title: Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment.
abstract: OBJECTIVE
  Antibody formation to therapeutic peptides is common. This analysis characterizes the time-course and cross-reactivity of anti-exenatide antibodies and potential effects on efficacy and safety.
  
  
  METHODS
  Data from intent-to-treat patients in 12 controlled (n = 2225,12-52 weeks) and 5 uncontrolled (n = 1538, up to 3 years) exenatide twice-daily (BID) trials and 4 controlled (n = 653,24-30 weeks) exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52 weeks) were analysed.
  
  
  RESULTS
  Mean titres peaked early (6-22 weeks) and subsequently declined. At 30 weeks, 36.7% of exenatide BID patients were antibody-positive; 31.7% exhibited low titres (≤125) and 5.0% had higher titres (≥625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of exenatide QW patients were antibody-positive (45.0% low/11.8% higher titre) at 24-30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment-emergent anti-exenatide antibodies from a subset of patients tested did not cross-react with human GLP-1 or glucagon. Other than injection-site reactions, adverse event rates in antibody-positive and antibody-negative patients were similar. Efficacy was robust in both antibody-negative and antibody-positive patients (mean HbA1c change: -1.0 and -0.9%, respectively, exenatide BID; -1.6% and -1.3% exenatide QW). No correlation between change in HbA1c and titre was observed for exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for exenatide QW with no difference between antibody-negative and low-titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres.
  
  
  CONCLUSIONS
  Low-titre anti-exenatide antibodies were common with exenatide treatment (32% exenatide BID, 45% exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% exenatide BID, 12% exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for exenatide QW. Other than injection-site reactions, anti-exenatide antibodies did not impact the safety of exenatide.
authors.affiliation: Elcelyx Therapeutics, Inc., San Diego, CA 92130, USA. mark.fineman@elcelyx.com
authors.forename: Mark S
authors.initials: MS
authors.lastname: Fineman
authors.forename: K F
authors.initials: KF
authors.lastname: Mace
authors.forename: M
authors.initials: M
authors.lastname: Diamant
authors.forename: T
authors.initials: T
authors.lastname: Darsow
authors.forename: B B
authors.initials: BB
authors.lastname: Cirincione
authors.forename: T K
authors.initials: TK
authors.lastname: Booker Porter
authors.forename: L A
authors.initials: LA
authors.lastname: Kinninger
authors.forename: M E
authors.initials: ME
authors.lastname: Trautmann
mesh_terms: D000328:Adult; D000368:Aged; D000888:Antibodies, Anti-Idiotypic / Q000009:adverse effects / Q000276:immunology*; D001786:Blood Glucose / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D003429:Cross Reactions / Q000187:drug effects / Q000276:immunology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000077270:Exenatide; D005260:Female; D005934:Glucagon / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage / Q000276:immunology*; D013997:Time Factors; D016896:Treatment Outcome; D014688:Venoms / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D005934:Glucagon; D000077270:Exenatide