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Phase 1 dose-escalation study of a siRNA targeting the RTP801 gene in age-related macular degeneration patients
Q D Nguyen1, R A Schachar, C I Nduaka
1Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA.
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.
Conclusion:
A single IVT injection of PF-0523655 ≤ 3000 μg seems safe and well tolerated in eyes with neovascular AMD.
Insights
A single intravitreal injection of PF-04523655 was found to be safe and well-tolerated in patients with neovascular age-related macular degeneration (AMD). This novel RNA interference therapeutic showed no dose-limiting toxicities over 24 months.
Area of Science:
- Ophthalmology
- Genetics
- Pharmacology
Background:
- Investigating novel RNA interference therapeutics for neovascular age-related macular degeneration (AMD).
- Evaluating PF-04523655, a double-stranded small interfering ribonucleic acid targeting the RTP801 gene.
Purpose of the Study:
- Assess the safety, tolerability, pharmacokinetics, and dose-limiting toxicities of single intravitreal (IVT) injections of PF-04523655.
- Determine the maximum tolerated dose and pharmacokinetic profile of PF-04523655 in patients with neovascular AMD.
Main Methods:
- Phase 1, prospective, multicenter clinical trial involving 54 patients with neovascular AMD.
- Dose-escalating, open-label (stratum 1) and parallel, masked study (stratum 2) with varying doses of PF-04523655.
- Primary outcomes included safety, tolerability, and pharmacokinetic profiling post-IVT injection.
Main Results:
- PF-04523655 doses ≥ 400 μg were detectable in plasma post-injection, with levels below quantification by day 14.
- Single IVT injections ranging from 50 to 3000 μg were generally safe and well-tolerated over 24 months.
- No dose-limiting toxicities were observed during the study.
Conclusions:
- Single IVT injections of PF-04523655 up to 3000 μg appear safe and well-tolerated in patients with neovascular AMD.
- PF-04523655 demonstrates a favorable safety profile for potential therapeutic use in AMD.
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