Isturisa Effective in Treating Cushing’s Syndrome Other Than Cushing’s Disease, Phase 2 Trial Shows

Recordati’s Isturisa (osilodrostat) safely and effectively normalizes urinary levels of cortisol in people with endogenous Cushing’s syndrome other than Cushing’s disease, according to data from a Phase 2 clinical trial in Japan.

Endogenous Cushing’s syndrome occurs when the body produces abnormally high levels of the hormone cortisol due to a tumor in the pituitary gland (Cushing’s disease) or elsewhere in the body.

This was the first study to report Isturisa’s safety and effectiveness in this particular subset of Cushing’s patients, as previous Isturisa trials included only people with Cushing’s disease.

These findings may be particularly relevant to patients in Japan, where there is a higher proportion of endogenous Cushing’s syndrome other than Cushing’s disease, compared with Western countries.

In March, Recordati filed a marketing application to Japan’s Ministry of Health, Labour and Welfare seeking Isturisa’s approval for the treatment of people with Cushing’s syndrome.

The trial’s results, “A multicenter, phase 2 study to evaluate the efficacy and safety of osilodrostat, a new 11β-hydroxylase inhibitor, in Japanese patients with endogenous Cushing’s syndrome other than Cushing’s disease,” were published in Endocrine Journal.

Isturisa, developed originally by Novartis and acquired by Recordati in 2019, is an orally available small molecule that blocks 11-beta-hydroxylase, an enzyme essential for cortisol synthesis. This helps reduce or even normalize cortisol levels in the body, easing Cushing’s symptoms.

Its mechanism of action is similar to the commonly used therapy Metopirone (metyrapone), but Isturisa has stronger inhibitory activity and remains active for longer periods of time, requiring less frequent administrations.

Isturisa, taken as a film-coated tablet twice a day, is approved in the U.S. for Cushing’s disease patients whose disease returned after pituitary gland surgery or who cannot undergo surgery, and in the European Union for people with endogenous Cushing’s syndrome.

The approvals were supported by data from the LINC-3 Phase 3 clinical trial (NCT02180217), which showed that Isturisa was superior to a placebo at normalizing urinary cortisol levels in people with persistent Cushing’s disease.

To date, no trial has assessed Isturisa’s effects in people with other types of endogenous Cushing’s syndrome. These data would be particularly relevant in Japan, where the proportion of patients with Cushing’s syndrome other than Cushing’s disease is estimated to be twice as high as that reported for Western countries (64% vs. 30%).

Isturisa currently is under regulatory review for the treatment of endogenous Cushing’s syndrome in Japan.

The Novartis-sponsored, multi-center, Phase 2 trial (NCT02468193) evaluated Isturisa’s safety and effectiveness in nine Japanese patients (seven women and two men) with various types of endogenous Cushing’s syndrome other than Cushing’s disease.

A therapeutic dose for each individual was established during the first 12 weeks (about three months), after which participants continued to receive the therapeutic dose for an additional 36-week period (about nine months).

Those who continued to show clinical benefit had the option to enter an extension period, in which all would receive treatment for an additional six months or until therapy discontinuation. All patients had a 30-day safety follow-up after the last Isturisa dose.

The trial’s main goal was to assess patients’ change in mean levels of cortisol in the urine after 12 weeks. Secondary goals included such changes at weeks 24 and 48, the proportion of patients with complete or partial responses, and patients’ quality of life.

A drop in urinary cortisol levels to below the upper limit of the normal range was considered a complete response, while having levels above this upper limit with a reduction of at least 50% was considered a partial response.

At data cut-of date of October 2018, seven participants completed the first 12-week period, two completed 48 weeks of treatment, and none had completed the extension period. Main reasons for discontinuation were adverse events (four patients), followed by patient/guardian decision (two patients). Mean treatment duration was 12 weeks.

Results showed that at week 12, patients’ urinary cortisol levels were dropped by a median of 94.5%, with six patients achieving complete responses and one having a partial response. A more than 95% drop in cortisol levels also was observed in the last assessment of the two patients discontinuing treatment before week 12.

At week 24 (three patients) and 48 (two patients), cortisol levels were reduced by a median of more than 90%, and one patient showed a partial response at both time points. Similar fast drops in cortisol levels were observed between patients previously treated or not taking Metopirone.

There were no significant changes in patients’ quality of life, which was not surprising to the researchers, due to the short duration of treatment in this study.

Isturisa’s safety profile was consistent with that reported in previous trials, with manageable adverse events (a medical term for side effects), no life-threatening events or deaths, and no new safety concerns.

All patients reported at least one side effect, with adrenal insufficiency as the most common (seven patients). Four participants (44.4%) had serious adverse events, with adrenal insufficiency (in two patients) as the only event suspected by the investigator to be related to treatment.

These findings highlighted that Isturisa resulted in a clinically significant drop in urinary cortisol levels in all nine patients with endogenous Cushing’s syndrome other than Cushing’s disease.

Combined with results from previous trials in Cushing’s disease patients, the data suggest that Isturisa is a safe and effective therapy option for people with endogenous Cushing’s syndrome, regardless of disease type.

The team emphasized that larger studies that include patients from around the world are required to confirm Isturisa’s effects in all types of endogenous Cushing’s syndrome.