title: Single-Chain Antibody Fragment VEGF Inhibitor RTH258 for Neovascular Age-Related Macular Degeneration: A Randomized Controlled Study.
abstract: OBJECTIVE
  To assess the safety and efficacy of different doses of RTH258 applied as single intravitreal administration compared with ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration (AMD).
  
  
  METHODS
  Six-month, phase 1/2, prospective, multicenter, double-masked, randomized, ascending single-dose, active-controlled, parallel-group study.
  
  
  METHODS
  A total of 194 treatment-naive patients, aged ≥50 years, with primary subfoveal choroidal neovascularization secondary to AMD.
  
  
  METHODS
  Patients received a single intravitreal injection of RTH258 0.5 mg (n = 11), 3.0 mg (n = 31), 4.5 mg (n = 47), or 6.0 mg (n = 44), or ranibizumab 0.5 mg (n = 61).
  
  
  METHODS
  The primary efficacy end point was the change from baseline to month 1 in central subfield thickness (CSFT) measured by spectral-domain optical coherence tomography. The secondary efficacy end point was the duration of treatment effect measured as time from the initial injection to receipt of post-baseline therapy (PBT) guided by protocol-defined criteria. Adverse events (AEs) were recorded throughout the study.
  
  
  RESULTS
  RTH258 demonstrated noninferiority compared with ranibizumab in mean change in CSFT from baseline to month 1 for the 4.5- and 6.0-mg dose groups (margin: 40 μm, 1-sided alpha 0.05). The difference in CSFT change at month 1 comparison with ranibizumab was 22.86 μm (90% confidence interval [CI], -9.28 to 54.99) and 19.40 μm (95% CI, -9.00 to 47.80) for RTH258 4.5 and 6 mg, respectively. The median time to PBT after baseline therapy was 60 and 75 days for patients in the RTH258 4.5- and 6.0-mg groups, respectively, compared with 45 days for ranibizumab. Changes in best-corrected visual acuity with RTH258 were comparable to those observed with ranibizumab. The most frequent AEs reported for the RTH258 groups were conjunctival hemorrhage, eye pain, and conjunctival hyperemia; the majority of these events were mild in intensity.
  
  
  CONCLUSIONS
  This first-in-human study of RTH258 demonstrated noninferiority in the change in CSFT at 1 month for the 4.5- and 6.0-mg doses compared with ranibizumab and an increase of 30 days in the median time to PBT for the 6.0-mg dose. There were no unexpected safety concerns, and the results support the continued development of RTH258 for the treatment of neovascular AMD.
authors.affiliation: Department of Ophthalmology, University of Bonn, Bonn, Germany.
authors.forename: Frank G
authors.initials: FG
authors.lastname: Holz
authors.affiliation: Retinal Consultants of Arizona, Phoenix, Arizona; USC Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California. Electronic address: pdugel@gmail.com.
authors.forename: Pravin U
authors.initials: PU
authors.lastname: Dugel
authors.affiliation: Alcon, a Novartis company, Fort Worth, Texas.
authors.forename: Georges
authors.initials: G
authors.lastname: Weissgerber
authors.affiliation: NIHR BRC at Moorfields Eye Hospital and Moorfields Eye Hospital, NHS Foundation Trust, Ophthalmology, London, United Kingdom.
authors.forename: Robin
authors.initials: R
authors.lastname: Hamilton
authors.affiliation: Centro Hospitalar e Universitário de Coimbra, Faculty of Medicine, University of Coimbra, and Association for Innovation and Biomedical Research on Light and Image, Coimbra, Portugal.
authors.forename: Rufino
authors.initials: R
authors.lastname: Silva
authors.affiliation: Università Vita-Salute, Istituto Scientifico San Raffaele, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bandello
authors.affiliation: Department of Ophthalmology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Larsen
authors.affiliation: Alcon, a Novartis company, Fort Worth, Texas.
authors.forename: Andreas
authors.initials: A
authors.lastname: Weichselberger
authors.affiliation: Alcon, a Novartis company, Fort Worth, Texas.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wenzel
authors.affiliation: ESBATech, A Novartis company, Zurich, Switzerland.
authors.forename: Anne
authors.initials: A
authors.lastname: Schmidt
authors.affiliation: ESBATech, A Novartis company, Zurich, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Escher
authors.affiliation: Hospital General de Catalunya, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Sararols
authors.affiliation: Service Universitaire d'Ophtalmologie, Hôpital Intercommunal, Université Paris Est, Créteil, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Souied
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D007128:Immunoglobulin Fragments / Q000276:immunology*; D058449:Intravitreal Injections; D008297:Male; D011446:Prospective Studies; D000069579:Ranibizumab / Q000008:administration & dosage*; D057127:Single-Chain Antibodies / Q000276:immunology*; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D014792:Visual Acuity; D057135:Wet Macular Degeneration / Q000175:diagnosis / Q000503:physiopathology / Q000628:therapy*
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D007128:Immunoglobulin Fragments; D057127:Single-Chain Antibodies; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab