International consortium for innovation and quality: An industry perspective on the nonclinical and early clinical development of intravitreal drugs.

The eye, which is under constant exposure to environmental pathogens, has evolved various anatomic and immunological barriers critical to the protection of tissues lacking regenerative capacity, and the maintenance of a clear optic pathway essential to vision. By bypassing the ocular barriers, intravitreal (IVT) injection has become the mainstay for the delivery of drugs to treat conditions that affect the back of the eye. Both small molecules and biotherapeutics have been successfully administered intravitreally, and several drugs have been approved for the treatment of (wet) age-related macular degeneration and diabetic macular edema. However, IVT injection is an invasive procedure, which requires sufficient technical expertise from the healthcare professional administering the drug. Potential side effects include bleeding, retinal tear, cataracts, infection, uveitis, loss of vision, and increased ocular pressure. Pharmaceutical companies often differ in their drug development plan, including drug administration techniques, collection of ocular tissues and fluids, ophthalmology monitoring, and overall conduct of nonclinical and clinical studies. The present effort, under the aegis of the Innovation & Quality Ophthalmic Working Group, aims at understanding these differences, identifying pros and cons of the various approaches, determining the gaps in knowledge, and suggesting feasible good practices for nonclinical and early clinical IVT drug development.

Scientific and Regulatory Policy Committee Points to Consider: Fixation, Trimming, and Sectioning of Nonrodent Eyes and Ocular Tissues for Examination in Ocular and General Toxicity Studies.

A Working Group of the Society of Toxicologic Pathology's Scientific and Regulatory Policy Committee conducted a technical and scientific review of current practices relating to the fixation, trimming, and sectioning of the nonrodent eye to identify key points and species-specific anatomical landmarks to consider when preparing and evaluating eyes of rabbits, dogs, minipigs, and nonhuman primates from ocular and general toxicity studies. The topics addressed in this Points to Consider article include determination of situations when more comprehensive evaluation of the globe and/or associated extraocular tissues should be implemented (expanded ocular sampling), and what constitutes expanded ocular sampling. In addition, this manuscript highlights the practical aspects of fixing, trimming, and sectioning the eye to ensure adequate histopathological evaluation of all major ocular structures, including the cone-dense areas (visual streak/macula/fovea) of the retina for rabbits, dogs, minipigs, and nonhuman primates, which is a current regulatory expectation for ocular toxicity studies.[Box: see text].

Inflammation of a Posterior Ciliary Artery in a Naive Cynomolgus Macaque.

This brief communication describes a previously unreported background lesion in the eye of a naive cynomolgus macaque. Inflammation of a posterior ciliary artery was, in this case, morphologically similar to vascular inflammation of other tissues described in naive cynomolgus macaques. However, the available literature does not describe this lesion at this anatomical site. The affected animal did not present with any abnormal clinical signs and ophthalmological examinations were within normal limits. Toxicologic pathologists should be aware of this finding in order to help differentiate it from a test item-related finding.

Nonclinical Toxicology and Biocompatibility Program Supporting Clinical Development and Registration of the Port Delivery System With Ranibizumab for Neovascular Age-Related Macular Degeneration.

The Port Delivery System with ranibizumab (PDS) is an investigational drug delivery system designed to provide continuous intravitreal release of ranibizumab for extended durations. The PDS consists of a permanent, surgically placed, refillable intraocular implant; a customized formulation of ranibizumab; and ancillary devices to support surgery and refill procedures. A toxicology program was conducted to evaluate the ocular toxicology and biocompatibility of the PDS to support its clinical development program and product registrational activities. PDS safety studies included a 6-month chronic toxicology evaluation in minipigs as well as evaluation of nonfunctional surrogate implants (comprised of the same implant materials but without ranibizumab) in rabbits. Biocompatibility of the implant and ancillary devices was evaluated in both in vitro and in vivo studies. Implants and extracts from implants and ancillary devices were nongenotoxic, noncytotoxic, nonsensitizing, and nonirritating. Ocular findings were comparable between implanted and sham-operated eyes, and no systemic toxicity was observed. The results of this nonclinical toxicology program demonstrated that the PDS was biocompatible and that intravitreal delivery of ranibizumab via the PDS did not introduce any new toxicology-related safety concerns relative to intravitreal injections, supporting ongoing PDS clinical development and product registrational evaluation.

EVALUATION OF SURGICAL FACTORS AFFECTING VITREOUS HEMORRHAGE FOLLOWING PORT DELIVERY SYSTEM WITH RANIBIZUMAB IMPLANT INSERTION IN A MINIPIG MODEL.

PURPOSE: To develop an animal model of vitreous hemorrhage (VH) to explore the impact of surgical parameters on VH associated with insertion of the Port Delivery System with ranibizumab (PDS) implant. METHODS: Ninety eyes from 45 treatment-naive male Yucatan minipigs received PDS implant insertion or a sham procedure. The effect of prophylactic pars plana hemostasis, scleral incision length, scleral cauterization, surgical blade type/size, and viscoelastic usage on postsurgical VH was investigated. RESULTS: Postsurgical VH was detected in 60.0% (54/90) of implanted eyes. A systematic effect on VH was only detected for pars plana hemostasis before the pars plana incision. The percentage of eyes with VH was 96.6% (28/29) among eyes that did not receive prophylactic pars plana hemostasis and 42.4% (24/58) among eyes that did. There was no VH in eyes that received laser ablation of the pars plana using overlapping 1,000-ms spots; pars plana cautery or diathermy was less effective. The majority of all VH cases (83.3% [45/54]) were of mild to moderate severity (involving ≤25% of the fundus). CONCLUSION: In this minipig surgical model of VH, scleral dissection followed by pars plana laser ablation before pars plana incision most effectively mitigated VH secondary to PDS implant insertion.

Degree of Cajal-Retzius Cell Mislocalization Correlates with the Severity of Structural Brain Defects in Mouse Models of Dystroglycanopathy.

The secondary dystroglycanopathies are characterized by the hypoglycosylation of alpha dystroglycan, and are associated with mutations in at least 18 genes that act on the glycosylation of this cell surface receptor rather than the Dag1 gene itself. At the severe end of the disease spectrum, there are substantial structural brain defects, the most striking of which is often cobblestone lissencephaly. The aim of this study was to determine the gene-specific aspects of the dystroglycanopathy brain phenotype through a detailed investigation of the structural brain defects present at birth in three mouse models of dystroglycanopathy-the FKRP(KD) , which has an 80% reduction in Fkrp transcript levels; the Pomgnt1null , which carries a deletion of exons 7-16 of the Pomgnt1 gene; and the Large(myd) mouse, which carries a deletion of exons 5-7 of the Large gene. We show a rostrocaudal and mediolateral gradient in the severity of brain lesions in FKRP(KD) , and to a lesser extent Pomgnt1null mice. Furthermore, the mislocalization of Cajal-Retzius cells is correlated with the gradient of these lesions and the severity of the brain phenotype in these models. Overall these observations implicate gene-specific differences in the pathogenesis of brain lesions in this group of disorders.