Promising results related to symptoms also presented at DDW
By Amy Ratner, director of scientific affairs
A drug designed to break gluten into harmless fragments successfully protected against damage of the small intestine in celiac disease patients, according to results of a study presented recently at Digestive Disease Week (DDW).
Latiglutenase, a treatment for celiac disease being developed by ImmunogenX Inc., also reduced or prevented symptoms, research presented by Joseph Murray, MD, lead study author, showed.
In the phase 2 study, called CeliacShield, 25 participants with celiac disease on a gluten-free diet received 1,200 milligrams of latiglutenase daily. A second group of 25 study participants received a placebo.
Both groups were given a daily challenge of 2 grams of gluten for six weeks. The challenge consisted of breadcrumbs that study participants ate with their evening meal along with the drug or placebo. The study occurred in the middle of the early part of the COVID-19 pandemic, which caused a few study participants to drop out, Murray said.
Latiglutenase is a combination of two enzymes that work complimentarily to break down and degrade gluten proteins in the stomach, making them inactive and less likely to cause symptoms and damage to the small intestine in people who have celiac disease. It is intended to be used in addition to the gluten-free diet to protect those with celiac disease against damage from inadvertent gluten exposure. In the study, the drug was mixed with water and a flavor packet to produce a clear drink-based medication consumed with meals. The placebo group got an identical flavor packet that did not contain the active drug.
Study participants had biopsies taken before and after the gluten challenge and researchers from ImmunogenX and the Mayo Clinic, where the study was conducted, measured changes in the lining of the upper portion of the small intestine. This included the villous-height-to-crypt-depth-ratio and intraepithelial lymphocytes. The villous-height-to-crypt-depth-ratio evaluates injury to the intestinal lining. Intraepithelial lymphocytes are the first immune cells in the intestinal lining that react to invaders. A decrease in the villous-height-to-crypt- depth-ratio a sign of damage from gluten, as is an increase in intraepithelial lymphocytes.
The villous-height-to-crypt-depth-ratio measurement was the primary endpoint of the study. The primary endpoint is the main result measured at the end of a study to see if a given treatment works. Other study results, including the measurement of the intraepithelial lymphocytes, symptoms, gluten in urine, and blood tests for antibodies to gluten found in celiac disease patients were secondary endpoints.
Results showed that those who received the placebo had damage to the small intestinal lining, which was shown by a drop in the villous-height-to-crypt-depth-ratio, said Murray. “That drop was not seen in the patients treated with latiglutenase,” he noted in his presentation at DDW. DDW is an annual conference for physicians, researchers and academics in the fields of gastroenterology, hepatology, endoscopy and gastrointestinal surgery.
Most placebo-treated study participants also had an increase in the count of intraepithelial lymphocytes, which was not seen in those treated with the drug, Murray said.
“There is significant worsening of many of the patients who [were] treated with placebo induced by the gluten challenge, an effect that is blocked [in] patients treated with latiglutenase,” Murray noted.
Compared to those in the placebo group, those who received latiglutenase had 88 percent less damage to the upper portion of their small intestinal lining and 60 percent fewer intraepithelial lymphocytes in the same location.
Urine samples were collected from all study participants before, during and after the gluten challenge and analyzed for the presence of gluten immunogenic peptides (GIP). When gluten is consumed, these peptides pass through the intestinal system and are secreted and can be measured in urine.
The study is the first clinical trial investigating a celiac disease drug to use GIP measurement, according to study authors.
Measurements of GIP in urine showed a more than 90 percent reduction of gluten for those who got latiglutenase versus the placebo, according to the study. “Latiglutenase greatly reduced the recoverable GIP found in the urine during the gluten challenge,” Murray said.
Many in the placebo group had a “substantial increase” in GIP throughout the challenge, as would be expected, Murray added, while those who got the drug did not. This supports the mechanism of action of latiglutenase, which is that it breaks down or targets the immunogenic gluten peptides in the stomach. Murray estimated about a 95 percent reduction.
However, a number of study participants who got the placebo also did not have a measurable increase in gluten in their urine during the challenge. When researchers analyzed a variety of data from the placebo treated study participants, they found that those who did not have an increase in GIP also had little intestinal change. Meanwhile, those who had increased concentration of GIP also had signs of intestinal damage.
Murray said this raises the issue of whether all in the placebo group were taking the 2 grams of gluten per day challenge, which was self-administered. The use of GIP as an objective measure that confirms whether study participants really do consume a gluten challenge could be useful in future clinical trials that include a self-administered challenge, he noted. However, although non-compliance is suggested, the effect of the way the drug moved through the body can’t be ruled out, the study notes.
During the gluten challenge, there was significant worsening of symptoms for the study participants who got the placebo, the study showed. “They are effects we essentially don’t see hardly, if at all, in the patients treated with latiglutenase,” Murray said.
Symptoms severity, as reported by those receiving latiglutenase during the gluten challenge were 93 percent less for abdominal pain, 53 percent less for bloating and 99 percent less for tiredness compared to those receiving placebo. Study participants used the Celiac Disease Symptom diary to keep track of symptoms.
“Latiglutenase durably [reduced] or blocked the gluten induced symptoms over the duration of the six-week challenge,” Murray said.
Results of several blood tests for antibodies to gluten found in those who have celiac disease taken before and during the challenge showed a trend toward worsening for the placebo group and improvement for latiglutenase group.
This is what you would expect if there is protection from latiglutenase, Murray noted.
While participants in the Celiac Shield study received latiglutenase once a day, should it eventually be approved and made available to celiac disease patients in its current design, it would be taken three times a day, with meals.
Meanwhile, ImmunogenX is currently conducting another study, called Solutions for Celiac, which is designed to monitor how well latiglutenase relieves symptoms and improves quality of life in people with celiac disease in both real-world and known gluten exposure situations. You can find out more about Solutions for Celiac here.
Beyond Celiac helped ImmunogenX, a clinical stage biotherapeutics company, recruit study participants for Celiac Shield, and is helping recruit for Solutions for Celiac as a part of its commitment to accelerating research