Cinqair

“Pivotal nonclinical studies were conducted in CD-1 mice and Cynomolgus monkeys; both were identified as relevant species in a series of pharmacology studies.”

“Reslizumab binds with similar affinity to human, monkey, and mouse IL-5 (KD = 24, 20, and 31 pM; respectively, as determined by BIAcore biosensor assays).”

“The nonclinical program for reslizumab included studies conducted in mice, rabbits, and monkeys, which were all considered pharmacologically relevant species based on data from in vivo eosinophilia models in sensitized animals”

“The nonclinical general toxicology program with reslizumab was conducted in CD-1 mice and Cynomolgus monkeys, both of which were determined to be pharmacologically relevant test species.”

“Reproductive and developmental toxicology studies were conducted in CD-1 mice (fertility, embryo-fetal development, and pre-natal/post-natal development) and New Zealand rabbits (embryo-fetal development).”

“The applicant conducted a 26-week study in Tg.rasH2 mice to assess the carcinogenic potential of reslizumab.”

“The nonclinical program for reslizumab included studies conducted in mice, rabbits, and monkeys, which were all considered pharmacologically relevant species based on data from in vivo eosinophilia models in sensitized animals”

“In toxicology studies up to 6 months duration, no target organs of toxicity were identified in either mice or monkeys at an IV dose up to 25 mg/kg once every 4 weeks.”

“In toxicology studies up to 6 months duration, no target organs of toxicity were identified in either mice or monkeys at an IV dose up to 25 mg/kg once every 4 weeks.”

“Repeat-dose GLP toxicology studies were conducted in CD-1 mice, CByB6F1- Tg(HRAS)2Jic mice, and cynomolgus monkeys using the IV route of administration.”

“Genetic toxicity studies were not applicable for this therapeutic biologic protein though reslizumab was negative in two in vitro assays.”

“A transgenic mouse (Tg.rasH2) carcinogenicity study was conducted with dose concurrence by the Executive Carcinogenicity Assessment Committee (ECAC). No drug-related neoplasms were found after dosing up to 500 mg/kg IV once every two weeks.”

“No effects on fertility or development parameters were identified at doses up to 50 mg/kg IV; exposure margins of approximately 6-fold were available in the mouse studies.”

“Reslizumab administered iv at a dose of 100 mg/kg (600 mg/m2) to rats (DS-2014-080) and 25 mg/kg (300 mg/m2) to monkeys (SN96333) did not elicit effects on the most important parameters related to organ functions (cardiovascular, CNS, or gastrointestinal).”

“Reslizumab tested negative in a bacterial mutagenicity (Ames) assay and a chromosomal aberration assay in cultured human lymphocytes.”

“Reslizumab tested negative in a bacterial mutagenicity (Ames) assay and a chromosomal aberration assay in cultured human lymphocytes.”

“Genetic toxicity studies were not applicable for this therapeutic biologic protein though reslizumab was negative in two in vitro assays.”

“A transgenic mouse (Tg.rasH2) carcinogenicity study was conducted with dose concurrence by the Executive Carcinogenicity Assessment Committee (ECAC). No drug-related neoplasms were found after dosing up to 500 mg/kg IV once every two weeks.”

“Carcinogenicity: A 6-month carcinogenicity study was conducted in HRAS transgenic mice, a confirmed pharmacologically relevant mouse strain.”

“Reslizumab administered iv at a dose of 100 mg/kg (600 mg/m2) to rats (DS-2014-080) and 25 mg/kg (300 mg/m2) to monkeys (SN96333) did not elicit effects on the most important parameters related to organ functions (cardiovascular, CNS, or gastrointestinal).”

“This product has been used in Europe in an initial phase 1 single dose, dose escalation trial for treatment of 32 subjects with severe asthma (I96-350). Doses ranged from 0.03 mg/kg to 1.0 mg/kg.”

“The NOAELs of 25 mg/kg provided a safety margin of approximately 3-fold compared to the recommended clinical dose based on systemic exposure comparisons.”

“Immunogenicity noted in 3 animals in the pivotal toxicity study (1 at 5 mg/kg, 2 at 25 mg/kg); 1 of the 25 mg/kg animals had repeated infusion reactions c/w hypersensitivity”

“In human tissue, binding was observed in spinal cord, brain and optic nerve. No binding was seen to peripheral nerves, or any other human tissue examined.”

“Lack of recovery of eosinophils, increased risk of parasitic infections, nonspecific CNS toxicity due to potential tissue binding, hypersensitivity responses.”

“There was evidence of ADA formation in all nonclinical species tested. Analysis of PK parameters in ADA-positive animals found that the antibodies were neutralizing, as reslizumab was not detected in the blood of these animals.”

“In placebo-controlled studies, a treatment-emergent anti-reslizumab antibody response developed in 53/983 (5.4%) of CINQAIR-treated patients (3 mg/kg).”

“This product has been used in Europe in an initial phase 1 single dose, dose escalation trial for treatment of 32 subjects with severe asthma (I96-350).”

“This product has been used in Europe in an initial phase 1 single dose, dose escalation trial for treatment of 32 subjects with severe asthma (I96-350). Doses ranged from 0.03 mg/kg to 1.0 mg/kg.”

“Standard toxicological evaluations were conducted after intravenous administration of 0, 1, 5, 25 mg/kg in monkeys every 4-weeks for 6-months (total of 7 doses) with 3-month recovery period. A similar dosing schedule of 28-days for a total of 7 doses was used for administration of 0, 2, 5, 25 mg/kg reslizumab in mice.”

“In toxicology studies up to 6 months duration, no target organs of toxicity were identified in either mice or monkeys at an IV dose up to 25 mg/kg once every 4 weeks.”

“Reproductive and developmental toxicology studies were conducted in CD-1 mice (fertility, embryo-fetal development, and pre-natal/post-natal development) and New Zealand rabbits (embryo-fetal development).”

“No effects on fertility or development parameters were identified at doses up to 50 mg/kg IV; exposure margins of approximately 6-fold were available in the mouse studies.”

“Reproductive and developmental toxicology studies were conducted in CD-1 mice (fertility, embryo-fetal development, and pre-natal/post-natal development) and New Zealand rabbits (embryo-fetal development).”

“The applicant conducted a 26-week study in Tg.rasH2 mice to assess the carcinogenic potential of reslizumab.”

“A transgenic mouse (Tg.rasH2) carcinogenicity study was conducted with dose concurrence by the Executive Carcinogenicity Assessment Committee (ECAC). No drug-related neoplasms were found after dosing up to 500 mg/kg IV once every two weeks.”

“Carcinogenicity: A 6-month carcinogenicity study was conducted in HRAS transgenic mice, a confirmed pharmacologically relevant mouse strain.”

“This NOAEL also provides adequate safety margin (3-fold on an AUC basis) for the proposed clinical dose of 3 mg/kg IV q4 weeks.”

“The NOAELs of 25 mg/kg provided a safety margin of approximately 3-fold compared to the recommended clinical dose based on systemic exposure comparisons.”

“Treatment with reslizumab decreased pulmonary eosinophilia after ovalbumin challenge in mice and guinea pigs, as well as in Ascaris-challenged monkeys. Reslizumab also reduced eosinophil influx into the skin of antigen challenged New Zealand rabbits.”

“Reslizumab binds with similar affinity to human, monkey, and mouse IL-5 (KD = 24, 20, and 31 pM; respectively, as determined by BIAcore biosensor assays).”

“Testing of reslizumab in different animal models on asthma supports a therapeutic potential for reslizumab in airway eosinophilic conditions. It is however noted that the effect of reslizumab on eosinophils in circulation has not been investigated in any of the non-clinical pharmacology studies included in the dossier.”