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

Daveson, A. James M., Ee, Hooi C., Andrews, Jane M., King, Timothy, Goldstein, Kaela E., Dzuris, John L., MacDougall, James A., Williams, Leslie J., Treohan, Anita, Cooreman, Michael P. and Anderson, Robert P. (2017) 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. EBioMedicine, 26 78-90. doi:10.1016/j.ebiom.2017.11.018


Author Daveson, A. James M.
Ee, Hooi C.
Andrews, Jane M.
King, Timothy
Goldstein, Kaela E.
Dzuris, John L.
MacDougall, James A.
Williams, Leslie J.
Treohan, Anita
Cooreman, Michael P.
Anderson, Robert P.
Title 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
Journal name EBioMedicine   Check publisher's open access policy
ISSN 2352-3964
Publication date 2017-11-22
Year available 2017
Sub-type Article (original research)
DOI 10.1016/j.ebiom.2017.11.018
Open Access Status DOI
Volume 26
Start page 78
End page 90
Total pages 13
Place of publication Amsterdam, Netherlands
Publisher Elsevier
Language eng
Subject 1300 Biochemistry, Genetics and Molecular Biology
Abstract 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 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-DQ2.5 non-homozygotes. Adverse events with Nexvax2 treatment were less common in cohorts 1 and 2 with the starting dose of 3. μg (72 for 11 participants) than with the starting dose of 30. μg (91 for six participants). Adverse events during the treatment period in placebo-treated participants (46 for nine participants) were similar to those in Nexvax2-treated participants when the starting dose was 3. μg in cohort 1 (16 for five participants), cohort 2 (56 for six participants), and cohort 3 (44 for 10 participants). Two participants in cohort 2 and one in cohort 3 who received Nexvax2 starting at 3. μg did not report any adverse event, while the other 33 participants experienced at least one adverse event. One participant, who was in cohort 1, withdrew from the study due to adverse events, which included abdominal pain graded moderate or severe and associated with nausea after receiving the starting dose of 30. μg and one 60. μg dose. The most common treatment-emergent adverse events in the Nexvax2 participants were headache (52%), diarrhoea (48%), nausea (37%), abdominal pain (26%), and abdominal discomfort (19%). Administration of Nexvax2 at dose levels from 150. μg to 900. μg preceded by dose escalation was not associated with elevations in plasma cytokines at 4. h. Nexvax2 treatment was associated with trends towards improved duodenal histology. Plasma concentrations of Nexvax2 peptides were dose-dependent. Interpretation: We show that antigenic peptides recognized by CD4-positive T cells in an autoimmune disease can be safely administered to patients at high maintenance dose levels without immune activation if preceded by gradual dose escalation. These findings facilitate efficacy studies that test high-dose epitope-specific immunotherapy in celiac disease.
Keyword Celiac disease
Immunotherapy
Nexvax2
Peptide
Randomized controlled trial
T cell
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

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Sub-type: Article (original research)
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Created: Sun, 17 Dec 2017, 00:53:36 EST