title: Treatment of diabetic macular edema with a designed ankyrin repeat protein that binds vascular endothelial growth factor: a phase I/II study.
abstract: OBJECTIVE
  To evaluate the safety and bioactivity of MP0112, a designed ankyrin repeat protein (DARPin) that specifically binds vascular endothelial growth factor (VEGF) in patients with diabetic macular edema (DME). DARPins are a novel class of proteins selected for specific, high-affinity binding to a target protein.
  
  
  METHODS
  Phase I/II, open-label, multicenter dose-escalation trial.
  
  
  METHODS
  After a single intravitreal injection of MP0112, the main outcomes were safety assessments, aqueous MP0112 levels, change in best-corrected visual acuity (BCVA), and foveal thickness measured by optical coherence tomography. Six cohorts were planned, but only 3 were enrolled (0.04, 0.15, 0.4 mg), because a maximally tolerated dose of 1.0 mg was identified in a parallel age-related macular degeneration trial.
  
  
  RESULTS
  Median aqueous concentration of MP0112 was 555 nM 1 week and >10 nM in 3 of 4 patients 12 weeks post injection of 0.4 mg. Median BCVA improvement at week 12 was 4, 6, and 10 letters in cohorts 1, 2, and 3. Ocular inflammation was observed in 11 patients (61%) and was severe in 1. High-resolution chromatography separated proinflammatory impurities from MP0112, resulting in a new formulation.
  
  
  CONCLUSIONS
  A single intraocular injection of 0.4 mg MP0112 resulted in levels above the half-maximal inhibitory concentration and neutralization of VEGF in aqueous humor for 8-12 weeks. Despite inflammation in several patients, there was prolonged edema reduction and improvement in vision in several patients. The source of the inflammation was eliminated from a new preparation that is being tested in an ongoing clinical trial.
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA. pcampo@jhmi.edu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Campochiaro
authors.forename: Roomasa
authors.initials: R
authors.lastname: Channa
authors.forename: Brian B
authors.initials: BB
authors.lastname: Berger
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Heier
authors.forename: David M
authors.initials: DM
authors.lastname: Brown
authors.forename: Ulrike
authors.initials: U
authors.lastname: Fiedler
authors.forename: Julia
authors.initials: J
authors.lastname: Hepp
authors.forename: Michael T
authors.initials: MT
authors.lastname: Stumpp
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D017089:Ankyrin Repeat; D001082:Aqueous Humor / Q000378:metabolism; D001682:Biological Availability; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D003930:Diabetic Retinopathy / Q000188:drug therapy* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005584:Fovea Centralis / Q000473:pathology; D006801:Humans; D058449:Intravitreal Injections; D008269:Macular Edema / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D011485:Protein Binding; D041623:Tomography, Optical Coherence; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D014792:Visual Acuity / Q000502:physiology
chemical_list: C581258:MP0112; D010455:Peptides; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A