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A more gradual increase in oral osilodrostat (Isturisa) dosing was better tolerated among patients with Cushing's disease, compared with those who had more accelerated increases, a researcher reported.

Looking at outcomes from two phase III trials assessing osilodrostat, only 27% of patients had hypocortisolism-related adverse events if dosing was gradually increased every 3 weeks, said Maria Fleseriu, MD, of Oregon Health & Science University in Portland, in a presentation at the virtual meeting of the American Association of Clinical Endocrinology (AACE).

On the other hand, 51% of patients experienced a hypocortisolism-related adverse event if osilodrostat dose was increased to once every 2 weeks.

Acting as a potent oral 11-beta-hydroxylase inhibitor, osilodrostat was for adults with Cushing's disease who either cannot undergo pituitary gland surgery or have undergone the surgery but still have the disease. The drug is currently available in 1 mg, 5 mg, and 10 mg film-coated tablets.

The approval came based off of the positive findings from the complementary LINC3 and LINC4 trials.

The LINC3 trial included 137 adults with Cushing's disease with a mean 24-hour urinary free cortisol concentration (mUFC) 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).

During the open-label, dose-escalation period, all the participants were given 2 mg of osilodrostat twice per day, 12 hours apart. Over this 12-week titration phase, dose escalations were allowed once every 2 weeks if there were no tolerability issues to achieve a maximum dose of 30 mg twice a day.

After this 12-week dose-escalation schedule, additional bumps up in dose were permitted every 4 weeks. The median daily osilodrostat dose was 7.1 mg.

The LINC4 trial included 73 patients with Cushing's disease with an mUFC over 1.3 times the upper limit of normal. The 48 patients randomized to receive treatment were likewise started on 2 mg bid of osilodrostat. However, this trial had a more gradual dose-escalation schedule, as doses were increased only every 3 weeks to achieve a 20 mg bid dose.

After the 12-week dose-escalation phase, patients on a dose over 2 mg bid were restarted on 2 mg bid at week 12, where dose escalations were permitted once every 3 weeks thereafter to achieve a maximum 30 mg bid dose during this additional 36-week extension phase.

Patients in this trial achieved a median daily osilodrostat dose of 5.0 mg.

In both studies, patients' median age was about 40 years, the majority of patients were female, and about 88% had undergone a previous pituitary surgery.

When comparing the adverse event profiles of both trials, Fleseriu and colleagues found that more than half of patients on the 2-week dose-escalation schedule experienced any grade of hypercortisolism-related adverse events. About 10.2% of these events were considered grade 3.

About 28% of these patients had adrenal insufficiency -- the most common hypercortisolism-related adverse event reported. This was a catch-all term that include events like glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased cortisol, Fleseriu explained.

Conversely, only 27.4% of patients on a 3-week dose escalation schedule experienced a hypercortisolism-related adverse event, and only 2.7% of these were grade 3.

No grade 4 events occurred in either trial, and most events were considered mild or moderate in severity.

"These adverse events were not associated with any specific osilodrostat dose of mean UFC level," Fleseriu said, adding that most of these events occurred during the initial dose-escalation periods.

About 60% and 58% of all hypocortisolism-related adverse events occurred during the dose titration period in the 2-week and 3-week dose-escalation schedules, respectively. These events were managed via dose reduction, a temporary interruption in medication, and/or a concomitant medication.

Very few patients in either trial permanently discontinued treatment due to these adverse events, Fleseriu noted.

"Despite differences in the frequency of dose escalation, the time to first mUFC normalization was similar in the LINC3 and LINC4 studies," she said, adding that "gradual increases in osilodrostat dose from a starting dose of 2 mg bid can mitigate hypocortisolism-related adverse events without affecting mUFC control."

"For patients with Cushing's disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response and tolerability aimed at normalizing cortisol levels," Fleseriu concluded.

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