An experimental biologic drug showed promise for reducing symptoms and inflammation in patients with celiac disease following gluten exposure, according to data from a phase 2 proof-of-concept study released in advance of DDW 2018.
The development of an effective drug for preventing the effects of gluten exposure in celiac disease is crucial, as a gluten-free diet is the only available treatment option, but it is “virtually impossible” to completely and permanently avoid gluten, according to study director Francisco Leon, MD, PhD.
“Contamination with gluten happens during food processing, food packaging, cooking, inadequate labeling, and gluten is present in unsuspected places like lipstick, toothpaste, even medicines,” he said during a press briefing. As a result, half of celiac patients continue to have mucosal inflammation on a gluten-free diet, he noted.
The new phase 2 data researchers will present at DDW demonstrate the potential of AMG 714 (Amgen/Celimmune) for addressing this issue. The agent is an investigational monoclonal antibody that blocks interleukin (IL)-15, an important mediator of celiac disease.
“IL-15 has been found to be a key driver of the intraepithelial lymphocytes (IELs), which are the key immune cell in our gut in the innate immune system, and it is what drives the responsiveness to gluten in the first place,” Leon said during the Q&A session of the press briefing. “It also has been found to be the key driver for malignization of the IELs becoming lymphoma, which is the worst complication of celiac disease. So, what AMG 714 does is to prevent the signaling of the IL-15 receptor complex on the cell surface of the IELs, and this leads to the interruption of their proliferation and ... activation.”
In a double-blind trial, Leon and colleagues randomly assigned patients with celiac disease to receive one of two doses of AMG 714 (150 or 300 mg) or placebo, administered subcutaneously six times over 12 weeks. One subgroup of 49 patients underwent a high-dose gluten challenge of about 2.5 g daily for 10 weeks during the treatment period. Another subgroup with baseline mucosal atrophy tested positive for gluten contamination using urine and stool tests and did not undergo an additional gluten challenge.
While the study did not meet its primary endpoint of fully preventing mucosal injury in the gluten challenge group, investigators reported that both doses of AMG 714 reduced the effects of gluten vs. placebo.
The agent did reduce intestinal inflammation in the gluten challenge group and produced a trend toward reduced intestinal damage in those who did not undertake a gluten challenge, but this did not reach statistical significance.
Patient reported symptoms were notably reduced, especially with the higher dose of the drug.
No gluten-induced symptoms were observed in patients who did not undertake a gluten challenge, and unlike patients who received placebo, the treatment group did not experience an increase in diarrhea. Additionally, no patients who undertook a gluten challenge and received the 300 mg dose had active disease at week 12, whereas one-third of the placebo group did, investigators reported.
Among the gluten challenge group, the 300-mg dose significantly improved Celiac Disease Patient Reported Outcome (CeD-PRO) scores vs. placebo (P = .02), and both doses reduced the number of weeks with diarrhea as measured by the Bristol Stool Form Scale (P = .01 for the 150-mg dose; P = .0002 for the 300-mg dose).
Investigators observed no serious adverse events or safety signals, and the most common drug-related adverse events were injection site reactions and pain, headache and upper respiratory tract infection. Injection site reactions were the only dose-related trends.
Leon noted that further research will be undertaken to determine the best dosing regimen.
“It’s important to note that this drug is being investigated for its potential to protect against modest contamination, not deliberately eating large amounts of gluten, like bread or pasta,” Leon said in a press release. “Our hope is that this drug may allow celiac patients on a gluten-free diet to experience fewer gluten-triggered events.” – by Adam Leitenberger
Disclosures: Leon reports he is a consultant for Amgen and co-founder of Celimmune.