Diet and a New Drug: A One-Two Punch Against Gluten?

Digestive Disease Week (DDW) 2018

William F. Balistreri, MD


August 01, 2018

AMG 714

Because it is difficult for a patient with CD to completely avoid gluten exposure, another level of protection—beyond a gluten-free diet—is needed.

Two studies presented an alternative strategy: the use of an experimental biologic drug to reduce symptoms and inflammation after gluten exposure. This new agent, AMG 714, is an investigational monoclonal antibody that blocks the effect of interleukin 15 (IL-15), a known intestinal inflammatory mediator in patients with CD.

In a randomized, double-blind, placebo-controlled phase 2a study, patients received six subcutaneous doses of AMG 714 (150 mg or 300 mg) or matching placebo over a 10-week period.[3] From weeks 2 to 12, selected patients received a high-dose gluten challenge (approximately 2.5 g/day for 10 weeks). The primary endpoint, the effect on the villus height to crypt depth ratio, was not statistically significant, but AMG 714 reduced gluten-triggered effects across several endpoints. Among the gluten challenge group, the 300-mg dose significantly improved patient reported outcome scores, and both doses reduced the number of weeks with diarrhea.

This agent may also be useful for refractory celiac disease type II, also called "pre-enteropathy-associated T-cell lymphoma" (pre-EATL), which arises as a complication of CD. This condition is a devastating and rare small bowel in situ lymphoma. The prognosis is poor; 50% of patients progress to EATL, and 5-year survival is about 45%.[4]

The presence of pre-EATL is defined by an aberrant monoclonal intraepithelial lymphocyte (IEL) population. IL-15 plays a major role in pre-EATL; it exerts antiapoptotic effects on aberrant IELs and is the key driver for transformation of IELs during lymphoma development. AMG 714 (anti–IL-15) prevents signaling of the IL-15 receptor complex on the cell surface of the IELs and halts proliferation and activation.

In a randomized, double-blind, placebo-controlled phase 2a study conducted by Cellier and colleagues,[4] patients received seven doses of AMG 714 (8 mg/kg) or matching placebo over 10 weeks. The primary endpoint, reduction in aberrant intestinal IELs, was not statistically significant between the groups. However, AMG 714 was associated with interruption in the progression of the disease. In addition, a numeric reduction occurred in the percentage of small-bowel aberrant IELs (2.5% increase from baseline) compared with placebo (7.3% increase from baseline). There was a 27% improvement in villous atrophy versus no improvement in placebo recipients.

In both studies, there were no serious adverse events or safety signals associated with AMG 714. Immunogenicity was low, and neutralizing antibodies were not detected.

These proof-of-concept and proof-of-mechanism studies indicate that AMG 714 (anti–IL-15) is effective in ameliorating the effects of gluten in patients with CD. Therefore, AMG 714 merits development as an adjunct to a gluten-free diet, offering a potential medical approach to alleviating symptoms for patients inadvertently exposed to gluten. However, the investigators caution that this approach is intended to protect against modest gluten contamination; it is not designed to counteract the effects of regularly eaten large amounts of gluten.

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