TAK-101 Nanoparticles Induce Gluten-Specific Tolerance in Celiac Disease: A Randomized, Double-Blind, Placebo-Controlled Study

ABSTRACT BACKGROUND & AIMS In celiac disease (CeD), gluten induces immune activation, leading to enteropathy. TAK-101, gluten protein (gliadin) encapsulated in negatively charged poly( dl -lactide-co-glycolic acid) nanoparticles, is designed to induce gluten-specific tolerance. METHODS TAK-101 was evaluated in phase 1 dose escalation safety and phase 2a double-blind, randomized, placebo-controlled studies. Primary endpoints included pharmacokinetics, safety, and tolerability of TAK-101 (phase 1) and change from baseline in circulating gliadin-specific IFN-γ-producing cells at day 6 of gluten challenge, in patients with CeD (phase 2a). Secondary endpoints in the phase 2a study included changes from baseline in enteropathy (villus height to crypt depth ratio [Vh:Cd]), and frequency of intestinal intraepithelial lymphocytes (IELs) and peripheral gut-homing T cells. RESULTS In phase 2a, thirty-three randomized patients completed the 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in IFN-γ spot-forming units versus placebo (2.01 vs 17.58, P=.006). Vh:Cd deteriorated in the placebo group (−0.63, P=.002), but not in the TAK-101 group (−0.18, P=.110), although the intergroup change from baseline was not significant (P=0.08). IEL numbers remained equal. TAK-101 reduced changes in circulating α4β7+CD4+ (0.26 vs 1.05, P=.032), αEβ7+CD8+ (0.69 vs 3.64, P=.003), and γδ (0.15 vs 1.59, P=.010) effector memory T cells. TAK-101 (up to 8 mg/kg) induced no clinically meaningful changes in vital signs or routine clinical laboratory evaluations. No serious adverse events occurred. CONCLUSIONS TAK-101 was well tolerated and prevented gluten-induced immune activation in CeD. The findings from the present clinical trial suggest that antigen-specific tolerance was induced and represent a novel approach translatable to other immune-mediated diseases.