Novel Therapy Eases Cushing’s Symptoms in Pivotal Trial

by Kristen Monaco, Staff Writer, MedPage Today

LOS ANGELES — An investigational therapy improved quality of life and reduced disease symptoms for patients with endogenous Cushing’s syndrome, according to new findings from the phase III SONICS study.

Patients taking oral levoketoconazole twice daily had significant reductions in mean scores for acne (-1.8), peripheral edema (-0.4), and hirsutism (-2.6), all secondary endpoints of the pivotal trial (P<0.03 for all), reported Maria Fleseriu, MD, of Oregon Health and Science University in Portland.

“We’re looking forward to see the results of further studies and to add this therapy to the landscape of Cushing’s,” Fleseriu said here during a presentation of the findings at AACE 2019, the annual meeting of the American Association of Clinical Endocrinologists. “We have a newer medication and still we cannot make a dent in the outcomes of Cushing’s, especially for patient-reported outcomes.”

Free testosterone levels significantly decreased in women taking levoketoconazole (a ketoconazole stereoisomer and potent steroidogenesis inhibitor), from an average of 0.32 ng/dL down to 0.12 ng/dL (0.011 to 0.004 nmol/L, P<0.0001). Men had a non-significant increase: 5.1 ng/dL up to 5.8 ng/dL (0.177 to 0.202 nmol/L).

There were no significant changes from baseline to the end of maintenance for other secondary endpoints in the analysis: moon facies, facial plethora, striae, bruising, supraclavicular fat, irregular menstruation, and dysmenorrhea. However, significant improvements after 6 months of therapy were seen in patient-reported quality of life compared with baseline (mean 10.6 change on the Cushing QOL questionnaire) as well as a significant reduction in depressive symptoms (mean -4.3 change on the Beck Depression Inventory II).

The open-label, multicenter SONICS (Study of Levoketoconazole in Cushing’s Syndrome) trial included 94 adult men and women with a confirmed diagnosis of Cushing’s syndrome and elevated 24-hour mean urinary free cortisol (mUFC) levels at least 1.5 times the upper limit of normal.

In the dose-titration phase of the study (weeks 2 to 21), patients were titrated up to a max dose of 600 mg levoketoconazole twice daily until mUFC normalization. A 6-month maintenance phase followed with no dose increases, but decreases were allowed if adverse events emerged. An additional 6-month extended evaluation phase followed thereafter.

The study met it’s previously reported primary endpoint, with 30% of patients achieving normalized mUFC levels after 6 months of maintenance therapy without a dose increase (95% CI 21%-40%, P=0.0154).

Levoketoconazole was well tolerated, with only 12.8% of patients discontinuing treatment due to adverse events. The most commonly reported adverse events were nausea (31.9%), headache (27.7%), peripheral edema (19.1%), hypertension (17%), and fatigue (16%), some of which were expected due to steroid withdrawal, Fleseriu said.

Serious adverse events were reported in 14 patients, including prolonged QTc interval in two patients, elevated liver function in one patient, and adrenal insufficiency in another, events similar to those seen with ketoconazole (Nizoral) therapy.

Fleseriu explained that drug-drug interaction is a problem in Cushing’s, as all of the available medications prolong QT interval.

She noted that in SONICS, QT prolongation with levoketoconazole was observed in few patients. It’s still a “concern,” said Fleseriu, especially for patients on other drugs that prolong QT.

Although not yet approved, levoketoconazole has received orphan drug designation from the FDA and the European Medicines Agency for endogenous Cushing’s syndrome. The tentative brand name is Recorlev.

The study was supported by Strongbridge Biopharma.

Fleseriu reported relationships with Strongbridge, Millendo Therapeutics, and Novartis. Co-authors also disclosed relevant relationships with industry.

From https://www.medpagetoday.com/meetingcoverage/aace/79465

Endocrine Society issues new guidelines on hypopituitarism

The Endocrine Society today issued a Clinical Practice Guideline that recommends treating insufficient hormone levels in individuals with hypopituitarism by replacing hormones at levels as close to the body’s natural patterns as possible.

The guideline, titled “Hormonal Replacement in Hypopituitarism in Adults: An Endocrine Society Clinical Practice Guideline,” was published online and will appear in the November 2016 print issue of The Journal of Clinical Endocrinology & Metabolism (JCEM), a publication of the Endocrine Society.

Hypopituitarism, or pituitary insufficiency, occurs when the pituitary gland does not produce sufficient amounts of hormones–the chemical signals that regulate respiration, reproduction, growth, metabolism, sexual function and other important biological functions. The pituitary gland is often called the master gland because the hormones it produces impact many bodily functions. As a result, hypopituitarism can cause a range of symptoms, according to the Hormone Health Network.

The rare disorder can occur due to abnormal development or later in life as a result of a tumor, traumatic brain injury, hemorrhage or autoimmune condition, according to the Society’s

“Hypopituitarism can manifest as low levels of a variety of hormones, including cortisol, thyroid hormone, estrogen, testosterone and growth hormone,” said Maria Fleseriu, MD, FACE, of Oregon Health & Science University in Portland, OR. Fleseriu chaired the task force that developed the guideline. “The goal of treatment should be to restore hormone levels as close to healthy levels as possible The interactions between these hormones also are very important, and patients might require dose changes of one or more of the replacement hormones after starting or discontinuing another one.”

In recommending treatment options, the guideline task force followed the overriding principle of using hormone replacement therapy dose size and timing to mimic the body’s natural functioning as closely as possible.

Accurate and reliable measurements of hormones play a central role in diagnosing hypopituitarism and monitoring the effectiveness of treatments, Fleseriu said. Healthcare providers need to keep in mind technical considerations to ensure the testing procedure is as accurate as possible.

The guideline addresses special circumstances that may affect the treatment of patients with hypopituitarism, including pregnancy care, post-surgical care following pituitary or other operations, treatment in combination with anti-epilepsy medication, and care following pituitary apoplexy–a serious condition that occurs when there is bleeding into the gland or blood flow to it is blocked.

Recommendations from the guideline include:

  • Measurements of both free thyroxine and thyroid-stimulating hormone are needed to evaluate central hypothyroidism, a condition where the thyroid gland does not produce enough hormones because it isn’t stimulated by the pituitary gland.
  • People who have central hypothyroidism should be treated with levothyroxine in doses sufficient to raise levels of the thyroid hormone free thyroxine to the upper half of the reference range.
  • Growth hormone stimulation testing should be used to diagnose patients with suspected growth hormone deficiency.
  • People who have proven cases of growth hormone deficiency and no contraindications should be offered growth hormone replacement as a treatment option.
  • Premenopausal women who have central hypogonadism, a condition where the sex glands produce minimal amounts or no hormones, can undergo hormone treatment, provided there are no contraindications.
  • People producing abnormally large volumes of dilute urine should be tested for central diabetes insipidus–a rare condition that leads to frequent urination–by analyzing the concentration of their blood and urine.
  • For patients who have low levels of glucocorticoid hormones, hydrocortisone can be given in a daily single or divided dose.
  • All hypopituitarism patients should be instructed to obtain an emergency card, bracelet or necklace warning about the possibility of adrenal insufficiency.
  • Patients who are suspected of having an adrenal crisis due to secondary adrenal insufficiency should receive an immediate injection of 50 to 100 milligrams of hydrocortisone.
  • People who have central adrenal insufficiency should receive the lowest tolerable dose of hydrocortisone replacement on a long-term basis to reduce the risk of metabolic and cardiovascular disease.
Source:

The Endocrine Society

From http://www.news-medical.net/news/20161013/Endocrine-Society-issues-new-guidelines-on-hypopituitarism.aspx

Osilodrostat for Cushing’s

The study looked at a drug to treat Cushing’s disease. The article, in the journal Pituitary, is called Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing’s disease.
Fleseriu M, Pivonello R, Young J, Hamrahian AH, Molitch ME, Shimizu C, Tanaka T, Shimatsu A, White T, Hilliard A, Tian C, Sauter N, Biller BM, Bertagna X.
Pituitary. 2015 Nov 5. [Epub ahead of print]

Abstract

PURPOSE:
In a 10-week proof-of-concept study (LINC 1), the potent oral 11β-hydroxylase inhibitor osilodrostat (LCI699) normalized urinary free cortisol (UFC) in 11/12 patients with Cushing’s disease. The current 22-week study (LINC 2; NCT01331239) further evaluated osilodrostat in patients with Cushing’s disease.

METHODS:
Phase II, open-label, prospective study of two patient cohorts. Follow-up cohort: 4/12 patients previously enrolled in LINC 1, offered re-enrollment if baseline mean UFC was above ULN. Expansion cohort: 15 newly enrolled patients with baseline UFC > 1.5 × ULN. In the follow-up cohort, patients initiated osilodrostat twice daily at the penultimate efficacious/tolerable dose in LINC 1; dose was adjusted as needed. In the expansion cohort, osilodrostat was initiated at 4 mg/day (10 mg/day if baseline UFC > 3 × ULN), with dose escalated every 2 weeks to 10, 20, 40, and 60 mg/day until UFC ≤ ULN. Main efficacy endpoint was the proportion of responders (UFC ≤ ULN or ≥50 % decrease from baseline) at weeks 10 and 22.

RESULTS:
Overall response rate was 89.5 % (n/N = 17/19) at 10 weeks and 78.9 % (n/N = 15/19) at 22 weeks; at week 22, all responding patients had UFC ≤ ULN. The most common AEs observed during osilodrostat treatment were nausea, diarrhea, asthenia, and adrenal insufficiency (n = 6 for each). New or worsening hirsutism (n = 2) and/or acne (n = 3) were reported among four female patients, all of whom had increased testosterone levels.

CONCLUSIONS:
Osilodrostat treatment reduced UFC in all patients; 78.9 % (n/N = 15/19) had normal UFC at week 22. Treatment with osilodrostat was generally well tolerated.

KEYWORDS:
11β-hydroxylase; Cortisol; Cushing’s; LCI699; Osilodrostat

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

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