Budesonide for EoE: Why the FDA denial is so hard to swallow
In December 2021, the FDA issued a complete response letter to Takeda Pharmaceutical Company for its new drug application for budesonide oral suspension for the treatment of eosinophilic esophagitis in adolescents and adults.
The complete response letter (CRL) denied approval for budesonide oral suspension (BOS) and recommended additional clinical study to resolve FDA feedback. While the details of the CRL have not been publicly disclosed, the evidence supporting the new drug application is available in several peer-reviewed publications over the 15-year drug development program.
Peer-Reviewed Publications
The pivotal studies for BOS include a phase 2, double-blind, placebo-controlled randomized 12-week trial of 93 adolescents and adults with EoE and a similarly designed, phase 3 trial of 318 adolescents and adults with EoE. Both trials enrolled highly symptomatic patients with marked disease activity (esophageal eosinophil counts several-fold higher than the diagnostic threshold). In addition, most patients in the phase 3 trial had previously tried medical or dietary therapies, and more than 40% had undergone at least one esophageal dilation.
Following FDA guidance, both phase 2 and 3 trials used co-primary endpoints of symptom and histologic response. The symptom response used a patient-reported outcome instrument (PRO) specifically validated for measuring dysphagia in EoE. (This was, in fact, the first phase 3 trial in EoE to use a validated PRO as a primary outcome.) The histologic endpoint required achieving six eosinophils or less per high power field, a more stringent threshold than used in clinical practice (< 15 eos/hpf). Thus, the BOS trials not only enrolled patients with greater disease severity but also required a higher degree of clinical response than used in routine clinical practice.
Despite these high hurdles, both the phase 2 and 3 trials achieved their co-primary endpoints at week 12. Furthermore, both trials substantiated the efficacy of BOS by demonstrating significant improvement in endoscopic disease activity (EREFS) and a more comprehensive histologic activity score (EoE-HSS). EREFS and EoE-HSS are both validated, disease-activity measures that objectively assess disease inflammation and tissue remodeling activity beyond eosinophil density.
Guidelines
Considering the success of the phase 2 and 3 trials in meeting the stringent metrics in FDA guidance, the agency’s denial is disappointing, confusing and surprising. Swallowed topical corticosteroids have been successfully used off-label by clinicians around the world for more than two decades in the treatment of EoE in children and adults, using formulations designed for asthma.
Their use has been uniformly endorsed in United States and European gastroenterology and allergy society guidelines and consensus recommendations. In the most recent guideline by the AGA in conjunction with the Joint Task Force on Allergy-Immunoloy Practice Parameters, swallowed topical steroids were the only therapeutic class given a strong recommendation. In fact, a phase 3 trial conducted in Europe led to the approval of a budesonide tablet formulation by the European Medicines Agency in 2018 without the use of a validated PRO as a primary endpoint. Safety of BOS and the therapeutic class has been excellent; oral and esophageal candidiasis occurs in a small proportion of patients but seldom produces symptoms.
BOS and the therapeutic class of swallowed topical steroids do have limitations. While histologic and endoscopic efficacy were both robust and clear, symptom efficacy, while statistically significant, was relatively modest compared with placebo. It should be emphasized, however, that symptom efficacy in EoE is extremely challenging for two reasons: First, symptom severity correlates poorly with disease activity measures, due to patient anxiety and hypervigilant behavior as well as adaptive eating behaviors. These psychosocial determinants likely explain the high placebo-symptom response in trials for BOS and other EoE therapeutics. Second, dysphagia is caused by esophageal luminal narrowing induced by esophageal fibrostenosis as well as esophageal eosinophilic inflammation. Hence, demonstration of even a modest improvement in symptoms with a medical therapeutic in the absence of esophageal dilation is truly remarkable and clinically meaningful.
In clinical practice, esophageal dilation — not medical therapy — is the most effective short-term approach to alleviate dysphagia in EoE. For centuries, in fact, esophageal dysphagia from any etiology (eg, Schatzki ring, peptic stricture, achalasia, caustic injury, radiation stricture) has been primarily managed with mechanical dilation or surgery rather than medical therapy.
Long-term efficacy is another concern with BOS. Following the successful response to 12-week induction therapy with BOS, responders underwent randomization to continue BOS or placebo (a prespecified, randomized withdrawal sub-study of only 48 patients). Treatment for an additional 16 weeks after induction (28 cumulative weeks of BOS therapy) significantly and robustly maintained symptom and histologic efficacy. During the 36-week maintenance, however, 24% of BOS patients had relapsed compared with 44% given placebo, a difference that was not statistically significant (Dellon et al). Study design issues combined with the small sample size limited the ability to achieve statistical significance. Nevertheless, 76% of BOS patients remained in symptom and histologic response with prolonged administration of BOS.
In the European budesonide tablet maintenance trial, about 75% of patients maintained clinical remission for 48 weeks with continued therapy. Looking at both the United States and European experiences, it appears that about 25% of patients responsive to induction therapy with budesonide may relapse with prolonged therapy. Nevertheless, the prolonged symptom and histologic benefits of maintenance therapy with swallowed topical budesonide for the majority of EoE patients are evident.
Unmet Needs for EoE
There is a large unmet need for therapies for EoE. While the prevalence of EoE continues to rise, there are no FDA-approved therapies. Elimination diets are conceptually attractive, but long-term adherence is difficult and can adversely affect quality of life through restriction of commonly enjoyed table foods, including dairy products and wheat. Untreated EoE is associated with clinical consequences of progressive fibrostenotic disease with increasing need for esophageal dilation and risk of food impaction. Treatment of EoE with swallowed topical steroids, on the other hand, reduces the need for esophageal dilation and risk for food impaction with minimal risk.
As BOS is both efficacious and safe, the FDA denial of BOS is a decision that both providers and their patients will find hard to swallow.
- References:
- Dellon ES, et al. Am J Gastroenterol. 2013;doi:10.1038/ajg.2013.71.
- Dellon ES, et al. Gastroenterology. 2017;doi:10.1053/j.gastro.2016.11.021.
- Dellon ES, et al. Clin Gastroenterol Hepatol. 2021;doi:10.1016/j.cgh.2021.06.020.
- Eosinophilic esophagitis: Developing drugs for treatment. Guidance for industry. U.S Department of Health and Human Services. Food and Drug Administration Center for Drug Evaluation and Research. September 2020.
- Hirano I, et al. Gastroenterology. 2020;doi:10.1053/j.gastro.2020.02.038.
- Hirano I. J Gastroenterol. 2020;doi:10.1007/s00535-019-01624-3.
- Hirano I, et al. Clin Gastroenterol Hepatol. 2021;doi:10.1016/j.cgh.2021.04.022.
- Liacouras CA, et al. J Allergy Clin Immunol. 2011;doi:10.1016/j.jaci.2011.02.040.
- Lucendo AJ, et al. United European Gastroenterol J. 2017;doi:10.1177/2050640616689525.
- Lucendo AJ, et al. Gastroenterology. 2019;doi:10.1053/j.gastro.2019.03.025.
- Straumann A, et al. Gastroenterology. 2020;doi:10.1053/j.gastro.2020.07.039.
- Taft TH, et al. Gastroenterology. 2021;doi:10.1053/j.gastro.2021.06.023.
- For more information:
- Ikuo Hirano, MD, is a professor of medicine at Northwestern University Feinberg School of Medicine.
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