TAK-062, a novel, computationally designed endopeptidase by Takeda Pharmaceuticals International was found in a pharmacokinetic, safety, and tolerability phase 1 trial to be effective at rapidly degrading large amounts of gluten. These findings were published in Gastroenterology.

Individuals with (n=9) and without (n=15) celiac disease (CeD) were recruited for an in vitro, dose-escalation trial. Participants were given 2 meals via nasogastric tube delivery of common foods containing a total of 9 grams of gluten. Liquid formulation of TAK-062 was administered in 100 mg or 300 mg doses and gluten degradation was assessed up to 60 minutes.

During the phase 1 portion of this study, healthy controls (n=13) and patients with CeD (n=7) were evaluated for safety of TAK-062 in 100 mg, 300 mg, and 900 mg doses. During part 2 of phase 1, degradation of gluten among healthy controls (n=46) after treatment with 300 mg, 600 mg, or 900 mg TAK-062 liquid or capsule formulation with or without 7 days of proton pump inhibitors (PPIs) was assessed via gastric aspiration using R5 and G12 monoclonal antibody assays.


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The healthy controls and patients with CeD included in the phase 1 trial were aged mean 45.7±8.7 and 38.1±10.5 years, BMI was average 25.8±3.0 kg/m2 and 24.14±2.6 kg/m2, 93.3% and 11.1% were men, and 40% and 100% were White, respectively.

During the in vitro degradation assay, >99% of the 9 g of gluten was degraded by 300 mg of TAK-062 at 5 minutes and 97%-98% of the 9 g was degraded by 100 mg TAK-062. At 10 minutes, both doses had degraded >99%.

As assessed by the dynamic gastric model, 3387.2±209.5 mg of gluten would have entered the duodenum of the placebo experiments and 10.5±0.6 mg of gluten for the TAK-062 experiment.

The degradation of 3 g gluten at 35 minutes, as assessed by R5 monoclonal antibodies compared with placebo, was median 97.6% (range, 62.8%-99.8%) after 900 mg of the liquid formulation, 99.2% (range, 89.0%-99.8%) for 900 mg liquid formulation with PPIs, and 99.4% (range, 49.0%-99.8%) for the 600 mg capsule formulation. As assessed by G12 monoclonal antibodies, the degradation of gluten was median 98.9% (range, 72.5%-99.8%), 99.6% (range, 95.6%-99.9%), and 99.7% (range, 19.5%-99.9%) for the same treatment groups, respectively.

Patients with CeD who received TAK-062 reported headaches (n=2) and those who received placebo reported headaches (n=1), nausea (n=1), and abdominal distension (n=1). During part 2 of the phase 1 trial, healthy participants reported headache (n=4), nausea (n=2), epistaxis (n=1), and vomiting (n=1).

The major limitation of this study was the choice to not include patients with CeD during part 2 of the trial. It remains unclear whether TAK-062 will assist in gluten digestion or have an effect on the mucosa of the small intestine.

These data indicated there was a high potency for degradation of gluten in the human stomach following ingestion of TAK-062, making it a potential oral treatment for patients with CeD.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.

Reference

Pultz IS, Hill M, Vitanza JM, et al. Gluten degradation, pharmacokinetics, safety, and tolerability of TAK-062, an engineered enzyme to treat celiac disease. Gastroenterol. Published online March 19, 2021. doi:10.1053/j.gastro.2021.03.019.