Fluorescent Metabolite Might Help Surgeons Remove Pituitary Tumors

The resection of microadenomas — small, benign tumors in the pituitary gland underlying Cushing’s disease — could be aided by a fluorescent marker that is naturally produced by the tumor, a new study shows.

The findings were presented recently at the 2018 George Washington Research Days in a poster titled, “Enhanced 5-ALA Induced Fluorescence in Hormone Secreting Pituitary Adenomas.

Cushing’s disease is characterized by high cortisol levels that cause debilitating physical, mental, and hormonal symptoms. The excess cortisol is caused by tiny benign tumors in the pituitary gland, called microadenomas, with a size of less than 10 millimeters.

On account of their small size, these microadenomas pose imaging challenges to physicians. Up to 40 percent of microadenomas remain undetected in the gold-standard magnetic resonance imaging (MRI).

Pituitary adenomas, however, have a characteristic that distinguishes them from the surrounding healthy tissue. They process (metabolize) a natural haemoglobin metabolite, called 5-aminolevulinic acid (5-ALA), into protoporphyrin IX (PpIX) at much higher rates — up to 20 to 50 times higher — than normal tissues.

Importantly, PpIX emits red fluorescence when excited with blue light.

This means that exogenous 5-ALA is taken up by the adenoma cells and rapidly metabolized into the fluorescent metabolite, PpIX, which may establish its use for fluorescence-guided resection of pituitary adenomas.

To test this, researchers incubated human-derived corticotropinoma, as well as the adjacent normal gland cells with 5-ALA. They did the same with mouse model normal pituitary cells and a mouse model pituitary tumor cell line, called AtT20.

They then analyzed the cells’ fluorescence profile by microscopy and with a technique called flow cytometry.

The analysis showed that compared to normal pituitary tissue, human-derived adenomatous cells had a significant increase of tenfold in 5-ALA-induced PpIX fluorescence intensity.

Similarly, mouse pituitary tumor cells (AtT20 cell line) fluoresced seven times more intensely than normal murine pituitary tissue.

The microscopy analysis revealed that the 5-ALA localized in subcellular organelles called mitochondria.

On June 6, 2017, the U.S. Food and Drug Administration approved the use of 5-ALA (under the brand name Gleolan) as an optical imaging agent for patients with gliomas (brain tumors), as an add-on compound to assist surgeons in identifying the malignant tissue during surgery.

Now, these findings suggest that 5-ALA also may be used for fluorescence-guided surgery of microadenomas in Cushing’s disease.

“The supraphysiological levels of glucocorticoids, as seen in CD [Cushing’s disease], may enhance the 5-ALA fluorescence in corticotropinomas,” researchers wrote.

From https://cushingsdiseasenews.com/2018/04/13/fluorescent-metabolite-might-help-surgeons-removepituitary-tumors/

Gene test for growth hormone deficiency developed

A new test developed by University of Manchester and NHS scientists could revolutionise the way children with growth hormone deficiency are diagnosed.

Children suspected of having GHD – which cause growth to slow down or stop and other serious physical problems—currently require a test involving fasting for up to 12 hours.

The fasting is followed by an intravenous infusion in hospital and up to 10 blood tests over half a day to measure growth hormone production.

Because the current test is unreliable, it often has to be done twice before growth hormone injections can be prescribed.

Now the discovery—which the team think could be available within 2 to 5 years -could reduce the process to a single blood test, freeing up valuable time and space for the NHS.

Dr. Adam Stevens from The University of Manchester and Dr. Philip Murray from Manchester University NHS Foundation Trust, were part of the team whose results are published in JCI Insight today.

Dr. Stevens said: “We think this is an important development in the way doctors will be able to diagnose growth hormone deficiency – a condition which causes distress to many thousands of children in the UK

“This sort of diagnostic would not be available even a few years ago but thanks to the enormous computing power we have, and advances in genetics, it is now possible for this aspect of care to be made so much easier for patients – and the NHS.

“These volume of data involved is so huge and complicated that traditional data-processing application software is inadequate to deal with it.”

Comparing data from 72 patients with GHD and 26 healthy children, they used high powered computers to examine 30,000 genes—the full gene expression- of each child.

A sophisticated mathematical technique called Random Forest Analysis analysed around three million separate data points to compare different gene patterns between the children with and without GHD.

The research identified 347 genes which when analysed with the computer algorithm can determine whether a child has GHD or not and thus whether they will benefit from treatment.

Growth hormone deficiency (GHD) occurs when the pituitary gland—which is size of a pea- fails to produce enough growth hormone. It more commonly affects children than adults.

Many teenagers with GHD have poor bone strength, fatigue and lack stamina as well as depression, lack of concentration, poor memory and anxiety problems.

GHD occurs in roughly 1 in 5,000 people. Since the mid-1980s, synthetic growth hormones have been successfully used to treat children—and adults—with the deficiency.

Dr. Murray added: “This study provides strong proof of concept, but before it is in a position to be adopted by the NHS, we must carry out a further validation exercise which will involve comparing our new diagnostic with the existing test.

“Once we have crossed that hurdle, we hope to be in a position for this to be adopted within 2 to 5 years – and that can’t come soon enough for these children.”

Child Growth Foundation manager Jenny Child’s daughter has Growth Hormone Deficiency.

She said: Growth Hormone Deficiency isn’t just about growth, as lack of growth hormone impacts the child in many ways, such as lack of strength and they can find it difficult to keep up physically with their peers. It impacts the child’s self-esteem as they are often treated as being much younger, because of their size. Growth hormone treatment allows the child to grow to their genetic potential.

“A growth hormone stimulation test can be very daunting for both child and parents. The test can make the child feel quite unwell and they can experience headaches, nausea and unconsciousness through hypoglycaemia.”

 Explore further: Northern climes make a difference with growth hormone treatment

More information: Philip G. Murray et al. Transcriptomics and machine learning predict diagnosis and severity of growth hormone deficiency, JCI Insight (2018). DOI: 10.1172/jci.insight.93247

Korlym: How an abortion pill turned out to be a treatment for a rare disease

Even though the $550 yellow pills sold as Korlym have a controversial origin as the abortion pill, Leslie Edwin said they “gave me life.”

The 40-year-old Georgia resident lives with Cushing’s syndrome, a potentially deadly condition that causes high levels of the hormone cortisol to wreak havoc on a body. When first diagnosed, she said, she gained about 100 pounds, her blood sugars were “out of control,” and she suffered acne, the inability to sleep and constant anxiety.

“I wouldn’t leave the house,” Edwin said of her first bout with the condition. “I quit my job after a certain point. I just couldn’t keep being in front of people.”

That’s when Edwin endured surgeries, including one to remove her pituitary gland. She went into remission, but then, in 2016, her weight shot up 30 pounds and the anxious feelings returned. Her doctors prescribed Korlym.

The drug’s active ingredient is mifepristone, once called RU-486 and better known as the abortion pill because it causes a miscarriage when taken early in a pregnancy. Nearly two decades ago, Danco Laboratories won approval to market Mifeprex in the United States as the abortion drug, with tight restrictions on use. Corcept Therapeutics, a Silicon Valley-based drug company, began marketing Korlym six years ago as a specialty drug for about 10,000 rare-disease patients such as Edwin.

The difference in price between Korlym and Mifeprex is striking, even though the ingredients are the same: One 200-milligram pill to prompt an abortion costs about $80. In contrast, a 300-milligram pill prescribed for Cushing’s runs about $550 before discounts. (Patients wanting an abortion take only one pill. People with Cushing’s often take up to three pills a day for months or years.)

Joseph Belanoff, chief executive of the drug’s maker, Corcept, said Korlym’s average cost per patient is $180,000 annually and concedes that “we have an expensive drug. There’s no getting around that.” But, he said, he believes Corcept has a “social contract” to take care of patients and pledged that any patient who is prescribed Korlym will get it regardless of insurance coverage or costs.

The story of Korlym highlights how America’s drug development system can turn an old drug into a new one that treats relatively few — but often very desperate — patients.

When the Food and Drug Administration approved Korlym in 2012, it was designated as an orphan drug, giving Corcept seven years of market exclusivity as well as other economic incentives. Congress approved orphan drug incentives to encourage the development of medicines for rare diseases that affect fewer than 200,000 patients. Since the drug’s approval, Korlym’s price has risen about 150 percent, and last year the company’s revenue nearly doubled to $159.2 million and it reported a net income of $129.1 million. (Korlym is the company’s only product, and it treats about 1,000 patients in the United States.)

Belanoff said the profits from Korlym pay for the company’s past spending on the drug’s research and development as well as its effort to create new drugs. The company recently reported an encouraging Phase 2 trial update on Korlym’s successor, relacorilant, a drug that could treat Cushing’s without the side effects for some women of endometrial thickening and vaginal bleeding that can occur with Korlym.

The company’s pipeline is also full of potential oncology drugs that hold the promise of using molecules to influence the cortisol receptors, with wide-ranging effects in the body. Korlym in combination with another drug is being tested for the treatment of metastatic triple-negative breast cancer, which tends to be more aggressive than other types of breast cancer. And relacorilant is in the very early stages of testing to treat castration-resistant prostate cancer.

While many of the second-generation drugs are not related to Korlym structurally, Korlym did “provide the funding. . . . If there had not been orphan-drug pricing and the [Orphan Drug] Act, you would have to look for a different way to develop those drugs,” Belanoff said.

Korlym came to market in 2012 with an average wholesale price of $223.20 per pill before discounts, according to the health-care technology firm Connecture. By December 2017, each pill had an average wholesale price of $549.60 before any discounts or rebates were negotiated for patients.

Teva Pharmaceutical Industries recently announced it had filed an application to produce a generic version of the drug. Teva declined to comment for this report.

A ‘pioneering substance’

Cushing’s syndrome happens when the body produces too much cortisol, which normally helps keep the cardiovascular system functioning well and allows the body to turn proteins, carbohydrates and fats into energy. But too much cortisol can be destructive. It can cause cognitive difficulties, depression, fatigue, high blood pressure, bone loss and, in some cases, Type 2 diabetes. Those affected by the syndrome can develop a fatty hump between their shoulders and a rounded face. Without treatment, patients can die of a variety of complications, including sepsis after the hormone compromises the immune system.

Mifepristone, the active ingredient in Korlym, helps Cushing’s patients by blocking the body’s ability to process cortisol. It induces an abortion by blocking another of the body’s receptors, for progesterone, which causes the uterine wall to break down and the pregnancy to end.

When the FDA approved Korlym for a specific set of Cushing’s patients, the agency required a “TERMINATION OF PREGNANCY” warning box at the top of the label.

Endocrinologist Constantine Stratakis, scientific director at the National Institute of Child Health and Human Development, who specializes in treating people with Cushing’s syndrome, calls mifepristone a “pioneering substance” because it “has a lot of crossover” to other receptors in the body.

That means the drug has a lot of potential uses. Belanoff and Alan Schatzberg, a Stanford University psychiatrist and scientist, co-founded Corcept in 1998 to explore whether mifepristone could help treat major depression. In 2002, Schatzberg said the drug “may be the equivalent of shock treatments in a pill.” But clinical trials were not successful.

Social contract

By 2007, Corcept had found another possibility and filed an application to see whether mifepristone might work for Cushing’s patients.

Developing the drug cost about $300 million, according to Belanoff, and involved long-term toxicology tests to ensure that patients could safely take high doses for months or years. Korlym is approved to treat Cushing’s patients who have failed to relieve their symptoms through surgery or do not qualify for surgery, so some patients expect to take it for the rest of their lives while others just a few months.

Most patients are covered by private insurance, Belanoff said, but Medicare and Medicaid pay for the drug as well. According to Medicare Part D data, 52 Korlym patients cost Medicare $2.6 million in 2013. Two years later, 115 beneficiaries filed claims of $11.4 million.

Edwin is on private insurance and describes herself as being in “a really high tax bracket,” yet she never paid more than $25 a month through Corcept’s patient assistance program . She stopped taking the drug last year after her Cushing’s symptoms retreated.

“Across the board, it would be very difficult to find any patient that pays the full price,” said Edwin, who volunteers as president of the nonprofit patient advocacy group Cushing’s Support and Research Foundation.

The small organization, which reported $50,000 in contributions and grants in 2015, notes on its website that Corcept as well as Novartis Oncology provide financial support to the organization. The group’s federal tax filing details that the majority of its expenses go to distributing a quarterly newsletter, contacting members and patients “to promote mission,” and referring patients to doctors.

Specialty drugs such as Korlym often have sky-high price tags and are often distributed through special pharmacy programs. Drug companies commonly work with insurers and patient assistance programs to lower the patient’s out-of-pocket costs.

But for Corcept, the effort to brand the drug as a Cushing’s medication was also important, Belanoff said: “We were starting with a notorious drug.”

“There is a real infrastructure in caring for these patients,” he said. “It is not just like getting your medicine at [a drug store] and figuring out what to do with it.”

Sherwin D’Souza, an internal medicine doctor at St. Luke’s Boise Medical Center in Idaho, prescribed Korlym for the first time last year to Vonda Huddleston, who was uninsured. D’Souza said he knew Corcept would provide financial assistance until Huddleston could get insurance to help pay for surgery to remove a tumor in her adrenal gland that is suspected of causing her high cortisol levels.

Huddleston, though, did not feel well on the drug and gained weight. D’Souza took her off Korlym and scheduled surgery. “I was sort of trying to buy time and treat her conditions,” D’Souza said. “It’s very expensive . . . but they do have a very good program for patients in need of the drug.”

Kaiser Health News

Kaiser Health News is a nonprofit news service covering health issues. It is an editorially independent program of the Kaiser Family Foundation that is not affiliated with Kaiser Permanente.

SteroTherapeutics Receives FDA Orphan-Drug Designation

PHILADELPHIA, April 04, 2018 — SteroTherapeutics, a privately held biopharmaceutical company developing therapies focused on metabolic diseases including non-alcoholic steatohepatitis (NASH), announced today that the U.S. Food and Drug Administration has granted orphan drug designation for ST-002 in the treatment of nonalcoholic fatty liver disease, nonalcoholic steatosis and hyperglycemia in patients with Cushing’s syndrome.

“We are pursuing a drug that has a very real potential to become the optimal agent of choice and a standard of care for these Cushing’s patients,” said Manohar Katakam Ph. D., CEO of SteroTherapeutics. “Our clinical trial will target multiple critical metabolic-related outcomes including the reduction of triglycerides, insulin resistance, weight loss, and the prevention and/or abrogation of hepatic steatosis and fibrosis.”

“The FDA’s orphan-drug designation for Fluasterone highlights the significant unmet and underserved needs for treatment in these individuals,” added Dr. Katakam. “We look forward to realizing the benefits and promise of this potential for Fluasterone in Cushing’s syndrome patients.”

The Orphan Drug Act became law in 1983. Fewer than 5,000 applicants have received this designation, according to the FDA website. Rare conditions are often described as orphan diseases or disorders when there are few or no treatment options. There are approximately 7,000 known orphan diseases.

The FDA’s Orphan Drug Designation program provides orphan status to drugs and biologics which are defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States.

The designation allows the sponsor of the drug to be eligible for various incentives, including a seven-year period of U.S. marketing exclusivity upon regulatory approval of the drug, as well as tax credits for clinical research costs, annual grant funding, clinical trial design assistance, and the waiver of Prescription Drug User Fee Act (PDUFA) filing fees.

Cushing syndrome occurs when a patient’s body is exposed to high levels of the hormone cortisol over a long period of time (chronic hypercortisolemia) . Cushing syndrome, sometimes called hypercortisolism, affects 15,000 to 20,000 patients in the United States.

Too much cortisol can produce some of the hallmark signs of Cushing syndrome — a fatty hump between a patient’s shoulders, a rounded face, and pink or purple stretch marks on the skin. Cushing syndrome can also result in high blood pressure, bone loss and upper body obesity, increased fat around the neck, and relatively slender arms and legs. Diabetes is frequently a complication found in Cushing’s syndrome patients. These patients also develop nonalcoholic fatty disease and steatosis as a result of the chronic hypercortisolism.

About SteroTherapeutics

SteroTherapeutics, a Philadelphia, PA area based company, is focused on developing novel therapies for significant unmet needs in metabolic disease including liver diseases.

SteroTherapeutics lead products have been proven in previous human studies to possess a strong safety profile and established mechanisms of action. The company’s strategic intent is to focus on understanding disease pathways and how to safely treat and restore an optimal quality of life.  SteroTherapeutics is managed by a veteran team that has significant experience in the pharmaceutical and biotechnology industry. The team has specific experiences in the development, manufacturing and commercialization of small molecule and biologics based products.

INVESTOR RELATIONS CONTACT:
Tony Schor, Investor Awareness, Inc. on behalf of
SteroTherapeutics, LLC
tschor@sterotx.com/ (847) 945-2222 ext. 221

From https://www.econotimes.com/SteroTherapeutics-Receives-FDA-Orphan-Drug-Designation-1236099

Rare Nasal Cancer May Have Caused Cushing’s Syndrome

A very rare case of Cushing’s syndrome developing as a result of a large and also rare cancer of the nasal sinuses gives insights into how to screen and treat such an anomaly, of which fewer than 25 cases have been reported in literature.

Paraneoplastic esthesioneuroblastoma (ENB), a very rare type of nasal tumor, may sometimes produce excess adrenocorticotrophic hormone (ACTH), leading to symptoms of Cushing’s syndrome, according to a recent case report that describes a case of ACTH-secreting ENB. The report aims to demonstrate the importance of recognizing its pathophysiology and treatment.

The case report, “A Case of Cushing’s Syndrome due to Ectopic Adrenocorticotropic Hormone Secretion from Esthesioneuroblastoma with Long Term Follow-Up after Resection,” was published in the journal Case Reports in Endocrinology.

It describes a 52-year-old Caucasian male who had a history of high blood pressure, severe weakness, abnormal production of urine, extreme thirstiness, and confusion.

He was scheduled to undergo surgery for a 7-centimeter skull base mass; the surgery was postponed due to severe high serum potassium concentrations and abnormally high pH levels. His plasma ACTH levels also were elevated and Cushing’s syndrome was suspected. Since imaging of the chest, abdomen, and pelvis did not show any ectopic (abnormal) sources of ACTH, the ENB was suspected to be the source.

Surgery was performed to remove the tumor, which was later found to be secreting ACTH. Consequently, following the procedure, his ACTH levels dropped to normal (below detection limit) and he did not need medication to normalize serum potassium levels. He then underwent subsequent chemoradiation and has shown no sign of recurrence 30 months after the operation, which is considered to be one of the longest follow-up periods for such a case.

Researchers declared it “a case of olfactory neuroblastoma with ectopic ACTH secretion that was treated with resection and adjuvant chemoradiation.”

“Given the paucity of this diagnosis, little is known about how best to treat these patients and how best to screen for complications such as adrenal insufficiency and follow-up,” they wrote. “Our case adds more data for better understanding of this disease.”

From https://cushingsdiseasenews.com/2018/04/03/rare-nasal-cancer-caused-cushings-syndrome-case-report-says/

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