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FDA grants breakthrough designation to investigational drugs for EoE, PFIC2
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The FDA has granted breakthrough therapy designation to two investigational drugs for eosinophilic esophagitis and progressive familial intrahepatic cholestasis type 2, respectively, the manufacturer announced.
SHP621 (budesonide oral suspension, Shire), is a topically active, oral viscous formulation of budesonide specifically formulated to treat EoE, which was superior to nebulized and swallowed budesonide in an open-label clinical trial, according to a press release.
The FDA’s breakthrough therapy designation follows results from a phase 2 trial showing treatment with budesonide oral suspension for 12 weeks significantly improved dysphagia symptoms and histologic response compared with placebo in adolescents and adults with EoE. Cortisol levels, growth velocity and adverse events were comparable between study arms, though one individual treated with budesonide oral suspension developed esophageal candidiasis.
The FDA previously granted orphan drug designation to budesonide oral suspension, and researchers are currently evaluating the drug in a phase 3 clinical trial.
Preclinical data suggest SHP625 (maralixibat, Shire) is a potent, selective apical sodium-dependent bile acid transporter (ASBT) inhibitor, designed to block reabsorption of bile acid in the ileum and increase fecal bile acid excretion, according to the press release. The drug is under investigation for several rare cholestatic liver diseases in both children and adults, and researchers are currently developing it as an oral solution formulation for children. The FDA and the European Medicines Agency both previously granted orphan designation to the drug, and researchers are currently evaluating it in phase 2 trials for progressive familial intrahepatic cholestasis (PFIC), a group of autosomal-recessive liver disorders that begin in childhood, disrupting bile formation and presenting with cholestasis.
The FDA’s breakthrough therapy designation for maralixibat in PFIC type 2, the most common type of PFIC, follows interim results from the phase 2, single-arm, open-label INDIGO study in children with PFIC. These data did not show statistically significant reductions in mean serum bile levels in children with PFIC overall, but those with PFIC2 had reduced serum bile acids and pruritus, and normalized liver parameters in patients with elevated liver enzymes at baseline.
Serious treatment-emergent adverse events occurred in 12 of the 33 patients enrolled, four of whom had five serious treatment-emergent adverse events, which were deemed causally related to treatment. These included abdominal pain, diarrhea, cholangitis, increased blood bilirubin and increased international normalized ratio, according to the press release.
PFIC is generally treated surgically, including partial external biliary diversion or liver transplantation, and there are currently no therapeutic options indicated specifically for PFIC.
Perspective
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W. Asher Wolf, MD, MPH
In the absence of a medication designed to treat esophageal inflammation in eosinophilic esophagitis, physicians have developed creative strategies to deliver medication to the esophagus. Fluticasone and budesonide, typically formulated for pulmonary diseases, have been the mainstays. Common approaches include swallowing the puffs of medication from an inhaler or taking the respules designed for a nebulizer, mixing the contents with a thickener such as Splenda to create a slurry, and then drinking the mixture.
Scintigraphy has been used to demonstrate that these methods are imperfect: esophageal dwell time of medication is suboptimal and drug is delivered well beyond the esophageal target. At the same time, multiple esophageal formulations, primarily of budesonide, have been studied with delivery mechanisms ranging from dissolving tablets to liquid suspensions. The results have been reliably excellent, but these drugs have struggled in the FDA approval process because successful treatment of eosinophilic esophagitis remains undefined.
The FDA breakthrough designation for a budesonide formulation is an exciting moment, moving an esophageal formulation of budesonide closer to use by physicians and patients suffering from eosinophilic esophagitis. This approval is the result of countless hours of research and a thoughtful approach by the FDA. Important questions regarding the cost and insurance coverage remain to be answered, but the move has the potential to help optimize therapy for a disease that is rapidly increasing in incidence and prevalence. Further research is needed to help us understand the etiology of eosinophilic esophagitis, and those results will likely shift our therapeutic approach in the future. For now, though, an esophageal formulation of budesonide is the best therapy for this disease.
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