Neutralising the gluten threat: are we on the cusp of a coeliac disease breakthrough? 

Gluten is a protein commonly found in wheat, barley and rye and is a common cause of food allergies or intolerances. Coeliac disease is often used as a synonym for a gluten intolerance or allergy; however this is common misconception as they are two separate conditions that require individual attention. 

Allergies or intolerances to gluten often cause unpleasant symptoms, such as bloating, abdominal pain and fatigue, these are usually short-term. In contrast, while Coeliac disease may cause the same unpleasant gastrointestinal (GI) symptoms, it is a serious, genetic autoimmune disease that also has long-term medical consequences for sufferers. 

When a person who is genetically predisposed to coeliac disease eats gluten, which is turned into gliadin by enzymes, the body’s immune system identifies the gliadin as a poison and over-reacts, which causes long-term gut damage. The villi that line the small intestine become inflamed and flattened as a result of this immune attack on the gut, meaning there is less surface area for absorbing nutrients from food. 

Dutch doctor Willem Dicke first noticed that children with coeliac disease saw improvement during the 1944 Dutch famine, when there were severe shortages of wheat. For nearly a century, adhering to a gluten-free diet has remained the only treatment for this serious disease. 

Once gluten is removed from a coeliac patient’s diet, their gut slowly begins to heal, and the symptoms start to resolve themselves. While it may be a step in the right direction, this recovery can take several years, and if that patient consumes gluten at any point in the future, its back to square one and the whole process starts again.

A key issue with the gluten-free diet is adherence. It is incredibly difficult to avoid consuming gluten, primarily due to inadvertent exposure. Gluten is in 80% of food stuffs, and also found in other products like toothpaste, medicines and lip balm. 

Very small amounts of gluten – “50mg per day, [which is] the amount of flour that can fit under your pinky fingernail” – can trigger intestinal damage in coeliac patients and undermine the gut’s healing process, US charity Celiac Foundation CEO Marilyn Geller explains. 

Importantly, as this is a chronic condition, it also has negative impacts on other aspects of patients’ health. Since the condition damages the villi in the gut and prevents them absorbing nutrients properly, it is common for coeliac patients to experience vitamin deficiencies, osteoporosis and weight loss. 

This situation is only compounded by the gluten-free diet itself, which is hard to keep balanced with the right levels of important vitamins and minerals, like calcium, vitamin D and iron.  

“We now know that the impact of not being able to absorb your nutrients has complete systemic body-wide effect”, Geller adds. 

She emphasises that coeliac patients have a higher general morality risk, quadruple the risk of developing intestinal cancers, like small bowel cancer, and double the risk of coronary artery disease. This is in addition to a heightened risk of developing multiple sclerosis and other neurological conditions, such as epilepsy and migraines. 

This creates a situation where there is significant need for new, innovative treatment options and now there is hope of this dream being realised in the near future. Although coeliac disease research is flourishing, furthest ahead in drug development is North Carolina-based 9 Meters Biopharma. 

Named after the average length of the GI tract, 9 Meters’ larazotide is the first coeliac drug to enter Phase III trials. If things go to plan, larazotide could be approved by 2023, thereby overcoming the unmet needs that remain in this condition despite adherence to a gluten-free diet. 

Despite the burden and adherence challenges of the gluten-free diet, like most other GI diseases, there has been limited progress in drug research and development for coeliac disease. This is primarily linked with diagnosis challenges and the range of symptoms associated with the conditions, according to Geller. 

But this is beginning to change with GI specialist companies like 9 Meters Biopharma, which are determined to transform coeliac disease into a more manageable and less burdensome disease. 

9 Meters Biopharma's drug larazotide is a short peptide that aims to reduce leakiness from the disrupted tight junctions between cells in gut that appear when a coeliac patient ingests gluten. So, larazotide prevents gliadin (the outcome of enzymes breaking down gluten) from entering systemic circulation and leading to the damaging autoimmune response, which, in turn triggers unpleasant GI symptoms. 

CEO of 9 Meters Biopharma John Temperato explains larazotide is being developed, and will be commercialised, as an adjunctive therapy. This means that patients must adhere to a gluten-free diet, but they will also take the drug roughly 15 minutes before meals three times a day. This means the drug can “help those that are not always able to adhere to the diet” and help to prevent inadvertent exposure and the associated negative GI symptoms, according to Temperato. 

The best way to understand larazotide as a coeliac drug is to compare it with the treatment for heart disease where statins accompany a low-cholesterol diet. 

9 Meters Biopharma is currently studying larazotide in a Phase III study of 525 patients at more than 100 sites. The primary endpoint of the study is the change in patient reported GI symptoms over 12 weeks compared to placebo. Evaluation relies on the Celiac Disease Patient-Reported Outcome tool, which 9 Meters Biopharma developed for its Phase II study. This endpoint has been agreed with the US Food and Drug Administration (FDA). 

The FDA has also recognised larazotide’s excellent safety profile. This contributes, alongside promising efficacy results in Phase II trials, to Temperato’s optimism that 9 Meters will be able to progress to a FDA review in 2022 and then onto the market by 2023 with conditional approval. 

Geller is encouraged by 9 Meters Biopharma bringing larazotide into Phase III that the coeliac community might see a drug in the next five years; something which Geller has been promised since her son was first diagnosed with the condition in 2008.

Although having the first treatment approved for coeliac disease would be a huge milestone, Geller notes having a “medicine to address symptoms is one thing, but the goal is to reduce the gut damage”. 

This is the focus of some of the drugs slightly earlier along in the development process. One such company picked out by Geller is Provention Bio’s PRV-015 – this is being studied in Phase II as an adjunct to a gluten-free diet. 

This anti-interleukin-15 monoclonal antibody is a repurposed therapy originally developed by Amgen for rheumatoid arthritis. It works by inhibiting cytokines that are involved in the pathophysiology of coeliac disease and therefore reduces inflammation in the intestine.

Another example that Geller mentions is ImmunogenX’s latiglutenase (IMGX003), a mixture of two-gluten specific enzymes that, when combined with a gluten-free diet, reduced the severity of coeliac symptoms, as well as combatted induced intestinal mucosal injury in Phase II studies. 

The next stage would be to resolve the underlying cause of the disease that leads to this immune response. This could create a situation where patients may not need to adhere to a strict gluten-free diet at all. 

One approach could be to tolerise the immune system against gluten, which Geller describes as the ‘Holy Grail’ and notes that the industry has not given up on despite the failure of ImmusanT’s coeliac vaccine candidate last year. “With sufficient research dollars, we are going to be able to find the Holy Grail eventually,” Geller concludes.