title: Safety, tolerability, and activity of ALV003: results from two phase 1 single, escalating-dose clinical trials.
abstract: BACKGROUND
  Celiac disease is the most common hereditary autoimmune disease in humans. The only treatment option for non-refractory celiac disease patients is adherence to a strict life-long gluten-free diet, which often fails to normalize small bowel histology. ALV003 is a mixture of two proteases that degrades gluten and is in clinical development as an oral therapy for patients with celiac disease.
  
  
  OBJECTIVE
  The safety, tolerability, and activity of ALV003 were assessed in two phase 1 clinical trials.
  
  
  METHODS
  In study 1 (N = 28) the study drug was administered in the fasted state; in study 2 (N = 53) the study drug was administered together with a gluten-containing meal. Both studies were single-dose, single-blind, placebo-controlled, cross-over trials. ALV003 was dosed at escalating dose levels by cohort (100, 300, 900, and 1,800 mg) and gastric samples were aspirated using a nasogastric tube. Adverse events, serum drug levels, and anti-drug antibody titers were measured. Gastric samples were assessed for ALV003 enzymatic activity over time (gastric pharmacokinetics) and gluten degradation (gastric pharmacodynamics).
  
  
  RESULTS
  All doses were well tolerated, and no serious adverse events or allergic reactions were observed. Gastric aspirates collected 30 min following a meal showed that 100 and 300 mg ALV003 degraded 75 ± 10% (N = 8) and 88 ± 5% (N = 8), respectively, of one gram of wheat bread gluten.
  
  
  CONCLUSIONS
  ALV003 is an orally active protease that appears to be stable in the fed stomach and degrades dietary gluten in this compartment. Single doses of oral ALV003 were not associated with serious adverse reactions.
authors.affiliation: Alvine Pharmaceuticals, 75 Shoreway Road, Suite B, San Carlos, CA 94070, USA. msiegel@alvinepharma.com
authors.forename: Matthew
authors.initials: M
authors.lastname: Siegel
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Garber
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Spencer
authors.forename: Wendy
authors.initials: W
authors.lastname: Botwick
authors.forename: Pawan
authors.initials: P
authors.lastname: Kumar
authors.forename: Robert N
authors.initials: RN
authors.lastname: Williams
authors.forename: Kenji
authors.initials: K
authors.lastname: Kozuka
authors.forename: Revati
authors.initials: R
authors.lastname: Shreeniwas
authors.forename: Vijaya
authors.initials: V
authors.lastname: Pratha
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Adelman
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D002446:Celiac Disease / Q000188:drug therapy*; D018592:Cross-Over Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005983:Glutens / Q000737:chemistry; D006801:Humans; D008297:Male; D010447:Peptide Hydrolases / Q000008:administration & dosage*; D016037:Single-Blind Method; D013270:Stomach / Q000201:enzymology; D055815:Young Adult
chemical_list: D005983:Glutens; C571240:ALV003; D010447:Peptide Hydrolases