Retina Today - Developments in the Treatment of Diabetic Macular Edema (April 2014)

摘要

Treatments for diabetic macular edema (DME) continue to be developed. Retina Today recently spoke with Quan Dong Nguyen, MD, MSc, to learn more about treatment options in the pipeline, how far along the clinical trials for these potential therapeutic agents are, and what research still must be done. Retina Today: What are some possible treatments for DME that we might see in the near future? Quan Dong Nguyen, MD, MSc: There is constant major work being performed to find new treatments for DME, which is great for our patients. Some studies are looking at the drug PF-655 (Quark Pharmaceuticals), a synthetic small interfering RNA (siRNA) that targets the gene RTP801, which is overexpressed in patients with wet age-related macular degeneration (AMD) and diabetic retinopathy. Other studies are looking at iCo-007 (iCo Therapeutics), a single-stranded antisense that degrades messenger RNA (mRNA), preventing the creation of ribosomal proteins and potentially down-regulating certain agents associated with DME. Other possibilities include examining the effect of AKB-9778 (Aerpio Therapeutics), which activates the Tie-2 pathway, a key control axis for retinal vascular stability. Tie-2 activation, via VEGF suppression, particularly in combination with anti-VEGF agents, may also block development of choroidal neovascularization (CNV) and promote regression of new CNV. These studies are in various stages of clinical trial. The results thus far have been encouraging. RT: What is the RTP801 gene, and how does it relate to DME? Dr. Nguyen: RTP801 is a gene that is triggered by various stimuli in vitro such as oxidative stress and DNA damage and is expressed in patients with various retinal disorders such as diabetic retinopathy and neovascular AMD. The RTP801 gene is unnecessary for normal organism function. PF-655 readily distributes into retinal and other ocular tissues following intravitreal injection, and targets RTP801. In animal models, diabetic mice that received intravitreal injections of PF-655 had a 50% reduction in blood vessel leakage compared with diabetic mice injected with control siRNA. Plasma concentrations of PF-655 are very low (less than 10,000 times the vitreous concentration); pre-clinical studies show that concentrations in ocular tissues and plasmas declined in parallel over 10 days. There are 2 phase 2 studies examining the effects of PF-655 on patients with DME: the DEGAS study and the MATISSE study. The DEGAS study is a phase 2, multicenter, dose-ranging, laser comparator study examining 184 patients equally randomized into 4 treatment groups: 0.4 mg PF-655, 1 mg PF-655, 3 mg PF-655, and laser. Patients receive treatment at baseline, week 1, week 2, and monthly for 36 months. At month 12, the treatment group receiving 3 mg PF-655 showed a trend toward best corrected visual acuity (BCVA) improvement. The mean gain in BCVA in the 3-mg treatment group was 5.77 letters vs 2.39 letters for laser (P = .08). There appeared to be a dose response, with the higher dosage of PF-655 showing greater bioactivity. The MATISSE study is a phase 2b study examining the safety and efficacy of PF-655 in larger doses, either as monotherapy or in combination with ranibizumab (Lucentis, Genentech). The MATISSE study, which finished recruitment in December 2013, is looking at dose-limiting toxicity, maximum tolerated dosage, and the efficacy of monotherapy vs combination therapy. RT: What work is being done vis-à-vis iCo-007? Dr. Nguyen: The iDEAL study is evaluating a different treatment option for DME. Researchers in the study are investigating how iCo-007 affects patients with center-involving DME. The drug iCo-007 is a second generation antisense inhibitor targeting C-raf kinase mRNA, which is involved in angiogenesis and vascular permeability. More stable, more potent, and less inflammatory than its first-generation counterpart, iCo-007 has a half-life of 6 to 8 weeks, and in animal models h