Digestive Diseases and Sciences

, Volume 62, Issue 9, pp 2428–2432 | Cite as

Latiglutenase Improves Symptoms in Seropositive Celiac Disease Patients While on a Gluten-Free Diet

  • Jack A. Syage
  • Joseph A. MurrayEmail author
  • Peter H. R. Green
  • Chaitan Khosla
Original Article


Background and Aims

Celiac disease (CD) is a widespread condition triggered by dietary gluten and treated with a lifelong gluten-free diet (GFD); however, inadvertent exposure to gluten can result in episodic symptoms. A previous trial of latiglutenase (; NCT01917630), an orally administered mixture of two recombinant gluten-specific proteases, was undertaken in symptomatic subjects with persistent injury. The primary endpoint for histologic improvement was not met, presumably due to a trial effect. In this post hoc analysis, we investigated the efficacy of latiglutenase for reducing symptoms in subgroups of the study participants based on their seropositivity.


The study involved symptomatic CD patients following a GFD for at least one year prior to randomization. Patients were treated for 12 weeks with latiglutenase or placebo. Of 398 completed patients, 173 (43%) were seropositive at baseline. Symptoms were recorded daily, and weekly symptom scores were compiled. p values were calculated by analysis of covariance.


A statistically significant, dose-dependent reduction was detected in the severity and frequency of symptoms in seropositive but not seronegative patients. The severity of abdominal pain and bloating was reduced by 58 and 44%, respectively, in the cohort receiving the highest latiglutenase dose (900 mg, n = 14) relative to placebo (n = 54). Symptom improvement increased from week 6 to week 12. There was also a trend toward greater symptom improvement with greater baseline symptom severity.


Seropositive CD patients show symptomatic improvement from latiglutenase taken with meals and would benefit from the availability of this treatment.


Celiac disease Latiglutenase Therapy Symptoms 



Clinical trial NCT01917630 was sponsored by Alvine Pharmaceuticals; all data from this trial are presently owned by ImmunogenX. The data analysis reported here was supported in part by a Grant from the National Institutes of Health (R01 DK063158 to C.K.).

Authors’ contributions

JAS, JAM, PHRG, and CK were involved in the acquisition of data; JAS and CK analyzed and interpreted the data; JAS, and CK provided technical and material support; JAS, PHRG, and CK were involved in drafting of manuscript; JAS, JAM, PHRG, and CK were involved in the critical revision of the manuscript and important intellectual content.

Compliance with ethical standards

Conflict of interest

JAS is a founder of and owns stock in ImmunogenX. JAM has received grant support from the National Institutes of Health, Alvine Pharmaceuticals, and Alba Therapeutics; receives ongoing support from Oberkotter Foundation and Broad Medical Research Program at CCFA; serves on the advisory board of Celimmune, LLC and ImmunogenX; was a consultant to, BioLineRx, GlaxoSmithKline (GSK), Genentech, and Glenmark Pharmaceuticals Ltd; and is a consultant to ImmunosanT, Institute for Protein Design (PvP Biologics), Takeda Pharmaceutical Company, Ltd., Innovate Biopharmaceuticals, Inc., and Intrexon. PHRG is an advisor to ImmusanT and ImmunogenX. CK is a director of Protagonist Pharmaceuticals and an advisor to Sitari Pharmaceuticals and holds stock in both companies.


  1. 1.
    Rubio-Tapia A, Murray JA. Celiac disease. Curr Opin Gastroenterol. 2010;26:116–122.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Tennyson CA, Simpson S, Lebwohl B, Lewis S, Green PH. Interest in medical therapy for celiac disease. Ther Adv Gastroenterol. 2013;6:358–364.CrossRefGoogle Scholar
  3. 3.
    Aziz I, Evans KE, Papageorgiou V, Sanders DS. Are patients with coeliac disease seeking alternative therapies to a gluten-free diet? J Gastrointestin Liver Dis. 2011;20:27–31.PubMedGoogle Scholar
  4. 4.
    Gottlieb K, Dawson J, Hussain F, Murray JA. Development of drugs for celiac disease: review of endpoints for phase 2 and 3 trials. Gastroenterol Rep (Oxf). 2015;3:91–102.CrossRefGoogle Scholar
  5. 5.
    Lahdeaho ML, Kaukinen K, Laurila K, et al. Glutenase alv003 attenuates gluten-induced mucosal injury in patients with celiac disease. Gastroenterology. 2014;146:1649–1658.CrossRefPubMedGoogle Scholar
  6. 6.
    Wolf C, Siegel JB, Tinberg C, et al. Engineering of kuma030: a gliadin peptidase that rapidly degrades immunogenic gliadin peptides in gastric conditions. J Am Chem Soc. 2015;137:13106–13113.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Leffler DA, Kelly CP, Green PH, et al. Larazotide acetate for persistent symptoms of celiac disease despite a gluten-free diet: a randomized controlled trial. Gastroenterology. 2015;148:1311–1319.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Gass J, Bethune MT, Siegel M, Spencer A, Khosla C. Combination enzyme therapy for gastric digestion of dietary gluten in patients with celiac sprue. Gastroenterology. 2007;133:472–480.CrossRefPubMedGoogle Scholar
  9. 9.
    Catassi C, Fabiani E, Iacono G, et al. A prospective, double-blind, placebo-controlled trial to establish a safe gluten threshold for patients with celiac disease. Am J Clin Nutr. 2007;85:160–166.PubMedGoogle Scholar
  10. 10.
    Murray JA, Kelly CP, Green PH, et al. No difference between latiglutenase and placebo in reducing villous atrophy or improving symptoms in patients with symptomatic celiac disease. Gastroenterology. 2017;152:787–798.CrossRefPubMedGoogle Scholar
  11. 11.
    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.CrossRefPubMedGoogle Scholar
  12. 12.
    Leffler DA, Acaster S, Gallop K, et al. A novel patient-derived conceptual model of the impact of celiac disease in adults: implications for patient-reported outcome and hela-related quality-of-life instrument development. Value Health. 2017. doi: 10.1016/jjval201612016.PubMedGoogle Scholar
  13. 13.
    Hindryckx P, Levesque BG, Holvoet T, et al. Disease activity indices in coeliac disease: systematic review and recommendations for clinical trials. Gut. 2016. doi: 10.1136/gutjnl-2016-312762.PubMedCentralGoogle Scholar
  14. 14.
    Leffler DA, Dennis M, Hyett B, Kelly E, Schuppan D, Kelly CP. Etiologies and predictors of diagnosis in nonresponsive celiac disease. Clin Gastroenterol Hepatol. 2007;5:445–450.CrossRefPubMedGoogle Scholar
  15. 15.
    Abdulkarim AS, Burgart LJ, See J, Murray JA. Etiology of nonresponsive celiac disease: results of a systematic approach. Am J Gastroenterol. 2002;97:2016–2021.CrossRefPubMedGoogle Scholar
  16. 16.
    Brar P, Kwon GY, Egbuna I, et al. Lack of correlation of degree of villous atrophy with severity of clinical presentation of coeliac disease. Dig Liver Dis. 2007;39:26–29.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Jack A. Syage
    • 1
  • Joseph A. Murray
    • 2
    Email author
  • Peter H. R. Green
    • 3
  • Chaitan Khosla
    • 4
  1. 1.ImmunogenXNewport BeachUSA
  2. 2.Division of Gastroenterology and HepatologyMayo ClinicRochesterUSA
  3. 3.Celiac Disease Center at Columbia UniversityNew YorkUSA
  4. 4.Departments of Chemical Engineering and ChemistryStanford UniversityStanfordUSA

Personalised recommendations