Cortisol Modulator Shows Early Signs of Safety, Efficacy in Healthy Volunteers

The glucocorticoid receptor antagonist CORT125134 is safe and has shown preliminary signs of efficacy in healthy volunteers participating in a Phase 1 trial, say researchers in England.

Their study, “Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study,” appeared in the journal Clinical Pharmacology in Drug Development.”

Cortisol signaling is indirectly controlled by the glucocorticoid receptor (GR). When cortisol binds the GR, the receptor becomes activated and migrates to the nucleus, where it regulates the expression of many genes. This influences a myriad of processes, including inflammation, immune response and brain function.

CORT125134, also known as relacorilant, is being developed by Corcept Therapeutics of Menlo Park, California, for Cushing’s disease patients and others who may benefit from it. The drug is a GR antagonist, blocking the receptor’s activity.

In order to evaluate the safety and tolerability of CORT125134, and learn how it behaves in the body, Corcept researchers conduced a Phase 1 trial in healthy subjects.

The British study, conducted at the Quotient Clinical in Nottingham, included 81 adults who received a single ascending-dose of CORT125134 or placebo, and 48 subjects who received multiple-ascending doses of the drug versus placebo.

Single doses were tested in nine distinct groups. Six tested six different doses of CORT125134, one tested a 150 mg dose in subjects receiving a high-fat meal, and two groups included patients receiving prednisone (a well-known GR activator), prednisone plus Korlym (mifepristone), or prednisone plus CORT125134.

Korlym is a medicine approved for Cushing’s  patients with high blood sugar levels due to high cortisol in circulation. But the drug targets the progesterone receptor and is associated with side effects like pregnancy termination and irregular vaginal bleeding.

Multiple doses, given for up to 14 days, were tested in four additional cohorts. Researchers observed that CORT125134 was rapidly absorbed and eliminated, presenting a suitable profile for once-daily dosing.

Efficacy was determined by CORT125134’s ability to counteract the effects of prednisone. In addition, a single dose of 500 mg or multiple dosing with 250 mg had similar effects as those seen with 600 mg of Korlym — the therapeutic dose used for Cushing’s treatments.

Most common treatment-related adverse events reported in the single-ascending dose part of the study were nausea, vomiting and thirst; most were mild. In those given multiple-ascending doses, adverse events included mild musculoskeletal and connective tissue disorders, as well as gastrointestinal system disorders.

Multiple 500 mg doses exceeded the maximum tolerated dose, as it led to musculoskeletal symptoms that forced researchers to stop treatment.

“This first-in-human study has demonstrated that CORT125134 is well tolerated following single doses up to 500 mg and repeated doses up to 250 mg once daily for 14 days,” researchers wrote. “Pharmacological activity was confirmed following the administration of a single 500-mg dose and daily administration of 250 mg.”

Corcept is now enrolling participants into a Phase 2 open-label trial (NCT02804750) to evaluate CORT125134 in patients with Cushing’s syndrome. This trial is being conducted in the United States and Europe and will include 80 participants. Top-line results are expected in the first quarter of 2018.

From https://cushingsdiseasenews.com/2017/10/10/phase-1-data-demonstrates-efficacy-safety-of-cort125134-in-healthy-volunteers/

Health Care Expenditure Burden High in Adrenal Insufficiency

Patients with adrenal insufficiency may accrue substantial health care costs and have more hospital stays and outpatient visits compared with healthy controls, according to findings published in the Journal of the Endocrine Society.

Candace Gunnarsson, PhD, vice president of health economics and outcomes research at CTI Clinical Trial and Consulting in Cincinnati, and colleagues evaluated data from a U.S.-based payer database on 10,383 patients with adrenal insufficiency to determine the estimated annual health care burden among them.

Participants were divided into groups based on their type of adrenal insufficiency: primary adrenal insufficiency (n = 1,014), adrenal insufficiency secondary to pituitary disease (n = 8,818) or congenital adrenal hyperplasia (n = 551). A group of matched controls was also evaluated for comparison.

Total annual health care expenditures were significantly higher in the primary adrenal insufficiency group ($18,624 vs. $4,320), adrenal insufficiency secondary to pituitary disease group ($32,218 vs. $6,956) and the congenital adrenal hyperplasia group ($7,677 vs. $4,203) compared with controls. The adrenal insufficiency secondary to pituitary disease group had the highest health care expenditure estimated with an incremental health care burden of $25,262, followed by the primary adrenal insufficiency group ($14,304) and the congenital adrenal hyperplasia group ($3,474).

Compared with controls, participants with adrenal insufficiency spent eight to 10 times more days in the hospital and had up to twice as many outpatient visits per year.

“When comparing [adrenal insufficiency] patients within each cohort based on their drug regimen, patients receiving prednisone therapy vs. hydrocortisone therapy had significantly higher total annual expenditures in the [primary adrenal insufficiency] and [congenital adrenal hyperplasia] and significantly lower total expenditures in the [pituitary disease] cohort,” the researchers wrote. “Patients taking only hydrocortisone and meeting the threshold of 50% adherence were found to have lower expenditures when medication adherence was 75% or higher.” – by Amber Cox

Disclosure: Gunnarsson reports being an employee of CTI Clinical Trial and Consulting. Please see the full study for a list of all other authors’ relevant financial disclosures.

From http://www.healio.com/endocrinology/adrenal/news/in-the-journals/%7B8f92bd0c-0c72-4902-beb5-663c356a61cb%7D/health-care-expenditure-burden-high-in-adrenal-insufficiency

Causes of Cushing’s Syndrome

Cushing’s syndrome—also referred to as hypercortisolism—is fairly rare. However, researchers have boiled down a few key causes of Cushing’s syndrome, which you’ll read about below.

The cause of Cushing’s syndrome boils down to: Your body is exposed to too much cortisol. There are a few ways that this over-exposure can happen, including taking certain medications and having a tumor on your pituitary gland or adrenal gland.

Can Taking Corticosteroids Cause Cushing’s Disease?
One particular type of medication can cause Cushing’s syndrome: corticosteroids. But rest assured: Not all steroid medications cause Cushing’s syndrome. It’s more common to develop Cushing’s syndrome from steroids you take in pill form or steroids you inject. Steroid creams and steroids you inhale are not common causes of Cushing’s syndrome.

Some steroid medications have the same effect as the hormone cortisol does when produced in your body. But as with an excessive production of cortisol in your body, taking too much corticosteroid medications can, over time, lead to Cushing’s syndrome.

It’s common for people with asthma, rheumatoid arthritis, and lupus to take corticosteroids. Prednisone (eg, Deltasone) is an example of a corticosteroid medication.

Other Cushing’s Disease Causes
Your body can over-produce cortisol or adrenocorticotropic hormone (ACTH). The pituitary gland secretes ACTH, which is in charge of stimulating the adrenal glands to produce cortisol, and the adrenal glands are responsible for releasing cortisol into the bloodstream.

Cortisol performs important tasks in your body, such as helping to maintain blood pressure and regulate how your body metabolizes proteins, fats, and carbohydrates, so it’s necessary for your body to maintain normal levels of it.

The following can cause excessive production of cortisol or ACTH, leading to Cushing’s syndrome.

  • Pituitary gland tumors: A benign (non-cancerous) tumor of the pituitary gland can secrete an excess amount of ACTH, which can cause Cushing’s syndrome. Also known as pituitary adenomas, benign tumors of the pituitary gland affect women 5 times more often than men.
  • Adrenal gland tumors: A tumor in one of your adrenal glands can lead to Cushing’s syndrome by causing too much cortisol to enter your bloodstream. Most of these tumors are non-cancerous (called adrenal adenomas).

    Cancerous adrenal tumors—called adrenocortical carcinomas—are relatively rare. These types of tumors typically cause extremely high levels of cortisol and very rapid development of symptoms.

  • Other tumors in the body: Certain tumors that develop outside the pituitary gland can also produce ACTH. When this happens, it’s known as ectopic ACTH syndrome. Ectopic means that something is in an abnormal place or position. In this case, only the pituitary gland should produce ACTH, so if there is a tumor producing ACTH and it isn’t located on the pituitary, it’s ectopic.

    It’s unusual to have a tumor that secretes ACTH outside the pituitary. These tumors are usually found in the pancreas, lungs, or thyroid, and they can be benign or malignant (cancerous).

    The most common forms of ACTH-producing tumors are small cell lung cancer, which accounts for about 13% of all lung cancer cases, and carcinoid tumors—small, slow-growing tumors that arise from hormone-producing cells in various parts of the body.

  • Familial Cushing’s syndrome: Although it’s rare, Cushing’s syndrome can develop from an inherited tendency to have tumors on one or more of your endocrine glands. Some inherited conditions, such as multiple endocrine neoplasia (MEN 1), can involve tumors that over-produce cortisol or ACTH, leading to Cushing’s syndrome.

If you think you could have Cushing’s syndrome or you have questions about the causes of Cushing’s syndrome, talk to your doctor immediately.

Written by | Reviewed by Daniel J. Toft MD, PhD, adapted from  http://www.endocrineweb.com/conditions/cushings-syndrome/cushings-syndrome-causes

Cushing’s Syndrome

The Seven Dwarves of Cushing's

 

Posted Oct. 1st, 2015 by

Q: Would you please explain Cushing’s disease. How is it diagnosed? What are the symptoms?

A: Cushing syndrome results from excess levels of the hormone cortisol. It is produced in various glands, usually the adrenal that is situated above the kidneys on both sides, and the pituitary gland, which is in the centre of the brain.

Cortisol also regulates the way fats, carbohydrates and proteins are turned into usable forms of energy. These glands produce other hormones that affect things such as blood pressure and the body’s response to stress.

Cortisol may be added from outside the body by taking medications such as prednisone, often used for the control of chronic inflammatory or autoimmune diseases like lupus or rheumatoid arthritis.

Prednisone is also used for the treatment of acute illnesses such as severe allergies. Poison ivy is often treated this way.

Women in the last three months of pregnancy also have increased blood levels of cortisol and may temporarily display some of symptoms of Cushing’s syndrome.

Any problem with the pituitary gland, the nearby hypothalamus in the brain or adrenals can lead to Cushing’s syndrome. The most common is a benign tumour of the pituitary gland known as a pituitary adenoma.

This type of tumour may produce an excessive amount of a stimulating hormone known as ACTH, which in turn activates the hormones in the adrenal glands. On rare occasions, some types of lung or thyroid cancer can also behave in a similar way.

The most obvious sign of Cushing’s disease is marked weight gain, mostly in the abdomen, face and neck, while the arms and legs remain relatively thin.

As the skin in these areas becomes thinner, there may be purple coloured stripes or stretch marks. Women may also lose their periods and grow facial or body hair.

Blood pressure is usually high and sufferers feel weak and tired.

Cushing’s disease is diagnosed by measuring the amount of cortisol in a person’s urine during a 24 hour period.

If there is a tumour it will require surgical removal. If Cushing’s syndrome is a result of prescribed medication, the dosage can be reduced gradually or another type of medication can be tried. Prednisone must never be suddenly discontinued or the person’s blood pressure could drop dramatically, which could be serious and potentially fatal.

Clare Rowson is a retired medical doctor in Belleville, Ont. Contact: health@producer.com

From http://www.producer.com/2015/10/cushings-syndrome/

Experts recommend tumor removal as first-line treatment for Cushing’s syndrome

The Endocrine Society today issued a Clinical Practice Guideline (CPG) on strategies for treating Cushing’s syndrome, a condition caused by overexposure to the hormone cortisol.

The CPG, entitled “Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline,” was published online and will appear in the August 2015 print issue of the Journal of Clinical Endocrinology and Metabolism (JCEM), a publication of the Endocrine Society.

Cushing’s syndrome occurs when a person has excess cortisol in the blood for an extended period, according to the Hormone Health Network. When it is present in normal amounts, cortisol is involved in the body’s response to stress, maintains blood pressure and cardiovascular function, keeps the immune system in check, and converts fat, carbohydrates and proteins into energy. Chronic overexposure to the hormone can contribute to the development of cardiovascular disease, infections and blood clots in veins.

People who take cortisol-like medications such as prednisone to treat inflammatory conditions, including asthma and rheumatoid arthritis, can develop Cushing’s syndrome. The high cortisol levels return to normal when they stop taking the medication. This is called exogenous Cushing’s syndrome.

In other cases, tumors found on the adrenal or pituitary glands or elsewhere in the body cause the overproduction of cortisol and lead to the development of Cushing’s syndrome. The Clinical Practice Guidelines focus on this form of the condition, known as endogenous Cushing’s syndrome.

“People who have active Cushing’s syndrome face a greater risk of death – anywhere from nearly twice as high to nearly five times higher – than the general population,” said Lynnette K. Nieman, MD, of the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, MD, and chair of the task force that authored the guideline. “To reduce the risk of fatal cardiovascular disease, infections or blood clots, it is critical to identify the cause of the Cushing’s syndrome and restore cortisol levels to the normal range.”

In the CPG, the Endocrine Society recommends that the first-line treatment for endogenous Cushing’s syndrome be the removal of the tumor unless surgery is not possible or unlikely to address the excess cortisol. Surgical removal of the tumor is optimal because it leaves intact the hypothalamic-pituitary-adrenal axis, which is integral to the body’s central stress response.

Other recommendations from the CPG include:

  • Tumors should be removed by experienced surgeons in the following situations:— A tumor has formed on one or both of the two adrenal glands.— A tumor that secretes adrenocorticotropic hormone (ACTH) – the hormone that signals the adrenal glands to produce cortisol – has formed somewhere in the body other than the adrenal or pituitary gland.

    — A tumor has formed on the pituitary gland itself.

  • Patients who continue to have high levels of cortisol in the blood after surgery should undergo additional treatment.
  • People who had an ACTH-producing tumor should be screened regularly for the rest of their lives for high cortisol levels to spot recurrences.
  • If patients’ cortisol levels are too low following surgery, they should receive glucocorticoid replacement medications and be educated about adrenal insufficiency, a condition where the adrenal glands produce too little cortisol. This condition often resolves in 1-2 years.
  • Morning cortisol and/or ACTH stimulation tests, or insulin-induced hypoglycemia, can be used to test for the recovery of the hypothalamic-pituitary-adrenal axis in people who have low cortisol levels after surgery. Once the tests results return to normal, glucocorticoid replacement can be stopped.
  • People who have undergone pituitary surgery should be re-evaluated for other pituitary hormone deficiencies during the post-operative period.
  • Patients who have a pituitary tumor and have undergone surgery to remove both adrenal glands should be regularly evaluated for tumor progression using pituitary MRIs and tests for ACTH levels.
  • Radiation therapy may be used to treat a pituitary tumor, especially if it is growing. While awaiting the effect of radiation, which may take months to years, treatment with medication is advised.
  • To assess the effect of radiation therapy, the patient’s cortisol levels should be measured at 6- to 12-month intervals.
  • Medications may be used to control cortisol levels as a second-line treatment after surgery for a pituitary gland tumor, as a primary treatment for ACTH-secreting tumors that have spread to other parts of the body or suspected ACTH-secreting tumors that cannot be detected on scans. Medications also can be used as adjunctive treatment to reduce cortisol levels in people with adrenal cortical carcinoma, a rare condition where a cancerous growth develops in the adrenal gland.
  • People with Cushing’s syndrome should be treated for conditions associated with the disease, such as cardiovascular disease risk factors, osteoporosis and psychiatric symptoms.
  • Patients should be tested for recurrence throughout their lives except in cases where the person had a benign adrenal tumor removed.
  • Patients should undergo urgent treatment within 24 to 72 hours of detecting excess cortisol if life-threatening complications such as serious infection, pulmonary thromboembolism, cardiovascular complications and acute psychosis are present.

More information: The Hormone Health Network offers resources on Cushing’s syndrome at www.hormone.org/questions-and-answers/2012/cushing-syndrome

%d bloggers like this: