title: Clinical evaluation of pazopanib eye drops versus ranibizumab intravitreal injections in subjects with neovascular age-related macular degeneration.
abstract: OBJECTIVE
  To evaluate pazopanib eye drops in subjects with active subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD).
  
  
  METHODS
  Multicountry, randomized, parallel-group, double-masked, active and placebo-controlled, dose-ranging study of eye drops.
  
  
  METHODS
  A total of 510 subjects (93% white; 58% female; mean age, 75.3 years) whose AMD was previously managed by anti-vascular endothelial growth factor intravitreal injections.
  
  
  METHODS
  Treatments administered for 52 weeks included placebo eye drops instilled 4 times daily (n=73); pazopanib 5 mg/ml instilled 3 (n=72) or 4 times daily (n=74); pazopanib 10 mg/ml instilled 2 (n=73), 3 (n=73), or 4 times daily (n=72); or ranibizumab injection administered once every 4 weeks (n=73). In addition, for all eye drop treatment groups, open-label ranibizumab was administered as needed.
  
  
  METHODS
  The main outcome measures were best-corrected visual acuity (BCVA) and injection frequency assessed at week 52. Safety was assessed every 4 weeks and pazopanib plasma concentrations were determined at weeks 4 and 24.
  
  
  RESULTS
  At week 52, pazopanib, with allowance for as-needed ranibizumab injections, was noninferior to monthly ranibizumab as well as to as-needed ranibizumab administered with placebo eye drops in maintaining BCVA (estimated BCVA gains of 0.3-1.8 vs. 1.4 vs. 0.2 letters, respectively). Pazopanib treatment did not reduce as-needed ranibizumab injections by ≥50% (prespecified efficacy criterion). At week 52, there were no clinically meaningful changes from baseline in retinal thickness or morphology, CNV size, or lesion characteristics on optical coherence tomography or fluorescein angiography. Complement factor H genotype had no effect on the responses to pazopanib and/or ranibizumab (BCVA, injection rate, or optical coherence tomography/fluorescein angiography changes). Steady-state concentrations of pazopanib in plasma seemed to be reached by week 4. The most common ocular adverse events related to pazopanib and ranibizumab were application site pain (3%) and injection site hemorrhage (1%), respectively. No treatment-related serious adverse events were reported.
  
  
  CONCLUSIONS
  Pazopanib was well tolerated. Daily pazopanib eye drops in neovascular AMD subjects did not result in therapeutic benefit beyond that obtained with ranibizumab alone.
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas.
authors.forename: Karl G
authors.initials: KG
authors.lastname: Csaky
authors.affiliation: Retinal Consultants of Arizona, Phoenix, Arizona.
authors.forename: Pravin U
authors.initials: PU
authors.lastname: Dugel
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Pierce
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Fries
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Kelly
authors.affiliation: Ophthalmology and Visual Sciences, University of Wisconsin, Madison, Wisconsin.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Danis
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania. Electronic address: wurzelma@gmail.com.
authors.forename: John I
authors.initials: JI
authors.lastname: Wurzelmann
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Chun-Fang
authors.initials: CF
authors.lastname: Xu
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hossain
authors.affiliation: GlaxoSmithKline, King of Prussia, Pennsylvania.
authors.forename: Trupti
authors.initials: T
authors.lastname: Trivedi
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D007191:Indazoles; D058449:Intravitreal Injections; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics; D009883:Ophthalmic Solutions; D010597:Pharmacogenetics; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D000069579:Ranibizumab; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D057135:Wet Macular Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D007191:Indazoles; D009363:Neoplasm Proteins; D009883:Ophthalmic Solutions; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D040262:Receptors, Vascular Endothelial Growth Factor; D000069579:Ranibizumab