Isturisa Helps Control Cortisol for 1.5+ Years in LINC-3 Study

Most patients report fewer symptoms and no new side effects in extension phase

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Treatment with Isturisa (osilodrostat) for 1.5 years or longer kept urine cortisol levels close to normal in patients with Cushing’s disease, and this translated into fewer symptoms with no new side effects, a study has found.

The findings come from an extension of LINC-3 (NCT02180217), a Phase 3 trial of 137 patients with Cushing’s disease where Isturisa was shown to be better than a placebo at rapidly lowering the levels of cortisol and keeping them under control for up to 48 weeks.

“These data support Isturisa as a viable long-term medical therapy option to maintain control of cortisol levels and signs and symptoms related to hypercortisolism [excessive cortisol] in patients with Cushing’s disease,” Alberto M. Pedroncelli, head of clinical development and medical affairs of global endocrinology at Recordati Rare Diseases, which markets Isturisa, said in a press release.

The findings were detailed in a study, “Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension,” published in the European Journal of Endocrinology.

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Cushing’s disease is caused by having too much of a hormone called cortisol in the body. Excess cortisol in Cushing’s disease is driven by the overproduction of another hormone called adrenocorticotropic hormone by the brain’s pituitary gland due to the presence of tumors in the gland.

This brings about a variety of symptoms, ranging from weight gain, fat accumulation, and skin that bruises easily to muscle weakness, high blood pressure (hypertension), and changes in mental health.

Isturisa is used to treat adults with Cushing’s disease who are not candidates for surgery to remove the pituitary gland — the first-line treatment for the condition — or had pituitary surgery but were not cured. The medicine helps ease Cushing’s symptoms by blocking the activity of an enzyme involved in cortisol production and bringing its levels back to normal.

Patients who took part in LINC-3 had the option to enter into its extension phase. Of the 137 participants (106 women and 31 men), 113 (82.5%) completed the study’s 48-week core phase, and 106 (77.4%) chose to enter its open-label extension phase, in which they continued to receive Isturisa for 72 weeks (about a year and 5 months), or longer.

As in the core phase of LINC-3, the dose of Isturisa was adjusted for each patient until their cortisol levels were under control and within the normal range. The median average dose was 7.4 mg/day, and doses ranged from 0.8 to 46.6 mg/day.

Most patients (71.5%) completed 72 weeks of treatment. The median duration of exposure to treatment was 130 weeks (about 2.5 years) from the start of the study, and the longest duration was 245 weeks (roughly 4.5 years).

At the end of the core phase, 91 (66.4%) patients had normal urine cortisol levels. This was determined using the 24-hour urinary free cortisol, which indicates the levels of the active form of the hormone in the body.

81% of patients in extension study had normal cortisol levels after 1.5 years

Cortisol levels remained under control during the extension phase, with 86 (81.1%) of the 106 patients having a mean 24-hour urinary free cortisol equal to or lower than the upper limit of the normal range after 72 weeks of treatment.

This occurred “alongside clinical benefits in most patients,” the researchers wrote.

At the start of the study, most patients showed physical manifestations of hypercortisolism, most commonly fat accumulation between the shoulders (dorsal fat pads) or above the collarbone (supraclavicular fat pads) and facial flushing. Some physical symptoms improved during the core phase of LINC-3, which were maintained or further improved during the extension phase.

This included an improvement in excessive hair growth (hirsutism) in 33 (86.8%) of 38 women after 72 weeks of treatment. The mean levels of testosterone, a male sex hormone, doubled in female patients during the core phase of LINC-3  from 1.3 to 2.6 nanomoles per liter (nmol/L). However, they dropped during the study’s extension phase to 2.1 nmol/L at week 72 and to 1.8 nmol/L at the last measurement taken. These data are consistent with those presented earlier this year by the company at the annual ENDO 2022 meeting.

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Improvements were also observed in hypertension and diabetes, two common complications of Cushing’s disease, and quality of life reported by the patients using CushingQoL and the Beck Depression Inventory.

Twelve (11.3%) of the 106 patients who entered the extension phase stopped taking Isturisa due to side effects. The most common side effects were nausea (45.3%), headache (36.5%), and fatigue (32.8%). No new or unexpected side effects were reported.

“Importantly, as well as providing long-term normalization of cortisol, continued treatment with [Isturisa] for over 72 weeks led to sustained improvements in clinical signs and physical manifestations of hypercortisolism and was generally well tolerated,” said Maria Fleseriu, MD, who is a professor of medicine and neurological surgery at Oregon Health & Science University, one of the study’s clinical sites. Fleseriu also directs the university’s Pituitary Center.

LINC-3 was funded by Novartis, which developed the treatment before it was bought by Recordati.