Shire plc, a leading global biotechnology company, announced that the US Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for two investigational products for rare diseases: SHP621 (budesonide oral suspension, or BOS) for eosinophilic esophagitis (EoE), and SHP625 (maralixibat) for progressive familial intrahepatic cholestasis type 2 (PFIC2).
EoE is a serious, chronic and rare disease that stems from an elevated number of eosinophils, a type of white blood cell, that infiltrate the walls of the esophagus. EoE is characterized by an inflammation of the esophagus that may lead to difficulty swallowing (dysphagia).PFIC refers to a group of autosomal-recessive liver disorders of childhood that disrupt bile formation and present with cholestasis. BOS is a novel, topically active, oral viscous formulation of budesonide.
Breakthrough Therapy Designation was granted based on the results from a phase 2 trial in adolescents and adults (ages 11-40) with EoE. The co-primary endpoints were met and, compared with placebo, 12 weeks of budesonide oral suspension treatment significantly reduced both dysphagia symptoms and achieved higher proportion of subjects with histologic response (< 6 eos/hpf for all biopsies). There were no differences in cortisol levels, growth velocity (for age <18), or adverse events between the BOS and placebo groups. One subject on BOS developed esophageal candidiasis.
BOS has received orphan drug designation from the FDA. SHP621 BOS is currently in Phase 3; the clinical trial program investigating BOS in adolescents and adults ages 11-55 years with EoE was initiated in late 2015. EoE is a chronic rare disease that has been increasingly recognized over the past decade. Although the exact cause of EoE is unknown, it is believed to be triggered by a variety of stimuli including certain foods and environmental allergens
Maralixibat (LUM001) is being evaluated in several rare cholestatic liver diseases for both pediatric and adult populations. Preclinical models suggest that maralixibat is a potent, selective inhibitor of the apical sodium-dependent bile acid transporter (ASBT). Shire is developing maralixibat as an oral solution formulation for pediatric indications. Maralixibat was granted orphan designation by both the FDA and the European Medicines Agency (EMA). Maralixibat is currently in Phase 2 trials for PFIC.
The Breakthrough Therapy Designation for maralixibat in PFIC2 was supported by the interim results of Shire’s phase 2 single-arm, open-label study LUM001-501 (INDIGO) in pediatric patients with PFIC. Twelve of the 33 patients enrolled (36.4%) experienced a serious treatment-emergent adverse event, of whom 4 patients (12.1%) experienced a total of 5 serious treatment-emergent adverse events which were assessed by investigator as causally related to treatment (abdominal pain upper, diarrhea, cholangitis, blood bilirubin increased, and international normalized ratio increased).
Three types of PFIC have been identified and related to mutations in hepatocellular transport system genes involved in bile formation. PFIC2 usually appears in the first months of life. Treatment options for PFIC are generally focused on surgical treatment, such as partial external biliary diversion (PEBD) or liver transplantation. PFIC is the cause of 10–15% of liver transplant indications in children. Currently, there are no therapeutic options specifically indicated for the treatment of PFIC.
