Epitope-Specific Immunotherapy Targeting CD4-Positive T Cells in Celiac Disease: Safety, Pharmacokinetics, and Effects on Intestinal Histology and Plasma Cytokines with Escalating Dose Regimens of Nexvax2 in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study

• Main Authors: A. James M. Daveson, Hooi C. Ee, Jane M. Andrews, Timothy King, Kaela E. Goldstein, John L. Dzuris, James A. MacDougall, Leslie J. Williams, Anita Treohan, Michael P. Cooreman, Robert P. Anderson
• Format: Article
• Language: English

Content Partner: Directory of Open Access Journals. Background: Nexvax2® is a novel, peptide-based, epitope-specific immunotherapy intended to be administered by regular injections at dose levels that increase the threshold for clinical reactivity to natural exposure to gluten and ultimately restore tolerance to gluten in patients with celiac disease. Celiac disease patients administered fixed intradermal doses of Nexvax2 become unresponsive to the HLA-DQ2·5-restricted gluten epitopes in Nexvax2, but gastrointestinal symptoms and cytokine release mimicking gluten exposure, that accompany the first dose, limit the maximum tolerated dose to 150 μg. Our aim was to test whether stepwise dose escalation attenuated the first dose effect of Nexvax2 in celiac disease patients. Methods: We conducted a randomized, double-blind, placebo-controlled trial at four community sites in Australia (3) and New Zealand (1) in HLA-DQ2·5 genotype positive adults with celiac disease who were on a gluten-free diet. Participants were assigned to cohort 1 if they were HLA-DQ2·5 homozygotes; other participants were assigned to cohort 2, or to cohort 3 subsequent to completion of cohort 2. Manual central randomization without blocking was used to assign treatment for each cohort. Initially, Nexvax2-treated participants in cohorts 1 and 2 received an intradermal dose of 30 μg (consisting of 10 μg of each constituent peptide), followed by 60 μg, 90 μg, 150 μg, and then eight doses of 300 μg over six weeks, but this was amended to include doses of 3 μg and 9 μg and extended over a total of seven weeks. Nexvax2-treated participants in cohort 3 received doses of 3 μg, 9 μg, 30 μg, 60 μg, 90 μg, 150 μg, 300 μg, 450 μg, 600 μg, 750 μg, and then eight of 900 μg over nine weeks. The dose interval was 3 or 4 days. Participants, care providers, data managers, sponsor personnel, and study site personnel were blinded to treatment assignment. The primary outcome was the number of adverse events and percentage of participants with adverse events during the treatment period. This completed trial is registered with ClinicalTrials.gov, number NCT02528799. Findings: From the 73 participants who we screened from 19 August 2015 to 31 October 2016, 24 did not meet eligibility criteria, and 36 were ultimately randomized and received study drug. For cohort 1, seven participants received Nexvax2 (two with the starting dose of 30 μg and then five at 3 μg) and three received placebo. For cohort 2, 10 participan