Subgroup Analysis from Phase 3 Study Shows Subgroup of Cushing Patients with Diabetes May Benefit from Investigational Therapy

Subgroup Analysis from Phase 3 Study Shows Subgroup of Cushing Patients with Diabetes May Benefit from Investigational Therapy

A small publicly traded Irish and American biotech called Strongbridge Biopharma plc (Nasdaq: SBBP) recently announced the results from a sub analyses of patients with diabetes mellitus from the Phase 3 SONICS study of RECORLEV (levoketoconazole) for potential treatment of endogenous Cushing’s syndrome. The experimental oral therapy led to sustained improvements in cortisol and blood sugar control among not only Cushing’s patients but also diabetes. The results of the study recently published in the peer-reviewed journal, Frontiers in Endocrinology. The data still needs verification from independent study.

The Condition

Endogenous Cushing’s syndrome, is a rare, serious, and potentially lethal endocrine disease caused by chronic elevated cortisol exposure – often the result of a benign tumor of the pituitary gland. This benign tumor tells the body to overproduce high levels of cortisol for a sustained period of time, and this often results in undesirable physical changes. The disease is most common among adults between the ages of 30 to 50, and it affects women two times more often than men. Women with Cushing’s syndrome may experience a variety of health issues including menstrual problems, difficulty becoming pregnant, excess male hormones (androgens), primarily testosterone which can cause hirsutism (growth of coarse body hair in a male pattern), oily skin, and acne. Additionally, the internal manifestations of the disease are potentially life threatening. These include metabolic changes such as high blood sugar, or diabetes, high blood pressure, high cholesterol, fragility of various tissues including blood vessels, skin, muscle and bone, and psychological disturbances such as depression, anxiety and insomnia. Untreated, the five-year survival rate is only approximately 50 percent.

The Study

This Phase 3 multinational multi-site study (NCT01838551) investigates Recorlev’s ability to normalize patient’s average 24-hour urinary free cortisol (mUFC) levels  for half a year of maintenance therapy, precluding any dose increases during the period.  This study involves three phases including 1) dose-titration phase, 2) six-month maintenance phase and 3) six-month extended monitoring and evaluation to better understand the impact of this therapy.

The Results

The manuscript, entitled “Levoketoconazole in the Treatment of Patients with Cushing’s Syndrome and Diabetes Mellitus: Phase 3 SONICS Results,” demonstrates that treatment with RECORLEV results in significant cortisol control in patients with Cushing’s syndrome and diabetes mellitus, as well as meaningful improvements in key glycemic measures, such as hemoglobin A1c (HbA1c) and fasting blood glucose (FBG), and cardiovascular risk markers such as low-density lipoprotein (LDL)-cholesterol. These results were observed following a dose titration phase and a six-month maintenance phase.

  • Mean urinary-free cortisol (mUFC) normalization rate was similar in patients with and without diabetes at the end of the maintenance phase.
  • Mean improvements in HbA1c and FBG in the maintenance phase were more meaningful among patients with comorbid diabetes mellitus than in those without. These improvements in glycemia markers were not due to changes in antidiabetic medication use, which were overall stable during treatment.
  • Significant mean reductions from baseline, representing improvement in cardiovascular risk markers of LDL-cholesterol, weight, and body mass index were seen in patients with and without diabetes mellitus.
  • Adverse events that were more common in patients with diabetes mellitus included nausea (58.3%), vomiting (19.4%), and urinary tract infection (16.7%); none prompted study drug withdrawal. As noted in the Phase 3 SONICS results published in The Lancet Diabetes & Endocrinology, nausea and headache were the most common adverse events in the overall study population. These events rarely affected treatment and did not appear to be dose related.

The recent manuscript was published in Frontiers in Endocrinology

Subgroup Analysis

This data deemed exploratory still must be verified by an additional independent study. However, the results of this subgroup analysis showed that “treatment with [Recorlev] led to sustained normalization of mUFC and improvement in glycemic control that was more pronounced in patients with [diabetes],” the researchers wrote.


Stonebridge Biopharma was founded in 1996 in Sweden as Cortendo AB with an original focus on the regulation of cortisol secretion in patients with diabetes. The company has been busy targeting and achieving milestones including a strategic acquisition in 2016 of the U.S. rights to KEVEYIS, (dichlorphenamide) part of a rare disease drug development strategy.

With its primary center of activity in Pennsylvania, the firm employs between 50 and 100. Trading at 2.63, the company reports most recently revenue of approximately $30 million and losses of $45 million. With approximately $87 million cash in the bank, the company is primarily owned by institutional investors (10% owned by insiders).

Lead Research/Investigators

  • Rosario Povinelli, Università Federico II di Napoli, Naples, Italy
  • Atanaska Elenkova, Medical University-Sofia, Sofia, Bulgaria
  • Maria Fleseriu, Diabetes and Clinical Nutrition, and Department of Neurological Surgery, Oregon Health and Science University, Portland, OR, United States
  • Richard A. Feelders, Erasmus University Medical Center, Rotterdam, Netherlands
  • Przemyslaw Witek, Medical University of Warsaw, Warsaw, Poland
  • Yona Greenman, Tel Aviv-Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  • Eliza B. Geer, Memorial Sloan Kettering Cancer Center, New York, NY, United States
  • Paola Perotti, University of Turin, Orbassano, Italy
  • Leonard Saiegh, Bnai-Zion Medical Center, Haifa, Israel
  • Fredric Cohen, Strongbridge Biopharma, Trevose, PA
  • Giorgio Arnaldi, Polytechnic University of Marche Region, Ancona, Italy