SUN-454 Rationale and Methods for a Phase II Trial Evaluating Osilodrostat in Pediatric Patients with Cushing's Disease

Abstract

Background: Cushing’s disease (CD) is a rare disease associated with significant morbidity and mortality, with 2-5 new cases per million per year, of which 10% occur in children (Stratakis CA. Endocrinol Metab Clin North Am 2012;41:793-803). In children, CD presents with a combination of weight gain and slowed linear growth. First-line surgery is the treatment of choice for most patients, with a success rate of 60-98% in pediatric patients if performed by an expert pituitary surgeon (Keil MF. J Clin Endocrinol Metab 2013;98:2667-78). When surgery is not successful, patients require additional pharmacologic interventions, which are currently limited in children. Osilodrostat is a potent oral 11β-hydroxylase inhibitor in clinical development for the treatment of CD. This Phase II, multicenter, open-label, non-comparative study will evaluate the pharmacokinetics (PK), pharmacodynamics and safety/tolerability of osilodrostat in patients aged 6-<18 years with Cushing’s disease (clinicaltrials.gov identifier: NCT03708900). Methods: This single-arm study will enroll 12 evaluable patients aged 6-<18 years with confirmed CD for whom pituitary surgery is not an option, for whom surgery has failed, or who are awaiting surgery. CD will be confirmed by the clinical criteria of decreasing growth percentiles with increasing weight (defined by height SDS <0, BMI SDS >0, and a strong clinical suspicion of CD), an abnormal low-dose dexamethasone suppression test, measurable morning ACTH levels, and two 24-hour UFC measurements >1.3 x ULN. This study consists of two phases: a 12-week core phase and an optional 9-month extension period for patients who obtain a clinical benefit from osilodrostat as judged by the investigator. The primary objective is to assess the PK (Cmax and Ctrough) of osilodrostat during the 12-week core study. A secondary objective is to assess the proportion of patients with normal mean UFC (mUFC; determined from two 24-hour UFC samples) at weeks 6 and 12. Other secondary objectives include: assessment of safety and tolerability up to week 12 of the core phase and up to month 12 of the extension phase; assessment of efficacy up to month 12. The starting dose of osilodrostat will be 1 mg once daily and 1 mg twice daily for patients weighing <60 kg and ≥60 kg, respectively. The dose may be titrated based on mUFC response. PK parameter estimates will be calculated by pooling individual plasma osilodrostat concentration-time data and analyzed using non-compartmental analysis. Conclusion: This Phase II, multicenter, open-label, non-comparative study will be the first study of osilodrostat in pediatric patients with CD. The results of this study may allow further clinical development of osilodrostat in children with CD.