A drug has been found that can relieve the most rare and serious form of celiac disease. While approval for treatment will still take several years, experts hope it could also treat milder cases of the disease.
The drug AMG 714 is a form of a human antibody, anti-interleukin 15. It prevents inflammation and damage to the lining of the small intestine on exposure to small amounts of gluten.
California-based pharmaceutical company Amgen previously licensed AMG 714 to Celimmune, a smaller company focused exclusively on celiac research, to conduct early trials in people with celiac. In 2018, Celimmune reported AMG 714 relieved symptoms and stopped progress of the disease in patients with refractory celiac type II (RCDII). This is a severe, often fatal condition in which inflammation evolves into a type of cancer (see sidebar).
“While I’ve seen a reasonable number of RCDII patients in the past, they’ve all done very poorly and died,” says Peter Green, MD, director of the celiac disease center at Columbia University in New York, who worked on the study. “It is uncommon, but when one sees them, they sometimes don’t survive all that long. It is a disease that is in need of a therapy.”
The yet-unpublished study highlights how rare the condition is. Within the United States, Green says he found only two patients to enroll, one in the east and one in the west.
“I called most of the university gastrointestinal divisions in the eastern side of the country to see if they had patients,” he explains. “Either the patients are not there, or they’re not being recognized, or they’re not being looked after in university medical centers.”
However, results of the study were hopeful, says Fernando Leon, PhD, a cofounder of Celimmune.
“We showed that anti-IL 15 was able to ameliorate or reduce the effects of gluten consumption in celiac patients,” says Leon. It reduced gut inflammation and improved symptoms while being well tolerated by the patients.
Evidence in celiac monkeys
Support for the drug has come from treatment of rhesus macaque monkeys with celiac-like disease. In a recent study, six gluten-sensitive monkeys showed improvement when treated with the drug while on a normal, gluten-containing diet.
Karol Sestak, PhD, core scientist at Tulane National Primate Research Center in Covington, Louisiana, has spent 12 years describing and comparing celiac in monkeys with that in humans. Medical research has more often used mice genetically engineered to be gluten-sensitive. However, macaques are more similar to humans both genetically and physiologically, offering advantages when studying therapy for humans.
Besides, they do not need to be genetically altered. The disease naturally occurs in a small percentage of macaques as it does in people. Sestak says his team discovered this while studying digestive problems in the primate colony in 2006. Various viral infections in the monkeys had already been isolated.
“Occasionally, there would also be some disease in these nonhuman primates where you cannot trace any kind of infectious agent when they have chronic diarrhea. Back then, we were wondering what that could be,” says Sestak. “We reformulated their diet. We removed all the gluten sources from the monkey chow. It was our first gluten-free diet. Their conditions dramatically improved.”
The researchers then found the celiac monkeys had the same disease antibodies detected in humans. Those antibodies decreased when the animals were treated with a gluten-free diet. Another similarity with human patients is that gluten-sensitive macaques display a wide spectrum of disease. Some are seriously affected, some moderately and some mildly. When identified in their routine check-ups, these individuals are placed on a gluten-free diet or can be assigned to try out another promising therapy.
In AMG 714 trials, it reversed inflammation and damage in all six animals regardless of the seriousness of their disease. Their recovery was checked using biopsy for a close look at the gut lining. The treatment also improved some but not all markers for immune disease outside the intestine, such as antibodies detected by blood tests.
AMG 714 works by suppressing IL 15, which appears to be a major immune agent but not the only one active in celiac. Since the drug healed intestinal tissue but did not reduce all disease markers, this suggests it might work best alongside a gluten-free diet or other therapy.
Next step for AMG 714
After the trial in humans, Amgen acquired Celimmune. Then, later last year, Amgen offered AMG 714 for further study to Provention Bio, which focuses on autoimmune diseases. Leon is once again a cofounder and chief scientific officer of this smaller company, based in Washington, D.C.
Provention Bio will conduct the next stage of research in non-responsive celiac. This condition includes patients who have persistent disease despite a gluten-free diet, but it is not as severe as RCDII. Toxicology tests must first be performed.
“With any molecule that you block in the immune system, you’re always blocking physiological function. Then the question is, what is essential for our survival and what is not essential?” says Leon. “The goal of drug development is to identify a target which is more important in disease than it is in healthy life. That’s when you get a good benefit-risk profile.”
Amgen initially developed AMG 714 to treat rheumatoid arthritis. These large human trials already showed the drug is well tolerated by patients, says Leon. For the next round, however, more evidence is needed to support using it over a longer period of six months. This will delay starting a study in non-responsive celiac patients until 2020, Leon says. If warranted, studies of safety and effectiveness in progressively larger groups will take several more years.
“I think we’re going to see the first drugs in celiac in the next four to six years,” says Leon.
Neither AMG 714 nor any other therapy currently under study is designed to replace the gluten-free diet, says Green. Medical research prioritizes therapy for people who remain sick despite a gluten-free diet. Once such drugs are approved, further efforts could investigate a drug’s ability to restore gluten tolerance.
Leon says, “We shouldn’t leave patients on their own like we’ve been doing for decades: ‘Just avoid gluten, goodbye.’ Celiac patients need to be provided tools corresponding to the severity of this disease. They need to be provided first and foremost with a nutritional tool: How to avoid gluten. They need to be provided with diagnostics to confirm the gluten-free diet. Finally, for patients who despite best efforts do not manage to avoid gluten, they need to be provided with medicine.”
Meanwhile, drug companies can make treatments like AMG 714 available on compassionate grounds for people with life-threatening illness like RCDII, says Green, “but I’m not sure. I don’t have any patient currently on the drug. It’s not clear how many patients with RCDII are out there, as they aren’t being seen at the few celiac centers where people are equipped to look after them.”
Patients with severe forms of celiac could play an important role in medical research, Green adds. However, they must go to university celiac centers where therapies are being developed.
Degrees of celiac disease
Are you following a gluten-free diet but still experiencing symptoms? First, give it time. Even in the absence of gluten, the gut lining can take a while to heal. If symptoms continue more than a few months, they should be investigated by a doctor. Here is what can happen with poorly controlled celiac.
Non-responsive celiac disease
Symptoms continue and the small intestine fails to heal despite adherence to a gluten-free diet. This can occur for various reasons that need thorough investigation with a doctor. The most likely cause is unknown sources of gluten. A dietitian knowledgeable about the gluten-free diet can help sort it out.
RCDI might occur if gluten exposure continues to damage the small intestine. In rare cases, the immune system produces abnormal attack cells in its ongoing defense against gluten.
This is different from non-responsive celiac. RCDI is rare even among celiac patients who continue to experience symptoms. However, people with non-responsive celiac have an increased risk of developing refractory celiac disease. Likewise, patients with RCDI have a 50 percent risk of developing the next, most serious condition.
Refractory celiac type II
RCDII occurs when one abnormal attack cell starts reproducing itself uncontrollably. This is a type of blood cancer, specifically non-Hodgkin lymphoma localized in the intestinal lining. RCDII is rare, affecting an unknown minority of adult celiac patients, probably 2 percent or less. Unfortunately, the prognosis is poor.
How AMG 714 works
Interleukin 15 (IL 15) is a small protein the immune system uses to send signals between cells. Normally it helps defend the body against viral infections. When a virus is detected, immune cells release IL 15 to stimulate production of natural killer (NK) cells and killer T-cells. They in turn destroy virus-infected cells.
However, NK cells and killer T-cells act indiscriminately. In celiac, they attack cells in the gut lining when gluten is present.
AMG 714 is a human antibody that neutralizes IL 15, breaking the signal to attack. It stops killer cells from reproducing themselves and halts damage to the small intestine.