The US Food and Drug Administration (FDA) has approved Isturisa (osilodrostrat) for Cushing’s disease (CD) for patients that cannot undergo pituitary gland surgery for various reasons or who have undergone surgery but still have the disease. This development is significant because for these patients, first and second line of therapy options were not effective and they had limited therapy options, so hopefully, this development will help address patients’ unmet needs and consequently improve patient’s quality of life.
In 2014, the FDA granted Isturisa an orphan drug designation. This is a special status granted to a drug to a treat a rare disease or condition. The regulatory authority has provided 7-year market exclusivity to Isturisa. This is done because developing medicine for a niche market has little commercial benefit for some pharmaceutical companies, therefore by granting an orphan designation, regulatory authorities will offer range of incentives such as market exclusivity once the medicine is on the market to encourage the development of orphan medicines.
What is Cushing’s Disease ?
Cushing’s disease is a subset of a larger disease called Cushing’s Syndrome(CS), which is a rare disorder resulting from a prolonged exposure to excess levels of cortisol. Cortisol, which is the body’s main stress hormone, is normally produced in a stressful situation, but it also has other functions such as maintaining blood pressure, regulating blood glucose levels, reducing inflammation and metabolism - when these systems are dysregulated, it can cause the disease state seen in Cushing’s Syndrome.
There are two types of CS: Exogenous (caused by factors outside the body) or endogenous (caused by factors within the body).
Exogenous CS is mainly caused by patients taking glucocorticoids medications such as prednisone which is used to treat inflammatory disorders such as asthma and rheumatoid arthritis. This is why it is important to ensure that patients on steroid medications are not on treatment for more than 2 years or their dosage is adjusted to avoid the development of clinical signs and symptoms.
The other form is endogenous CS; this can either be adrenocorticotropic hormone (ACTH) independent or ACTH dependent. ACTH-dependent CS is always caused by primary adrenal disease. The hyperfunctioning primary adrenal disease secretes cortisol and results in CS. This type of CS, also known as CD, accounts for around 85% of patients with endogenous CS. ACTH-independent CS is due to an adenoma or carcinoma in the majority of cases but on rare occasions may be caused by other diseases, including primary pigmented nodular adrenal dysplasia (PPNAD) and ACTH-independent macronodular hyperplasia (AIMAH) .
Significant levels of cortisol in the bloodstream results in co-morbidities such as high blood pressure, which occurs in 85% of people with Cushing’s Syndrome. Other comorbidities include obesity, osteoporosis due to progressive bone thinning and type 2 diabetes. Patients with CS also suffer from psychological problems such as depression, cognitive dysfunction and emotional lability . It has been reported that the presence of the co-morbidities in CS patients, has been identified as a predictive factor for mortality. One study confirmed that cardiovascular diseases represents the main cause of death in patients with CS/CD patients, with male gender, age at diagnosis, disease duration and other clinical complications increasing the risk of mortality in CD patients . Other studies have shown that patients with active disease , mainly those with recurrent or persistent or recurrent disease after surgery, have increased mortality rate. Therefore, Isturisa, which is indicated for patients that are not responsive to typical treatment (which have shown to effectively normalise cortisol levels), will help to prevent further complications thus reducing mortality and improving quality of life in this niche patient population.
Current treatments for Cushing’s Disease
There are different therapeutic options for patients with Cushing’s disease, depending on the severity of the disease and how patients respond to initial treatment.
The therapy option for exogenous CS patients is to reduce the dosage of glucocorticoids over a period of time.
Patients with CD are eligible for surgery, which removes the pituitary tumours. If the surgery is not effective or the surgeon can’t remove the tumour, radiation therapy is used in conjunction with the operation. This will ultimately reduce cortisol levels and patients will take cortisol replacement medication to provide the body with the correct amount of cortisol after surgery, however adrenal production of cortisol will eventually return to normal.
Medication is also used to control cortisol production, when surgery and radiation don’t work. Isturisa, the newly approved drug, will join other therapies approved for CS. In 2012, the FDA approved mifepristone (Korlym), an antagonist of the cortisol receptors in the body, for patients with CS with type 2 diabetes. Unlike Isturisa, mifepristone doesn’t reduce cortisol production but only blocks the effect of cortisol on the tissues. In some cases, the drug can even increase the cortisol levels significantly. This demonstrates the drug is only treating the clinical symptoms of the drug, and not actually targeting the initial pathology of the disease. Furthermore, this drug surely protects patients from developing cardiovascular complications but only for short period of time- patients will become unresponsive due to receptors becoming desensitised, and this significant increase in cortisol will cause further complications .
Another approved drug for Cushing’s disease is pasireotide (Signifor); this contains somatostatin analogue. This works by activating somatostatin receptors in the pituitary adenoma, which consequently inhibits excessive ACTH and reduces cortisol production. Unlike Isturisa, this drug is only available in injection form which can affect the compliance of the drug.
What is Isturisa?
This is the first FDA-approved drug which directly inhibits the overproduction of cortisol in CD by blocking the enzyme 11-beta-hydroxylase: the body’s main stress hormone, involved in the synthesis of cortisol.
The approval of this drug was based on a clinical trial that evaluated the safety and effectiveness of the drug in 137 adult patients. Majority of the patients that took part in the clinical trial had undergone surgery, but it failed to cure their disease, or they were not a suitable candidate for surgery. In the 24-week, single-arm, open-label period, all patients received a starting dose of 2 milligrams (mg) of Isturisa twice a day, which increased every two weeks up to 30 mg twice a day. At the end of the 24-week period, about half of the patients had cortisol levels within normal limits. After this period, 71 patients who didn’t need further dose or tolerated the drug for the last 12 weeks, entered an eight-week, double-blind, randomised withdrawal study where they received Isturisa or a placebo. At the end of the study, 86% of patients receiving Isturisa maintained normal cortisol range compared to 30% of the placebo group, which demonstrates the significant effectiveness of Isturisa .
The FDA has noted that the most common adverse events reported during clinical trials were adrenal insufficiency, headache, vomiting, nausea and fatigue. However, the benefits of this orphan drug clearly outweighed the side effects, hence the approval. This is expected to be available in the second or third quarter of 2020 and it will be supplied as an oral tablet in 1 mg, 5 mg and 10 mg of strengths depending on the severity of the disease and how patients respond to the lowest dosage.
This therapy is a significantly important for patients suffering with CD, especially the fact that it directly inhibits the overproduction and synthesis of cortisol, making it a target therapy which actually treats the underlying condition. Furthermore, administration routes may influence compliance rate; the fact that the drug is available in an oral form with good safety and efficacy profile, would increase compliance because of the convenience for patients, and would ultimately improve patient’s quality of life.
How many patients are affected?
Epidemiology surrounding the incidence of Cushing’s syndrome is scarce due to the rarity of the disease, but estimated annual cases of Cushing’s Syndrome in EU5 in EU5 (France, UK, Germany, Spain and Italy) is around 1.65 per 1,000,000 people, which corresponds to around 530 cases annually. Of these, around 90% of patients suffer from CD 1. It’s challenging to diagnose patients with CS due to the fact that the clinical signs and symptoms can be similar to other conditions such as obesity, hypertension and depression – this probably means that there are undiagnosed patients with Cushing’s syndrome, so the true incidence is likely underestimated
CD is a severe disease associated with increased mortality mainly related to cardiovascular diseases and infectious diseases. It has a significant burden on patients’ life mostly due to psychiatric disorders and metabolic conditions. This is why it’s essential to develop a therapy, which normalises cortisol levels in order to avoid further complications and prevent co-morbidities. The fact that there are slightly more available agents such as Isturisa, to normalise cortisol levels by targeting different proteins raises the opportunity of combined therapy for some patients. This improves the patient’s quality of life while being safe.
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Ridwaan Ibrahim - Disease Epidemiology Analyst
 Epiomic Database (2020). Prevalence of Cushing’s Syndrome. https://www.epiomic.com/epidemiology-databases/epiomic-segmentation/diseases/cushings-syndrome
 Rockall AG et al (2004). CT and MR Imaging of the Adrenal Glands in ACTH-independent Cushing Syndrome. Radiographics. 24(2),pp. 435-452.
 National Organisation for Rare Disorders (2020). Rare disease database – Cushing Syndrome. https://rarediseases.org/rare-diseases/cushing-syndrome/
 Cushing’s Support & Research Foundation (2020). Mifepristone (Korlym): First FDA-Approved Medication for the Treatment of Cushing’s Syndrome. https://csrf.net/doctors-articles/medications-for-cushings/mifepristone-korlym-first-fda-approved-medication-for-the-treatment-of-cushings-syndrome/
 U.S. Food and Drug Administration, (2020). ‘FDA Approves New Treatment for Adults with Cushing’s Disease.’, www.fda.gov.