Ronald A. Schachar

Dose-ranging evaluation of intravitreal siRNA PF-04523655 for diabetic macular edema (the DEGAS study).

PURPOSE To evaluate the safety and efficacy of three doses of PF-04523655, a 19-nucleotide methylated double stranded siRNA targeting the RTP801 gene, for the treatment of diabetic macular edema (DME) compared to focal/grid laser photocoagulation. METHODS This multicenter, prospective, masked, randomized, active-controlled, phase 2 interventional clinical trial enrolled 184 DME patients with best corrected visual acuity (BCVA) of 20/40 to 20/320 inclusive in the study eye. Patients were randomly assigned to 0.4-mg, 1-mg, 3-mg PF-04523655 intravitreal injections or laser. The main outcome measure was the change in BCVA from baseline to month 12. RESULTS All doses of PF-04523655 improved BCVA from baseline through month 12. At month 12, the PF-04523655 3-mg group showed a trend for greater improvement in BCVA from baseline than laser (respectively 5.77 vs. 2.39 letters; P = 0.08; 2-sided α = 0.10). The study was terminated early at month 12 based on predetermined futility criteria for efficacy and discontinuation rates. PF-04523655 was generally safe and well-tolerated, with few adverse events considered treatment-related. By month 12, the discontinuation rates in the PF-04523655 groups were higher than the laser group and were inversely related to dose levels. CONCLUSIONS PF-04523655 showed a dose-related tendency for improvement in BCVA in DME patients. Studies of higher doses are planned to determine the optimal efficacious dose of PF-04523655. PF-04523655 may offer a new mode of therapeutic action in the management of DME. (ClinicalTrials.gov number, NCT00701181.).

Evaluation of the siRNA PF-04523655 versus Ranibizumab for the Treatment of Neovascular Age-related Macular Degeneration (MONET Study)

OBJECTIVE To evaluate the efficacy of different dosing paradigms of PF-04523655 (PF) versus ranibizumab (comparator) in subjects with neovascular age-related macular degeneration (AMD). DESIGN Multicenter, open-label, prospective, randomized, comparator-controlled exploratory study. PARTICIPANTS A total of 151 patients with subfoveal choroidal neovascularization (CNV) secondary to neovascular AMD who were naive to AMD therapy. METHODS In this phase 2 study, patients were randomized to 1 of 5 treatment groups with equal ratio. All groups received ranibizumab 0.5 mg at baseline and (a) PF 1 mg every 4 weeks (Q4W) from week 4 to week 12; (b) PF 3 mg Q4W from week 4 to week 12; (c) PF 3 mg every 2 weeks (Q2W) from week 4 to week 12; (d) PF 1 mg + ranibizumab (combination) Q4W from baseline to week 12; and (e) ranibizumab Q4W to week 12. All study treatments were given as intravitreal injections. MAIN OUTCOME MEASURES The primary end point was the mean change in best-corrected visual acuity (BCVA) from baseline at week 16; secondary end points included the percentage of patients gaining ≥ 10 and ≥ 15 letters in BCVA and mean change in retinal central subfield thickness, lesion thickness, and CNV area. RESULTS At week 16, the PF 1 mg + ranibizumab combination group achieved numerically greater improvement in mean BCVA from baseline (9.5 letters) than the ranibizumab group (6.8 letters). The difference was not statistically significant. The BCVA improvement in the PF monotherapy groups was less than in the ranibizumab group. Similar trends were observed in the percentage of patients who gained ≥ 10 and ≥ 15 letters. From baseline to week 16 (last observed carried forward), the combination and ranibizumab groups had similar mean reductions in central subfield retinal thickness and total CNV area, which were greater than in all PF monotherapy groups. There were no clinically meaningful differences in reduction of lesion thickness among treatment groups. CONCLUSIONS In this early, underpowered study evaluating treatments for neovascular AMD, the combination of PF with ranibizumab led to an average gain in BCVA that was more than with ranibizumab monotherapy. No safety concerns were identified.

A Phase 2, Randomized, Dose-Response Trial of Taprenepag Isopropyl (PF-04217329) Versus Latanoprost 0.005% in Open-Angle Glaucoma and Ocular Hypertension

Purpose: To evaluate the safety of escalating doses of taprenepag isopropyl (PF-04217329), a selective EP2 receptor agonist administered as a topical ophthalmic solution, versus its vehicle (Stage I), and dose-response of taprenepag isopropyl alone and in unfixed combination with latanoprost ophthalmic solution 0.005% versus latanoprost alone (Stage II). Subjects and Methods: Randomized, vehicle- and active-controlled, double-masked, two-stage, dose-finding trial in primary open-angle glaucoma (POAG) or ocular hypertension; first taprenepag isopropyl study in patients (NCT00572455). Study eye: 26 mmHg ≤ intraocular pressure (IOP) <36 mmHg at 8 am and 22 mmHg ≤ IOP <36 mmHg at 10 am, 1 pm, 4 pm. Stage I: 3 cohorts (total n = 67) received 1 drop of taprenepag isopropyl unit dose formulation qPM/eye for 14 days: low dose: 0.0025%, 0.005%, vehicle; middle dose: 0.01%, 0.015%, vehicle; high dose: 0.02%, 0.03%, vehicle. Stage II: 7 groups (total n = 250) received 1 drop of taprenepag isopropyl multidose formulation qPM/eye for 28 days: 0.005%, 0.01%, 0.015% monotherapy; each in unfixed combination with latanoprost 0.005%, or latanoprost monotherapy. Main outcomes: mean change in diurnal IOP, baseline to last visit; adverse events. Results: Stage I at Day 14: statistically significantly greater IOP reductions were observed at all taprenepag isopropyl doses versus vehicle. Stage II at Day 28: statistically significantly greater IOP reductions were observed at all doses of the unfixed combination versus latanoprost monotherapy. At least 1 treatment-emergent adverse event reported for 29/67 (43.3%) subjects in Stage I and 158/250 (63.2%) in Stage II. Conclusions: Taprenepag isopropyl significantly reduces IOP in POAG and ocular hypertension. Taprenepag isopropyl monotherapy is comparable to latanoprost 0.005% in reducing IOP. As demonstrated in this report, the activity of taprenepag isopropyl is additive to that of latanoprost 0.005%. Further studies are required to determine whether it shows similar additivity when administered with other ocular antihypertensive medications.

Subclinical Increased Anterior Stromal Reflectivity With Topical Taprenepag Isopropyl

Purpose: To assess the effect of topical taprenepag isopropyl on each layer of the cornea by confocal microscopy. Methods: Thirty-two ocular hypertensive or glaucoma patients were randomized into a 2-period, crossover study of 14 days of 0.1% taprenepag alone and in unfixed combination with 0.005% latanoprost (combination therapy). Baseline and sequential slit-lamp biomicroscopy, fluorescein staining, central ultrasonic pachymetry, and confocal microscopy were performed. Confocal images were analyzed for the density of the central superficial and basal epithelium, midstromal keratocytes, and endothelium, as well as endothelial coefficient of variation and percentage of hexagonal cells, and reflectivity of anterior stromal and midstromal layers. Results: Corneal staining increased from baseline, reaching a peak at day 13 (69% and 63% of subjects treated with monotherapy and combination therapy, respectively), which resolved by day 35. A statistically significant increase in mean corneal thickness for both eyes and both treatments occurred on days 7 and 13 (range, 20–27 &mgr;m; P < 0.001) but recovered (⩽6 &mgr;m) by day 35. No statistically significant changes were observed in the basal epithelial, midstromal, or endothelial cells. Mean ratio of average reflectivity of anterior stroma to midstroma increased on days 13 and 35 in period 1 for each treatment (range, 1.2–1.9; P < 0.001), and this increase persisted during period 2. Conclusions: Anterior stromal reflectivity may remain increased even when biomicroscopic and confocal images of corneal layers remain normal or have recovered after topical taprenepag. This subclinical measure may be useful to detect a persistent adverse effect of a topical agent on the cornea.

A CCR2/5 Inhibitor, PF-04634817, Is Inferior to Monthly Ranibizumab in the Treatment of Diabetic Macular Edema

Purpose Ligands for the proinflammatory C-C chemokine receptor types 2 and 5 (CCR2 and CCR5) are elevated in the eyes of patients with diabetic macular edema (DME). We evaluated the efficacy and safety of PF-04634817, an oral CCR2/5 dual antagonist, versus intravitreal ranibizumab, in adult subjects with DME. Methods In this phase II, randomized, placebo-controlled, double-masked study, eligible subjects (≥18 years of age) had type 1 or 2 diabetes and DME with best-corrected visual acuity (BCVA) of 20/32 or worse (letter score ≤ 78), and up to 20/320 or better (≥24 letter score), in the study eye. Subjects were assigned randomly 1:1 to once-daily (QD) oral PF-04634817 200 mg plus masked sham therapy as placebo or monthly intravitreal ranibizumab 0.3/0.5 mg plus QD oral placebo. The primary objective was to evaluate the efficacy of PF-04634817 compared with ranibizumab in change from baseline in BCVA after 12 weeks in a noninferiority design. Noninferiority was based on BCVA 80% confidence interval (CI): there had to be a less than three letter loss in the PF-04634817 arm compared with the ranibizumab arm. Results A total of 199 subjects were randomized. Least squares mean difference in change in BCVA from baseline to week 12 in the study eye for the PF-04634817 arm was -2.41 letters (80% CI: -3.91, -0.91; P = 0.04) compared with ranibizumab. PF-04634817 was well tolerated. Conclusions Treatment with oral CCR2/5 receptor dual antagonist PF-04634817 was associated with a modest improvement in BCVA, but did not meet the predefined noninferiority criteria compared with intravitreal ranibizumab.