Zycubo
copper histidinate
Species
Rat
Longest study
13 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Not conducted Not conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Juvenile rat only
“A 13-week juvenile animal study in rats was conducted to evaluate the safety of CuHis and support administration of the product in a pediatric population.”
Why that species
Juvenile rats used to support administration in a pediatric population
“A 13-week juvenile animal study in rats was conducted to evaluate the safety of CuHis and support administration of the product in a pediatric population.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Juvenile rats with normal baseline copper levels were administered CuHis in a 13-week subcutaneous toxicity and toxicokinetic study.”
Study lengthopen answer page →
Longest pivotal study
13 (13-week juvenile rat)
“Juvenile rats with normal baseline copper levels were administered CuHis in a 13-week subcutaneous toxicity and toxicokinetic study.”
Pivotal GLP studies
13-week subcutaneous juvenile rat study; no chronic rodent or nonrodent studies
“Repeat-dose chronic toxicity studies in rodents and nonrodents have not been conducted with CuHis.”
Route in tox
Subcutaneous
“Juvenile rats with normal baseline copper levels were administered CuHis in a 13-week subcutaneous toxicity and toxicokinetic study.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro TK6 micronucleus and rat bone marrow micronucleus assays
“ZYCUBO was not mutagenic or clastogenic in a standard battery of genotoxicity tests [bacterial mutagenicity (Ames), micronucleus assay in TK6 cells (in vitro) , and rat bone marrow micronucleus assay (in vivo)] .”
Carcinogenicity
Not conducted (limited life expectancy in Menkes disease, ICH S1A waiver)
“Rodent carcinogenicity studies have not been conducted with CuHis. The limited life expectancy associated with classical MD is consistent with the International Council for Harmonisation S1A guidance criteria for waiving the requirement for carcinogenicity studies.”
Reproductive & developmental
Not conducted; DART studies waived as Menkes disease affects predominantly male infants
“DART studies, including FEED, EFD, and PPND studies to evaluate the reproductive toxicity potential of CuHis in patients with MD can be waived as MD manifests predominantly in male infants.”
Safety pharmacology
Not conducted
“Safety pharmacology studies have not been conducted with CuHis.”
First doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Zycubo don't say how the first human dose was chosen. That rationale is in the IND, which is confidential, so it is missing for most approved products.
How it's usually set for small molecules outside oncology
Find the highest dose with no adverse effects (NOAEL) in each animal species, convert it to a human equivalent dose, usually by body surface area, pick the most appropriate species, then divide by a safety factor (default 10) to get the maximum recommended starting dose.
“In general, one should consider using a safety factor of at least 10. The MRSD should be obtained by dividing the HED by the safety factor.”
This product's starting point
NOAEL / key findings: Kidney, liver and spleen findings at all doses (from 1 mg/kg/day); NOAEL not determined (FDA integrated review, p. 150)
NOAEL / key findings
Kidney, liver and spleen findings at all doses (from 1 mg/kg/day); NOAEL not determined
“CuHis-related microscopic and clinical pathology in kidneys, liver, and spleen occurred as low as 1 mg/kg/day; thus, the no-observed-adverse-effect level could not be determined.”
Risksopen answer page →
Immune & cytokine safety
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Biodistribution & persistence
Not stated in public reviews
Not reported in the public reviews. Reviewers summarise selectively, so this usually means it wasn't discussed publicly, not that it wasn't studied.
Modality-specific risk
Copper accumulation and toxicity (kidney, liver, spleen, hematology)
“A 13-week juvenile rat nonclinical toxicokinetic study revealed CuHis-related microscopic and clinical pathology findings in the kidneys, hematology, liver, and spleen (see Section 7.1).”