Phase 3 Trial of Budesonide for Eosinophilic Esophagitis & COVID-19 Deaths in U.S.

NY Times article:  U.S. Coronavirus Cases Are Rising Sharply, but Deaths Are Still Down

This article explains why deaths from COVID-19 have not increased despite increasing number of infections.  Three main reasons: increased testing -detects many with less severe symptoms, younger population are being infected, and new treatment approaches may be helping.  However, “the dip in coronavirus mortality will not necessarily last. As more people socialize, those with milder infections might end up ferrying the pathogen to vulnerable individuals…Recent upswings in coronavirus case numbers leave experts apprehensive of what’s to come. Death, when it occurs, tends to trail infection by about two to four weeks.”


The Budesonide Oral Suspension (BOS) resulted in 62% of BOS patients meeting the threshold of < 15 eos/hpf compared to 1% of placebo patients. From lead author, Ikuo Hirano: “the results of the BOS trial showed that BOS successfully treated both the symptoms and signs of EoE. The positive results will hopefully lead to an approved, safe and effective therapy for EoE.”

Abstract from ACG Meeting October 2019:

Abstract: Efficacy of Budesonide Oral Suspension for Eosinophilic Esophagitis in Adolescents and Adults: Results From a Phase 3, Randomized, Placebo-Controlled Trial

Introduction: Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease for which there is an unmet clinical need for new therapies. The safety and efficacy of budesonide oral suspension (BOS) for the treatment of EoE has been demonstrated in a previous phase 2 study. The current phase 3 study evaluated the efficacy and safety of BOS in a large cohort of patients with EoE. 

Methods: This randomized, double-blind, placebo-controlled trial (SHP621-301; NCT02605837) investigated the safety and efficacy of BOS in patients (11–55 years) with EoE and dysphagia. Patients were randomized 2:1 to 2.0 mg BOS or placebo twice daily (b.i.d.) for 12 weeks (Figure 1). Co-primary endpoints were histologic (peak eosinophil count ≤6 eosinophils/high-powered field [eos/hpf]) and dysphagia symptom (≥30% decrease in symptoms as measured by the Dysphagia Symptom Questionnaire [DSQ]) responses after 12 weeks of therapy. Secondary endpoints included change in DSQ score and change in EoE Endoscopic Reference Score (EREFS) from baseline to final treatment period. Safety was also assessed.

Results: A total of 322 patients were randomized (BOS, n=215; placebo, n=107), of whom 318 patients received at least one dose of double-blind therapy (BOS, n=213; placebo, n=105) (Table). The primary outcomes were achieved, with significantly more histologic and symptom responders in the BOS-treated than the placebo-treated group (53.1% vs 1.0%, p< 0.001; 52.6% vs 39.1%, p=0.024, respectively; Figure 2). Improvements in mean DSQ score from baseline to week 12 were significantly greater in the BOS group (n=197) than the placebo group (n=89) (−13.0 vs −9.1; p=0.015). Similarly, improvements in mean EREFS scores were significantly greater with BOS (n=202) than placebo (n=93) (−4.0 vs −2.2; p< 0.001). In total, 61.0% of patients reported a treatment-emergent adverse event (TEAE) (BOS, 61.0%; placebo, 61.0%). Only 2.5% of patients experienced a TEAE leading to dose discontinuation (BOS, 1.4%; placebo, 4.8%). Few patients had severe or serious TEAEs on BOS or placebo.  No life-threatening TEAEs were reported.

Discussion: This phase 3 trial demonstrated the efficacy of BOS as induction therapy for EoE. BOS resulted in significant improvements in histologic, symptomatic and endoscopic endpoints compared with placebo. The majority of TEAEs were mild to moderate and comparable between placebo and BOS. A double-blind, placebo-controlled maintenance study (SHP621-302) is ongoing.

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Island Ford, Sandy Springs

 

 

 

Eosinophilic Esophagitis -Up to Date Dietary Management Review

A recent terrific review article (H Bashaw et al. JPEN 2020; https://doi.org/10.1002/jpen.1738) provides a good advice on nutritional therapy for eosinophilic esophagitis (Thanks to Kipp Ellsworth for sharing this reference).

Full text: Tutorial: Nutrition Therapy in Eosinophilic Esophagitis—Outcomes and Deficiencies

An excerpt:

  • “Diet elimination addresses the root cause of inflammation, treats EoE by removing the underlying trigger(s) of inflammation, and is a preferred approach for many patients… A registered dietitian is essential to ensure adequate macronutrients and micronutrients are present in the diet and to educate families in learning to read labels and prevent contamination.”
  • ” Each type of elimination diet is associated with inherent nutrition risks.” Table 1 lists the potential nutrient deficiencies with each diet.

While the response rate is lower with fewer food group elimination, “the benefits of eliminating fewer foods from the diet include improved adherence, greater dietary variety, and a shorter time frame for reintroduction, with fewer endoscopies needed to identify triggers”

My take: As with topical steroids and PPI treatment, dietary treatment for EoE has to be maintained to be effective.  Concerns for adherence with medications are applicable for dietary therapy as well.

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Wishing friends, family and colleagues a healthy and happy New Year.

Morning in Sandy Springs, GA

 

Transnasal Endoscopy in Unsedated Children to Monitor Eosinophilic Esophagitis

A recent retrospective study (N Nguyen et al. Clin Gastroenterol Hepatol 2019; 17: 2455-2462) describe the feasibility of unsedated transnasal endoscopy (TNE) for monitoring eosinophilic esophagitis (EoE) in children (n=190, subject ages 3-22 years).

TNE was facilitated by distraction with either video google or virtual reality (starting 2016).  NPO time was 2 hours before the TNE.

Key points:

  • Over 294 TNEs were completed from 300 attempts (98% success)
  • Cost of TNE was halved: $4393 compared to $9444 for EGD (does not count pathology costs)
  • Adverse events: 8 (2.7%) with vomiting, 9 (3.1%) spit up, 11 (3.7%) with epistaxis
  • By 2017, TNE accounted for 31.8% of upper endoscopies in 2017

The authors recommend that TNE be offered starting at age 5 years in those without a known stricture.

My take: I am looking forward to less invasive/less costly ways of monitoring treatment response in EoE.  I think TNE can lower costs –though I am a little surprised that the cost of TNE in their institution was still more than $4000.  In our outpatient endoscopy center, costs for an upper endoscopy/biopsy with anesthesia are typically about one-third the cost of an EGD in their study and about three-fourths the cost of a study TNE.

Related study: A Krigel et al. Clin Gastroenterol Hepatol 2019; 17: 2489-96. This study showed increasing use of anesthesia assistance (AA) for colonoscopy in adults from 16.7% in 2006 to 58.1% in 2015. This data was derived from the Premier Perspective database with more than 4.6 million patients who had an outpatient colonoscopy. AA was associated with a median increase in cost of $182 for patients with commercial insurance.

Related blog post: Waiting for the String Test for EoE

 

Eosinophilic Esophagitis and Inflammatory Bowel Disease

A recent study (Limketkai BN, et al. Gut. 2019;doi:10.1136/gutjnl-2018-318074.) shows that the likelihood of eosinophilic esophagitis (EoE) is higher in patients with inflammatory bowel disease (IBD) and that the likelihood of IBD is higher in EoE patients.

Summary from Healio Gastroenterology –Risk for EoE higher in patients with IBD, and vice versa:

  • Researchers conducted a prospective cohort analysis using the Truven MarketScan database from 2009 to 2016 to define the epidemiology and clinical implications of concurrent EoE and IBD diagnoses.
  • Among their cohort comprising 134,013,536 individuals, the incidence of EoE was 23.1 per 100,000 person-years, CD was 51.2 and ulcerative colitis was 55.2.
  • Compared with patients without either diagnosis, the risk for EoE was higher in patients with CD (IRR = 5.4, P < .01; prevalence ratio [PR] = 7.8, P < .01) and UC (IRR = 3.5, P < .01; PR = 5, P < .01). Meanwhile, the risk for IBD was higher among patients with EoE (CD: IRR = 5.7, P < .01; PR = 7.6, P < .01; UC: IRR = 3.4, P < .01; PR = 4.9, P < .01).

Promising Biologic for Eosinophilic Esophagitis

A recent study (I Hirano et al. Gastroenterol 2019; 156: 592-603) showed that RPC4046, a monoclonal antibody against IL13 is a promising agent for eosinophilic esophagitis. This multicenter double-blind study with 99 adults compared RPC4046 at doses of either 180 mg or 360 mg to placebo for 16 weeks.  Endoscopy was performed at baseline and at 16 weeks.  The study population included a high number who were considered steroid-refractory and excluded patients who were responsive to proton pump inhibitors. The study drug was administered initially as an IV load followed by weekly subcutaneous injections.

Key findings:

  • Mean changes in esophageal eosinophil count dropped by 94.8 in patients receiving 180 mg dosing and 99.9 in patients receiving 360 mg dosing.  In contrast, placebo-treated patients had a meager reduction of 4.4.
  • In this phase II study, there were no serious safety issues identified
  • There were no significant changes relative to placebo in dysphagia symptoms using the DSD (dysphagia symptom diary) composite score. Though there was improvement in global PRO measures compared to placebo.

There is an associated editorial (pg 545) explains the need for better therapies.  While both dietary therapies and topical steroids are likely effective in >70%, dietary therapy is plagued by problems with long-term adherence and there may become less effective with longer-term administration.

My take: Particularly for patients with refractory EoE, newer therapies are needed.  Given the chronic nature of EoE, cost of new treatments could be another hurdle.

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Negligible Effect of Eosinophilic Esophagitis Treatment on Longitudinal Growth

Briefly noted: ET Jensen et al. JPGN 2019; 68: 50-5. This retrospective study with 409 patients with eosinophilic esophagitis (EoE) examined longitudinal growth over 12 months.  “In general, treatment approach was not associated with any significant increase or decrease in expected growth.” In a subset of patients with combined elemental diet and topical steroids (n=13), there was a subtle decrease in linear growth with a change in height z-score of -0.04, CI -0.08 to  -0.01. Interestingly, in these patients with EoE, the baseline height z-scores were lower than expected indicating that a subset may have impaired growth prior to treatment.

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pictures from Zabriskie Point at sunrise, Death Valley

 

Sex-Based Differences in Incidence of Inflammatory Bowel Disease

Briefly noted: SC Shah, H Khalili et al. Gastroenterol 2018; 155: 1079-89.

This study evaluated pooled data with 207,600 incident cases of IBD from a population of 478 million. Key findings:

  • Female patients had lower a lower risk of Crohn’s disease during childhood until 10-14 years of age, but then a risk afterwards
  • For ulcerative colitis, there was a divergence in risk after 45 years of age, when men had a significantly higher incidence.

My take: the differences indicate that genetic factors (men with a Y chromosome and only one chromosome X) along with sex hormones play a role in the pathogenesis of IBD.

Graphs depict Female/Male Incidence Rate Ratio

AGREE proceedings: Briefly noted: ES Dellon, CA Liacouras, J Molina-Infante, GT Furuta et al. Gastroenterology 2018; 155: 1022-33.  This report provides updated recommendations from AGREE conference –which have been widely cited previously on this blog and elsewhere.  One of the remarkable features on this report is the fact that there are 64 authors (by my count) –thus reading the affiliations and the conflict of interest disclosures alone would take some time.

For a good review on this topic:

Time to Diagnosis in Eosinophilic Esophagitis

According to a recent retrospective study (CC Reed et al. Clin Gastroenterol Hepatol 2018; 16: 1667-9) the time to diagnosis of eosinophilic esophagitis (EoE) has NOT improved  between 2000 and 2014.  In this single tertiary-care center study with 677 cases, the predicted length of symptoms prior to diagnosis was the following:

  • 2000-2006: 6.1 years
  • 2007-2011: 7.2 years
  • 2011-2014: 7.2 years

While in the pediatric cohort the trend was the same, the length of symptoms preceding diagnosis was shorter: 2.8 years, 3.5 years and 3.7 years respectively for the above-mentioned time periods.

My take: In GI circles, EoE is quickly considered for a variety of clinical presentations.  This study suggests that

  • #1 for families and primary care doctors that many are unaware of this entity
  • #2 the symptoms of EoE are often insidious

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Updated Consensus Guidelines for Eosinophilic Esophagitis

Full text: ES Dellon, CA Liacouras,  J Molina-Infante, GT Furuta et al. Gastroenterol 2018; 155: 1022-33.

This article provides a thorough review of EoE -including clinical features, differential diagnosis, diagnostic criteria, and treatments.

Key point: “The evidence suggests that PPIs are better classified as a treatment for esophageal eosinophilia that may be due to EoE than as a diagnostic criterion, and we have developed updated consensus criteria for EoE that reflect this change.”

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