Cortendo gains $11M for late-stage Cushing’s study

Posted on October 31, 2014 by MaryO

Cortendo is coming to America. Founded in Sweden, the little biotech has a new CEO who’s building the executive team in the Philadelphia area. And he’s dropping plans for a listing on the Oslo exchange in favor of a U.S. IPO after raising $11 million in bridge financing.

Cortendo CEO Matthew Pauls

The big idea at Cortendo is to take an existing drug–ketoconazole, which is used off-label for Cushing’s disease–and tinker with it to make it safer and more effective. HealthCap, the Third Swedish National Pension Fund (“AP3”), Storebrand and Arctic Fund Management are putting up the venture round. And their money is funding an on-going Phase III study designed to make their case with the FDA.

“It is a nice bridge to the U.S. which also allows us from funding perspective to drive that critically important Phase III to closure,” says CEO Matthew Pauls, an ex-Shire ($SHPG) and Insmed exec from the commercial side of the industry who joined the company a couple of months ago.

Cushing’s is characterized by elevated levels of cortisol, which trigger a host of serious and potentially lethal side effects. The new drug–dubbed COR-003–is designed to hit key enzymes in the cortisol synthesis pathway, using a more targeted segment of ketoconazole.

“We took basically the better half of the molecule and are using it explicitly for Cushing’s syndrome,” says the CEO. Now Cortendo–which is run by a core team of 6, which Pauls plans to expand–will drive for final late-stage data in 2017, setting up a prospective application with the FDA that could allow the company to proceed with plans to create its own commercial operations.

There are about 20,000 to 25,000 Cushing’s patients in the U.S., adds Pauls, with maybe 30,000 to 40,000 in Europe. About half of those patients can expect surgery to address the disease, with the rest candidates for medicinal therapies.

The U.S. represents the company’s largest market opportunity, says Pauls. So it makes sense to drop the Oslo listing in favor of a U.S. exchange. Exactly when that filing could come and where, he adds, hasn’t been determined yet.

– here’s the release

From http://www.fiercebiotech.com/story/little-cortendo-gains-11m-late-stage-cushings-study-hatches-us-ipo-plans/2014-10-30

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Rare neuroendocrine tumours may be misdiagnosed as Cushing’s disease

Posted on October 31, 2014 by MaryO

By Eleanor McDermid, Senior medwireNews Reporter

Ectopic tumours secreting corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) are very rare in children and can result in a misdiagnosis of Cushing’s disease (CD), say researchers.

Three of the patients in the reported case series had pituitary hyperplasia and underwent transsphenoidal surgery for apparent CD before the tumour that was actually causing their symptoms was located. The hyperplasia was probably caused by release of CRH from the ectopic tumour, which stimulated the pituitary gland, giving the impression of an ACTH-secreting pituitary adenoma, explain Maya Lodish (National Institutes of Health, Bethesda, Maryland, USA) and study co-authors.

These three patients were part of a series of seven, which Lodish et al describe as “a relatively large number of patients, considering the infrequency of this disease.”

The patients were aged between 1.8 and 21.3 years. Three had neuroendocrine tumours located in the pancreas ranging in size from 1.4 to 7.0 cm, two had thymic carcinoids ranging from 6.0 mm to 11.5 cm, one patient had a 12.0 cm tumour in the liver and one had a 1.3 cm bronchogenic carcinoid tumour of the right pulmonary lobe.

Four of the patients had metastatic disease and, during up to 57 months of follow-up, three died of metastatic disease or associated complications and two patients had recurrent disease.

“Our series demonstrates that these are aggressive tumors with a high mortality rate,” write the researchers in the Journal of Clinical Endocrinology & Metabolism. “It is important to follow the appropriate work up, regarding both biochemical and imaging tests, which can lead to the correct diagnosis and to the most beneficial therapeutic approach.”

The team found the CRH stimulation test to be helpful, noting, for example, that none of the patients had a rise in cortisol that was consistent with CD, with all patients showing smaller responses ranging from 2% to 15%. Likewise, just one patient had an ACTH rise higher than 35% on CRH administration, and four patients had a “flat” response, which has previously been associated with ectopic neuroendocrine tumours.

Of note, six patients had normal or high plasma CRH levels, despite all having high cortisol levels, which would be expected to result in undetectable plasma CRH due to negative feedback, implying another source of CRH production. Five patients had blunted diurnal variation of both cortisol and ACTH levels consistent with Cushing’s syndrome.

The patients also underwent a variety of imaging procedures to identify the source of ACTH/CRH production, some of which, such as octreotide scans, are specialist and not available in most hospitals, the researchers note, potentially contributing to inappropriate diagnosis and management.

From http://www.news-medical.net/news/20141030/Rare-neuroendocrine-tumours-may-be-misdiagnosed-as-Cushinge28099s-disease.aspx

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Safety of DR-HC for adrenal insufficiency

Posted on October 22, 2014 by MaryO

Conventional treatment of adrenal insufficiency involves cortisol replacement therapy with twice- or thrice-daily oral hydrocortisone. Recently dual-release hydrocortisone (DR-HC) administered once daily to provide high levels of cortisol during the morning, followed by a gradual decrease throughout the day is being used. This results in considerably lower cortisol exposure during the afternoon and evening compared with immediate-release thrice-daily hydrocortisone, thereby mimicking normal cortisol secretion more closely than conventional therapy.

Nilsson et al. conducted a study to evaluate the long-term safety of DR-HC and whether the difference in the incidence of adverse events persisted over time and if it was related to different levels of exposure to cortisol. They conducted a randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. The results of the study of the newly developed DR-HC showed that long-term maintenance treatment and rescue therapy was well tolerated up to 27 months of continuous treatment.

Read full article titled ‘Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency’ by Nilsson et al., European Journal of Endocrinology 171 pp 369 – 377, DOI: 10.1530/EJE-14-0327

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Mutation of ARMC5 gene characterized as the cause of meningeal tumour growth

Posted on October 13, 2014 by MaryO

Scientists at the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have published their findings that mutations in a gene known as “ARMC5” promote the growth of benign tumours in the adrenal glands and on the meninges: ARMC5 appears to belong to the group of so-called tumour suppressor genes. It is the first time in years that scientists have characterized such a gene.

The ARMC5 gene was discovered by independent workgroups studying – so-called adrenal adenomas – in connection with Cushing’s syndrome. In this disease, the body produces too much of the . Now, for the first time, a mutation of ARMC5 has been characterized as the cause behind the growth of meningeal tumours. The results on this tumour syndrome, obtained by the group of Dr. Patrick May and PD. Dr. Jochen Schneider together with colleagues from Charité Berlin (Dr. Ulf Elbelt) and the Universities of Würzburg (Prof. Dr. Bruno Allolio) and Cologne (Dr. Michael Kloth), have been published recently in the Journal of Clinical Endocrinology Metabolism.

Cortisol is an important hormone. It influences many metabolic pathways in the body and has a suppressing effect on the immune system. Accordingly, it is commonly employed as an anti-inflammatory medication. Prolonged, elevated levels of cortisol in the body can lead to obesity, muscular dystrophy, depression and other symptoms. To maintain the correct concentration in the blood, the body has a refined regulation system: Certain areas of the brain produce the hormone corticotropin as a stimulator of cortisol release; the actual formation of cortisol takes place in the . As the concentration of cortisol in the blood rises, the brain reduces the production of corticotropin.

In search of the causes of Cushing’s syndrome, scientists recently encountered certain genetic causes of benign tumours of the adrenal cortex. Growth of these adrenal cortex adenomas is based on a combination of hereditary and spontaneous mutations: It affects people in whom one of two “alternative copies” – one of the so-called alleles – of the ARMC5 gene is mutated from birth. If the second allele of ARMC5 later also undergoes a spontaneous mutation in the adrenal cortex, then the gene no longer functions. “What is interesting is that the failure of ARMC5 has no direct influence on cortisol production. However, because the tumour cells multiply faster than other body cells, and the number of cells in the tumour increases, the blood cortisol level rises in the course of the disease”, says Dr Schneider. Then, the level in the body rises and ultimately results in the onset of Cushing’s syndrome.

When other scientific workgroups discovered that further benign tumours – in this case meningeal tumours – occur more often in ARMC5-Cushing families, the group of Patrick May and Jochen Schneider sequenced the ARMC5 gene and studied it using bioinformatic techniques. “We demonstrated for the first time, in a patient with an adrenal cortex tumour and simultaneously a meningeal tumour, that somatic, that is non-hereditary, ARMC5 mutations are present in both tumours. This observation suggests that ARMC5 is a true tumour-suppressor gene.”

It must now be explored, Schneider continues, to what extent patients with adrenal cortex tumours ought to be screened for simultaneous presence of meningioma, and in which other types of tumour ARMC5 mutations are responsible for tumour growth: “Building upon that, we can learn whether the gene and the metabolic pathways it influences offer new approaches for treating the tumour syndrome.”

Explore further: Are you carrying adrenal Cushing’s syndrome without knowing it?

More information: “Molecular and Clinical Evidence for an ARMC5 Tumor Syndrome: Concurrent Inactivating Germline and Somatic Mutations are Associated with both Primary Macronodular Adrenal Hyperplasia and Meningioma.” Journal of Clinical Endocrinology Metabolism, October 2014. DOI: 10.1210/jc.2014-2648

Journal reference: Journal of Clinical Endocrinology & Metabolism search and more info website

Provided by University of Luxembourg search and more info

From http://medicalxpress.com/news/2014-10-mutation-armc5-gene-characterized-meningeal.html

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EU Looks to Okay Ketoconazole for Use in Cushing’s Syndrome

Posted on September 27, 2014 by MaryO

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended granting a marketing authorization for ketoconazole (Ketoconazole HRA; Laboratoire HRA Pharma) for the treatment of Cushing’s syndrome, a rare hormonal disorder sometimes called hypercortisolism.

Cushing’s syndrome is characterized by an excess of the hormone cortisol in the blood, which may be caused by a tumor. Treatment options currently available in the European Union include surgery to remove the tumor responsible for the high cortisol levels and radiotherapy, as well as several medicines that reduce the production of cortisol.

But pharmacological options remain very limited, and there is an unmet medical need for additional treatments, especially when surgery fails or for patients who cannot undergo surgery or take other medications. For this reason, the EMA’s CHMP evaluated the medicine under expedited review.

The opinion adopted by the CHMP at its September 2014 meeting is an intermediary step on Ketoconazole HRA’s path to patient access.

The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorization. Once a marketing authorization has been granted, decisions about price and reimbursement will then take place at the level of each member state considering the potential role/use of this medicine in the context of the national health system of that country.

The recommendation is that Ketoconazole HRA is to be prescribed only by physicians specialized in treating Cushing’s syndrome, as the dosing needs to be individualized for each patient.

This is because oral ketoconazole was previously suspended in the European Union for the indication it was first approved for, fungal infections, due to risk for liver injury. The US Food and Drug Administration (FDA) also decreed, at the same time, that doctors should no longer prescribe ketoconazole tablets as a first-line therapy for any fungal infection, for the same reason.

Information will be sent to healthcare professionals to allow them to advise patients and prescribe the medicine safely and effectively.

A Medicine Used Off-Label for More than 30 Years

Doctors have used ketoconazole to treat Cushing’s syndrome for more than 30 years, although it has never been authorized for this indication in the European Union. The drug is also frequently used off-label in the United States and elsewhere for this purpose.

The CHMP’s recommendation builds on information from published literature and documented off-label use in clinical practice.

At the time of the suspension of ketoconazole for fungal infections, healthcare professionals and patients were concerned that ketoconazole would no longer be available for patients with Cushing’s syndrome.

The CHMP therefore reviewed Ketoconazole HRA through accelerated assessment to facilitate patients’ access to a fully authorized medicine as soon as possible with evidence-based information for patients and doctors.

When assessing Ketoconazole HRA for the treatment of Cushing’s syndrome, the CHMP considered that “in this rare and potentially life-threatening condition, the medicine’s benefits are greater than its risks, which can be manageable in clinical practice by specific measures mitigating the risk of liver toxicity, including close monitoring of the patients’ liver function.”

In 2012, it was estimated that the disease affected approximately 46,000 people in the European Union. Cushing’s syndrome is a long-lasting condition that can be life-threatening because of its complications, including diabetes, high blood pressure, and depression.

From http://www.medscape.com/viewarticle/832399?src=rss

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