Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients

• Published in: Eye (London) Vol. 26; no. 8; pp. 1099 - 1105
• Main Authors: Nguyen, Q D, Schachar, R A, Nduaka, C I, Sperling, M, Basile, A S, Klamerus, K J, Chi-Burris, K, Yan, E, Paggiarino, D A, Rosenblatt, I, Khan, A, Aitchison, R, Erlich, S S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-08-2012; Nature Publishing Group
• Subjects: 631/378/1689/1626; 631/92/436/1729; 631/92/436/2388; Aged; Aged, 80 and over; Area Under Curve; Biological and medical sciences; Biological Availability; Choroidal Neovascularization - diagnosis; Choroidal Neovascularization - drug therapy; Choroidal Neovascularization - metabolism; Clinical Study; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Intravitreal Injections; Laboratory Medicine; Macular Degeneration - diagnosis; Macular Degeneration - drug therapy; Macular Degeneration - metabolism; Male; Maximum Tolerated Dose; Medical sciences; Medicine; Medicine & Public Health; Microscopy, Acoustic; Miscellaneous; Ophthalmology; Pharmaceutical Sciences/Technology; Prospective Studies; Retinopathies; RNA Interference; RNA, Double-Stranded - genetics; RNA, Small Interfering - administration & dosage; RNA, Small Interfering - adverse effects; RNA, Small Interfering - pharmacokinetics; Surgery; Surgical Oncology; Tomography, Optical Coherence; Transcription Factors - genetics; Visual Acuity - physiology; neovascular age-related macular degeneration; phase 1; siRNA; Human; Eye disease; Retinopathy; Phase; Targeting; Gene; Age related macular degeneration; Neovascularization; Ophthalmology
• ISSN: 0950-222X; 1476-5454
• DOI: 10.1038/eye.2012.106

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 
μ
g 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 
μ
g 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 
μ
g 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 
μ
g of PF-045237655 was generally safe and well tolerated over 24 months. There were no dose-limiting toxicities.
Conclusion
A single IVT injection of PF-0523655 ≤3000 
μ
g seems safe and well tolerated in eyes with neovascular AMD.