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.

Scientists Find Potential Therapeutic Target for Cushing’s Disease

Scientists at the Salk Institute for Biological Studies have identified a protein that drives the formation of pituitary tumors in Cushing’s disease, a development that may give clinicians a therapeutic target to treat this potentially life-threatening disorder.

The protein, called TR4 (testicular orphan nuclear receptor 4), is one of the human body’s 48 nuclear receptors, a class of proteins found in cells that are responsible for sensing hormones and, in response, regulating the expression of specific genes. Using a genome scan, the Salk team discovered that TR4 regulates a gene that produces adrenocorticotropic hormone (ACTH), which is overproduced by pituitary tumors in Cushing’s disease (CD). The findings were published in the May 6, 2013 early online edition of Proceedings of the National Academy of Sciences.

The diagram shows how adrenocorticotropin hormone is secreted in Cushing's disease.

“We were surprised by the scan, as TR4 and ACTH were not known to be functionally linked,” says senior author Ronald M. Evans, a professor in Salk’s Gene Expression Laboratory and a lead researcher in the Institute’s Helmsley Center for Genomic Medicine. “TR4 is driving the growth and overexpression of ACTH. Targeting this pathway could therapeutically benefit treatment of CD.”

In their study, Evans and his colleagues discovered that forced overexpression of TR4 in both human and mouse cells increased production of ACTH, cellular proliferation and tumor invasion rates. All of these events were reversed when TR4 expression was reduced.

First described more than 80 years ago, Cushing’s disease is a rare disorder that is caused by pituitary tumors or excess growth of the pituitary gland located at the base of the brain. People with CD have too much ACTH, which stimulates the production and release of cortisol, a hormone that is normally produced during stressful situations.

While these pituitary tumors are almost always benign, they result in excess ACTH and cortisol secretion, which can result in various disabling symptoms, including diabetes, hypertension, osteoporosis, obesity and psychological disturbances. Surgical removal of the tumors is the first-line therapy, with remission rates of approximately 80 percent; however, the disease recurs in up to 25 percent of cases.

Drugs such as cabergoline, which is used to treat certain pituitary tumors, alone or in combination with ketoconazole, a drug normally used to treat fungal infections, have been shown to be effective in some patients with Cushing’s disease. More recently, mefipristone-best known as the abortion pill RU-486-was approved by the FDA to treat CD. Despite these advances in medical therapy, the Salk scientists say additional therapeutic approaches are needed for CD.

“Pituitary tumors are extremely difficult to control,” says Michael Downes, a senior staff scientist in the Gene Expression Laboratory and a co-author of the study. “To control them, you have to kill cells in the pituitary gland that are proliferating, which could prevent the production of a vital hormone.”

Previous studies have found that, by itself, TR4 is a natural target for other signaling molecules in the pituitary. Small-molecule inhibitors that have been developed for other cancers could be potentially applied to disrupt this signaling cascade. “Our discovery,” says Evans, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology, “might lead clinicians to an existing drug that could be used to treat Cushing’s disease.

Notes about this neurogenetics and Cushing’s disease research

Other researchers on the study were Li Du, Marvin Bergsneider, Leili Mirsadraei, Stephen H. Young, William H. Yong and Anthony P. Heaney of the David A. Geffen School of Medicine at the University of California, Los Angeles, and Johan W. Jonker of the University of Groningen.

The study was supported by the National Institutes of Health, the Leona M. and Harry B. Helmsley Charitable Trust, the Samuel Waxman Cancer Research Foundation, the Jonsson Comprehensive Cancer Center at UCLA, and Ipsen/Biomeasure.

Contact: Andy Hoang – Salk Institute
Source: Salk Institute press release
Image Source: The ACTH Cushing’s disease diagram is credited to NIDDK/NIH and is available in the public domain.
Original Research: Abstract for “Evidence for orphan nuclear receptor TR4 in the etiology of Cushing disease” by Li Du, Marvin Bergsneider, Leili Mirsadraei, Steven H. Young, Johan W. Jonker, Michael Downes, William H. Yong, Ronald M. Evans, and Anthony P. Heaney in Proceedings of the National Academy of Sciences. Published May 6 2013 doi: 10.1073/pnas.1306182110

From http://neurosciencenews.com/tr4-cushings-disease-acth-neurogenetics-120/

No High-Quality Studies for Cushing’s Drugs

By Salynn Boyles, Contributing Writer, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

There is a paucity of clinical trial data supporting the efficacy of most drugs used to treat Cushing’s disease, researchers reported.

Just one drug — pasireotide — has been evaluated in a randomized, double-blind trial, but even it was judged by the researchers to have only a ‘moderate’ level of evidence supporting its effectiveness and safety.

The review of the literature evaluating drug treatments for Cushing’s disease, a rare pituitary disorder, is the first to employ a rigorous systematic approach with strict, predefined inclusion criteria and formal analysis of the quality of evidence using an established standard, researcher Monica Gadelha, MD, PhD, of Brazil’s Federal University of Rio de Janeiro, and colleagues wrote in the journal Clinical Endocrinology.

“This systematic review indicates that the majority of medical therapies currently used in the treatment of Cushing’s disease are supported by a low level of evidence,” the researchers wrote. “Further well-designed prospective studies of medications in Cushing’s disease would help to inform clinical practice further.”

Cushing’s disease is the most common form of endogenous Cushing’s syndrome, a hormonal disorder resulting from persistent exposure to abnormally high levels of the hormone cortisol. In the case of Cushing’s disease, the cortisol is secreted by a pituitary adenoma.

Prolonged exposure to high levels of cortisol raises the risk for diabetes mellitus, cardiovascular disease, osteoporosis and nephrolithiasis. Patients with persistent Cushing’s disease have a 3- to 5-fold higher mortality than the general population.

Surgery to remove the pituitary adenoma is the first-line treatment for Cushing’s disease in the U.S., and when the procedure is performed by an experienced surgeon, remission rates in patients with smaller tumors range from 65% to 90%. The long-term remission rate is lower, however, because many patients develop recurrent disease.

Several medical therapies are widely used to treat patients who are not candidates for surgery or who experience relapse following surgery.

Novartis Oncology’s somatostatin analog drug pasireotide (Signifor) became the only drug approved for this indication in December of last year. And the progesterone-blocking drug mifepristone, best known as the abortion pill once called RU-486, was approved in February of 2012 for the treatment of Cushing’s disease-associated hyperglycemia.

Other drugs — including metyrapone, mitotane, cabergoline, and ketoconazole — are also used off-label in the treatment of Cushing’s, and several have shown better response rates than pasireotide in small studies.

In their systematic review, Gadelha and colleagues identified 15 studies that included at least 10 adults with Cushing’s disease and reported treatment responses as the proportion of patients reaching a specified definition of response. Studies examining combinations of medications were excluded from the analysis, as were studies with indefinite diagnoses of Cushing’s disease.

For medications other than mifepristone, studies had to report the proportion of patients with normalized urinary free cortisol (UFC), midnight salivary cortisol or midnight serum cortisol.

The studies were scored according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system for rating quality of evidence.

Ten of the 15 included studies reported outcomes specifically for patients with Cushing’s disease and the remaining five included patients with other forms of Cushing’s syndrome.

The researchers reported that:

  • Pasireotide was the only treatment assessed in a randomized trial, and it was judged to have a ‘moderate’ level of evidence supporting its use. Response rates from three prospective studies of the drug ranged from 17% to 29%.
  • The remaining medications were supported by a ‘low’ or ‘very low’ level of evidence.
  • The highest response rates were reported in a small retrospective studies of metyrapone (75%, one study) and mitotane (72%, one study).
  • Response rates were 25% to 50% for cabergoline (four studies) and 45% for ketoconazole (one study).
  • Among studies that included patients with other forms of Cushing’s syndrome, response rates were 53% to 88% for ketoconazole (three studies), 70% for mitotane (one study), 57% for metyrapone (one study), and 38% to 60% for mifepristone (one study).

 

But the researchers urged caution in comparing the drugs, citing the variability in the study designs and patient selection endpoints, among other limitations in the research literature.

“The wide variation in the time-frames over which response to treatment was measured makes comparison a challenge,” they wrote. “Comparison of response rates reported in the included studies is also complicated by the variation in methodology used to assess response.”

They noted that well-designed clinical trials are needed to determine which drugs or drug combinations are most effective in the treatment of Cushing’s disease patients.

“Combinations of medical therapies with different modes of action might aid in optimizing the balance of efficacy and safety,” they wrote. “Investigational medications, such as bexarotene, LC1699 and retinoic acid, may help to expand the range of future therapeutic options.”

Maria Fleseriu, MD, who was not involved in the review, agreed that more drug treatments are needed. But she added that Cushing’s patients today have many more drug options than they did just a few years ago.

Fleseriu directs the Pituitary Center at Oregon Health & Science University, where she is an associate professor of medicine and endocrinology.

In a recently published analysis, Fleseriu wrote that pituitary-targeted medical therapies should soon play a more prominent role in treating Cushing’s disease, and may become first-line treatments when surgery fails or is contraindicated.

“We now have one drug approved for Cushing’s and another approved for diabetes symptoms associated with the disease,” she told MedPage Today. “We are moving forward, but we are not where we would like to be. Combination therapy is probably where we are heading, but further studies are needed.”

Financial support for this research was provided by Novartis Pharmaceuticals.

Researcher Monica Gadelha reports receiving speaker fees and participating on advisory boards for Novartis. Gadelha and co-author Leonardo Vieira Neto were investigators in Novartis’ clinical trials of pasireotide.

 

From http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/42043

Salk scientists find potential therapeutic target for Cushing’s disease

LA JOLLA, CA—Scientists at the Salk Institute for Biological Studies have identified a protein that drives the formation of pituitary tumors in Cushing’s disease, a development that may give clinicians a therapeutic target to treat this potentially life-threatening disorder.

The protein, called TR4 (testicular orphan nuclear receptor 4), is one of the human body’s 48 nuclear receptors, a class of proteins found in cells that are responsible for sensing hormones and, in response, regulating the expression of specific genes. Using a genome scan, the Salk team discovered that TR4 regulates a gene that produces adrenocorticotropic hormone (ACTH), which is overproduced by pituitary tumors in Cushing’s disease (CD). The findings were published in the May 6 early online edition of Proceedings of the National Academy of Sciences.

“We were surprised by the scan, as TR4 and ACTH were not known to be functionally linked,” says senior author Ronald M. Evans, a professor in Salk’s Gene Expression Laboratory and a lead researcher in the Institute’s Helmsley Center for Genomic Medicine. “TR4 is driving the growth and overexpression of ACTH. Targeting this pathway could therapeutically benefit treatment of CD.”

In their study, Evans and his colleagues discovered that forced overexpression of TR4 in both human and mouse cells increased production of ACTH, cellular proliferation and tumor invasion rates. All of these events were reversed when TR4 expression was reduced.

First described more than 80 years ago, Cushing’s disease is a rare disorder that is caused by pituitary tumors or excess growth of the pituitary gland located at the base of the brain. People with CD have too much ACTH, which stimulates the production and release of cortisol, a hormone that is normally produced during stressful situations.

While these pituitary tumors are almost always benign, they result in excess ACTH and cortisol secretion, which can result in various disabling symptoms, including diabetes, hypertension, osteoporosis, obesity and psychological disturbances. Surgical removal of the tumors is the first-line therapy, with remission rates of approximately 80 percent; however, the disease recurs in up to 25 percent of cases.

Drugs such as cabergoline, which is used to treat certain pituitary tumors, alone or in combination with ketoconazole, a drug normally used to treat fungal infections, have been shown to be effective in some patients with Cushing’s disease. More recently, mefipristone-best known as the abortion pill RU-486-was approved by the FDA to treat CD. Despite these advances in medical therapy, the Salk scientists say additional therapeutic approaches are needed for CD.

“Pituitary tumors are extremely difficult to control,” says Michael Downes, a senior staff scientist in the Gene Expression Laboratory and a co-author of the study. “To control them, you have to kill cells in the pituitary gland that are proliferating, which could prevent the production of a vital hormone.”

Previous studies have found that, by itself, TR4 is a natural target for other signaling molecules in the pituitary. Small-molecule inhibitors that have been developed for other cancers could be potentially applied to disrupt this signaling cascade. “Our discovery,” says Evans, a Howard Hughes Medical Institute investigator and holder of the March of Dimes Chair in Molecular and Developmental Biology, “might lead clinicians to an existing drug that could be used to treat Cushing’s disease.”

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