In the Journals

Nexvax2 alters immune response to gluten in patients with celiac disease

Nexvax2, an investigational therapeutic vaccine designed to protect patients with celiac disease against the effects of gluten exposure, was safe and well tolerated, and demonstrated a modified immune response to gluten in two phase 1 randomized controlled trials.

These results suggest that Nexvax2 (ImmusanT), which is an epitope-specific immunotherapy consisting of three peptides with immunodominant epitopes for gluten-specific CD4-positive T cells, “demonstrates relevant bioactivity and target engagement,” Robert Anderson, MBChB, PhD, chief scientific officer of ImmusanT, said in a press release. “Moreover, patients treated with Nexvax2 in these trials experienced a modification in the recall immune response to gluten without apparent duodenal injury. The findings indicate that Nexvax2 reduces the responsiveness of gluten-specific T cells to antigenic stimulation in celiac disease.”

To evaluate the safety and pharmacodynamics of the intradermal vaccine in HLA-DQ2.5-positive celiac patients who followed a gluten-free diet, investigators performed two double blind trials at 12 centers in Australia, New Zealand and the U.S. In the first study, researchers randomly assigned patients to receive three fixed doses of vaccine or placebo once weekly for 3 weeks, and in the second study, they randomly assigned patients to receive 16 fixed doses of vaccine or placebo twice weekly for 8 weeks. Both studies included screening and post-treatment periods in which patients participated in double blind, crossover, placebo-controlled oral gluten challenges.

Numbers and proportions of adverse events served as the primary endpoints, which were met in both studies. The investigators reported that some patients experienced symptoms after the first dose that were comparable to those that occur after gluten ingestion, including nausea and vomiting, but the clinical effects of later doses were comparable to placebo. The first dose also stimulated acute immune responses that were comparable to those caused by eating gluten, but again these lessened or disappeared after later doses.

Finally, the studies established a maximum tolerated dose, and after this was administered twice daily for 8 weeks, recipients’ duodenal histology appeared similar to those who received placebo.

“The results published today demonstrate encouraging clinical and biologic effects for Nexvax2 consistent with its potential to protect against gluten exposure,” Ramnik Xavier, MD, chief of the gastrointestinal unit at Massachusetts General Hospital, said in the press release, which also noted that he and colleagues at the Center for Computational and Integrative Biology at Massachusetts General Hospital performed additional analyses “to confirm that activation of T cells by the vaccine was absent after repeated dosing without inducing any immunogenic effects.”

“In total, four phase 1 clinical studies with Nexvax2 have supported the safety, tolerability and relevant bioactivity of Nexvax2 as an antigen-specific immunotherapy in celiac disease,” Leslie J. Williams, CEO of ImmusanT, said in the press release. “This provides a strong basis for advancing the clinical development of Nexvax2 which is the first therapeutic vaccine designed for patients with celiac disease on a gluten-free diet.”

In a related editorial, Antonio Di Sabatino, MD, and Gino Roberto Corazza, of the San Matteo Hospital Foundation, University of Pavia, Italy, noted that a shortcoming to this vaccine is that it can only benefit celiac patients with both an HLA-DQ2.5 haplotype and a positive whole blood interferon release assay. “Therefore, about a third of patients with celiac disease would [be] unable to benefit from this treatment,” they wrote.

It is also uncertain whether the vaccine would protect against long-term complications of celiac disease like refractoriness and enteropathy-associated T-cell lymphoma, they added.

“Although it is too early to establish on the basis of the results of this study whether great strides have been made toward finding a vaccine for celiac disease, the topic of epitope-specific immunotherapy is clinically relevant, because most people with celiac disease are unsatisfied with life-long exclusion of gluten from their diet,” they concluded. – by Adam Leitenberger

Disclosures: Anderson and Williams are employed by ImmusanT. Xavier and other researchers report financial relationships with ImmusanT. The editorial authors report no relevant financial disclosures.

Nexvax2, an investigational therapeutic vaccine designed to protect patients with celiac disease against the effects of gluten exposure, was safe and well tolerated, and demonstrated a modified immune response to gluten in two phase 1 randomized controlled trials.

These results suggest that Nexvax2 (ImmusanT), which is an epitope-specific immunotherapy consisting of three peptides with immunodominant epitopes for gluten-specific CD4-positive T cells, “demonstrates relevant bioactivity and target engagement,” Robert Anderson, MBChB, PhD, chief scientific officer of ImmusanT, said in a press release. “Moreover, patients treated with Nexvax2 in these trials experienced a modification in the recall immune response to gluten without apparent duodenal injury. The findings indicate that Nexvax2 reduces the responsiveness of gluten-specific T cells to antigenic stimulation in celiac disease.”

To evaluate the safety and pharmacodynamics of the intradermal vaccine in HLA-DQ2.5-positive celiac patients who followed a gluten-free diet, investigators performed two double blind trials at 12 centers in Australia, New Zealand and the U.S. In the first study, researchers randomly assigned patients to receive three fixed doses of vaccine or placebo once weekly for 3 weeks, and in the second study, they randomly assigned patients to receive 16 fixed doses of vaccine or placebo twice weekly for 8 weeks. Both studies included screening and post-treatment periods in which patients participated in double blind, crossover, placebo-controlled oral gluten challenges.

Numbers and proportions of adverse events served as the primary endpoints, which were met in both studies. The investigators reported that some patients experienced symptoms after the first dose that were comparable to those that occur after gluten ingestion, including nausea and vomiting, but the clinical effects of later doses were comparable to placebo. The first dose also stimulated acute immune responses that were comparable to those caused by eating gluten, but again these lessened or disappeared after later doses.

Finally, the studies established a maximum tolerated dose, and after this was administered twice daily for 8 weeks, recipients’ duodenal histology appeared similar to those who received placebo.

“The results published today demonstrate encouraging clinical and biologic effects for Nexvax2 consistent with its potential to protect against gluten exposure,” Ramnik Xavier, MD, chief of the gastrointestinal unit at Massachusetts General Hospital, said in the press release, which also noted that he and colleagues at the Center for Computational and Integrative Biology at Massachusetts General Hospital performed additional analyses “to confirm that activation of T cells by the vaccine was absent after repeated dosing without inducing any immunogenic effects.”

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“In total, four phase 1 clinical studies with Nexvax2 have supported the safety, tolerability and relevant bioactivity of Nexvax2 as an antigen-specific immunotherapy in celiac disease,” Leslie J. Williams, CEO of ImmusanT, said in the press release. “This provides a strong basis for advancing the clinical development of Nexvax2 which is the first therapeutic vaccine designed for patients with celiac disease on a gluten-free diet.”

In a related editorial, Antonio Di Sabatino, MD, and Gino Roberto Corazza, of the San Matteo Hospital Foundation, University of Pavia, Italy, noted that a shortcoming to this vaccine is that it can only benefit celiac patients with both an HLA-DQ2.5 haplotype and a positive whole blood interferon release assay. “Therefore, about a third of patients with celiac disease would [be] unable to benefit from this treatment,” they wrote.

It is also uncertain whether the vaccine would protect against long-term complications of celiac disease like refractoriness and enteropathy-associated T-cell lymphoma, they added.

“Although it is too early to establish on the basis of the results of this study whether great strides have been made toward finding a vaccine for celiac disease, the topic of epitope-specific immunotherapy is clinically relevant, because most people with celiac disease are unsatisfied with life-long exclusion of gluten from their diet,” they concluded. – by Adam Leitenberger

Disclosures: Anderson and Williams are employed by ImmusanT. Xavier and other researchers report financial relationships with ImmusanT. The editorial authors report no relevant financial disclosures.