New Drug Therapies & Effective Treatments For Celiac Disease
At this point in time, the only way for sufferers of celiac disease to effectively manage their condition is to follow a strict gluten-free diet at all times; but that could change in the near future with a number of new drug therapies undergoing clinical trials, and several others at the pre-clinical trial phase. While it could still be a number of years before any of these therapies is approved for widespread use, the data acquired from the initial testing phase for many of these drugs has been extremely positive.
According to the Canadian Celiac Society, it is predicted that one in every one hundred and thirty three people suffer from celiac disease in Canada, which is a condition that can result in damage to the small intestine being sustained if the sufferer’s diet includes items that contain gluten. This damage can severely affect the person’s health, making it difficult to impossible to absorb nutrients that are essential to growth and good health. Dr. Klaus Gottlieb, the lead author from a report discussing these potential drug treatments that was recently released, states that there a couple of investigational treatment options that are rumoured to be undergoing larger confirmatory testing in the near future that show real promise. You can read about some of these new drugs below and you can access the full article here.
Research and development ‘pipeline’ for celiac disease drugs & continuing clinical trials
Clinical trials on drugs to treat celiac disease are at an early stage of evolution, with no products having reached Phase 3 to date (Figure 1). Products in development include:
- ALV003, Alvine Pharmaceuticals’ lead clinical candidate for celiac disease, which is currently being studied in Phase 2b [20].
ALV003 is an orally administered mixture of two recombinant gluten-specific proteases—a cysteine protease (EP-B2) and a prolyl endopeptidase (PEP)—which have been shown in vitro to degrade gluten. In a Phase 2 study with ALV003, adults with biopsy-proven celiac disease were randomly assigned to groups receiving ALV003 (n¼20) or placebo (n¼21), together with a daily 2 g gluten challenge. Duodenal biopsies were collected at baseline and after the gluten challenge. The ratio of villus-height-to-cryptdepth and densities of intra-epithelial lymphocytes were the primary endpoints. Biopsies from subjects in the placebo group showed evidence of mucosal injury after gluten challenge (mean villus height-to-crypt depth ratio changed from 2.8 before challenge to 2.0 afterward; P¼0.0007; density of CD3þ intraepithelial lymphocytes changed from 61 to 91 cells/mm
after challenge; P¼0.0003). In contrast, no significant mucosal deterioration was observed in biopsies from the ALV003 group. Between groups, morphologic changes and CD3þ intraepithelial lymphocyte counts differed significantly from baseline to Week 6 (P¼0.0133 and P¼0.0123, respectively). Interestingly, there were no statistically significant differences in symptoms
between groups [21].Based on the promising Phase 2a results, a Phase 2b study is now being conducted. The study is evaluating the safety and efficacy of ALV003 at different dose levels administered over a twelve-week period in 500 celiac disease patients in the USA, Canada and Europe, who are symptomatic despite attempting to follow a GFD. The primary efficacy endpoint for the study is the change in small intestinal mucosal morphology, as measured by the change in villus-height-to-crypt-depth ratio (Vh:Cd) from baseline and week 12 assessments. Secondary endpoints are the changes in density in intestinal intraepithelial lymphocytes and celiac disease-specific symptoms during the study. Other outcomes to be evaluated include changes in celiac disease
serologies and quality-of-life measures [20].Aspergillus niger prolyl endoprotease (AN-PEP) is an endopeptidase,like the PEP component of ALV003, which can break down gluten. The enzyme is active between pH 2 and pH 8, with an optimum activity at pH 4–5, and is therefore effective at the pH levels present in the stomach and small intestine [22]. ANPEP was evaluated in a recent small, double-blind, placebo controlled, randomized trial on 16 patients with a diagnosis of celiac disease—as confirmed by positive serology—with sub-total or total villous atrophy on duodenal biopsies, who adhered to a strict GFD, resulting in normalized antibodies and mucosal healing classified as Marsh 0 or I [22]. In a randomized, doubleblind, placebo-controlled pilot study, patients consumed toast (approximately 7 g/day gluten) with AN-PEP for 2 weeks (safety phase). After a 2-week washout period with adherence to the usual GFD, 14 patients were randomized to gluten intake with either AN-PEP or placebo for 2 weeks (efficacy phase). No serious adverse events occurred and no patients withdrew during the trial. The mean score for the gastrointestinal subcategory of the celiac disease quality (CDQ) was relatively high throughout the study, indicating that AN-PEP was well tolerated. In the efficacy phase, the CDQ scores of patients consuming gluten with placebo or gluten with AN-PEP did not significantly deteriorate and, moreover, no differences between the groups were observed. The authors conclude in their discussion that “with hindsight, the study should possibly have been designed for a much longer period of time with many more patients” [22].
- Larazotide acetate (AT-1001) is Alba Therapeutics Corporation’s investigational product, a first-in-class tight junction regulator, intended for the treatment of patients with celiac disease. It has been hypothesized that celiac disease is accompanied by raised paracellular permeability, accompanied by an inflammatory cascade within the bowel, which is controlled by tight junctions. Alba has reported positive results from a double-blind, placebocontrolled, Phase 2b trial in February 2014 [23]. This evaluated the efficacy and safety of larazotide acetate in 342 celiac disease patients who had symptoms despite being on a GFD. The trial consisted of a four-week placebo run-in, 12 weeks of randomized therapy, and four weeks of post-treatment follow-up. Patients were randomized to four groups: a placebo group or larazotide 0.5, 1.0, or 2.0 mg, three times per day. Treatment with the lowest of three doses of larazotide was associated with significant improvement in the primary outcome, i.e. the average ontreatment score in the Celiac Disease Gastrointestinal Symptom Rating Scale (CeD GSRS) domains of Diarrhea, Indigestion, and Abdominal pain. Analysis of individual components of the rating scale, proprietary to Alba Therapeutics [24], showed consistent improvement with larazotide for each parameter [25].
The Phase 2b study discussed above was preceded by a separate, dose-ranging, placebo-controlled study of 86 patients with celiac disease controlled through diet [26]. The aim of this study was to evaluate the efficacy and tolerability of larazotide in protecting against gluten-induced intestinal permeability and worsening gastrointestinal symptoms. Study participants were
randomly assigned to larazotide acetate (0.25, 1, 4, or 8 mg) or placebo three times a day, with or without gluten challenge (2.4 g/day) for 14 days. The primary efficacy outcome, an improvement in the lactulose/mannitol (LAMA) fractional excretion ratio (an experimental biomarker for intestinal permeability) was not met; however, the 0.25 and 4.0mg doses of larazotide acetate showed statistically significant prevention of severe worsening of gastrointestinal symptoms.
An exploratory study published in 2013 [27] examined the effect of larazotide acetate on intestinal permeability, development of antibodies to tTG and celiac disease symptoms during a gluten challenge that exceeded the likely level of accidental gluten ingestion in individuals whose disease was well controlled by a GFD. In the larazotide acetate 1 mg group, a reduction in the expected increase was seen in the urinary LAMA ratio but the difference was not statistically significant as compared with placebo. Changes in pre-specified secondary endpoints suggest that larazotide acetate reduced antigen exposure, as shown by lowered production of anti-tTG antibodies. Larazotide acetate also reduced gastrointestinal symptoms upon gluten challenge.
- Nexvax2: ImmusanT’s peptide-based therapeutic celiac disease vaccine.
According to press releases from ImmusanT [28], the therapeutic vaccine Nexvax2 combines three proprietary peptides that elicit an immune response in celiac disease patients who carry the immune recognition gene HLA-DQ2. Similarly to treatments for allergies, the vaccine is designed to reprogram gluten-specific T cells triggered by the patient’s immune response to the protein. According to ImmusanT, the objective is for Nexvax2 to restore celiac patients’ immune tolerance to gluten, reduce inflammation in the nutrient-absorbing villi that line the small intestine, return the intestine to a healthy state, and allow patients to eat a normal diet [28].
The company says that early clinical trials have so far proven promising, with Phase 1b trial results demonstrating clear proof of mechanism and Phase 2 trials expected to begin in 2015—but details are not known at the time of this writing (December 2014) [29].
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BL-7010: BiolineRx’s non-absorbable, high molecular weight polymer with a high affinity for gliadins, the immunogenic peptides present in gluten that cause celiac disease. The product acts by sequestering gliadins. Experiments in vivo in a murine model of celiac disease have shown that BL-7010 prevents pathological damage to the small intestine, helps to preserve the integrity of the intestinal mucosa and reduces inflammation [30]. Although the company website lists BL-7010 as being in pre-clinical development, clinicaltrials.gov shows an active recruiting Phase 1 safety study [31].
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AVX176, from Avaxia Biologics, is an investigational oral antibody drug that is the subject of U.S. composition of matter patent 8,071,101, “Antibody Therapy for Treatment of Diseases Associated with Gluten Intolerance.” The patent, which expires on May 27 2029, provides broad coverage for treating celiac disease using orally administered antibodies produced by Avaxia’s proprietary platformtechnology [32].
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ActoGenX is carrying out discovery research in celiac disease with its range of ActoBioticsTM, which use Lactococcus lactis as an expression system to locally secrete bio-therapeutics such as cytokines, antibodies, hormones, etc. [33]. Early pre-clinical work with a genetically altered L. lactis secreting a peptide derived from gliadin demonstrated an in vivo suppression of gluten sensitization. Specifically, Huigbregtse et al. engineered L. lactis to secrete a deamidated DQ8 gliadin epitope (LL-eDQ8d) and studied the induction of Ag-specific tolerance in NOD ABo DQ8 transgenic mice [34].Although apparently not part of the ActoGenX development program, recent work by Galipeau et al. also deserves mention in this context. The group treated gluten-sensitive mice with elafin, a serineprotease inhibitor, delivered by the L. lactis vector, and found normalization of inflammation, improved permeability, and maintained ZO-1 expression. There is speculation that this is due to reduced deamidation of gliadin peptide [31].
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Chemocentryx’s CCR9 (vercirnon, which is also known as Traficet-EN, or CCX282B)—originally intended for patients with moderate-to-severe Crohn’s disease—has completed one Phase 2 trial in 67 patients with celiac disease [35]; however, despite the completion of the trial several years ago, no results relating to celiac disease have been made public or published.
The two more promising drugs that have been developed aim to provide a solution to celiac disease in different ways, but the end goal is the same – to prevent the body from reacting in a destructive manner to the presence of gluten. The first drug breaks down gluten into a series of other products which are non-harmful to celiac disease sufferers, thus eliminating the problem, while the second drug stops the gut from leaking the toxic substances that cause the damage. It’s estimated that should these drugs pass all testing phases and receive approval, they could be made available to the public within 3 to 5 years.
Have you been suffering from celiac disease for some time now? Or perhaps you’ve just recently been diagnosed? Whatever the specifics, this is a condition that can cause considerable disruption to your life and force you to incur considerable extra costs that you normally wouldn’t in order to maintain the right diet. You might be interested to know that you can receive financial support from the Canadian Government to compensate and Disability Credit Canada are experts at completing all of the necessary paperwork and filings to get you the money you deserve. Contact us today for more information.