Nulibry

“Repeat-dose toxicity studies in juvenile rats for 13 and 26 weeks and in juvenile dogs for 39 weeks (Table 15).”

“The MoCo-synthesis is considered highly conserved between species, and cPMP is considered identical between species. Thus, rat and dog are considered relevant species for toxicity studies.”

“In the 39-week toxicity study in juvenile dogs in which fosdenopterin HBr (coded ALXN1101) was administered at 1, 3, 5, and 10 mg/kg/day once daily, no adverse effects were observed.”

“Repeat-dose toxicity studies in juvenile rats for 13 and 26 weeks and in juvenile dogs for 39 weeks (Table 15).”

“fosdenopterin to pregnant rabbits once daily during the period of organogenesis (GD 7 to GD 20) at doses up to 200 mg/kg/day (approximately 89 times the human exposure at the MRHD, based on AUC) did not result in adverse developmental effects. In a pre- and postnatal development study, subcutaneous administration of fosdenopterin to pregnant mice”

“Carcinogenicity studies with fosdenopterin have not been conducted. A carcinogenicity study in a single species will be conducted as a postmarketing requirement.”

“Repeat-dose toxicity studies in juvenile rats for 13 and 26 weeks and in juvenile dogs for 39 weeks (Table 15).”

“Repeat-dose toxicity studies in juvenile rats for 13 and 26 weeks and in juvenile dogs for 39 weeks (Table 15).”

“Animals were dosed subcutaneously from PND 7 to PND 20, and then by intravenous bolus from PND 21 onwards.”

“Fosdenopterin was without genotoxic potential in vitro and in vivo in the standard battery of tests indicated in ICH S2(R1).”

“Carcinogenicity studies with fosdenopterin have not been conducted. A carcinogenicity study in a single species will be conducted as a postmarketing requirement.”

“Nonclinical reproductive and developmental toxicity studies with fosdenopterin have not been conducted. These studies will be conducted as a postmarketing requirement.”

“No fosdenopterin-related effects were observed in vitro or on cardiovascular, CNS or respiratory parameters in vivo. Due to low maximum dose levels, margins at no-observed-effect-level (NOEL) are low to non-existing.”

“Fosdenopterin was not genotoxic in a standard battery of in vitro (bacterial reverse mutation and human lymphocyte chromosomal aberration) and in vivo (rodent bone marrow micronucleus) assays.”

“Fosdenopterin was not genotoxic in a standard battery of in vitro (bacterial reverse mutation and human lymphocyte chromosomal aberration) and in vivo (rodent bone marrow micronucleus) assays.”

“Fosdenopterin was not genotoxic in a standard battery of in vitro (bacterial reverse mutation and human lymphocyte chromosomal aberration) and in vivo (rodent bone marrow micronucleus) assays.”

“Carcinogenicity studies with fosdenopterin have not been conducted. A carcinogenicity study in a single species will be conducted as a postmarketing requirement.”

“A two-year carcinogenicity study in mice is however planned as a post-marketing requirement from FDA.”

“In an automated screening assay for a number of ion channels (study 190129.PSN), there were no effects of fosdenopterin on the hERG current at concentrations up to 300 µM.”

“A total of 24 subjects was randomized into three sequential cohorts (6 active: 2 placebo) and received a single IV infusion of fosdenopterin at doses of 0.075, 0.25, and 0.68 mg/kg.”

“These findings were without histopathological correlates and were considered non-adverse. NOAELs for fosdenopterin were 5 mg/kg/day (rats) and 10 mg/kg/day (dogs), the highest dose levels evaluated.”

“No studies on antigenicity, immunotoxicity, dependence, or metabolites have been conducted.”

“In both the pigmented and nonpigmented rats, the highest concentrations of fosdenopterin were observed in the kidney, bone epiphyseal line, skin, liver, and esophagus.”

“A significant safety concern for phototoxicity with fosdenopterin was identified at doses ≥4.4× the maximum recommended human dose of 0.9 mg/kg/day (based on the human equivalent dose [HED]) in a standalone phototoxicity study in rats.”

“No studies on antigenicity, immunotoxicity, dependence, or metabolites have been conducted.”

“A total of 24 subjects was randomized into three sequential cohorts (6 active: 2 placebo) and received a single IV infusion of fosdenopterin at doses of 0.075, 0.25, and 0.68 mg/kg.”

“A 9-Month Intravenous Toxicity Study in Juvenile Beagle Dogs With a 3-Month Recovery Period”

“Repeat-dose toxicity studies in juvenile rats for 13 and 26 weeks and in juvenile dogs for 39 weeks (Table 15).”

“fosdenopterin to pregnant rabbits once daily during the period of organogenesis (GD 7 to GD 20) at doses up to 200 mg/kg/day (approximately 89 times the human exposure at the MRHD, based on AUC) did not result in adverse developmental effects. In a pre- and postnatal development study, subcutaneous administration of fosdenopterin to pregnant mice”

“Nonclinical reproductive and developmental toxicity studies with fosdenopterin have not been conducted. These studies will be conducted as a postmarketing requirement.”

“Pre- and postnatal development (PPND) study in mice. • 104-Week carcinogenicity study in mice. • Thorough QT/QTc Study. We are not requiring these studies pre-approval so as not to further delay approval of Nulibry”

“Carcinogenicity studies with fosdenopterin have not been conducted. A carcinogenicity study in a single species will be conducted as a postmarketing requirement.”

“Carcinogenicity studies with fosdenopterin have not been conducted. A carcinogenicity study in a single species will be conducted as a postmarketing requirement.”

“A two-year carcinogenicity study in mice is however planned as a post-marketing requirement from FDA.”

“No adverse effects (AEs) were observed in rats or dogs at doses up to 17.8× and 6.2×, respectively, the maximum recommended human dose, when compared to the human equivalent dose (mg/kg/day), based on body surface area.”

“These findings were without histopathological correlates and were considered non-adverse. NOAELs for fosdenopterin were 5 mg/kg/day (rats) and 10 mg/kg/day (dogs), the highest dose levels evaluated.”

“animal data from a knockout mouse model of MoCD Type A showing a reduction of plasma and brain SSC and improved mortality in treated mice compared to controls.”

“The MoCo synthesis pathway is highly conserved, and cPMP is considered identical between species.”

“Overall, primary pharmacodynamic studies support that fosdenopterin can replace endogenous cPMP in a knock-out mouse model of MoCD (MOCS1-/-), showing phenotypes with similar characteristics and biochemical anomalies as human MoCD Type A. In these animals, fosdenopterin treatment from PND1 prevented early death.”