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

Abstract

BackgroundNexvax2® 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.MethodsWe 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.FindingsFrom 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 participants received Nexvax2 (four with starting dose of 30 μg and then six at 3 μg) and four received placebo. For cohort 3, 10 participants received Nexvax2 and two received placebo. All 36 participants were included in safety and immune analyses, and 33 participants completed treatment and follow-up; in cohort 3, 11 participants were assessed and included in pharmacokinetics and duodenal histology analyses. Whereas the maximum dose of Nexvax2 had previously been limited by adverse events and cytokine release, no such effect was observed when dosing escalated from 3 μg up to 300 μg in HLA-DQ2·5 homozygotes or to 900 μg in HLA-D...

Baseline quantitative histology in therapeutics trials reveals villus atrophy in most patients with coeliac disease who appear well controlled on gluten‐free diet

“…Table shows the characteristics of the 93 patients who had pre‐treatment duodenal biopsies collected across three phase 1 trials and one phase 2 study investigating Nexvax2 in patients with coeliac disease. Disposition of patients in the phase 1 studies who had biopsies has been reported previously, and is shown in Figure for patients in the phase 2 study. Patient characteristics were similar for the four studies.…”

“…Biopsy collection, processing and quantitative histology methods in the first and second phase 1 studies have been described in detail elsewhere . Briefly, biopsies were collected from four sites: the duodenal bulb, and from the first, second and third parts of the duodenum.…”

Randomised clinical trial: a placebo‐controlled study of subcutaneous or intradermal NEXVAX2, an investigational immunomodulatory peptide therapy for coeliac disease

“…16 Using this approach, Nexvax2 was ultimately delivered at levels up to 900 µg, without dose-limiting side effects and well above the assessed maximum tolerated first dose (150 µg), which although tolerable, elicited dosedependent symptoms and a significant cytokine increase. 16 Using this approach, Nexvax2 was ultimately delivered at levels up to 900 µg, without dose-limiting side effects and well above the assessed maximum tolerated first dose (150 µg), which although tolerable, elicited dosedependent symptoms and a significant cytokine increase.…”

“…With evidence of rapid post-dose immune-system engagement, and the appearance of peak circulating peptide levels within an hour of intradermal administration, 13,16 we decided to explore the feasibility of subcutaneous injection. This report details the results of Phase-1 study to assess the clinical profile and general tolerability of a Nexvax2 subcutaneous dose-escalation regimen, and the respective pharmacokinetic and pharmacodynamic profiles of subsequent 900-µg doses of Nexvax2 administered via subcutaneous or intradermal injection to HLA-DQ2.5+ coeliac disease patients.…”

Editorial: a non‐dietary treatment for coeliac disease—two steps forward, one step back?

“…Previously published studies demonstrated the safety of intradermal administration of Nexvax2 in patients with coeliac disease and, though not powered for efficacy, showed signals for improvement in symptoms and duodenal histology . Theoretically, intradermal administration exposes cutaneous antigen‐presenting cells to gliadin peptides, which may represent an important mechanism of action.…”