Esophagus to Small Intestine
Lancet Gastroenterol Hepatol. 2023;8(5):446−57
Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (Nexvax2) in adults with celiac disease after bolus exposure to gluten (RESET CeD): An interim analysis of a terminated randomized, double-blind, place-bo-controlled phase 2 study
Background: A gluten-free diet is insufficient to treat celiac disease because intestinal injury persists and acute reactions with cytokine release follow gluten exposure. Nexvax2 is a specific immunotherapy using immunodominant peptides recognized by gluten-specific CD4+ T cells that might modify gluten-induced disease in celiac disease. The authors aimed to assess the effects of Nexvax2 on gluten-induced symptoms and immune activation in patients with celiac disease.
Methods: This was a randomized, double-blind, placebo-controlled phase 2 trial done at 41 sites (29 community, 1 secondary, and 11 tertiary centers) in the USA, Australia, and New Zealand. Patients with celiac disease aged 18−70 years who had excluded gluten for at least 1 year, were HLA-DQ2.5-positive, and had a worsening of symptoms after an unmasked 10 g vital gluten challenge were eligible for inclusion. Patients were stratified by HLA-DQ2.5 status (HLA-DQ2.5 non-homozygous vs. homozygous). Patients who were non-homozygous were centrally (ICON; Dublin, Ireland) randomly assigned (1:1) to receive subcutaneous Nexvax2 (non-homozygous Nexvax2 group) or saline (0.9% sodium chloride; non-homozygous placebo group) twice a week escalating from 1 μg to 750 μg during the first 5 weeks followed by 11 weeks of maintenance therapy at 900 μg per dose. The exploratory homozygous group was centrally randomly assigned (2:1) to receive Nexvax2 (homozygous Nexvax2 group) or placebo (homozygous placebo group); patients who were homozygous received the same dosage as those who were non-homozygous. The primary end point was change in celiac disease patient-reported outcomes (total gastrointestinal domain) from pretreat-ment baseline to the day of masked bolus 10 g vital gluten challenge given in week 14 analyzed in the non-homozygous intention-to-treat popu-lation.
Findings: Between September 21, 2018, and April 24, 2019, 383 volunteers were screened for inclusion, of whom 179 (47%; 133 women [74%], 46 men [26%]; median age 41 years [interquartile range, 33−55]) were randomly assigned. One of 179 patients (1%) was excluded from analysis due to misassignment of genotype. The non-homozygous Nexvax2 group included 76 patients, the non-homozygous placebo group included 78 patients, the homozygous Nexvax2 group included 16 patients, and the homozygous placebo group included 8 patients. The study was discon-tinued after planned interim analysis of 66 patients who were non-homozygous. The authors report an unmasked post-hoc analysis of all availa-ble data for the primary end point and secondary symptom-based end points combining data from 67 (66 were assessed in the planned interim analysis for the primary end point). Mean change from baseline to day of first masked gluten challenge in total gastrointestinal score for the non-homozygous Nexvax2 group was 2.86 (SD 2.28) compared with 2.63 (SD 2.07) for the non-homozygous placebo group (p = 0.43). Adverse events were similar between all patients who received Nexvax2 and those who received placebo. Serious adverse events were reported in 5 of 178 patients (3%; 2/92 [2%] who received Nexvax2 and 3/82 [4%] who received placebo). One patient in the non-homozygous Nexvax2 group had a serious adverse event that occurred during gluten challenge (left-sided mid-back muscle strain with imaging suggestive of partial left kidney infarction). Serious adverse events were reported for 3 of 78 patients (4%) in the non-homozygous placebo group (1 each with exacerbation of asthma and appendicitis, and 1 who had forehead abscess, conjunctivitis, and folliculitis) and 1 patient (1%) in the non-homozygous Nexvax2 group developed a pulmonary embolism. The most frequent adverse events in all 92 patients who received Nexvax2 compared with all 86 pa-tients who received placebo were nausea (44/92 patients [48%] who received Nexvax2 vs. 29/86 patients [34%] who received placebo), diarrhea (32 [35%] vs. 25 [29%]), abdominal pain (31 [34%] vs. 27 [31%]), headache (32 [35%] vs. 20 [23%]), and fatigue (24 [26%] vs. 31 [36%]).
Interpretation: Nexvax2 did not reduce acute gluten-induced symptoms. Masked bolus vital gluten challenge provides an alternative to extended gluten challenge in efficacy studies for celiac disease.