PurposeTo evaluate the efficacy of a therapy on improving characteristics of laser-induced choroidal neovascularization (CNV) via single intravitreal injection of a humanized anti-human VEGF monoclonal antibody (PRO-169) versus bevacizumab in a rhesus monkey model.MethodsTo induce experimental CNV, small high-energy laser spots were used to treat several areas, around the macula in the retinas of monkeys at Day −21. Eighteen rhesus monkeys were used for CNV induction. The efficacy endpoints were fluorescein leakage by FFA and retinal thickness by OCT. FFA examinations were performed 19 days after induction. Appropriate animals were enrolled for treatment and randomly divided into 3 groups: bevacizumab (n=5, 7 eyes), PRO-169 (n=5, 7 eyes), and vehicle controls (n=4, 7 eyes).ResultsIn 25 of 36 (69.4%) eyes, CNV lesions were identified. The average percent change of retinal thickness in the eyes of bevacizumab group was −159.3±62.2% and −154.0±45.1% (p<0.01 vs Vehicle) at Day 14 and Day 28, respectively; in the eyes of PRO-169 group it was −131.6±68.7% and −131.5±63.8% (p<0.01 vs Vehicle), respectively. The average percent change of leakage area in the eyes of bevacizumab group was −75.3±49.4% and −78.0±42.6% (p<0.01 vs Vehicle) at Day 14 and Day 28, respectively; in the eyes of PRO-169 group it was −82.0±19.3% and −81.4±21.0% (p<0.01 vs Vehicle), respectively. There were no abnormalities found in behavior, skin and hair, excretion and overall eye appearance before and after treatment in all groups.ConclusionAfter photocoagulation, the eyes enrolled in this studio showed CNV related characteristics including increased retinal thickness, and fluorescein leakage at laser spots. PRO-169 (1.25 mg per eye) can reduce the retinal thickness and fluorescein leakage area after treatment for 14 and 28 days in this rhesus monkeys model, without toxic effect or adverse events. These findings suggested that PRO-169 can inhibit CNV.

Purpose: To evaluate the efficacy of a preservative free sodium hyaluronate/chondroitin sulfate ophthalmic solution (SH/CS-PF) in patients with dry eye disease (DED). Methods: This was a randomized phase IV, multicentric, prospective, double-blind clinical trial. Intent-totreat (ITT) and per-protocol (PP) analyses were performed. Patients were assigned to receive either SH/CS-PF, Systane® Ultra (PEG/PG) or Systane® Ultra PF (PEG/PG-PF) for 90 days. A total of 326 patients were included in the ITT, and 217 in the PP analysis. Efficacy endpoints were goblet cell density, Nelson's grades (conjunctival impression cytology), tear break-up time (TBUT), Ocular Surface Disease Index (OSDI), and Schirmer's test. Other parameters included were tolerability, measured by the ocular symptomatology; and safety, measured through corneal staining, intraocular pressure, visual acuity and adverse events. Results: In the ITT, there was a significant increase in mean goblet cell density in all treatments compared with their baseline (28.4% vs 21.4% and 30.8%), without difference between arms (p = .159). Eyes exposed to SH/CS-PF, PEG/PG and PEG/PG-PF showed Grade 0-I squamous metaplasia (85.5%, 87.9% and 93.2%, respectively). Similar improvements were observed for TBUT (1.24 ± 2.3s vs 1.27 ± 2.4s and 1.39 ± 2.3s) and OSDI scores at day 90 (−8.81 ± 8.6 vs −7.95 ± 9.2 and −8.78 ± 9.8), although no significant intergroup difference was found. Schirmer's test also presented improvement compared to baseline (1.38 ± 4.9 vs 1.50 ± 4.7 and 2.63 ± 5.9), with a significantly higher variation for PEG/PG-PF. There were no significant differences between treatments for any tolerability and safety parameter, nor between ITT and PP analyses for any outcome. Conclusions:The topical application of SH/CS-PF is as effective, safe and well tolerated as that of PEG/PG or PEG/PG-PF. The results suggest that SH/CS-PF may lead to normalization of clinical parameters and symptom alleviation in patients treated for DED.

Background: The purpose of this study was to compare the efficacy and safety of difluprednate 0.05% (PRO-145) versus prednisolone acetate 1% (Prednefrin ® SF), for management of postoperative inflammation and pain, after cataract surgery. Methods: This was a Phase III, multicenter, prospective, double-blind, clinical trial. Intentto-treat population included 178 post-phacoemulsification patients that were assigned to receive either PRO-145, or prednisolone. One day after unilateral eye surgery, patients instilled a drop 4 times a day for 14 days (then tapering the dose downward for 14 days). The primary efficacy endpoints were anterior chamber (AC) cell grade and flare. Other parameters measured included: retinal central thickness (measured via OCT), conjunctival hyperemia, edema, pain and photophobia. Tolerability and safety were assessed through burning, itching, foreign body sensation, visual acuity (VA), intraocular pressure (IOP) and incidence of adverse events (AE). Results: A total of 171 subjects were randomized (1:1) and completed the study. Compared to day 1, there was a significant improvement in the AC cell count and flare in both groups by the final visit (80.2% vs 88.4%, p=1.000). Conjunctival hyperemia improved in a similar fashion (81.2% vs 79%, p=0.234) in both PRO-145 and prednisolone groups, without differences between them. This was also observed for edema (82.4% vs 82.5%, p=0.246), pain (15.3% vs 7%, p=0.497) and photophobia (16.4% vs 15.1%, p=0.246), respectively. There was no significant difference between treatments for any tolerability parameter studied. Finally, at the 4-week postoperative visit, there were no significant differences between treatments for VA, IOP and AE results (p-values; 0.095, 0.053 and 0.099, respectively). Conclusion: The results of this study suggest that PRO-145 is as effective and safe as prednisolone acetate in treating postoperative inflammation and pain in patients undergoing phacoemulsification. The study was registered at ClinicalTrials.gov as NCT03693989.

Background: To evaluate the retinal toxicity after repeated intravitreal injections of a humanized anti-VEGF-A monoclonal antibody (PRO-169) versus ranibizumab in New Zealand white (NZW) rabbit eyes. Methods: NZW rabbits were injected intravitreally with PRO-169 (n = 12), 1.25 mg/0.05 ml or ranibizumab (n = 12), 0.5 mg/0.05 ml into the right eye (OD), whereas the left eye (OS) of each rabbit was used as control. Three consecutive injections were administered at 30-days intervals. An electroretinogram (ERG) was recorded 30 days after each injection. Clinical examination was conducted before and after injections, including intraocular pressure determination and eye fundus exploration. Eyes were enucleated and retina, cornea, conjunctiva, ciliary body and optic nerve were prepared for histopathology assessment. Results: ERG of the experimental and control eyes in PRO-169 and ranibizumab groups were similar in amplitude and pattern throughout the follow-up period. Clinical examination found no alterations of intraocular pressure (IOP). No retinal damage was observed in both, the experimental and control eyes, of all the rabbits. The histopathologic studies showed similar results in both groups, showing no signs of structural damage. Conclusions: Our study did not find evidence of retinal toxicity from a repeated intravitreal injection of PRO-169 or ranibizumab (Lucentis ®) in NZW rabbits. These findings support intravitreal PRO-169 as a safe candidate to develop as a future alternative for the treatment of retinal neovascularization diseases.

BackgroundTo determine the concentration after a single dose of generic 0.05% difluprednate and commercial difluprednate in the aqueous humor, cornea, and conjunctiva of New Zealand rabbits, a preclinical study in 72 male New Zealand white rabbits was performed. A single dose (50 μL) of two 0.05% difluprednate ophthalmic formulations was instilled in both eyes. Conjunctiva, cornea, and aqueous humor samples were collected at nine time points over 8 h (four animals per time point). The active metabolite of difluprednate, 17-difluoroprednisolone-butyrate (DFB), concentrations was quantified using HPLC.ResultsMeasurable levels of DFB were quantified in all three ocular tissues. After a single instillation, the highest concentration of difluprednate was found between 30 and 60 min in the conjunctiva, cornea, and aqueous humor, respectively. There was no significant difference between both formulations in any tissue at any time point. After 3 h, no metabolites of either emulsion were found in any tissue.ConclusionsDifluprednate penetrates into different ocular tissues. Generic difluprednate has a similar pharmacokinetic profile compared with commercial difluprednate.