title: Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients.
abstract: BACKGROUND
  To evaluate the safety, tolerability, pharmacokinetics, and dose-limiting toxicities of a single intravitreal (IVT) injection of PF-04523655, a 19-nucleotide, O-methyl stabilized, double-stranded small interfering ribonucleic acid targeting the RTP801 gene in patients with neovascular age-related macular degeneration (AMD).
  
  
  METHODS
  Prospective, phase 1, clinical multicentre trial, enrolled 27 patients with neovascular AMD unresponsive to prior treatment and best corrected visual acuity (BCVA) ≤ 20/200 in the study eye in stratum 1: (dose-escalating, open-label: 50 to 3000 μg of PF-04523655) and 27 patients who had potential to benefit from therapy and BCVA of ≤ 20/100 and ≥ 20/800 in stratum 2 (parallel, masked study of 1000, 1500, 2250, and 3000 μg of PF-04523655). The primary outcome was safety and tolerability assessment as well as pharmacokinetic profiling following a single IVT injection of PF-04523655.
  
  
  RESULTS
  Doses of PF-04523655 ≥ 400 μg were generally detectable in the plasma at 1, 4, and 24 h post-injection. And all doses were below the lowest level of quantification by day 14. A single IVT injection of 50 to 3000 μg of PF-045237655 was generally safe and well tolerated over 24 months. There were no dose-limiting toxicities.
  
  
  CONCLUSIONS
  A single IVT injection of PF-0523655 ≤ 3000 μg seems safe and well tolerated in eyes with neovascular AMD.
authors.affiliation: Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: Q D
authors.initials: QD
authors.lastname: Nguyen
authors.forename: R A
authors.initials: RA
authors.lastname: Schachar
authors.forename: C I
authors.initials: CI
authors.lastname: Nduaka
authors.forename: M
authors.initials: M
authors.lastname: Sperling
authors.forename: A S
authors.initials: AS
authors.lastname: Basile
authors.forename: K J
authors.initials: KJ
authors.lastname: Klamerus
authors.forename: K
authors.initials: K
authors.lastname: Chi-Burris
authors.forename: E
authors.initials: E
authors.lastname: Yan
authors.forename: D A
authors.initials: DA
authors.lastname: Paggiarino
authors.forename: I
authors.initials: I
authors.lastname: Rosenblatt
authors.forename: A
authors.initials: A
authors.lastname: Khan
authors.forename: R
authors.initials: R
authors.lastname: Aitchison
authors.forename: S S
authors.initials: SS
authors.lastname: Erlich
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D001682:Biological Availability; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D033401:Microscopy, Acoustic; D011446:Prospective Studies; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D041623:Tomography, Optical Coherence; D014157:Transcription Factors / Q000235:genetics*; D014792:Visual Acuity / Q000502:physiology
chemical_list: C469991:DDIT4 protein, human; C576360:PF-04523655; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D014157:Transcription Factors