Latiglutenase
Latiglutenase (IMGX003) is an orally administered mixture of two gluten-specific recombinant proteases that degrades gluten proteins into small physiologically irrelevant fragments, and is to be administered as an adjunct to a gluten-free diet (GFD). As illustrated in the below figure, one protease (IMGX001) is effective at breaking glutamine-leucine bonds and the other protease (IMGX002) targets most proline bonds.
Figure 1. Schematic diagram illustrating the breaking of glutamine (Q) and proline (P) bond in a prototypical immunogenic gluten fragment.
In Phase 2a and 2b clinical trials Latiglutenase has been shown to mitigate gluten-induced intestinal mucosal injury as well reduce the severity and frequency of symptoms in celiac disease patients. Evidence of symptom relief was particularly pronounced for patients who continue to have positive serology to gluten-induced antibodies (seropositive) despite following a GFD as seen in the results shown below (Syage 2017, 2019). These studies also demonstrated that Latiglutenase is well tolerated by CD patients with no discernable difference in adverse event profile for active vs. placebo treated patients.
Figure 2. Percent reductions in symptom severity relative to placebo for the combined 600 mg and 900 mg treatment groups.
ImmunogenX completed the CeliacShieldTM trial (NCT03585478) conducted at Mayo Clinic (Murray 2022). This gluten-challenge trial measured several outcomes including histology, symptoms, serology, and gluten in urine. Histologic protection was assessed by measuring changes in villous height to crypt depth ratio (ΔVh:Cd) and intraepithelial lymphocytes (ΔIEL) before and after a 6-week, 2-g per day gluten challenge period. The attenuation of ΔVh:Cd and ΔIEL for the active (1200-mg latiglutenase, IMGX003) group relative to placebo was 88% and 60% with p-values of 0.0570 and 0.0181 (ANCOVA), respectively.
Measurements of gluten immunogenic peptides (GIP) in urine showed reduction of gluten of about 95% for latiglutenase vs. placebo with p < 0.0001 (Figure 3) demonstrating the mechanism of action. The reduction in symptom severity for latiglutenase relative to placebo ranged from 53% to 99% for abdominal pain, bloating, tiredness and the overall non-stool composite scale that also includes nausea. All of these symptoms showed consistent trends when monitored over three 2-week intervals with p values ranging from <0.001 to 0.030 (see Figure 4)
Figure 3. GIP concentration in urine before, during and after the gluten challenge treatment period
Figure 4. Mean change from baseline (% worsening) for non-stool composite for three 2-week gluten challenge treatment periods for IMGX003 vs. placebo.
CypCel
A majority of individuals with CD do not recover well under a GFD. Furthermore, there is still no effective means for monitoring the intestinal health of a recovering celiac other than an invasive biopsy and even that method is prone to interpretive analysis.
We are developing a metabolic marker compound that can measure the state of small-intestinal recovery of celiac patients undergoing GFDs. In this test (referred to as CypCel), a single oral dose of the widely used cholesterol-lowering agent, simvastatin (SV), is administered to a patient. SV has the unique property that it is highly metabolized by an enzyme on the intestinal villi before absorbing into the blood stream. So if the villi are healthy there is high metabolism and the SV concentration in blood will be low. Conversely if the villi are atrophied there is much less metabolism and the SV concentration in blood will be high. Therefore, the measure of the concentration of SV in blood serum is a direct measure of the health of the villi.
A successful proof of concept trial (Moron 2013) has been followed by two subsequent supportive trials. Figure 5 shows improvement of the intestinal villi in newly diagnosed celiac patients recovering on a GFD. This is a unique capability for which there are no other effective diagnostics.
Figure 5. SV concentration in blood serum for different subject groups showing reduction in these levels with continued treatment on a gluten-free diet.
Cited References
Syage JA, Murray JA, Green PHR, Khosla, C. Latiglutenase Improves Symptoms in Seropositive Celiac Disease Patients While on a Gluten-Free Diet. Dig Dis & Sci 2017;62:2428-2432. https://doi.org/10.1007/s10620-017-4687-7
Syage JA et al., Latiglutenase Treatment for Celiac Disease: Symptom and Quality of Life Improvement for Seropositive Patients on a Gluten-Free Diet. GastroHep 2019;1:293-301. https://doi.org/10.1002/ygh2.371
Murray JA, Syage, JA, Wu T-T, Dickason MA, et al. Latiglutenase Protects the Mucosa and Attenuates Symptom Severity in Patients with Celiac Disease Exposed to a Gluten Challenge, Gastroenterology 2022; 163:1510-1521. https://doi.org/10.1053/j.gastro.2022.07.071
Moron B, Verma AK, … Khosla C et al. CYP3A4-catalyzed simvastatin metabolism as a non-invasive marker of small intestinal health in celiac disease. Am J Gastroenterol 2013;108:1-8. https://doi.org/10.1038/ajg.2013.151
Additional References
Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology 2009;137:1912–33. https://doi.org/10.1053/j.gastro.2009.09.008
Rubio-Tapia A, Murray JA. Celiac disease. Curr Opin Gastroenterol 2010;26:116–22. https://doi.org/10.1097/mog.0b013e3283365263
Leffler D, Kupfer SS, Lebwohl B, Bugin K, Griebel D, et al., Development of Celiac Disease Therapeutics: Report of the Third Gastroenterology Regulatory Endpoints and Advancement of Therapeutics Workshop. Gastroenterology 2016;151:407–411. https://doi.org/10.1053/j.gastro.2016.07.025
Kelly CP, Bai, JC, Liu E, Leffler DA. Celiac disease: clinical spectrum and management. Gastroenterol 2015;148:1175-1186. https://doi.org/10.1053/j.gastro.2015.01.044
Green PHR, Lebwohl B, Greywoode R. Celiac disease. J Allergy Clin Immunol 2015;135:1099-1106. https://doi.org/10.1016/j.jaci.2015.01.044
Syage JA, et al. Determination of gluten consumption in celiac disease patients on a gluten-free diet. Am J Clin Nutr 2018;107:201-207. https://doi.org/10.1093/ajcn/nqx049