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).

“Receiving Breakthrough Therapy Designation on two pipeline products this past week reflects the potential of our strong and innovative pipeline of more than 60 programmes,” said Flemming Ornskov, M.D., MPH, and CEO, Shire. “Shire is committed to bringing innovation to the rare and specialty areas we focus on. We persevere to see compounds through the many stages of development through their challenges and successes, and always keep patients with unmet needs top of mind.”

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). The diagnosed prevalence of EoE ranges from approximately 15-55 cases per 100,000 persons, with high-end estimates reported by studies in Western regions.

PFIC refers to a group of autosomal-recessive liver disorders of childhood that disrupt bile formation and present with cholestasis. The symptoms of PFIC include severe itching of the skin (pruritus), and jaundice. PFIC is estimated to affect 1 in 50,000 to 1 in 100,000 births. PFIC2 is the most common type of PFIC, accounting for around half of cases.

According to the FDA, Breakthrough Therapy Designation is granted to a therapy that is intended to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on one or more clinically significant endpoints over current standard of care. Under the designation, the FDA provides intensive guidance, organizational commitment involving senior managers, and eligibility for rolling and priority review of the application; this process helps ensure patients have access to therapies as soon as possible, pending approval. Breakthrough Therapy Designation does not guarantee that FDA will ultimately approve BOS for EoE or maralixibat for PFIC2, and the timing of any such approval is uncertain.

“On behalf of patients in the United States with EoE and PFIC2, we are so pleased that the FDA has granted Breakthrough Therapy Designation to BOS and maralixibat,” said Philip J. Vickers, Ph.D., Head of R&D, Shire. “We look forward to working with the agency to continue their development and, pending FDA approval, deliver these therapeutic options to the patients who need them most.”

BOS is a novel, topically active, oral viscous formulation of budesonide. BOS is formulated specifically for EoE; in an open-label clinical trial, orally administered viscous budesonide was more effective than nebulized or swallowed budesonide for improving esophageal eosinophil counts and endoscopic findings in adults with a new diagnosis of EoE.

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. In severe cases, it can lead to strictures causing food impaction (food getting stuck in the esophagus), and in children it can lead to poor growth or weight loss due to feeding difficulties. Current management of EoE includes a trial of proton pump inhibitors and, if not effective, the elimination of certain food from patient diets, and different steroid formulations. Currently, there are no therapeutic options specifically indicated for the treatment of EoE.

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). ASBT inhibitors are designed to block bile acid reabsorption in the ileum and increases fecal bile acid excretion. 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.

While the interim results of INDIGO demonstrated no statistically significant reduction in mean serum bile levels from baseline across the study population as a whole, a subpopulation of patients with PFIC2 showed decreases from baseline in serum bile acids, marked reductions in pruritus, and normalization of liver parameters in those patients with liver enzymes that were elevated at baseline.

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.