TY - JOUR
T1 - TAK-101 Nanoparticles Induce Gluten-Specific Tolerance in Celiac Disease
T2 - A Randomized, Double-Blind, Placebo-Controlled Study
AU - TAK-101 Study Group
AU - Kelly, Ciarán P.
AU - Murray, Joseph A.
AU - Leffler, Daniel A.
AU - Getts, Daniel R.
AU - Bledsoe, Adam C.
AU - Smithson, Glennda
AU - First, M. Roy
AU - Morris, Amy
AU - Boyne, Michael
AU - Elhofy, Adam
AU - Wu, Tsung Teh
AU - Podojil, Joseph R.
AU - Miller, Stephen D.
AU - Fogel, Robert
AU - Freitag, Tobias L.
AU - Gerber, Michele
AU - Haynes, Paul K.
AU - Koren, Michael
AU - Matson, Mark
AU - Meri, Seppo
AU - Oliphant, Thomas H.
AU - Rizzardi, Barbara E.
AU - Silvester, Jocelyn
AU - Turner, Mark
N1 - Publisher Copyright:
© 2021 AGA Institute
PY - 2021/7
Y1 - 2021/7
N2 - 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 interferon-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 and peripheral gut-homing T cells. Results: In phase 2a, 33 randomized patients completed the 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in interferon-γ spot-forming units vs 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 = .08). Intraepithelial lymphocyte 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. ClinicalTrials.gov identifiers: NCT03486990 and NCT03738475.
AB - 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 interferon-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 and peripheral gut-homing T cells. Results: In phase 2a, 33 randomized patients completed the 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in interferon-γ spot-forming units vs 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 = .08). Intraepithelial lymphocyte 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. ClinicalTrials.gov identifiers: NCT03486990 and NCT03738475.
KW - Antigen-specific Immune Tolerance
KW - Gliadin
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U2 - 10.1053/j.gastro.2021.03.014
DO - 10.1053/j.gastro.2021.03.014
M3 - Article
C2 - 33722583
AN - SCOPUS:85106386447
SN - 0016-5085
VL - 161
SP - 66-80.e8
JO - Gastroenterology
JF - Gastroenterology
IS - 1
ER -