Nulibry
fosdenopterin
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Partial / alternative Partly stated
Speciesopen answer page →
Species
Rat and dog (juvenile)
“Repeat-dose toxicity studies in juvenile rats for 13 and 26 weeks and in juvenile dogs for 39 weeks (Table 15).”
Why that species
MoCo synthesis highly conserved and cPMP identical across species
“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.”
Surrogate molecule
No surrogate; the clinical compound was tested
“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.”
Study lengthopen answer page →
Longest pivotal study
39 (juvenile dog)
“Repeat-dose toxicity studies in juvenile rats for 13 and 26 weeks and in juvenile dogs for 39 weeks (Table 15).”
Pivotal GLP studies
13- and 26-week juvenile rat and 39-week juvenile dog studies
“Repeat-dose toxicity studies in juvenile rats for 13 and 26 weeks and in juvenile dogs for 39 weeks (Table 15).”
Route in tox
Subcutaneous in neonatal phase, then intravenous bolus
“Animals were dosed subcutaneously from PND 7 to PND 20, and then by intravenous bolus from PND 21 onwards.”
Skipped studiesopen answer page →
Genotoxicity
Negative in the standard ICH S2(R1) battery, in vitro and in vivo
“Fosdenopterin was without genotoxic potential in vitro and in vivo in the standard battery of tests indicated in ICH S2(R1).”
Carcinogenicity
Not conducted; postmarketing requirement
“Carcinogenicity studies with fosdenopterin have not been conducted. A carcinogenicity study in a single species will be conducted as a postmarketing requirement.”
Reproductive & developmental
Not conducted; postmarketing requirement
“Nonclinical reproductive and developmental toxicity studies with fosdenopterin have not been conducted. These studies will be conducted as a postmarketing requirement.”
Safety pharmacology
No effects in vitro (hERG) or on cardiovascular, CNS or respiratory parameters in vivo; NOEL margins low
“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.”
First doseopen answer page →
First-in-human starting dose
FIH single IV doses 0.075, 0.25 and 0.68 mg/kg in healthy subjects; starting-dose derivation not described
“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.”
NOAEL / key findings
No adverse findings; minor dog changes non-adverse; NOAELs 5 mg/kg/day (rat) and 10 mg/kg/day (dog), highest doses tested
“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.”
Risksopen answer page →
Immune & cytokine safety
No antigenicity or immunotoxicity studies conducted
“No studies on antigenicity, immunotoxicity, dependence, or metabolites have been conducted.”
Biodistribution & persistence
Extensive distribution; highest in kidney, bone epiphyseal line, skin, liver and esophagus
“In both the pigmented and nonpigmented rats, the highest concentrations of fosdenopterin were observed in the kidney, bone epiphyseal line, skin, liver, and esophagus.”
Modality-specific risk
Phototoxicity: skin reactions and ocular lesions in pigmented rats at >=4.4x MRHD
“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.”