Real-world study backs Isturisa for non-pituitary Cushing’s forms
Treatment reduced or normalized cortisol levels in 103 patients
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Isturisa (osilodrostat) can safely reduce, or even normalize, cortisol levels in people with various forms of endogenous Cushing’s syndrome that are not Cushing’s disease, according to data from a real-world study in France.
The study, “Real-world osilodrostat effectiveness and safety in non-pituitary Cushing syndrome,” was published in The Journal of Clinical Endocrinology & Metabolism. The work was funded by Recordati Rare Diseases, the company that sells Isturisa.
Endogenous Cushing’s syndrome refers to a group of disorders in which the body produces too much of the hormone cortisol. In Cushing’s disease, the most common form, this occurs when a tumor in the brain’s pituitary gland causes it to release unusually high levels of adrenocorticotropic hormone (ACTH). This then stimulates the adrenal glands, which sit atop the kidneys, to produce excess cortisol.
Excess ACTH can also come from a tumor elsewhere in the body, resulting in ectopic Cushing’s syndrome. In adrenal Cushing’s, cortisol overproduction is driven by problems within the adrenal glands themselves — most often a benign tumor or, in some cases, an adrenal cancer.
Isturisa is an oral therapy designed to reduce cortisol levels by blocking the activity of an enzyme involved in its production. The treatment is approved in the U.S. for Cushing’s disease and other forms of Cushing’s syndrome in people for whom surgery isn’t an option or hasn’t been effective.
Studies focus mainly on Cushing’s disease
Clinical trials have shown that the therapy is generally effective in reducing cortisol levels in Cushing’s. But because these studies have mostly enrolled patients with Cushing’s disease, data on Isturisa’s safety and effectiveness in other forms of the syndrome remain limited, the researchers noted.
The scientists conducted an observational study (NCT05633953), sponsored by Recordati, to evaluate Isturisa in 103 people with non-pituitary forms of endogenous Cushing’s syndrome who received at least one dose of the therapy from 2019 to 2022.
Participants had a mean age of 59.3, and approximately 61% were female. Fifty-three patients (51.5%) had ectopic Cushing’s syndrome, while 19 (18.4%) had adrenocortical carcinoma, a rare and aggressive cancer of the adrenal glands. Another 17 (16.5%) had benign adrenal adenomas, and the remaining 14 (13.6%) had bilateral adrenal nodular disease, a condition in which both adrenal glands develop hormone-producing nodules.
A total of 43 people (41.7%) remained on Isturisa throughout the entire follow-up period, while 60 (58.3%) discontinued treatment. Discontinuation was mainly due to death (28.8%), planned surgery (14.6%), side effects (6.8%), or disease progression (1.9%).
Most participants (68%) were treated with Isturisa alone. Of these, 61.2% had never been on any other treatment, while 6.8% switched to Isturisa after being on other treatments. The remaining 32% received Isturisa alongside another therapy for at least one day.
Overall, the median exposure to Isturisa was 37.3 weeks, or roughly 8.5 months. Among patients treated with Isturisa alone, the median starting dose was 4 mg per day. In those treated with a combination, the median starting dose was 10 mg per day. Doses were adjusted over time based on efficacy and side effects.
Before treatment, urinary cortisol levels were, on average, about 20 times higher than the upper limit of normal. Patients with ectopic Cushing’s syndrome had the highest initial cortisol levels, while those with bilateral adrenal nodular disease had the lowest.
By about three months, 44.2% of the 52 patients who had a urinary cortisol test at that visit had brought their levels back within the normal range. When looking only at the patients who were still on Isturisa and had a cortisol measurement available at that time, the proportion with normal urinary cortisol rose to about 54%.
Most of the remaining patients still showed reductions from their initial values, with only four showing a slight increase by their last on-treatment assessment.
Reductions occurred across all underlying causes of non-pituitary Cushing’s syndrome, and were also observed in patients who started with severely elevated cortisol levels.
Patients in the study generally tolerated Isturisa well. The most common side effects reported were adrenal insufficiency (28.2%), low potassium levels (17.5%), fatigue (13.6%), diarrhea (12.6%), and nausea (11.7%). Adrenal insufficiency occurs when cortisol levels drop too quickly or become too low, causing symptoms such as low blood pressure, dizziness, or, in more severe cases, fever and confusion.
According to the researchers, the therapy’s safety profile was consistent with what had been seen in clinical trials.
“Overall, this real-world study shows that [Isturisa] is a suitable treatment for endogenous Cushing syndrome of various non-pituitary [causes],” the researchers wrote. They also emphasized the importance of ensuring that patients are “monitored regularly and educated on the safety profile of [Isturisa] and the signs and symptoms of adrenal insufficiency,” to help minimize these events.
