Gluten Degradation, Pharmacokinetics, Safety, and Tolerability of TAK-062, an Engineered Enzyme to Treat Celiac Disease
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Gluten Degradation, Pharmacokinetics, Safety, and Tolerability of TAK-062, an Engineered Enzyme to Treat Celiac Disease. / Pultz, Ingrid Swanson; Hill, Malcolm; Vitanza, Joanne M.; Wolf, Clancey; Saaby, Lasse; Liu, Tina; Winkle, Peter; Leffler, Daniel A.
In: Gastroenterology, Vol. 161, No. 1, 07.2021, p. 81-93.e3.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Gluten Degradation, Pharmacokinetics, Safety, and Tolerability of TAK-062, an Engineered Enzyme to Treat Celiac Disease
AU - Pultz, Ingrid Swanson
AU - Hill, Malcolm
AU - Vitanza, Joanne M.
AU - Wolf, Clancey
AU - Saaby, Lasse
AU - Liu, Tina
AU - Winkle, Peter
AU - Leffler, Daniel A.
N1 - Publisher Copyright: © 2021 The Authors
PY - 2021/7
Y1 - 2021/7
N2 - Background and Aims: Celiac disease (CeD) is an immune-mediated disorder triggered by the ingestion of gluten. Despite adhering to a gluten-free diet (the only management option available to patients with CeD), many patients continue to experience symptoms and intestinal injury. Degradation of immunogenic fractions of gluten peptides in the stomach has been proposed as an approach to reduce toxicity of ingested gluten; however, no enzymes evaluated to date have demonstrated sufficient gluten degradation in complex meals. TAK-062 is a novel, computationally designed endopeptidase under development for the treatment of patients with CeD. Methods: Pharmacokinetics, safety, and tolerability of TAK-062 100–900 mg were evaluated in a phase I dose escalation study in healthy participants and patients with CeD. Gluten degradation by TAK-062 was evaluated under simulated gastric conditions in vitro and in healthy participants in the phase I study, with and without pretreatment with a proton pump inhibitor. Residual gluten (collected through gastric aspiration in the phase I study) was quantified using R5 and G12 monoclonal antibody enzyme-linked immunosorbent assays. Results: In vitro, TAK-062 degraded more than 99% of gluten (3 g and 9 g) within 10 minutes. In the phase I study, administration of TAK-062 was well tolerated and resulted in a median gluten degradation ranging from 97% to more than 99% in complex meals containing 1–6 g gluten at 20–65 minutes postdose. Conclusions: TAK-062 is well tolerated and rapidly and effectively degrades large amounts of gluten, supporting the development of this novel enzyme as an oral therapeutic for patients with CeD. (ClinicalTrials.gov: NCT03701555, https://clinicaltrials.gov/ct2/show/NCT03701555.)
AB - Background and Aims: Celiac disease (CeD) is an immune-mediated disorder triggered by the ingestion of gluten. Despite adhering to a gluten-free diet (the only management option available to patients with CeD), many patients continue to experience symptoms and intestinal injury. Degradation of immunogenic fractions of gluten peptides in the stomach has been proposed as an approach to reduce toxicity of ingested gluten; however, no enzymes evaluated to date have demonstrated sufficient gluten degradation in complex meals. TAK-062 is a novel, computationally designed endopeptidase under development for the treatment of patients with CeD. Methods: Pharmacokinetics, safety, and tolerability of TAK-062 100–900 mg were evaluated in a phase I dose escalation study in healthy participants and patients with CeD. Gluten degradation by TAK-062 was evaluated under simulated gastric conditions in vitro and in healthy participants in the phase I study, with and without pretreatment with a proton pump inhibitor. Residual gluten (collected through gastric aspiration in the phase I study) was quantified using R5 and G12 monoclonal antibody enzyme-linked immunosorbent assays. Results: In vitro, TAK-062 degraded more than 99% of gluten (3 g and 9 g) within 10 minutes. In the phase I study, administration of TAK-062 was well tolerated and resulted in a median gluten degradation ranging from 97% to more than 99% in complex meals containing 1–6 g gluten at 20–65 minutes postdose. Conclusions: TAK-062 is well tolerated and rapidly and effectively degrades large amounts of gluten, supporting the development of this novel enzyme as an oral therapeutic for patients with CeD. (ClinicalTrials.gov: NCT03701555, https://clinicaltrials.gov/ct2/show/NCT03701555.)
KW - Gliadin
KW - Glutenase
U2 - 10.1053/j.gastro.2021.03.019
DO - 10.1053/j.gastro.2021.03.019
M3 - Journal article
C2 - 33741317
AN - SCOPUS:85106349503
VL - 161
SP - 81-93.e3
JO - Gastroenterology
JF - Gastroenterology
SN - 0016-5085
IS - 1
ER -
ID: 327164034