Preclinical Development of EBI-005: An IL-1 Receptor-1 Inhibitor for the Topical Ocular Treatment of Ocular Surface Inflammatory Diseases.

OBJECTIVE: Topical interleukin (IL)-1 receptor (R)1 blockade is therapeutically active in reducing signs and symptoms of dry eye disease. Herein, we describe in vitro and in vivo nonclinical Investigational New Drug (IND)-enabling studies of EBI-005, a novel protein chimera of IL-1ß and IL-1 receptor antagonist (IL-1Ra or anakinra) that potently binds IL-1R1 and blocks signaling. These studies provide an assessment of receptor affinity, drug bioavailability, immunogenic response, safety, and tolerability in mice and rabbits. METHODS: In vitro and in silico along with Good Laboratory Practices (GLP) and non-GLP in vivo studies in mice and rabbits assessed the topical ocular and systemic immunogenicity and toxicology of EBI-005. Animals were treated with EBI-005 once daily subcutaneously or four times daily by topical ocular administration for up to 6 weeks (with 2-week recovery phase). RESULTS: EBI-005 has 500 times higher affinity than anakinra to IL-1R1. Predictive immunogenicity testing suggested that EBI-005 is not more immunogenic. Systemic bioavailability of EBI-005 is low (1.4% in mice and 0.2% in rabbits) after topical ocular administration. EBI-005 penetrated into the anterior ocular tissues within 15 min of topical ocular administration. However, it is low or undetectable after 4 hr and does not form a depot after repeated topical ocular administration. EBI-005 was safe and well tolerated, and exposure to drug was maintained despite an antidrug antibody response after systemic administration, based on IND-enabling toxicology and safety pharmacology studies. CONCLUSIONS: Ocular doses of EBI-005 at 50 mg/mL in mice and rabbits totaling 0.15 mg/eye in mice and 1.5 mg/eye in rabbits, administered 4 times daily, did not produce adverse effects, and demonstrated excellent bioavailability in target tissues with low systemic exposure. In addition, immunogenic response to the drug did not cause adverse effects or diminish the drug's activity in most cases. The results support drug administration of the highest anticipated human clinical study dose of a 20 mg/mL solution (40 µL 3 times daily in each eye).

Assessment of the likelihood of the introduction of foot-and-mouth disease through importation of live animals into the Malaysia-Thailand-Myanmar peninsula.

OBJECTIVE: To assess the likelihood of an introduction of foot-and-mouth disease (FMD) into the Malaysia-Thailand-Myanmar (MTM) peninsula through terrestrial movement of livestock. ANIMALS: 89,294 cattle and buffalo legally moved into the MTM peninsula. PROCEDURES: A quantitative risk assessment was conducted by use of a stochastic simulation. Patterns of livestock movement were ascertained through review of relevant governmental records and regulations and by interviewing farmers, traders, and local officers when the records did not exist. Parameters identified in the process were the probabilities of livestock having FMD and of FMD infection going undetected during import processes. The probability of an animal accepted for import having FMD was also assessed. Sensitivity analysis was performed to determine the effects that each parameter had on the model. RESULTS: The simulation yielded an average consignment prevalence of 10.95%. Typically, each animal in a quarantine facility had a 2.7% chance of having an inapparent form of FMD infection; hence, it was likely an animal would not be identified as infected. Findings revealed that the mean probability of an animal accepted for import having FMD was 2.9%, and the risk was as high as 11%. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the model allowed for the evaluation of movement regulations currently imposed in the MTM peninsula. Evidence from the study suggested that current practices in animal movement were far from efficient in preventing introduction of FMD-infected animals into the MTM region, and additional measures will be necessary.

Use of epidemiologic risk modeling to evaluate control of foot-and-mouth disease in southern Thailand.

OBJECTIVE: To assess the impacts of the introduction of foot-and-mouth disease (FMD) and various FMD control programs in southern Thailand. ANIMALS: A native population of 562,910 cattle and 33,088 buffalo as well as 89,294 animals legally transported into southern Thailand. PROCEDURES: A quantitative risk assessment was used to ascertain the probability of FMD introduction, and an intrinsic dynamic model was used to assess impacts. Value for the transmission rate (beta) was estimated. Five scenarios created to assess the impacts of nonstructural protein (NSP) testing, mass vaccination, and culling were examined. Impacts were assessed through an examination of the estimated annual cumulative incidence (ACI) of FMD. The ACIs of various scenarios were compared by use of the Tukey Studentized range technique. RESULTS: beta was estimated at 0.115. Approximately 35,000 cases of FMD would be expected from the baseline situation. A 30% reduction of ACI was detected with the introduction of NSP antibody testing. Prophylactic vaccination resulted in an 85% reduction of ACI. Concurrent use of NSP antibody testing and vaccination reduced the ACI by 96%, and the addition of an eradication policy resulted in a slightly greater decrease in the ACI (98%). CONCLUSIONS AND CLINICAL RELEVANCE: The study used epidemiologic models to investigate FMD control interventions. Results suggested that vaccination has more impact than the use of NSP testing. Use of the NSP test reduced ACI during peak seasons, whereas vaccination diminished the underlying incidence. The best mitigation plan was an integrated and strategic use of multiple control techniques.

The use of risk assessment to decide the control strategy for bluetongue in Italian ruminant populations.

The affiliation, assessment and management of risks is a traditional part of veterinary medicine. In the past, veterinary services involved in this type of activity usually assessed risks qualitatively. However, since the 1990s, quantitative methods have become increasingly important. The establishment of the World Trade Organization in 1994, and the promulgation of its Agreement on the Application of Sanitary and Phytosanitary Measures (the "SPS Agreement") led to an increased application of import risk analysis and to significant improvements in the methodology of risk analysis as applied to international trade policy for animals and animal products. However, there was very little development of risk analysis in veterinary fields other than international trade and management of health risks to consumers of animal products and little has been published on its use in the choice and definition of control or prophylaxis strategies for animal diseases. This article describes a quantitative risk assessment, which was undertaken in Italy to help choose an appropriate national response strategy following an incursion of bluetongue, an infectious disease of sheep and goats. The results obtained in this study support the use of risk analysis as a tool to assist in choosing an appropriate animal disease management strategy. The use of risk analysis in the evaluation of disease management strategies also offers advantages in international trade. It makes easier the comparison of different strategies applied in the various countries, and thus facilitates the assessment of equivalence of the guarantees provided by different strategies.

Progression from anomalous optic discs to visible optic disc drusen.

At age 5, a patient underwent fundus photography that disclosed elevated optic discs without drusen. A head computed tomography did not show optic nerve calcification. At age 9, no disc drusen were evident by ophthalmoscopy, but a CT now showed optic nerve calcification. At age 12, optic disc drusen were faintly evident on photographs; visual fields showed blind spot enlargement OD and an arcuate defect OS. At age 21, he had numerous discrete disc drusen in both eyes, disc pallor, and slight progression of the visual field defects. This case documents the progression from anomalous optic discs to ophthalmoscopically visible optic nerve drusen over a 16-year period.