Cortendo plans tax-fuelled shift to Dublin

Cortendo, a Swedish-American biopharmaceutical company that has invested millions developing treatments for rare conditions such as Cushing’s syndrome, is the latest global drug company to propose a move to Ireland for tax reasons.

The company operates from Pennsylvania, is listed in Norway but is incorporated in Sweden.

In recent days it told its investors it had submitted a prospectus to the Central Bank relating to the establishment of a Dublin-based public limited company.

Cortendo is proposing that the new Dublin company would become the parent of the group, replacing its current Swedish domicile. The Irish company would buy all of the outstanding stock in the current Cortendo parent, paying investors with an issuance of depositary receipts.

Depositary receipts have become popular financial instruments in the biopharma industry, and are typically used by non-US drug companies that want to trade in over-the-counter and traditional US markets.

Cortendo told its shareholders the move to Ireland “will have the effect of facilitating tax-efficient allocations of capital [and] tax-efficient returns of capital to shareholders”.

“Furthermore, the board expects that certain features of Irish company law will enable the Cortendo group to operate more flexibly and efficiently,” the company said.

Cortendo had not yet responded to a request prior to publication for details on what, if any, staff or operations would be shifted to Dublin as part of the move.

The company last month indicated it may seek to list its shares in the United States, although it did not discuss a valuation. It set up its Irish unit in May, according to company filings.

The company focuses on developing drugs to treat rare endocrine diseases, including the potentially fatal Cushing’s and acromegaly, inflammation of the hands and feet that can lead to diabetes.

Its main drugs have not yet been commercialised but it has high hopes for its treatment for Cushing’s , which is at a late stage of development. The company’s latest annual report shows an operating loss of about €8 million.


Does a Normal Urine Free Cortisol Result Rule out Cushing’s Syndrome?

Endocrine Society’s 97th Annual Meeting and Expo, March 5–8, 2015 – San Diego
Does a Normal Urine Free Cortisol Result Rule out Cushing’s Syndrome?
1 and 2

  • 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
  • 2National Institutes of Health, Bethesda, MD
Presentation Number: SAT-384
Date of Presentation: March 7, 2015
Abstract:Background: Urine free cortisol (UFC) has been traditionally used as one of the first steps in the diagnostic evaluation of Cushing’s syndrome (CS) (1). False positive results, especially values less than twice the upper limit of normal (ULN), can be seen in uncontrolled diabetes, obesity, depression, alcoholism, increased fluid intake, overcollection and stress. False negative results have also been reported with incomplete collection, in mild or cyclic CS and in patients with renal insufficiency (2-3). We evaluated the diagnostic accuracy of UFC and 24-hour urine 17-hydroxycorticosteroids (17OHCS) in patients with CS.Methods: Retrospective study of all CS patients evaluated at the National Institutes of Health (NIH) from 2009 to 2014. Screening tests used for CS included UFC, 17OHCS, late night salivary cortisol (LNSC), midnight serum cortisol and low dose (1mg overnight or 2-day 2mg/day) dexamethasone suppression test (DST). Values above reference range for UFC, 17OHCS and LNSC, a midnight serum cortisol ≥ 7.5 mcg/dL, and post-dexamethasone cortisol values ≥ 1.8 mcg/dL were considered abnormal. Hourly 24-hour sampling for cortisol was performed in a few cases with a mild clinical phenotype and equivocal test results. UFC was measured using liquid chromatography/tandem mass spectrometry (LC-MS/MS). 17OHCS was measured using colorimetric methodology with Porter-Silber reaction (reported as mg/g of creatinine). Mean of the first two UFC and 17OHCS values (appropriate collection by urine volume and creatinine) obtained within 30 days of initial NIH presentation were used for the purpose of this study.

Results: Seventy-two patients were diagnosed with CS (aged 18-77 years, 51 females). Of these, 51 had Cushing’s disease (CD), 10 had ectopic CS while 2 had an adrenal source of Cushing’s based on pathology. Biochemical tests including inferior petrosal sinus sampling (IPSS) suggested ectopic CS but no tumor was found (occult) in 6 patients. IPSS was indicative of a pituitary source in 2 patients with failed transsphenoidal surgery while one patient did not complete evaluation for ACTH-dependent CS. UFC results were available in all, 17OHCS in 70, LNSC in 21, midnight serum cortisol in 68 and DST results in 37 patients. UFC was falsely normal in six and only minimally elevated (< 2 x ULN) in 13 patients (normal renal function, no history of cyclicity, all had CD). Of these 19 patients, 24h 17OHCS was abnormal in all, LNSC was abnormal in 12, midnight serum cortisol was abnormal in 18 and DST was abnormal in 12 patients. Hourly 24-hour sampling for cortisol performed in 3 of these patients revealed abnormal nadir (> 7.5 mcg/dL) and mean daily serum cortisol (> 9 mcg/dL) levels.

Conclusion: UFC can be falsely normal or only minimally elevated in mild CS. Multiple collections and use of complimentary screening tests including 24-hour urine 17OHCS and LNSC can help make a diagnosis and prevent delay in treatment.

(1) Newell-Price J, et al. Cushing’s syndrome. Lancet. 2006;367(9522):1605-17.  (2) Alexandraki KI, et al. Is urinary free cortisol of value in the diagnosis of Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes. 2011;18:259–63.  (3) Kidambi S, et al. Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome. Eur J Endocrinol. 2007;157(6):725-31

Nothing to Disclose: STS, LKN

Sources of Research Support: This research was in part supported by the intramural research program of NICHD/NIH

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A Single Midnight Serum Cortisol Measurement Distinguishes Cushing’s Syndrome from Pseudo-Cushing States

Address all correspondence and requests for reprints to: Dimitris A. Papanicolaou, M.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862. E-mail:
Received: October 22, 1997
Accepted: January 05, 1998
First Published Online: July 01, 2013

Cushing’s syndrome (CS) may be difficult to distinguish from pseudo-Cushing states (PCS) based on physical findings or urinary glucocorticoid excretion. As the lack of diurnal variation in serum cortisol is characteristic of CS, we studied whether diurnal cortisol determinations could discriminate CS from PCS. Two hundred and sixty-three patients were evaluated: 240 had CS, and 23 had PCS. Urine was collected for 24 h for measurement of cortisol and 17-hydroxycorticosteroids (17OHCS). Blood was drawn at 2300, 2330, 0000, 0030, and 0100 h and at 0600, 0630, 0700, 0730, and 0800 h the next morning for serum cortisol determination. The main outcome measure was the sensitivity of these parameters for the diagnosis of CS at 100% specificity. A midnight cortisol value greater than 7.5 μg/dL correctly identified 225 of 234 patients with CS and all PCS patients. This sensitivity (96%) was superior to that obtained for any other measure, including urinary cortisol (45%), 17OHCS (22%), any other individual cortisol time point (10–92%), the morning (23%) or the evening (93%) cortisol mean, and the ratio (11%) of morning to evening values. We conclude that at 100% specificity, a single serum cortisol value above 7.5 μg/dL at midnight discriminates CS from PCS with higher sensitivity than 24-h urinary cortisol or 17OHCS, or other individual or combined measures of serum cortisol.

OVERPRODUCTION of cortisol is the biochemical hallmark of Cushing’s syndrome (CS) regardless of its etiology and is evidenced by increased urinary cortisol excretion, and a decrease in the circadian variation of serum cortisol (1).

Pseudo-Cushing states (PCS), as the name implies, share many of the features of Cushing’s syndrome, including cortisol overproduction. The hypercortisolism of PCS is hypothesized to be caused by increased activity of the CRH neuron, which, in turn, stimulates ACTH production and release (2). PCS are a heterogeneous group of disorders, including chronic alcoholism and alcohol withdrawal syndrome (3, 4), major depression (5), poorly controlled diabetes mellitus (6, 7), and obesity (8). Additionally, transient hypercortisolism may be associated with less obvious psychiatric conditions (e.g. anxiety) in patients with clinical features reminiscent of CS, such as obesity and hypertension, which are common in the general population. The substantial overlap in urinary free cortisol (UFC) excretion and clinical features between some patients with CS and those with PCS can make it difficult to distinguish between the two conditions (9). Thus, although persistent elevation of 24-h UFC in the presence of unequivocal signs of CS (particularly classic moon facies, prominent centripetal obesity, severe proximal muscle weakness, and violaceous striae) suggest the diagnosis of CS, patients with less obvious signs pose a diagnostic dilemma.

Several tests have been proposed to diagnose CS, including 24-h UFC measurements, the 1-mg overnight dexamethasone suppression test (DST) (10), the 2-day DST (1), and the dexamethasone-CRH (Dex-CRH) stimulation test (8). Each has drawbacks. Twenty-four-hour urinary collections are inconvenient and often incomplete. The 1-mg overnight DST is commonly used as a screening test to exclude the diagnosis of CS. This test has two caveats. First, a criterion for the level of serum cortisol suppression to exclude CS has not been developed using modern RIAs. Second, although the test has a false negative rate of only 2%, it has a significant false positive rate, especially in chronically ill (23%) or obese patients (13%) (11) and in patients with major depression (43%) or other psychiatric disorders (8–41%) (12). Even in normal individuals, the test may be consistent with CS in up to 30% (9).

Similarly, the 2-mg 2-day DST, often used as a confirmatory diagnostic test, has a diagnostic accuracy of only 71% (8). An additional problem is the variable metabolic clearance of dexamethasone (13), which is especially problematic in patients receiving medications that induce the cytochrome P450-related enzymes (e.g.phenytoin, rifampin, and phenobarbital) (14) or in patients with renal or hepatic failure. In such cases, neither DST gives reliable results. Finally, the drawbacks of 24-h urine collections apply to the DST as well.

We previously determined that the dexamethasone-CRH test has a diagnostic accuracy of 98% in the distinction of CS from PCS (8, 15). However, although accurate, this test has the drawbacks related to dexamethasone clearance, as discussed above.

Physiological cortisol secretion is characterized by circadian rhythmicity. Serum cortisol concentration reaches its zenith in the morning (0600–0800 h) and its nadir in the night during the first half of normal sleep. Krieger et al. defined the normal circadian rhythm of plasma corticosteroid levels as the pattern where all plasma glucocorticoid levels from 1600–2400 h were 75% or less of the 0800 h value (16). As previous studies have found that obese individuals retain a normal circadian cortisol rhythm (17), we hypothesized that differences in circadian plasma cortisol values would distinguish CS from PCS. To test this hypothesis, we prospectively measured serum cortisol values during the normal nadir and zenith periods in patients being evaluated for CS.

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