Isturisa Continues to Lower Cortisol Levels in Phase 2 Extension Trial

Cardiovascular symptoms controlled, no new safety signals seen after 7 years

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A total of 63.2% of participants in the extension trial responded to Isturisa by their last UFC measurement, with seven within normal range.

Isturisa (osilodrostat) led to sustained reductions in cortisol levels in people with Cushing’s disease over nearly seven years of treatment in an extension phase of the Phase 2 LINC-2 trial.

Cardiovascular symptoms were also well controlled throughout the study and no new safety signals were detected.

“These data support the use of long-term [Isturisa] as an effective treatment option in patients with persistent, recurrent or de novo [new] Cushing’s disease,” the researchers wrote.

The study, “Long-term efficacy and safety of osilodrostat in Cushing’s disease: final results from a Phase II study with an optional extension phase (LINC 2),” was published in Pituitary.

Isturisa is an oral therapy that works by inhibiting 11-beta-hydroxylase, an enzyme required for the final step of cortisol production. It works by preventing excess cortisol production, normalizing its levels in the body and easing Cushing’s symptoms.

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It’s approved in the U.S., Europe, and Japan for people in whom surgery isn’t an option or was ineffective. In Europe and Japan, this includes people with Cushing’s syndrome, and in the U.S., people with Cushing’s disease, a type of Cushing’s syndrome.

Originally developed by Novartis, Isturisa was acquired by Recordati in 2019.

The Novartis-sponsored Phase 2 LINC-2 trial (NCT01331239) sought to assess the safety and effectiveness of the therapy in Cushing’s disease patients, ages 18–75.

The primary goal was to determine whether it would lead to reductions in urinary free cortisol (UFC) levels, which indicate the amount of active cortisol circulating in the body. A complete treatment response was defined as achieving UFC within normal range and a partial response was at least a 50% reduction in UFC from the start of the study (baseline).

In the core part of the study, originally called LINC-1, 12 patients were given Isturisa at doses ranging from 2–50 mg twice daily, which was adjusted based on response over 10 weeks. Overall, 11 had normal UFC levels after treatment.

A protocol amendment created the LINC-2 trial, which evaluated Isturisa’s effects in a larger group, including four people involved in LINC-1 as well as 15 newly enrolled patients, all of whom had UFC levels above the normal range.

These 19 participants were given Isturisa twice daily with a maximum dose of 30 mg, depending on individual needs. The overall response rate was  78.9% at 22 weeks and all treatment responders had UFC levels within a normal range.

Common side effects included nausea, diarrhea, lack of energy, and adrenal insufficiency, which happens when the adrenal glands are unable to produce enough of certain hormones.

Isturisa outcomes in extension trial

Following the completion of the core study, all those who achieved a clinical benefit had the option to enter a long-term extension phase. The investigators reported results from this extension in the new publication.

Overall, 16 participants continued to the extension phase — 14 completed a first one-year extension phase and eight completed a second, open-ended extension. Median Isturisa exposure among them was 5.4 years, with a median average dose of 10.6 mg.

Of them, 13 (81.3%) were overall UFC responders at week 70, 12 complete responders. The treatment response rate remained between 50–88% up to month 70 of the extension phase.

Ultimately, 63.2% of participants were complete or partial responders as of their last UFC measurement and seven  had UFC values within normal range. Other cortisol measurements were similarly reduced.

“[Isturisa] led to a rapid, robust and durable reduction in mean UFC,” the researchers wrote, noting this is “important to alleviate the clinical burden of disease.”

Patients were also monitored for cardiovascular symptoms, which are common in Cushing’s patients and tend to worsen over time without treatment. Data showed most cardiovascular measures, including blood sugar, blood pressure, and body weight were well controlled with Isturisa throughout follow-up.

During the core study, levels of some hormones, including adrenal hormone precursors and testosterone in female patients, increased. Mean hormone levels fell closer to baseline values during the extension.

Safety was similar to that reported during the core phase, with no new safety signals detected. The most common side effects expected to be related to Isturisa were adrenal insufficiency, increased blood levels of the corticotropin hormone, nausea, and abnormal hormone levels. Most side effects were mild or moderate in severity and three people discontinued treatment due to them.

After the extension period, a separate rollover study became available for patients achieving clinical benefit to continue using Isturisa.

The long-term safety and effectiveness of Isturisa have also been demonstrated in two Phase 3, placebo-controlled, trials, called  LINC-3 (NCT02180217) and LINC-4 (NCT02697734). A Phase 2 trial (NCT03708900) is evaluating the safety and tolerability of Isturisa in children ages 6–17 with Cushing’s disease.