Coeliac disease is one of the most thankless diseases a gastroenterologist can be confronted with. The therapy of the autoimmune disease consists of lifelong avoidance of gluten and abstention from gluten-containing foods in the form of a gluten-free diet (GFD). However, despite the patients' best efforts and discipline, this treatment is imperfect and prone to failure.
Many patients suffer recurrent symptoms of their disease from the unintentional intake of gluten, ranging from diarrhoea, deficiencies and neurological symptoms, among others, to infertility and malignant haematological diseases.1,2
A current phase I study conducted by the company PvP Biologics, Inc. from San Diego, USA, together with other research-based pharmaceutical companies, could now for the first time hold out the prospect of a drug therapy for coeliac disease.3 According to the study, the tested, computer-designed active substance TAK-062 showed both in vitro and in vivo that it could break down immunogenic gluten peptides in the stomach to a sufficient extent to prevent symptomatic coeliac disease.
In addition to avoiding gluten-containing foods in the form of a GFD, it is therapeutically obvious to reduce the entry of gluten into the intestine through a medicinal degradation of the protein or its immunogenic components. Catassi et al. have determined an amount of around 50 mg of gluten per day as the critical threshold for patients to be free of symptoms.4.5 This tolerable maximum amount places high demands on gluten degradation. An average meal contains between 3 and 9 g of gluten. Of this amount, about 99% would have to be metabolised to avoid symptoms of coeliac disease. Another complicating factor is that the degradation has to take place in the stomach, where the pH value is basically acidic, but is subject to considerable fluctuations in the course of digestion and may also be modified by proton pump inhibitors (PPI) in many patients. Both factors severely limit the choice of suitable proteases for gluten cleavage.4,5
Previous studies have focused on biochemical manipulation of known proteases to optimise them for degradation of gluten in the stomach. In recent years, studies on the compound ALV003 (latiglutenase) have shown particular promise. However, it was not able to break down more than 75 or 88% of the gluten in a complex meal with an initial gluten content of 1 g.6 Even with this - compared to normal meals - reduced amount of gluten, the proteolytic capacity of the drug was not sufficient to bring the gluten content below the critical limit of 50 mg per day.
In a recent phase I study, the computer-designed enzyme TAK-062 was investigated. The study showed that TAK-062 was able to remove up to 6 g of gluten from complex meals in physiologically relevant periods of 20, 35 and 65 min. under simulated as well as real conditions in healthy test subjects. This was confirmed even when the test subjects had been pre-treated with a PPI for seven days. This means that the active substance should also be suitable for the effective treatment of those numerous coeliac patients who regularly take PPIs.
TAK-062 was taken in both liquid and encapsulated form. Both forms of preparation proved to be comparably effective, with the effect occurring later with the encapsulated active ingredient.
The proteolytic effect of TAK-062 was selected in such a way that it attacked specific peptide structures in the gluten component gliadin, which only very rarely occur in other body proteins. This, the study authors hypothesised, meant that even in complex meals, less proteolytic capacity was bound by non-gluten proteins and the effect of a TAK-062 dose remained predominantly concentrated on gluten.
TAK-062 could - regardless of the dosage - not be detected in the blood plasma of either healthy or coeliac patients in the study. Accordingly, no systemic effect of the drug could be demonstrated. In animal experiments, moreover, no toxicity was detectable up to extreme doses of up to 2 g/ kg bw/d. Also, both the healthy and the coeliac affected test subjects tolerated the active substance without complications. The authors of the study therefore assume that even in the case of delayed gastric emptying, poisoning by the substance will not occur.
The authors now want to quickly investigate the clinical testing of this pharmaceutical in a phase II study.
What do these results mean for coeliac patients?
The development of TAK-062 currently lights up the horizon for coeliac disease patients. All parameters investigated so far suggest that the compound might be able to sustainably improve the quality of life of patients on a GFD. Nevertheless, the decisive tests of the phase II and III trials remain to be seen and no promises should be made. The further development of TAK-062 will be followed with great interest.
References:
1. Green PH, et al. Celiac disease. J Allergy Clin Immunol. 2015; 135: 1099-106.
2. Rubio-Tapia A, et al. ACG Clinical Guidelines: Diagnosis and Management of Celiac Disease. Am J Gastroenterol 2013; 108: 656–676.
3. Pultz IS, et al. Gluten Degradation, Pharmacokinetics, Safety, and Tolerability of TAK-062, an Engineered Enzyme to Treat Celiac Disease. Gastroenterology 2021; 161: 81-93.
4. Catassi C, et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr 2007; 85: 160–166.
5. Akobeng AK, Thomas AG. Systematic review: tolerable amount of gluten for people with coeliac disease. Aliment Pharmacol Therap 2008; 27: 1044–1052.
6. Siegel M, et al. Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials. Dig Dis Sci 2012; 57: 440–450.