Recruitment for Cushing’s Syndrome Clinical Study

Posted on May 2, 2016 by MaryO
DESCRIPTION

This trial is testing the safety and effectiveness of a new investigational drug for the treatment of Cushing’s Syndrome. Under the supervision of qualified physicians, cortisol levels and symptoms of Cushing’s Syndrome will be closely followed along with any signs of side effects.

The link below will take you to the trial website where you can review additional information and the patient screener.

http://curec.lk/1X0J6kT

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Why Was This Woman Gaining Weight Despite Her Diet?

Posted on May 2, 2016 by MaryO

“I just can’t seem to lose weight,” the 59-year-old woman said quietly. She had tried everything, she told the young doctor, who was training to be an endocrinologist at Mount Sinai Hospital in New York City. Weight Watchers. Exercise. She ate more vegetables, less fat, then fewer carbs. But still she was gaining weight, 30 pounds during the past seven months, including 12 in the past two weeks. She had never been skinny, she continued, but shapely. In her mid-40s, she started gaining weight, slowly at first, then rapidly. She was considering bariatric surgery, but she wanted to make sure she wasn’t missing something obvious. She had low thyroid hormones and had to take medication. Could her thyroid be off again?

The doctor asked her about symptoms associated with a low thyroid-hormone level. Fatigue? Yes, she was always tired. Changes in her hair or skin? No. Constipation? No. Do you get cold easier? Never. Indeed, these days she usually felt hot and sweaty.

It was probably not the thyroid, the doctor said. She asked if the woman had any other medical problems. She had high blood pressure and high cholesterol — both well controlled with medications. She also had obstructive sleep apnea, a disorder in which the soft tissue at the back of the throat collapse during sleep, cutting off air flow and waking the person many times throughout the night. She had a machine that helped keep her airway open, and she used it every night. She also had back pain, knee pain and carpal-tunnel syndrome. The pain was so bad that she had to retire from her job years before she was ready.

Big, Bigger, Biggest

The doctor examined her, then went to get Dr. Donald Smith, an endocrinologist and director of lipids and metabolism at Mount Sinai’s cardiovascular institute. After hearing a summary of the case, Smith asked the patient if she had anything to add. She did: She didn’t understand why she was getting so much bigger. Her legs were huge. She used to have nice ankles, but now you could hardly see them. Her doctor had given her a diuretic, but it hadn’t done a thing. Everything was large — her feet, her hands, even her face seemed somehow bigger. She hardly recognized the woman in the mirror. Her doctors just encouraged her to keep trying to lose weight.

Worth a Thousand Words

“Let me show you a picture,” she said suddenly and reached over to her purse. The patient’s sister had made a comment recently that led the patient to wonder whether the changes she saw in the mirror were more than simple aging. The patient pulled out a photograph of an attractive middle-aged woman and handed it to Smith. That was me eight years ago, she told him. Looking at the two faces, it was hard to believe they belonged to the same woman. Smith suspected this was something more than the extra pounds.

Two possibilities came to mind. Each was a disease of hormonal excess; each caused rapid weight gain. The first was Cushing’s disease, caused by overproduction of one of the fight-or-flight hormones, cortisol. The doctor looked at the patient, seeking clues. On her upper back, just below her neck, the woman had a subtle area of enlargement. This discrete accumulation of fat, called a buffalo hump, can occur with normal weight gain but is frequently seen in patients with Cushing’s. Do you bruise more easily these days? he asked. Cushing’s makes the skin fragile. No, she said. Did she have stretch marks on her stomach from the weight gain? The rapid expansion of the abdomen can cause the fragile skin to develop dark purple stretch lines. No. So maybe it wasn’t Cushing’s.

Find out the answer at http://www.nytimes.com/interactive/2016/04/17/magazine/17mag-diagnosis.html#/#7

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‘Adrenal Fatigue’ Not Always Used Accurately

Posted on May 1, 2016 by MaryO

Dear Dr. Roach: I had apoplexy, a ruptured pituitary tumor, developed panhypopituitarism, then adrenal insufficiency. I am doing fairly well with cortisol replacement, thyroid supplement and oral diabetic medicine.

My problem is exhaustion that comes on very easily. I have other ailments to blame, too — chronic pain from fibromyalgia and tendinitis. I am 67. I am still able to work. Is adrenal fatigue a real issue, and if so, what can be done about it? — S.M.

Answer: The term “adrenal fatigue” is increasingly used, and not always correctly — or, at least, it is used in cases where it’s not clear if that is actually the case. But let me start by discussing what has happened to you. Pituitary apoplexy is bleeding into the pituitary gland, usually into a pituitary tumor, as in your case. This may cause severe headaches and vision changes, and often it prevents the pituitary from making the many important hormones that control the endocrine glands and regulate the body.

For example, without TSH from the pituitary gland, the thyroid won’t release thyroid hormone, and importantly, the adrenal gland can’t make cortisol without the influence of ACTH from the pituitary.

Rather than trying to replace TSH, ACTH and the other pituitary hormones, it is easier to directly replace the hormones made by the adrenal, thyroid and gonads. That’s why you are taking cortisol and thyroid hormone, and why younger women take estrogen and men testosterone. Although there is nothing wrong with your thyroid and adrenal glands, they simply won’t work unless stimulated.

Inadequate adrenal function from any cause leads to profound fatigue, and in the presence of severe stress, such as surgery or major infection, the body’s need for cortisol increases dramatically. Unless enough adrenal hormone is given in response, the result can be an immediate life-threatening condition called an Addisonian crisis.

Readers may email questions to ToYourGoodHealth@med.cornell.edu.

From http://www.vnews.com/To-Your-Good-Health–Adrenal-Fatigue–not-Always-Used-Accurately-1802516

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Promising Pre-Clinical and Phase 1 Data Support Advance of Selective Cortisol Modulator CORT125134 as Potential Treatment for Cushing’s Syndrome and Solid-Tumor Cancers

Posted on April 30, 2016 by MaryO

MENLO PARK, CA–(Marketwired – Apr 28, 2016) –  Corcept Therapeutics Incorporated (NASDAQ: CORT), a pharmaceutical company engaged in the discovery, development and commercialization of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of cortisol, today released data supporting the clinical advancement of its proprietary, selective cortisol modulator, CORT125134. The company has begun recruiting patients for a Phase 1/2 trial of the compound to treat patients with solid-tumor cancers. It also expects to begin recruiting patients for a Phase 2 study of CORT125134 to treat patients with Cushing’s syndrome this quarter.

“Advancing CORT125134 is an important step in protecting and extending our growing Cushing’s syndrome franchise and in developing cortisol modulation for a wide range of other serious diseases,” said Joseph K. Belanoff, MD, Corcept’s Chief Executive Officer. “This selective cortisol modulator has shown great promise. We are optimistic that, for some patients with Cushing’s syndrome, CORT125134 may be even better than our approved product, Korlym® — just as effective, but without the side effects associated with Korlym’s affinity for the progesterone receptor. Equally important, we look forward to investigating its potential as a treatment for solid-tumor cancers.”

CORT125134 is the lead compound in Corcept’s proprietary portfolio of selective cortisol modulators. It is a non-steroidal competitive antagonist of the glucocorticoid receptor (GR) that does not bind to the body’s other hormone receptors, including the progesterone receptor (PR). Korlym’s interaction with PR results in termination of pregnancy and can cause endometrial thickening and irregular vaginal bleeding in some women. CORT125134 is proprietary to Corcept and is protected by composition of matter and method of use patents extending to 2033.

Advancement to Phase 2 Trials Supported by Positive Pre-Clinical and Phase 1 Data
“The data generated so far make this compound a promising candidate to treat both Cushing’s syndrome and, potentially, a number of solid-tumor cancers,” said Hazel Hunt, Ph.D., Corcept’s Vice President of Research. “Its Phase 1 data showed that it shares Korlym’s potent affinity for GR, one of the receptors to which cortisol binds. Our clinical testing showed that it can prevent the effects of the steroid prednisone, a commonly-used synthetic GR agonist. Preventing the effects of prednisone is a very important finding, as it mirrors the essential quality of an effective medical treatment for patients with Cushing’s syndrome.”

Corcept’s Phase 1 trial of CORT125134 enrolled 124 healthy volunteers. GR antagonism was tested by measuring CORT125134’s ability to modulate prednisone’s effects on serum osteocalcin, white blood cell counts, glucose metabolism and expression of the FKBP5 gene — a marker of GR activation. With respect to all parameters, CORT125134 was as potent a modulator of prednisone’s activity as Korlym (see Figure 1; p value < 0.0003).

Pharmacokinetic data indicate that CORT125134 is suitable for once-daily dosing.

“Positive Phase 1 data, together with encouraging pre-clinical results, prompted us to advance CORT125134 as a treatment for Cushing’s syndrome as well as a treatment for cancer,” continued Dr. Hunt. “Substantial pre-clinical and clinical research suggests that cortisol modulation increases the effectiveness of chemotherapy in some solid-tumor cancers. Pre-clinical data suggest that CORT125134 may be even more potent than Korlym in treating some tumor types.”

Corcept and investigators at the University of Chicago have studied the effectiveness of CORT125134 in transgenic mouse models of triple-negative breast cancer (TNBC) and castration-resistant prostate cancer. Mice implanted with TNBC tumor cells were treated with a combination of paclitaxel and CORT125134. Mifepristone (the active ingredient in Korlym) in combination with paclitaxel served as a positive control. As expected, the combination of mifepristone and paclitaxel significantly slowed tumor progression. However, the combination of CORT125134 and paclitaxel slowed it even more (see Figure 2; p value = 0.0004). In a similar experiment, castrated mice seeded with prostate cancer tumor cells were treated with either mifepristone or CORT125134. The outcome was comparable to the TNBC study: When combined with castration (which in humans would be achieved pharmacologically by the administration of an androgen receptor antagonist such as enzalutamide), mifepristone retarded tumor progression, but CORT125134 had an even more pronounced effect (see Figure 3; p value = 0.037).

CORT125134 may also enhance the efficacy of immune-modulation therapy. In an animal model of colon cancer, the addition of CORT125134 to PD-1 monotherapy significantly slowed tumor progression (see Figure 4; p value = 0.013):

Oncology Trial Design
This trial’s initial phase will investigate nab-paclitaxel in combination with CORT125134 to treat any solid-tumor cancer susceptible to treatment with nab-paclitaxel. (“Nab-paclitaxel” is the generic name for Celgene’s drug, Abraxane®.) Once a maximum tolerated dose is identified, Corcept plans to open one or more expansion cohorts, each containing 20 patients, to test the combination’s efficacy in one or more of the solid-tumor cancers studied in the dose-finding phase. Possible target indications include TNBC, castration-resistant prostate cancer, ovarian cancer, pancreatic cancer and sarcoma. Other dose-finding cohorts may be enrolled to study CORT125134 in combination with different companion therapeutic agents, including PD-1 inhibitors.

The trial is open-label and will be conducted at sites in the United States, the first of which is open and has begun screening patients.

“That we are advancing the same selective cortisol modulator as a treatment for both a metabolic disease and one or more oncologic indications is a testament to the broad therapeutic potential of cortisol modulation,” said Robert S. Fishman, MD, Corcept’s Chief Medical Officer. “We are excited to start these trials.”

Cushing’s Syndrome Trial Design
This Phase 2 trial of CORT125134 will enroll 30 patients with endogenous Cushing’s syndrome. Patients will be assigned to a low- or high-dose group and will receive CORT125134 for 12 weeks, with up-titration possible in each group at weeks four and eight. The trial will be open label. Study centers will be located in both the European Union and the United States.

About Korlym®
Korlym modulates the effect of cortisol at GR, one of the two receptors to which cortisol binds, thereby inhibiting the effects of excess cortisol in patients with Cushing’s syndrome. Since 2012, Corcept has made Korlym available as a once-daily oral treatment of hyperglycemia secondary to endogenous Cushing’s syndrome in adult patients with glucose intolerance or diabetes mellitus type 2 who have failed surgery or are not candidates for surgery. Korlym was the first FDA-approved treatment for that illness and the FDA has designated it as an Orphan Drug for that indication.

About Cushing’s Syndrome
Endogenous Cushing’s syndrome is caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol and is generated by tumors that produce cortisol or ACTH. Cushing’s syndrome is an orphan indication that most commonly affects adults aged 20-50. An estimated 10-15 of every one million people are newly diagnosed with this syndrome each year, resulting in over 3,000 new patients annually in the United States. An estimated 20,000 patients in the United States have Cushing’s syndrome. Symptoms vary, but most people have one or more of the following manifestations: high blood sugar, diabetes, high blood pressure, upper body obesity, rounded face, increased fat around the neck, thinning arms and legs, severe fatigue and weak muscles. Irritability, anxiety, cognitive disturbances and depression are also common. Cushing’s syndrome can affect every organ system in the body and can be lethal if not treated effectively.

About Triple-Negative Breast Cancer
Triple-negative breast cancer is a form of the disease in which the three receptors that fuel most breast cancer growth — estrogen, progesterone and the HER-2/neu gene — are not present. Because the tumor cells lack the necessary receptors, treatments that target estrogen, progesterone and HER-2 receptors are ineffective. In 2013, approximately 40,000 women were diagnosed with TNBC. It is estimated that more than 75 percent of these women’s tumor cells expressed the GR receptor to which cortisol binds. There is no FDA-approved treatment and neither a targeted treatment nor an approved standard chemotherapy regimen for relapsed TNBC patients exists.

About Corcept Therapeutics Incorporated
Corcept is a pharmaceutical company engaged in the discovery, development and commercialization of drugs that treat severe metabolic, oncologic and psychiatric disorders by modulating the effects of cortisol. Korlym, a first-generation cortisol modulator, is the company’s first FDA-approved medication. The company is conducting a Phase 1/2 trial of mifepristone for the treatment of TNBC, a Phase 1/2 trial of CORT125134 to treat a variety of solid-tumor cancers and has a proprietary portfolio of other selective GR antagonists that modulate the effects of cortisol but not progesterone. Corcept owns extensive intellectual property covering the use of cortisol modulators, including mifepristone and CORT125134, in the treatment of a wide variety of metabolic, oncologic and psychiatric disorders. It also holds composition of matter patents for CORT125134 and its other selective cortisol modulators.

Forward-Looking Statements
Statements made in this news release, other than statements of historical fact, are forward-looking statements. These forward-looking statements, including statements regarding the initiation and advancement of clinical trials and the development of Corcept’s pre-clinical and clinical pipeline, are subject to known and unknown risks and uncertainties that might cause actual results to differ materially from those expressed or implied by such statements, including the pace of enrollment in or the outcome of the company’s Phase 1/2 study of CORT125134 to treat solid-tumor cancers and planned Phase 2 trial of CORT125134 to treat patients with Cushing’s syndrome, the effects of rapid technological change and competition, the protections afforded by Corcept’s intellectual property rights, or the cost, pace and success of Corcept’s other product development efforts. These and other risks are set forth in the company’s SEC filings, all of which are available from the company’s website (www.corcept.com) or from the SEC’s website (www.sec.gov). Corcept disclaims any intention or duty to update any forward-looking statement made in this news release.

Abraxane® is a registered trademark of Celgene Corporation.

From http://www.marketwired.com/press-release/promising-pre-clinical-phase-1-data-support-advance-selective-cortisol-modulator-cort125134-nasdaq-cort-2119635.htm

 

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Morning Cortisol Rules Out Adrenal Insufficiency

Posted on April 7, 2016 by MaryO

endo2016

 

Key clinical point: Skip ACTH stimulation if morning serum cortisol is above 11.1 mcg/dL.

Major finding: A morning serum cortisol above 11.1 mcg/dL is a test of adrenal function with 99% sensitivity.

Data source: Review of 3,300 adrenal insufficiency work-ups.

Disclosures: There was no outside funding for the work, and the investigators had no disclosures.

BOSTON – A random morning serum cortisol above 11.1 mcg/dL safely rules out adrenal insufficiency in both inpatients and outpatients, according to a review of 3,300 adrenal insufficiency work-ups at the Edinburgh Centre for Endocrinology and Diabetes.

The finding could help eliminate the cost and hassle of unnecessary adrenocorticotropic hormone (ACTH) stimulation tests; the investigators estimated that the cut point would eliminate almost half of them without any ill effects. “You can be very confident that patients aren’t insufficient if they are above that line,” with more than 99% sensitivity. If they are below it, “they may be normal, and they may be abnormal.” Below 1.8 mcg/dL, adrenal insufficiency is almost certain, but between the cutoffs, ACTH stimulation is necessary, said lead investigator Dr. Scott Mackenzie, a trainee at the center.

In short, “basal serum cortisol as a screening test … offers a convenient and accessible means of identifying patients who require further assessment,” he said at the annual meeting of the Endocrine Society.

Similar cut points have been suggested by previous studies, but the Scottish investigation is the first to validate its findings both inside and outside of the hospital.

The team arrived at the 11.1 mcg/dL morning cortisol cut point by comparing basal cortisol levels and synacthen results in 1,628 outpatients. They predefined a sensitivity of more than 99% for adrenal sufficiency to avoid missing anyone with true disease. The cut point’s predictive power was then validated in 875 outpatients and 797 inpatients. Morning basal cortisol levels proved superior to afternoon levels.

The investigators were thinking about cost-effectiveness, but they also wanted to increase screening. “We may be able to reduce the number of adrenal insufficiency cases we are missing because [primary care is] reluctant to send people to the clinic for synacthen tests” due to the cost and inconvenience. As with many locations in the United States, “our practice is to do [ACTH on] everyone.” If there was “a quick and easy 9 a.m. blood test” instead, it would help, Dr. Mackenzie said.

Adrenal insufficiency was on the differential for a wide variety of reasons, including hypogonadism, pituitary issues, prolactinemia, fatigue, hypoglycemia, postural hypotension, and hyponatremia. Most of the patients were middle aged, and they were about evenly split between men and women.

There was no outside funding for the work, and the investigators had no disclosures.

aotto@frontlinemedcom.com

From http://www.clinicalendocrinologynews.com/specialty-focus/pituitary-thyroid-adrenal-disorders/single-article-page/morning-cortisol-rules-out-adrenal-insufficiency/af59bab2bb014ca9d352c792f9d41653.html

Filed under: adrenal, adrenal crisis, Cushing's, Meetings and Conferences | Tagged: , , , , , , , , , , , , , | Leave a comment »

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