Isturisa found effective in Cushing’s disease patients of Asian origin
Cortisol level reductions similar to those seen in non-Asian patients: Study
Treatment with Isturisa (osilodrostat) is generally well tolerated and effective at reducing cortisol levels and easing Cushing’s disease symptoms in Asian patients, with results similar to those seen in non-Asian patients.
That’s according to a new study that compared both patient populations in two Phase 3 clinical trials — LINC-3 (NCT02180217) and LINC-4 (NCT02697734) — that assessed Isturisa’s efficacy and safety.
The findings showed that Isturisa treatment also led to improvements in quality of life and in several cardiovascular and metabolic parameters in both groups of patients.
However, “Asian patients generally required numerically lower [Isturisa] doses to achieve [urinary cortisol] control than non-Asian patients,” the researchers noted. That, along with “more common reporting of [low cortisol]-related [adverse events] suggest that Asian patients are more sensitive to [Isturisa] than non-Asian patients,” the team wrote.
The study, “Osilodrostat treatment in patients with Cushing’s disease of Asian or non-Asian origin: a pooled analysis of two Phase III randomized trials (LINC 3 and LINC 4),” was published in the Endocrine Journal.
Blood levels of Isturisa known to be higher in Asian patients
Cushing’s disease is caused by a tumor in the brain’s pituitary gland, usually a pituitary adenoma, that produces excessive amounts of adrenocorticotropic hormone, known as ACTH. Excess ACTH, in turn, causes the adrenal glands located atop the kidneys to overproduce cortisol, leading to a wide range of symptoms.
Isturisa is approved for the treatment of adults with Cushing’s disease for whom pituitary surgery is not possible or was not curative. It reduces cortisol production by blocking an enzyme called 11-beta-hydroxylase, which is expected to normalize cortisol levels and help ease Cushing’s symptoms.
However, according to the researchers, “in people of Asian origin, the amount of [Isturisa] in the blood from a tablet of the same dose is higher than in people of non-Asian origin.”
That led the international team of scientists to analyze whether Isturisa had comparable safety and efficacy in patients of Asian versus non-Asian origin.
“We wanted to examine whether [Isturisa] would have similar beneficial effects in people of Asian and non-Asian origin, and if any side effects would be different between the two groups,” the researchers wrote.
To that end, the team combined data from the LINC-3 and LINC-4 trials, calling it “a globally diverse population.” Altogether, they analyzed information from a total of 210 patients: 56 or 26.7% of Asian origin and 154 or 73.3% of non-Asian origin.
The Asian patients were generally younger than their non-Asian counterparts, with a median age of 38.5 versus 41. They also tended to have a lower body weight, height, and body mass index, or BMI, which is a ratio of weight to height.
Compared with non-Asian patients, a higher proportion of Asian individuals had a pituitary macroadenoma, or a tumor measuring 10 mm or more. That percentage was 33.9% for Asian patients versus 18.8% for non-Asian individuals. The Asian patients also had higher mean levels of urinary-free cortisol (mUFC) in 24 hours (10.2 vs. 4.2 times higher than the upper limit of normal) at the study’s start, or baseline.
Almost all patients in both groups had persistent or recurrent disease.
More Asian patients seen to stop treatment due to adverse events
Regarding treatment exposure, Asian patients received Isturisa for a longer period of time (median of 105 weeks vs. 96 weeks) and at a median lower dose (3.8 vs. 7.3 mg per day) compared with non-Asian patients.
The treatment was effective at normalizing urinary cortisol in both patient groups, with 68.1% of Asian and 75.8% of non-Asian patients seeing their cortisol levels dropping to levels equal to or below the upper normal limit after 72 weeks, or about 1.4 years, of treatment.
Overall, “numerically lower doses of [Isturisa were] required to achieve mUFC control doses” in Asian patients, the researchers noted.
Ultimately, the treatment was shown to ease Cushing’s physical manifestations in both groups of patients, while improving their quality of life and parameters associated with the risk for cardiovascular and metabolic disease. These included a reduction of weight, BMI, blood sugar levels, total cholesterol levels, and blood pressure, which were maintained during long-term treatment.
[Isturisa] is an effective and well tolerated treatment option for patients of Asian and non-Asian origin.
The most commonly reported adverse events in Asian patients were adrenal insufficiency (44.6%), nausea (33.9%), and decreased appetite and headache (both at 26.8%). Adrenal insufficiency occurs when the adrenal glands become unable to produce sufficient levels of cortisol or other hormones.
In non-Asian patients, the most frequently reported adverse events were nausea (45.5%), fatigue (40.9%), and headache (39%).
In both groups, high blood pressure was the most common severe adverse event, occurring in about 12% of the patients.
Low levels of cortisol occurred more frequently in Asian patients(58.9% vs. 40.3%), as did an enlargement of the pituitary adenoma (21.4% vs. 9.1%). A higher proportion of these patients also discontinued treatment due to adverse events (23.2% vs. 13.6%).
Despite the higher incidence of these adverse effects, “[Isturisa] is an effective and well tolerated treatment option for patients of Asian and non-Asian origin,” the researchers concluded.
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