BACKGROUND & AIMS:Eosinophilic esophagitis (EoE) is a chronic, immune-mediated disease for which there is currently no pharmacologic therapy approved by the U.S. Food and Drug Administration. METHODS:In this double-blind, placebo-controlled, phase 3 trial, patients 11-55 years of age with EoE and dysphagia were randomized 2:1 to receive budesonide oral suspension (BOS) 2.0 mg twice daily or placebo for 12 weeks at academic or community care practices. Co-primary endpoints were the proportion of stringent histologic responders (£6 eosinophils/high-power field) or dysphagia symptom responders ( ‡30% reduction in Dysphagia Symptom Questionnaire [DSQ] score) over 12 weeks. Changes in DSQ score (key secondary endpoint) and EoE Endoscopic Reference Score (EREFS) (secondary endpoint) from baseline to week 12, and safety parameters were examined. RESULTS:Overall, 318 patients (BOS, n [ 213; placebo, n [ 105) were randomized and received ‡1 dose of study treatment. More BOS-treated than placebo-treated patients achieved a stringent histologic response (53.1% vs 1.0%; D52% [95% confidence interval (CI), 43.3%-59.1%]; P < .001) or symptom response (52.6% vs 39.1%; D13% [95% CI, 1.6%-24.3%]; P [ .024) over 12 weeks. BOS-treated patients also had greater improvements in least-squares mean DSQ scores

NOTE. The primary investigators listed are those who enrolled at least 1 patient. NC, not contactable.

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 1). 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. CONCLUSION: 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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Objectives: Mipomersen (MIPO), a second generation antisense oligonucleotide, targets apoB mRNA, thereby inhibiting apolipoprotein B (apoB) synthesis. In humans, MIPO reduces plasma levels of low density lipoprotein-cholesterol (LDL-C), and plasma triglycerides (TG). We hypothesized that these changes are due to reduced assembly and secretion of very low density lipoproteins (VLDL) and lower production of LDL. Methods: Healthy volunteers (HVs) (9M, 8F), mean age 43.5 ± 14.2 yr, completed a single-blind, fixed-sequence, phase I study. They received sc-placebo injections once weekly for 3-wks followed by 200mg sc-MIPO injections once weekly for 7-9 wks. Stable isotope turnover studies were performed after each treatment. Blood samples were collected over 48-hrs to determine fractional catabolic rates (FCRs) and production rates (PRs) of apoB in VLDL, IDL, and LDL, and of TG in VLDL. Rates of de novo lipogenesis (DNL) were also measured. Results: MIPO treatment resulted in significant reductions in plasma LDL-C (45%), TG (29%), and apoB (40%). VLDL, IDL, and LDL apoB levels fell by 29%, 25%, and 42%, respectively. These changes were associated with increases in FCRs of VLDL apoB (42%) and LDL apoB (30%), and by reductions in PRs of IDL apoB (15%) and LDL apoB (27%). The PR of VLDL apoB was unaffected. The FCR of VLDL-TG increased 46% without change in PR. DNL did not change. Conclusion: In summary, 7 wks of MIPO significantly reduced levels of all apoB-lipoproteins in HVs by increasing the FCRs of VLDL and LDL apoB. The absence of a reduction in VLDL apoB secretion is consistent with many studies in isolated hepatocytes demonstrating both intracellular degradation and secretion of newly synthesized apoB. Thus, if MIPO submaximally inhibited apoB synthesis in this study, the liver could have compensated by increasing the efficiency of VLDL assembly and secretion. The basis of increases in VLDL and LDL FCRs requires further investigation.