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.

Background:The objective of this study was to validate an animal model for dry eye during and after the administration of 1% ophthalmic atropine sulfate (OAS) in New Zealand white (NZW) rabbits.Methods: OAS (1%) was applied three times per day to 30 eyes of 15 healthy NZW rabbits. Sacrifice, enucleation, and lacrimal gland removal took place on days 15, 21, and 30 (OAS group). A second group (n = 5) was used as control. Clinical evaluations took place on days 3, 10, 15, 18, 21, 24 and 30. The primary endpoints were: Schirmer I test, tear break-up time (TBUT), and corneal fluorescein staining. As secondary endpoints, clinical changes including intraocular pressure, and histopathology were evaluated.Results: While OAS was administered, the Schirmer I test showed a statistically significant reduction for OAS group versus control (p < 0.001), and versus basal production (p < 0.001). TBUT showed statistically significant differences between groups (days 3 and 10; p = 0.001) and versus basal values (day 3; p < 0.001). Fluorescein staining showed a statistically significant difference (day 3; p = 0.001). The most frequent clinical finding was conjunctival hyperemia (76.9% OAS vs. 20% control). For histopathology, all OAS subjects presented some degree of inflammation (86.7% minimal; 13.3% mild) whereas the control presented only 30% minimal inflammation. Goblet cell density showed no difference. Conclusions:The effectiveness of the OAS dry eye model in NZW rabbits as reported in previous studies was confirmed, provided that the application of the drug is maintained throughout the intervention; it is not a viable model after OAS administration is suspended.

Background: The purpose of this study was to evaluate the safety and tolerability profile of drugs used for treating common eye disorders when applied to normal healthy volunteers (NHV) as explored in phase 1 trials. Methods: A total of 166 NHV were identified in six phase 1 trials. These included the exposure to lubricant (n=88), hypotensive (n=48) or antibiotic (n=30) ophthalmic drugs, examined in a retrospective analysis. The primary endpoints were visual comfort, assessed by the ocular comfort index (OCI); and safety, evaluated through laboratory evaluations, vital signs, visual acuity (VA), intraocular pressure (IOP), lissamine green and fluorescein staining, conjunctival hyperemia, chemosis, and the incidence of adverse events (AE). Other measured parameters included discomfort (assessed by burning, itching and foreign body sensation) and conjunctival impression cytology. Results: Compared to baseline, 72.3%, 39.6% and 66.7% of participants (for lubricant, hypotensive and antibiotic treatments, respectively), improved their OCI score by their final visit (p=0.001). As expected for NHV, laboratory evaluations and vital signs were within normal ranges in 88% of NHV, with no significant differences observed between treatments. Similar results were found for VA, corneal and conjunctival staining and chemosis. IOP decreased significantly in the hypotensive agents group (p=0.001), trace to mild hyperemia was reported in 20.7%, 26% and 5.2% of NHV in each group (p=0.006). Additionally, lubricant and hypotensive investigational drugs (ID) had a lower risk of incidence of AE than approved drugs (AD) of these groups (OR 0.856, 95% CI [0.365, 1.999], and OR 0.636, 95% CI [0.096, 4.195], respectively). Meanwhile, on antibiotic drugs the risk for ID related AE was higher (OR 1.313, 95% CI [0.309, 5.583]). Conclusions: Phase 1 trials are important in order to ensure the safety and tolerability of ophthalmic medications. This study demonstrates that NHV do not face a significant risk of harm in these studies, since 98% of the reported AE were mild, and all AE were resolved by the end of the study in which they appeared. Furthermore, it was also demonstrated that the instillation of ID is as safe and tolerable as that of AD in NHV.Trial registration: The studies were registered at clinicaltrials.gov as follows: NCT04081610, NCT03524157, NCT03520348, NCT03966365, NCT03965052 and, NCT03519516.

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