disease (CD) is a rare endocrine disorder characterized by excess secretion of ACTH due to a pituitary adenoma. Current treatment options are limited and may pose additional risks. A literature review was conducted to assess the holistic burden of CD... To read more, click here.
  • Comorbidities in Cushing’s disease. S. T. Sharma, L. K. Nieman, R. A. Feelders. Pituitary: The Official Journal of the Pituitary Society. Volume 18. Number 2. Pages 188-94. 2015.
    • Abstract: Introduction: Cushing’s disease is a rare disorder characterized by overproduction of ACTH from a pituitary adenoma leading to hypercortisolemia that in turn leads to increased morbidity and mortality. Methods: Here we review the comorbidities associated with Cushing’s disease and their impact on quality of life and mortality. Results: Recent evidence suggests that correction of hypercortisolemia may not lead to complete resolution of comorbidities associated with this condition... To read more, click here.

Levoketoconazole-specific — RECORLEV (levoketoconazole)

  • 2S,4R-ketoconazole is the relevant enantiomer of ketoconazole for cortisol synthesis inhibition: steroidogenic P450s inhibition involves multiple mechanisms. R. J. Auchus, Y. Wu, J. Liu, H.-M. Peng. Strongbridge Biopharma plc. Poster presented at: Endocrine Society's 100th Annual Meeting and Expo; March 17-20, 2018; Chicago, IL.
    • Abstract: Background: 2S,4R-ketoconazole (COR-003) is in clinical trials for the treatment of Cushing syndrome. The data concerning its potency relative to its 2R,4S-enantiomer for the human steroidogenic enzymes and its mechanism(s) of action are limited. Objectives: To comprehensively characterize the potency and mechanism(s) of 2S,4R-ketoconazole inhibition on human steroidogenic enzymes using consistent systems and procedures. ... To view the poster, click here.
  • An open-label study to assess the safety and efficacy of levoketoconazole (COR-003) in the treatment of endogenous Cushing’s syndrome. R. Salvatori, A. DelConte, E. B. Geer, T. Koziol, D. Jorkasky. Strongbridge Biopharma plc. Poster presented at: Endocrine Society's 97th Annual Meeting and Expo; March 5—8, 2015; San Diego, CA.
    • Abstract: Endogenous Cushing´s syndrome (CS) is a rare but serious and potentially lethal disorder with an estimated incidence of 2-3 cases per million population persons per year and a prevalence of 30-60 cases per million. Incompletely controlled disease results in ≥5-fold increased mortality, mainly due to metabolic and cardiovascular complications. Racemic ketoconazole, an antifungal agent that at higher dosages reduces adrenal steroid production, is a commonly used off-label drug for the treatment of CS... To view the poster, click here.
  • Pharmacology of COR-003 (levoketoconazole), an investigational treatment for endogenous Cushing’s syndrome. R. Thieroff-Ekerdt, P. Lavin, M. Abou-Gharbia, N. France. Strongbridge Biopharma plc. Poster presented at: Endocrine Society's 98th Annual Meeting and Expo; April 1—4, 2016; Boston, MA.
    • Abstract: Ketoconazole is a 50/50 racemic mixture of two enantiomers (2S,4R and 2R,4S) used off-label in the US for the treatment of endogenous Cushing’s syndrome by virtue of adrenal cortisol synthesis inhibition... To view the poster, click here.
  • Differentiated pharmacokinetics of levoketoconazole (COR-003), the single 2S,4R-enantiomer of ketoconazole, a new investigational drug for the treatment of Cushing’s syndrome. R. I. Thieroff-Ekerdt, D. R. Mould. Strongbridge Biopharma plc. Poster presented at: European Society of Endocrinology's 18th European Congress of Endocrinology; May 28—31, 2016; Munich, Germany.
    • Abstract: Ketoconazole is a 50/50 racemic mixture of two enantiomers (2S,4R and 2R,4S) used off label in the US for the treatment of endogenous Cushing’s syndrome by virtue of adrenal cortisol synthesis inhibition.
      COR-003 (levoketoconazole) is the more potent single (2S,4R) enantiomer of ketoconazole (KTZ) to inhibit adrenal cortisol synthesis and is currently being investigated in a multinational Phase 3 study for the treatment of endogenous Cushing’s syndrome... To view the poster, click here.

Levoketoconazole-specific — Articles Related to Diobex Development of DIO-902 (development program for treatment of diabetes no longer active)

  • Ketoconazole enantiomer for the treatment of diabetes mellitus. R. Arakaki, B. Welles. Expert Opinion on Investigational Drugs. Volume 19. Number 2. Pages 185-94. 2010.
    • Abstract: The impact of hypercortisolism on multiple metabolic conditions is well recognized; the metabolic manifestations of Cushing’s syndrome overlap with those seen in type 2 diabetes and the metabolic syndrome. Ketoconazole (KTZ), a widely used antifungal agent that inhibits various enzymes in adrenal cortisol synthesis, is effective in treating hypercortisolemia, but its use is limited by toxicities... To read more, click here. (Subscription or purchase required.)
  • Differential effects of co-administration of racemic ketoconazole and levdexketoconazole on pharmacokinetic profile of atorvastatin (Poster). S. Boudriau, R. Demnati, D. Swearingen, T. Steward. MDS Pharma Services. Poster presented at: The American Society for Clinical Pharmacology and Therapeutics Annual Meeting.; April 2—5, 2008; Orlando, FL.
    • Abstract: This poster highlights the results of a study evaluating the effects of equal doses of the single enantiomer DIO-902 and racemic ketoconazole, on the pharmacokinetics of a single 80 mg dose of atorvastatin in healthy volunteers. Overall, repeated oral administration of DIO-902 tablets with atorvastatin was safe and well tolerated; in addition, DIO-902 significantly reduced cortisol levels compared with ketoconazole... To view the poster, click here.
  • Stereoisomers of ketoconazole: preparation and biological activity. D. M. Rotstein, D. J. Kertesz, K. A. M. Walker, D. C. Swinney. Journal of Medicinal Chemistry. Volume 35. Number 15. Pages 2818-25. 1992.
    • Abstract: The four stereoisomers of the antifungal agent ketoconazole (1) were prepared and evaluated for their selectivity in inhibiting a number of cytochrome P-450 enzymes. Large differences in selectivity among the isomers were observed for inhibition of the cytochromes P-450 involved in steroid biosynthesis, whereas little differences [sic] was observed for inhibition of those associated with hepatic drug metabolism... To read more, click here. (Subscription or purchase required.)
  • Safety profile and metabolic effects of 14 days of treatment with DIO-902: results of a phase IIa multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in patients with type 2 diabetes mellitus. S. L. Schwartz, M. Rendell, A. J. Ahmann, A. Thomas, C. J. Arauz-Pacheco, B. R. Welles. Clinical Therapeutics. Volume 30. Number 6. Pages 1081-8. 2008.
    • Abstract: Background: Elevated levels of cortisol have been implicated in the development of type 2 diabetes mellitus and the metabolic syndrome. Modulation of cortisol levels and activity may be useful in the treatment of type 2 diabetes and its comorbidities. Objective: The purpose of this study was to evaluate the safety profile and pharmacodynamics effects of DIO-902 (2S,4R-ketoconazole), an inhibitor of cortisol synthesis... To read more, click here. (Subscription or purchase required.)

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