Psychiatric symptoms are common in Cushing’s disease (CD) and seem only partly reversible following treatment.
Objective
To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up.
Design
Nationwide longitudinal register-based study.
Setting
University Hospitals in Sweden.
Subjects
CD patients diagnosed between 1990 and 2018 (N=372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed.
Main outcome measures
Data from the Swedish Prescribed Drug Register and the Patient Register.
Results
In the 5-year period before, and at diagnosis, use of antidepressants (OR 2.2[95%CI 1.3-3.7] and 2.3[1.6-3.5]), anxiolytics (2.9[1.6-5.3] and 3.9[2.3-6.6]) and sleeping pills (2.1[1.2-3.7] and 3.8[2.4-5.9]) was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants (2.4[1.5-3.9]) and sleeping pills (3.1[1.9-5.3]). Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (IQR 8.1-10.4) had higher use of antidepressants (OR 2.0[1.1-3.8]) and sleeping pills (2.4[1.3-4.7]), but not of drugs for hypertension.
Conclusions
Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.
Objective: This study was done to compare corticotroph hyperplasia and histopathologically proven adenomas in patients with Cushing disease by analyzing diagnostic features, surgical management, and clinical outcomes.
Methods: Patients with suspected pituitary Cushing disease were included in a retrospective cohort study and were excluded if results of pathological analysis of the surgical specimen were nondiagnostic or normal. Cases were reviewed by two experienced neuropathologists. Total lesion removal was used as a dichotomized surgical variable; it was defined as an extracapsular resection (including a rim of normal gland) in patients with an adenoma, and for hyperplasia patients it was defined as removal of the presumed lesion plus a rim of surrounding normal gland. Bivariate and multivariate analyses were performed. Recurrence-free survival was compared between the two groups.
Results: The final cohort consisted of 63 patients (15 with hyperplasia and 48 with adenoma). Normal pituitary acinar architecture was highly variable. Corticotroph hyperplasia was diagnosed based on the presence of expanded acini showing retained reticulin architecture and predominant staining for adrenocorticotropic hormone. Crooke’s hyaline change was seen in 46.7% of specimens, and its frequency was equal in nonlesional tissue of both groups. The two groups differed only by MRI findings (equivocal/diffuse lesion in 46% of hyperplasia and 17% of adenoma; p = 0.03). Diagnostic uncertainty in the hyperplasia group resulted in additional confirmatory testing by 24-hour urinary free cortisol. Total lesion removal was infrequent in patients with hyperplasia compared to those with adenoma (33% vs 65%; p = 0.03). Initial biochemical remission was similar (67% in hyperplasia and 85% in adenoma; p = 0.11). There was no difference in hypothalamic-pituitary-adrenal axis recovery or disease recurrence. The median follow-up was 1.9 years (IQR 0.7-7.6 years) for the hyperplasia group and 1.2 years (IQR 0.4-2.4 years) for the adenoma group. Lack of a discrete lesion and diagnostic uncertainty were the only significant predictors of hyperplasia (sensitivity 53.3%, specificity 97.7%, positive predictive value 88.9%, negative predictive value 85.7%). An adjusted Cox proportional hazards model showed similar recurrence-free survival in the two groups.
Conclusions: This study suggests an association between biochemically proven Cushing disease and histopathologically proven corticotroph hyperplasia. Imaging and operative findings can be ambiguous, and, compared to typical adenomas with a pseudocapsule, the surgical approach is more nuanced. Nevertheless, if treated appropriately, biochemical outcomes may be similar.
RECORDATI: ISTURISA® (OSILODROSTAT) PHASE III LINC-4 TRIAL MEETS ITS PRIMARY ENDPOINT IN CUSHING’S DISEASE
Isturisa® (osilodrostat) demonstrates significant and sustained benefit over placebo at normalizing mean urinary free cortisol (mUFC) levels in patients with Cushing’s disease
Milan, 17 June 2020 – Recordati today announces positive results from the large Phase III LINC-4 study of Isturisa® (osilodrostat) for the treatment of patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative. Data from the LINC-4 study demonstrate that a significantly higher proportion of patients receiving Isturisa® achieve normal mUFC, the primary treatment goal for Cushing’s disease, after 12 weeks of treatment versus placebo (77% vs 8%; P<0.0001). Improvements in mUFC levels are sustained over 36 weeks of treatment (81% of patients). Isturisa® is well tolerated and has a manageable safety profile, with the most common adverse events in LINC-4 being arthralgia, decreased appetite, fatigue, and nausea. The findings from LINC-4, the first Phase III study of a medical therapy in Cushing’s disease to contain an upfront placebo-controlled phase, builds on existing clinical evidence and affirms the effectiveness of Isturisa® in this hard-to-treat patient population.1-3
“Cushing’s disease is a chronic and debilitating condition that can be extremely challenging to manage and, if left inadequately treated, can have a significant impact on patients’ quality of life and increase the risk of mortality”, said Richard Feelders, MD, Professor of Endocrinology at the Erasmus University Medical Centre, Rotterdam. “Data from this important Phase III study show that Isturisa® (osilodrostat) is an effective and well-tolerated therapy for Cushing’s disease, which significantly reduces and normalizes mUFC levels in most patients. These data are encouraging given the high unmet medical need for patients with this rare disorder”.
“The compelling topline LINC-4 data confirm the effectiveness of Isturisa® for the treatment of this rare, potentially life-threatening disease”, stated Andrea Recordati, CEO. “We are deeply grateful to the patients, investigators, clinicians and study staff whose ongoing participation in the clinical development of Isturisa® has helped bring this therapy to patients in need.”
Data from the LINC 4 study reinforce the clinical benefits of Isturisa® as an effective and generally well‑tolerated oral treatment option for patients with Cushing’s disease. Isturisa® has recently received marketing authorization in the European Union (January 2020) and United States (March 2020) for the treatment of Cushing’s syndrome and Cushing’s disease, respectively.
About Cushing’s syndrome
Cushing’s syndrome is caused by an inappropriate and chronic exposure to excessive levels of cortisol. The source of this excess of cortisol can be endogenous or exogenous (ie medication). When the excess cortisol production is triggered by a pituitary adenoma (ie a tumor of the pituitary gland located in the brain) secreting excess adrenocorticotropic hormone (ACTH), the condition of the patient is defined as Cushing’s disease and comprises about 70% of Cushing’s syndrome cases.4 It is a rare, serious and difficult-to-treat disease that affects approximately one to two patients per million per year.5 Prolonged exposure to elevated cortisol levels is associated with considerable morbidity, mortality and impaired quality of life as a result of complications and comorbidities.6 Normalization of cortisol levels is therefore a primary objective in the treatment of Cushing’s syndrome.7
About LINC-4
LINC-4 is a large randomized, double-blinded, multicentre, 48-week trial with an initial 12-week placebo-controlled period to evaluate the safety and efficacy of osilodrostat in patients with Cushing’s disease. The primary endpoint in the LINC-4 trial is the proportion of patients randomized to Isturisa® and placebo, separately, with a mUFC ≤ULN at the end of the 12-week placebo-controlled period. The key secondary endpoint is the proportion of patients in both arms combined with a mUFC ≤ULN after 36 weeks. LINC-4 involved 73 patients with persistent or recurrent Cushing’s disease or those with de novo disease who were not candidates for surgery.
About Isturisa®
Isturisa® is a potent oral, reversible inhibitor of 11β-hydroxylase (CYP11B1), the enzyme that catalyses the final step of cortisol biosynthesis in the adrenal gland and is authorized in the EU and US for the treatment of adult patients with Cushing’s syndrome and Cushing’s disease, respectively.8,9 Isturisa® will be available as 1 mg, 5 mg and 10 mg film‐coated tablets. Please see prescribing information for detailed recommendations for the use of this product.8,9
Bertagna X et al. J Clin Endocrinol Metab 2014;99:1375–83
Fleseriu M et al. Pituitary 2016;19:138–48
Biller BMK et al. Abstract OR16-2. Oral presentation at the Endocrine Society Annual Congress 2019
Nieman LK et al. Am J Med 2005;118:1340–6
Signifor® and Signifor® LAR Summary of Product Characteristics, June 2018
Pivonello R et al. Lancet Diabetes Endocrinol 2016;4:611–29
Nieman LK et al. J Clin Endocrinol Metab 2015;100:2807–31
Isturisa® Summary of Product Characteristics. May 2020
Isturisa® Prescribing Information. March 2020
About the Recordati group
Recordati, established in 1926, is an international pharmaceutical group, listed on the Italian Stock Exchange (Reuters RECI.MI, Bloomberg REC IM, ISIN IT 0003828271), with a total staff of more than 4,300, dedicated to the research, development, manufacturing and marketing of pharmaceuticals. Headquartered in Milan, Italy, Recordati has operations throughout the whole of Europe, including Russia, Turkey, North Africa, the United States of America, Canada, Mexico, some South American countries, Japan and Australia. An efficient field force of medical representatives promotes a wide range of innovative pharmaceuticals, both proprietary and under license, in a number of therapeutic areas including a specialized business dedicated to treatments for rare diseases. Recordati is a partner of choice for new product licenses for its territories. Recordati is committed to the research and development of new specialties with a focus on treatments for rare diseases. Consolidated revenue for 2019 was € 1,481.8 million, operating income was € 465.3 million and net income was € 368.9 million.
Investor Relations Media Relations Marianne Tatschke Studio Noris Morano (39)0248787393 (39)0276004736, (39)0276004745 e-mail: investorelations@recordati.it e-mail: norismorano@studionorismorano.com
Statements contained in this release, other than historical facts, are “forward-looking statements” (as such term is defined in the Private Securities Litigation Reform Act of 1995). These statements are based on currently available information, on current best estimates, and on assumptions believed to be reasonable. This information, these estimates and assumptions may prove to be incomplete or erroneous, and involve numerous risks and uncertainties, beyond the Company’s control. Hence, actual results may differ materially from those expressed or implied by such forward-looking statements. All mentions and descriptions of Recordati products are intended solely as information on the general nature of the company’s activities and are not intended to indicate the advisability of administering any product in any particular instance.
The U.S. Food and Drug Administration today approved Isturisa (osilodrostat) oral tablets for adults with Cushing’s disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. Cushing’s disease is a rare disease in which the adrenal glands make too much of the cortisol hormone. Isturisa is the first FDA-approved drug to directly address this cortisol overproduction by blocking the enzyme known as 11-beta-hydroxylase and preventing cortisol synthesis.
“The FDA supports the development of safe and effective treatments for rare diseases, and this new therapy can help people with Cushing’s disease, a rare condition where excessive cortisol production puts them at risk for other medical issues,” said Mary Thanh Hai, M.D., acting director of the Office of Drug Evaluation II in the FDA’s Center for Drug Evaluation and Research. “By helping patients achieve normal cortisol levels, this medication is an important treatment option for adults with Cushing’s disease.”
Cushing’s disease is caused by a pituitary tumor that releases too much of a hormone called adrenocorticotropin, which stimulates the adrenal gland to produce an excessive amount of cortisol. The disease is most common among adults between the ages of 30 to 50, and it affects women three times more often than men. Cushing’s disease can cause significant health issues, such as high blood pressure, obesity, type 2 diabetes, blood clots in the legs and lungs, bone loss and fractures, a weakened immune system and depression. Patients may have thin arms and legs, a round red full face, increased fat around the neck, easy bruising, striae (purple stretch marks) and weak muscles.
Isturisa’s safety and effectiveness for treating Cushing’s disease among adults was evaluated in a study of 137 adult patients (about three-quarters women) with a mean age of 41 years. The majority of patients either had undergone pituitary surgery that did not cure Cushing’s disease or were not surgical candidates. In the 24-week, single-arm, open-label period, all patients received a starting dose of 2 milligrams (mg) of Isturisa twice a day that could be increased every two weeks up to 30 mg twice a day. At the end of this 24-week period, about half of patients had cortisol levels within normal limits. After this point, 71 patients who did not need further dose increases and tolerated the drug for the last 12 weeks entered an eight-week, double-blind, randomized withdrawal study where they either received Isturisa or a placebo (inactive treatment). At the end of this withdrawal period, 86% of patients receiving Isturisa maintained cortisol levels within normal limits compared to 30% of patients taking the placebo.
The most common side effects reported in the clinical trial for Isturisa were adrenal insufficiency, headache, vomiting, nausea, fatigue and edema (swelling caused by fluid retention). Hypocortisolism (low cortisol levels), QTc prolongation (a heart rhythm condition) and elevations in adrenal hormone precursors (inactive substance converted into a hormone) and androgens (hormone that regulates male characteristics) may also occur in people taking Isturisa.
Isturisa is taken by mouth twice a day, in the morning and evening as directed by a health care provider. After treatment has started, a provider may re-evaluate dosage, depending upon the patient’s response.
Isturisa received Orphan Drug Designation, which is a special status granted to a drug intended to treat a rare disease or condition.
The FDA granted the approval of Isturisa to Novartis.
Media Contact:Monique Richards, 240-402-3014 Consumer Inquiries: Email, 888-INFO-FDA
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
Each and every day since 1987, I tell anyone who will listen about Cushing’s. I pass out a LOT Cushing’s business cards. My husband also passes out cards and brochures.
Adding to websites, blogs and more which I have maintained continuously since 2000 – at mostly my own expense.
I had Cushing’s Disease due to a pituitary tumor. I was told to diet, told to take antidepressants and told that it was all my fault that I was so fat. My pituitary surgery in 1987 was a “success” but I still deal with the aftereffects of Cushing’s and of the surgery itself.
I also had another Rare Disease – Kidney Cancer, rare in younger, non-smoking women.
CushieBlog 