Selection of Concentrations in the Study Sample Clauses

Selection of Concentrations in the Study. A wide range of animal toxicology studies were conducted with RBM-007 Injectable Solution by both systemic and ocular routes. Systemic toxicity was seen only with high doses far above those doses contemplated for ocular administration. The NOAEL in GLP intravitreal monkey studies is 1 mg/eye. Using a volume of vitreous of 2.2 mL for monkey, this is a concentration of 0.45 mg/mL (Xxxxxx et al, 2013). The intended human doses for the first in human study (RBM-007-001) are 0.2 mg, 1.0 mg and 2.0 mg per eye administered once. Considering a value of human vitreous to be 5.2 mL (Xxxxx-Xxxxx, 1994), these concentrations are 0.038, 0.19 and 0.38 mg/mL for these clinical doses. Therefore, the NOAEL in monkey is 11-fold higher than the intended starting clinical dose and 1.1-fold higher than intended maximum human dose. The safety factor would have been even higher if the viscosity and injectable volume for RBM-007 Injectable Solution in animals (monkey and rabbit) were not limiting parameters. It should also be noted that the clinical protocol requires the review of safety data for each cohort (and also first patient in each cohort) by a Safety Review Team independent of Principal Investigators before escalating the clinical dose. With regard to systemic exposure, the highest concentration of RBM-007 seen in plasma after single intravitreal dosing was 1,560 ng/mL at a dose of 1 mg/eye in monkey and 65.1 ng/mL at a dose of 0.5 mg/eye (injection to both eyes at a dose of 0.5 mg/eye, total 1 mg/body) in rabbit. Toxicokinetic evaluation in GLP systemic studies in monkey suggests that blood level at which toxicity might occur is 691,000 ng/mL. Thus, even without correcting for the body weight differences between animals and humans, the safety margin is 221–5,307 at the maximum dose of 2.0 mg/eye for human. If the body weight for animals is taken into account (rabbit and monkey at 3 Kg and human at 70 Kg.), the safety margin is 5,156–123,830. Thus, the Sponsor contends that the preclinical toxicology studies support the planned clinical studies.‌‌