Gluten Degradation, Pharmacokinetics, Safety, and Tolerability of TAK-062, an Engineered Enzyme to Treat Celiac Disease

Abstract

BACKGROUND AND AIMS: Celiac disease (CeD) is an immunemediated 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.

Relative Rates of Gluten Digestion by Nine Commercial Dietary Digestive Supplements

“…Several additional supplements in development were not evaluated. These include a recombinant glutamine-specific endoprotease [EP-B2 from barley ( 23 )], a Sphingomonas capsulata prolyl endopeptidase termed ALV003, now Latiglutenase (ImmunogenX, Newport Beach, CA, USA) (ImmunogenX, Newport Beach, CA, USA) ( 24 , 25 ), a recombinant Alicyclobacillus sendaiensis serine endopeptidase [Kuma30 now Tak-062 (Takeda Pharmaceutical Company Limited, Japan, Feb 2020) ( 26 ), and an endopeptidase 40 (E40) ( 27 ).…”

Co-factors, Microbes, and Immunogenetics in Celiac Disease to Guide Novel Approaches for Diagnosis and Treatment

“…138,164,165 In the following we mention drugs that-in our personal view-showed potential in phase 1b and 2-3 studies. These include 1) highly active glutenases, such as Kuma-30 (TAK-062), a synthetic enzyme that rapidly digests the majority of immunogenic luminal gluten peptides before they may reach the duodenal lamina propria, 166 2) larazotide acetate (AT-1001), which decreases intestinal permeability and improved symptoms in symptomatic CeD, 167 3) ZED1227, a specific inhibitor of TG2 that prevents mucosal gluten deamidation, efficient binding of gluten peptides to HLA-DQ2 or -DQ8, and subsequent T-cell activation and mucosal dammage, 28 4) antibodies that block IL15 (and other cytokines that are central to the pathogenesis of CeD) in severe or premalignant disease, 42,168 and 5) TIMP-Glia (TAK-101), gliadin-loaded nanoparticles that are sequestered in the spleen to induce tolerance to gluten ingestion. 137 In line with expert consensus and regulatory requirements discussed in the previous chapter, [147][148][149] ZED1227, a drug that renders prolonged mucosal protection, demonstrated dose-dependent efficacy as assessed by loss of villous height and IEL density, and even by CeDspecific PROs, in a phase 2 gluten challenge study.…”

Reacciones adversas a los alimentos: ¿Cuál es el papel de los microorganismos?

“…14,72 Aunque parece complicado su uso en reacciones inmunogénicas rápidas y peligrosas, como las que se observan en las alergias y anafilaxis, el uso de bacterias probioticas metabolizadoras de antígenos, así como sus enzimas purificadas (terapia enzimática oral), ha sido propuesto en sensibilidades como la enfermedad celíaca. [73][74][75][76] Es difícil que estas terapias puedan sustituir a una dieta libre de gluten. Sin embargo, su uso puede ser de interés como terapia suplementaria o en la industria alimentaria ya que la contaminación cruzada de alimentos es un problema considerable en las sensibilidades alimentarias.…”