FDA Approves New Oral Treatment Isturisa for Cushing’s Disease

Isturisa (osilodrostat) is now approved in the U.S. for adults with Cushing’s disease for whom pituitary gland surgery is not an option or whose disease has returned after surgery, Recordati announced.

The therapy is the first U.S. Food and Drug Administration (FDA)-approved medicine for Cushing’s disease to directly address the root cause of the disease — the excessive production of the hormone cortisol caused by a tumor in the pituitary gland.

It is an oral medicine that inhibits cortisol production by blocking an enzyme called 11-beta-hydroxylase, which is involved in cortisol synthesis. Blocking the enzyme prevents the overproduction of cortisol, controlling or normalizing the hormone’s levels in the body, and reducing Cushing’s disease symptoms.

“We are pleased with FDA’s recognition of Isturisa as an effective and safe treatment for patients with Cushing’s disease,” Andrea Recordati, Recordati’s CEO said in a press release.

“We extend our deepest gratitude to the patients who participated in the clinical trials and their families and caregivers who supported them. We also appreciate the hard work of the investigators, clinicians and study staff to bring this therapy to patients in need. Recordati Rare Diseases is committed to working to ensure everyone who needs access to this therapy will receive it,” Recordati added.

The FDA’s decision follows the approval earlier this year of Isturisa by the European Commission (EC) for treating people with endogenous Cushing’s syndrome.

Both agencies based their resolutions on results from the LINC-3 Phase 3 clinical trial (NCT02180217), which showed that treatment with Isturisa tablets was more effective than a placebo at returning cortisol levels to normal.

The trial included 137 people with persistent Cushing’s disease (about three-quarters were women, average age 41 years), who first received 2 mg of Isturisa twice a day, with possible dose increases up to 30 mg twice a day, for 26 weeks.

At the end of that period, 71 patients who had normal cortisol levels at week 24, had not required a dose increase after week 12, and who tolerated the treatment well, were assigned randomly to continue Isturisa (36 patients) or switch to a placebo (35 patients), for an additional eight weeks (total of 34 weeks of treatment).

Afterward, patients could choose to continue taking Isturisa for another 12 weeks in an open-label extension of the study.

Results of the trial showed that significantly more patients taking Isturisa (86%) had normal urinary cortisol levels compared to placebo-receiving patients (29%) at the end of the 34-week period, which meant the trial met its primary efficacy goal.

Other positive results included half of the patients (53%) reaching normal cortisol levels at the end of the 24-week dosing period without requiring a dose increase after week 12.

The most common side effects (occurring in more than 20% of patients) associated with Isturisa were adrenal insufficiency (adrenal glands not producing adequate amounts of steroid hormones, primarily cortisol), headache, vomiting, nausea, fatigue, and edema (swelling caused by fluid retention).

Adverse side effects associated with low cortisol levels and elevated adrenal hormone precursors (pre-active substances converted into a hormone) also could occur in some people taking the medicine.

“Cushing’s disease results in an increased risk of cardiovascular and cerebrovascular diseases, as well as hypercoagulability, diabetes, infections, depression, and decreased quality of life,” said Maria Fleseriu, MD, professor and director of the Pituitary Center at Oregon Health Sciences University.

“Until now, patients in need of medications to reduce cortisol levels have had few approved options, either with limited efficacy or with too many adverse effects. With this demonstrated effective oral treatment, we have a therapeutic option that will help address patients’ needs in this underserved patient population,” she added.

A Phase 3 trial — LINC-4 (NCT02697734) — is ongoing to confirm these effectiveness and safety findings in 69 patients with Cushing’s disease. In the study, patients will receive Isturisa or a placebo in the first 12 weeks, and then all participants will be given Isturisa for another 36 weeks.

Novartis also is conducting a Phase 2 trial (NCT03708900) to determine Isturisa’s benefits and safety in children with Cushing’s disease, ages 6 and older, who are ineligible, are waiting for or had disease recurrence after surgery. Patient recruitment is ongoing in Europe. More information is available here.

Isturisa is available as film-coated tablets to be taken twice a day, and as prescribed by a healthcare provider. The provider may re-evaluate and readjust the dosage according to patient response.

The FDA granted Isturisa’s approval to Novartis, the company that originally developed the therapy, and whose worldwide rights are now owned by Recordati.

Under the orphan status granted to Isturisa, Recordati will have seven years of market exclusivity to commercialize the medicine in the U.S. The company expects Isturisa to be available in the country in the second or third quarter of 2020.