Osilodrostat Holds Promise for Treating Cushing's Disease

Miriam E Tucker

April 05, 2017

ORLANDO, Florida — The investigational drug osilodrostat (Novartis) is showing promise for the treatment of Cushing's disease.

Osilodrostat is an orally active inhibitor of 11ß-hydroxylase, the enzyme that catalyzes the last step of cortisol biosynthesis in the adrenal cortex. Its mechanism of action is similar to that of the older Cushing's drug metyrapone, but osilodrostat has a longer plasma half-life and is more potent against 11ß-hydroxylase.

In the initial 22-week prospective, phase 2, open-label LINC-2 study, osilodrostat reduced urinary free cortisol (UFC) in all 19 study subjects, normalized it in 15 (78.9%), and was generally well-tolerated (Pituitary. 2016;19:138-148).

Now Rosario Pivonello, MD, of the department of molecular and clinical endocrinology and oncology of the Federico II University of Naples, Italy, has reported new findings from a 31-month extension to the LINC-2 study here at ENDO 2017: The Endocrine Society Annual Meeting.

In this latest research, urinary free cortisol normalized in half of the 16 patients. Moreover, with removal of the data for four subjects (who dropped out prior to 31 weeks), there was a 100% response rate (defined as the proportion of patients with either UFC within normal levels or UFC greater than the upper limit of normal but at least 50% decreased from baseline), Dr Pivonello reported.

Asked to comment, session moderator Luma Ghalib, MD, assistant professor in the division of endocrinology, diabetes, and metabolism at Ohio State University Wexner Medical Center, Columbus, told Medscape Medical News, "It's exciting. I would like to believe the 100% response….That is unheard of for any other medical treatment in Cushing's disease."

She also noted, "It's almost like a reinvention of metyrapone, but hopefully with fewer side effects. Time will tell....We really need good medical treatment for Cushing's."

Phase 3 studies with osilodrostat are ongoing.

High Response Rate, Good Tolerability

Cushing's syndrome is a long-lasting condition that can be life-threatening because of its complications, including diabetes, high blood pressure, and depression. It is characterized by an excess of the hormone cortisol in the blood, which is usually caused by a tumor and is most often treated by initial resection of the primary lesion(s) underlying the syndrome. Medical therapy is an option if surgery isn't possible or as second-line treatment.

Dr Pivonello explained that patients who had responded in the core LINC-2 study were eligible to enter the extension phase using the same dose of osilodrostat, 2 mg to 30 mg twice daily. Dose adjustments were permitted in the extension. Of the 16 who entered, 12 remained at 31 months.

In an analysis including all 16 patients with the four who didn't complete the study counted as nonresponders, eight of the 16 (50%) were controlled (UFC at or below upper limit of normal) and one (6.3%) was partially controlled (UFC greater than the upper limit of normal but at least 50% decreased from baseline), giving a total response rate of 56.3% (9/16).

But with those four patients removed, those rates were 87.5% (14/16) controlled, 12.5% partially controlled (2/16), and 100% one or the other (responders). "At 31 months, no patients had escape from response," Dr Pivonello said.

Significant reductions were seen in body weight (from 83.8 kg at baseline to 74.1 kg at 31 months) and body mass index (from 29.6 to 26.2 kg/m2). Nonsignificant decreases also were seen in systolic and diastolic blood pressure and fasting plasma glucose.

As expected with the mechanism of action of osilodrostat, there were decreases in serum cortisol from baseline (29.5 to 13.2 µg/dL) and aldosterone (168.1 to 19.0 pmol/L) and increases in ACTH (20.0 to 54.0 pmol/L) and the cortisol precursor 11-deoxycortisol and aldosterone precursor 11-deoxycorticosterone. Testosterone levels rose from 7.4 to 11.2 nmol/L in males and from 1.1 to 1.9 nmol/L in females.

Most of the increase in 11-deoxycortisol and testosterone occurred during the first few months of the study but started to decline during the extension, in some cases returning to baseline, Dr Pivonello noted.

Pituitary tumor size was measured in six patients, at months 16 to 28. It had grown from baseline in three patients (by 1.0 to 3.9 mm) and shrank in the other three, by 1.0 to 5.1 mm. 

The most frequently reported adverse events decreased over time. From the first treatment to 22 weeks, they included asthenia in eight, fatigue in six, nasopharyngitis and nausea in four each, diarrhea and adrenal insufficiency in three each, and hypokalemia in two. By 31 months, adverse events included abdominal pain in just two patients, and one each with arthralgia, headache, hypokalema, nasopharyngitis, and nausea.

In all, hypocortisolism-related adverse events were reported in six patients, all nonserious.

A total of eight serious adverse events were reported in three patients, including electrocardiogram QT prolongation, food poisoning, gastroenteritis, headache, noncardiac chest pain, pituitary tumor–related (in two), and uncontrolled Cushing's disease.

Two ongoing phase 3 studies (LINC-3 and LINC-4) will evaluate osilodrostat in larger Cushing's disease patient populations.

"We are waiting for the results," Dr Pivonello said

Dr Ghalib commented, "There are so many current treatments for Cushing's, but none are optimal. Many have multiple complications. It would be nice to have more options."

Dr Pivonello has received research funding, honoraria, and/or consulting fees from Novartis, Shire, Pfizer, Ipsen, and Ferring Pharmaceuticals. Disclosures for the coauthors are listed in the abstract. Dr Ghalib has no relevant financial relationships.

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ENDO 2017. April 1, 2017; Orlando, FL. Abstract OR22-5

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