Drugs designed to break down gluten with enzymes report new developments

Another celiac disease drug may have potential in treating lung issues in COVID-19

By Amy Ratner, Medical and Science News Analyst

Several treatments for celiac disease currently under study have made progress recently, even as research into COVID-19 takes precedence around the world.

Two drugs that propose to treat celiac disease by breaking down gluten using enzymes are reporting advances in the clinical trial process. Both drugs differ from over-the-counter products that claim to be able to help in the digestion of gluten. A 2015 study found that digestive enzyme supplements are ineffective in degrading problematic gluten. In a 2019 broad review of celiac disease, experts continued to warn patients not to use digestive enzyme supplements on the market, pointing to the results of the 2015 study.

Meanwhile, a drug designed to treat celiac disease by closing the tight junctions between the cells in the gut, is now also being evaluated as a potential drug candidate for treating acute lung injury and respiratory distress in COVID-19.

TAK-062

An early phase clinical trial investigating TAK-062, an enzyme designed to break down gluten in the stomach, found that it was at least 95 percent effective and might help treat celiac disease along with a gluten-free diet.

The drug, currently being developed by Takeda Pharmaceutical Co., was tested in 46 adults who did not have celiac disease and 10 who do, according to Phase 1 results presented online at Digestive Disease Week in May. The study found no differences in the safety, tolerability or absorption of TAK-062 between healthy volunteers and celiac disease patients, said Daniel Leffler, MD, a study author and medical director at Takeda.

In the healthy volunteers, researchers also tested the drug’s ability to degrade gluten to a level below 50 milligrams (mg), the amount thought to trigger an immune response in those who have celiac disease.

Healthy volunteers were given varying doses of the drug or a placebo while consuming one to six grams of gluten. Researchers mixed ingredients containing fat, carbohydrates and protein in a bread crumb smoothie to simulate what would be in a normal meal, Leffler said.

Study participants’ stomach contents were collected through a tube running from the nose to the stomach at specific times after the drug or placebo was given. Researchers then calculated the amount of gluten digested. Results showed greater than 98 percent digestion when three grams of gluten was consumed, Leffler said.

The median amount of remaining gluten was less than 50 mg no matter how much gluten or TAK-062 was given to healthy study participants. However, some did show more than 50 mg of gluten after taking the drug. Possible explanations include an issue with the tube used to collect stomach contents or the gluten formulation, which will be changed in future studies, Leffler said.

He noted that the drug is intended to be used along with the gluten-free diet to protect against damage from accidental gluten, which would likely be much less than three grams. “We believe that for real life exposures, this would be very robust protection,” Leffler said, noting that this early study of Tak-062 seems to show it is more active in degrading gluten than other enzymes being investigated for treatment of celiac disease were in early trials. The drug was engineered to correct problems with other enzyme treatments being developed for celiac disease – lack of ability to target gluten and to remain effective in the acidic conditions of the stomach.

A larger Phase 2 clinical trial of TAK-062 is planned for spring 2021.

Based on results of the Phase 1 study, Takeda in February bought the PVP Biologics, the company that was developing the enzyme, for a pre-negotiated upfront payment as well as development and regulatory milestones totaling up to $330 million, according to Takeda. Takeda and PVP had a previous agreement under which PVP was responsible for research and development through Phase 1 in exchange for initial funding from Takeda.

The drug, formerly called Kuma-062, got its start as a project by students at University of Washington, Seattle, some of whom had friends who had celiac disease. The team of undergraduate students won a prestigious international biological science competition for their work on Kuma-062.

Latiglutenase

A review of mid-point data in a clinical trial investigating latiglutenase, a combination of two enzymes, supports previous studies that show the drug may reduce symptoms in celiac disease patients who accidentally ingest gluten, according to the company developing the drug.

Additionally, the data backs up earlier investigations that showed Latiglutenase may protect the intestinal lining from damage caused by gluten inadvertently consumed by celiac disease patients on a gluten-free diet, according to ImmunogenX.

The midterm assessment of the Phase 2 clinical trial, called Celiac Shield, gives researchers at the Mayo Clinic where the study is being done the go-ahead to continue their work.

Latiglutenase is designed to break down gluten in the stomach and render the harmful protein inactive when taken during meals. Researchers are evaluating how well it works by measuring whether there is intestinal damage after the gluten challenge among study participants who receive the drug. They are also evaluating symptoms reported by study participants and measuring how much gluten is found in the urine of those who received the drug compared to those who get the placebo during the gluten challenge.

Additionally, scientists will use CypCel, a diagnostic test based on a drug biomarker to measure how healthy the small intestine is before and after the gluten challenge. In the test, a single dose of the widely-used cholesterol-lowering agent, simvastatin, is given to a patient. Its concentration is then measured to determine how healthy the intestinal lining is, with a reduced concentration correlating with intestinal recovery.

Data and Safety Monitoring Board: a group of representatives knowledgeable and experienced in the responsible conduct of research that reviews data and goals of clinical research.

Jennifer A. Sealey Voyksner, PhD, chief scientific officer of ImmunogenX said the mid-point review of data by the Data and Safety Monitoring Board (DSMB), indicates that latiglutenase continues on a road to success.

“The investigative team is happy to get the go ahead from the DSMB whose analysis of data thus far has found that the study merits continuation,” said Joseph A. Murray, MD, who is leading the clinical trial at the Mayo Clinic. ImmunogenX received a $1.5 million grant from the National Institutes of Health to help fund the Celiac Shield study.

Previous research into latiglutenase was done in 2017 through the CeliAction study. That clinical trial did not meet its primary goal of showing that patients taking latiglutenase while consuming their real-life gluten-free diet had greater intestinal healing compared to those who did not get the drug. However, a follow-up analysis of results showed that patients who had positive blood tests for gluten- triggered antibodies and took latiglutenase showed improvement in some celiac disease symptoms.

ImmunogenX is also planning a Phase 2 real-world study in which the effect of latiglutenase will be measured in celiac disease patients following their regular gluten-free diet instead of receiving a gluten challenge.

Larazotide acetate

9 Meters Biopharma is currently studying larazotide acetate in celiac disease in a Phase 3 clinical trial, the furthest any celiac disease treatment has gotten.

Meanwhile, the company has received a patent for the drug in the investigation of its effectiveness in treating lung disease, including potentially when it occurs in COVID-19.

“This patent along with the vast pre-clinical and clinical data that has characterized larazotide, highlight the importance of normalizing leaky tight junctions in disparate disease states,” John Temperato, president and CEO of 9 Meters, said in a press release. “Given the potential clinical impact that may result from normalizing tight junctions in disorders beyond larazotide’s main target of celiac disease, we are allowing the exploration of the compound’s broader potential utility in certain cases.”

The 9 Meters’ patent shows  larazotide renormalizes abnormally increased permeability of lung tissue containing cellular tight junction, and treats the direct cause of [acute lung injury] and [acute respiratory distress syndrome] which can lead to fluid buildup within affected areas of the lungs, according to the company. 9 Meters said it is evaluating potential next steps for researching the compound’s impact on acute lung conditions associated with COVID-19.

In celiac disease, larazotide acetate is designed to tighten junctions between intestinal cells, the so-called leaky gut that occurs in celiac disease. Leaky gut is thought to be the gateway to many autoimmune diseases, including celiac disease. The drug would help restore the leaky junctions to a normal state and would be used in addition to the gluten-free diet.

Temperato describes larazotide acetate as working “a bit like shoelaces” to tighten the junctions between cells. 9 Meters expects larazotide to be prescribed alongside a gluten-free diet.

The celiac disease clinical trial is evaluating the drug for patients with celiac disease who continue to experience gastrointestinal symptoms while following a gluten-free diet. It is being tested at more than 100 clinical sites, with a goal of 525 study participants who are on a gluten-free diet but have ongoing abdominal symptoms. Researchers will measure changes in patient reported outcomes related to symptoms over 12 weeks, comparing two dose amounts of larazotide acetate to a placebo. Recruitment is ongoing, and results are expected by the end of 2021.

Innovate Biopharmaceuticals was developing larazotide acetate before merging with RDD Pharma and to from 9 Meters.