Jason A. Tie-Din, PhD

Credit: The Walter and Eliza Hall Institute

Nexvax2 did not result in a statistically significant reduction in gluten-induced symptoms in a study of both homozygous and non-homozygous patients with celiac disease.¹

A team, led by Jason A. Tie-Din, PhD, Immunology Division, The Walter and Eliza Hall Institute, assessed the effects of Nexvax2 on gluten-induced symptoms and immune activation in patients with celiac disease.

Celiac Disease

A gluten-free diet is often not enough to treat celiac disease. This is largely because intestinal injuries persist and acute reactions with cytokine release follow gluten exposure.

One treatment option is Nexvax2 a specific immunotherapy that uses immunodominant peptides recognized by gluten gluten-specific CD4+ T cells, which could modify gluten-induced disease in patients with celiac disease.

The Trial

In the randomized, double-blind, placebo-controlled phase 2 trial, the investigators examined patients aged 18-70 years with celiac disease at 29 community sites, 1 secondary site, and 11 tertiary centers in the US, Australia, and New Zealand. Each participant 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.

Each patient received either subcutaneous Nexvax2 or saline twice a week. The doses escalated from 1 μg to 750 μg during the first 5 weeks followed by 11 weeks of maintenance therapy at 900 μg per dose.

In addition, the exploratory homozygous group was assigned to receive either Nexvax2 or placebo, while patients who were homozygous were treated with the same dosage as patients who were non-homozygous.

The investigators sought primary endpoints of the change in celiac disease patient reported outcomes from pretreatment baseline to the day of masked bolus 10 g vital gluten challenge give in week 14 analyzed in the non-homozygous intention-to-treat population.

The investigators screened 383 individuals between September 21, 2018 and April 245, 2019, 178 of which were included in the final analysis.

The median age of the patient population was 41 years and 74% (n = 133) of the participants were women. There were 76 patients in the non-homozygous Nexvax2 group, 16 patients in the homozygous Nexvax2 group, 78 patients in the non-homozygous placebo group, and 8 patients in the homozygous placebo group.

However, the decision makers opted to discontinue the study after the planned interim analysis of 66 patients who were non-homozygous.

The results of an unmasked post-hoc analysis of all available data for the primary endpoint and secondary symptom-based endpoints coming data from 67 show the mean change from baseline to the day of the first masked gluten challenge in total gastrointestinal scores for the non-homozygous Nexvax2 group was 2.86 compared to 2.63 for the non-homozygous placebo group (P = 0.43).

In the safety analysis, serious adverse events occurred in 3% (n = 5) of the overall patient population, 2 (2%) in the Nexvax2 group and 3 (4%) in the placebo group.

There was 1 patients who had a serious adverse event during the gluten challenge in the non-homozygous Nexvax2 group of left-sided mid-back muscle strain with imaging suggestive of partial left kidney infarction.

In the non-homozygous placebo group, there were 3 (4%) serious adverse events one each with exacerbation of asthma and appendicitis, and (1 who had forehead abscess, conjunctivitis, and folliculitis) and 1 (1%) patient in the non-homozygous Nexvax2 group that developed a pulmonary embolism.

The most frequent adverse events in the Nexvax2 group compared to the placebo group were nausea (n = 44; 48% vs n = 29; 34%), diarrhea (n = 32; 35% vs n = 25; 29%), abdominal pain (n = 31; 34% vs n = 27; 31%), headache (n = 32; 35% vs n = 20; 23%), and fatigue (n = 24; 26% vs n = 31; 36%).

“Nexvax2 did not reduce acute gluten-induced symptoms,” the authors wrote. “Masked bolus vital gluten challenge provides an alternative to extended gluten challenge in efficacy studies for celiac disease.”

References:

Tye-Din, J. A., Daveson, A. J., Goel, G., Goldstein, K. E., Hand, H. L., Neff, K. M., Popp, A., Taavela, J., Maki, M., Isola, J., Williams, L. J., Truitt, K. E., Anderson, R. P., Adams, A., Andrews, J. M., Behrend, C. E., Brown, G. J., Chen Yi Mei, S. L., Coates, A. G., … Wilson, S. A. (2023). Efficacy and safety of gluten peptide-based antigen-specific immunotherapy (NEXVAX2) in adults with coeliac disease after bolus exposure to gluten (reset ced): An interim analysis of a terminated randomised, double-blind, placebo-controlled phase 2 study. The Lancet Gastroenterology & Hepatology. https://doi.org/10.1016/s2468-1253(22)00428-9