An analysis of the discontinued RESET CeD study in patients with coeliac disease has shown the Nexvax2 immunotherapy significantly improved intestinal histology but failed to restore tolerance to a gluten challenge.
The Australian-led phase 2 study was discontinued in 2019 after a planned interim analysis of 66 patients found the immunotherapy, compared to placebo, provided no statistically significant protection from a gluten challenge in adults with CD.
Now a post hoc analysis of all available data, published in The Lancet Gastroenterology & Hepatology [link here], confirms the primary endpoint was not met.
“The mean change in total gastrointestinal score between baseline and the day of first gluten challenge was 2·86 (SD 2·28) in 33 patients in the non-homozygous Nexvax2 group compared with 2·63 (2·07) in 34 patients in the non-homozygous placebo group (mean difference 0·41 [95% CI –0·62 to 1·44]; p=0·43),” the study said.
Similarly, secondary symptom-based endpoints across multiple domains were not met while the mean change in abdominal domain and the bloating individual symptom scores was significantly worse in the Nexvax2 group than in the placebo group.
Another secondary endpoint of serum IL-2 elevation 4 hr after the gluten challenge also showed no benefit of Nexvax2 treatment.
“As previously reported [link here], the masked gluten food challenge worsened symptoms compared with the masked sham food challenge.”
The study, led by Associate Professor Jason Tye-Din from the Walter and Eliza Hall Institute, did however find Nexvax2 improved histomorphometry on duodenal biopsy samples with statistically significant increases in villus height to crypt depth ratio.
It also found that twice a week subcutaneous administration of Nexvax2 commenced by up-dosing and maintained at a dose of 900 μg was safe and well tolerated.
“Collectively, combining the findings of previous clinical trials of Nexvax2 with those from this study, Nexvax2 seems to induce clinical and immunological hyporesponsiveness to itself, and suppresses Nexvax2 gluten epitope-specific CD4 + T-cell immunity.”
“But this level of immune tolerance to gluten peptides in Nexvax2 was inadequate for sudden exposure to a large amount of gluten after overnight fasting.”
They concluded that restoration of immune tolerance is graded and modification of symptoms caused by gluten might be more difficult to show than histology and immune endpoints.
Meanwhile, an accompanying Comment article in the journal [link here] said that despite the negative findings, there were “several novel takeaways” from the study.
“The finding that systemic exposure to gluten peptides in Nexvax2 through intradermal injections induced the same gastrointestinal symptoms and IL-2 release as oral gluten challenge is novel, and highlights the pathogenic role of gluten-specific CD4+ T cells,” it said.
“An immunological immune marker that is detected soon after gluten exposure suggests that patients with coeliac disease no longer need lengthy gluten challenges that might discourage them from participating in or dropping out of a study. Thus, over 20 years of vaccine development, IL-2 has emerged as a key biomarker in coeliac disease.”
It suggested that a single gluten challenge with accompanying symptoms and IL-2 responses could be used as a screening tool for inclusion or exclusion criteria in future trials.
“IL-2 could also be developed for the diagnosis of coeliac disease in patients who have already started a gluten-free diet.”
It said antigen-specific immunotherapy remained an exciting area in coeliac disease research and could test “different route of administration, different peptides, or inclusion of a tolerising drug” in the future.
“We remain hopeful that unexpected discoveries stemming from programmes, such as Nexvax2, will redirect and strengthen the drug development effort in coeliac disease and autoimmunity.”