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Oral osilodrostat (Isturisa) normalized cortisol levels in Cushing's disease patients who were ineligible for or not cured with pituitary surgery, according to the phase III LINC 3 trial.

After 24 weeks of open-label treatment with twice-daily osilodrostat, 53% of patients (72 of 137; 95% CI 43.9-61.1) were able to maintain a complete response -- marked by mean 24-hour urinary free cortisol concentration of the upper limit of normal or below -- without any uptitration in dosage after the initial 12-week buildup phase, reported Rosario Pivonello, MD, of the Università Federico II di Napoli in Italy, and colleagues.

As they explained in their study online in , following the 24-week open-label period these complete responders to treatment were then randomized 1:1 to either remain on osilodrostat or be switched to placebo.

During this 10-week randomization phase, 86% of patients maintained their complete cortisol response if they remained on osilodrostat versus only 29% of those who were switched to placebo (odds ratio 13.7, 95% CI 3.7-53.4, P<0.0001) -- meeting the trial's primary endpoint.

As for adverse events, more than half of patients experienced hypocortisolism, and the most common adverse events included nausea (42%), headache (34%), fatigue (28%), and adrenal insufficiency (28%).

"Alongside careful dose adjustments and monitoring of known risks associated with osilodrostat, our findings indicate a positive benefit-risk consideration of treatment for most patients with Cushing's disease," the researchers concluded.

This oral inhibitor of 11β-­hydroxylase -- the enzyme involved in the last step of cortisol synthesis -- was based on these findings, and is currently available in 1 mg, 5 mg, and 10 mg film-coated tablets.

The prospective trial, consisting of four periods, included individuals between the ages of 18 and 75 with confirmed persistent or recurrent Cushing's disease -- marked by a mean 24-h urinary free cortisol concentration over 1.5 times the upper limit of normal (50 μg/24 hours), along with morning plasma adrenocorticotropic hormone above the lower limit of normal (9 pg/mL). All individuals had either undergone prior pituitary surgery or irradiation, were not deemed to be candidates for surgery, or had refused to have surgery.

During the first open-label study period, all participants took 2 mg of oral osilodrostat twice daily, spaced 12 hours apart. This dose was then titrated up if the average of three 24-h urinary free cortisol concentration samples exceeded the upper limit of normal. During the second study period, which spanned weeks 12 through 24, all participants remained on their osilodrostat therapeutic dose. By week 24, about 62% of the participants were taking a therapeutic dose of 5 mg or less twice daily; only about 6% of patients needed a dose higher than 10 mg twice daily.

In the third study period, which spanned weeks 26 through 34, "complete responders" who achieved normal cortisol levels were then randomized to continue treatment or be switched to placebo, while those who did not fully respond to treatment continued on osilodrostat. For the fourth study period, from weeks 24 through 48, all participants were switched back to active treatment with osilodrostat.

Overall, 96% of participants were able to achieve a complete response at some point while on osilodrostat treatment, with two-thirds of these responders maintaining this normalized cortisol level for at least 6 months. The median time to first complete response was 41 days.

Metabolic profiles also improved along with this reduction in cortisol levels. These included improvements in body weight, body mass index, fasting plasma glucose, both systolic and diastolic blood pressures, and total cholesterol levels.

"Given the known clinical burden of cardiovascular risk associated with Cushing's disease, the improvement in clinical features shown here indicates important benefits of osilodrostat," the researchers said. "By improving multiple cardiovascular risk factors, our findings are likely to be clinically relevant."

Along with metabolic improvements, patients also had "clinically meaningful improvements" in quality of life, as well as reductions in depressive symptoms measured by the Beck Depression Inventory score, the investigators reported.

One limitation to the trial, they noted, was an inability to control for concomitant medications, since nearly all participants were taking other medications, particularly antihypertensive and antidiabetic therapies.

"Further examination of the effects of osilodrostat on the clinical signs of Cushing's disease, and the reasons for changes in concomitant medications and the association between such medications and clinical outcomes would be valuable," Pivonello's group said.

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