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.”
Species: general tox
Juvenile rat only (13-week)
“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.”
Species: DART
Not conducted (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.”
Species: carcinogenicity
Not conducted (limited life expectancy in Menkes disease)
“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.”
Surrogate used in
No surrogate used
“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.”
Genotox: Ames
Negative (Ames)
“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)] .”
Genotox: in vitro mammalian
In vitro TK6 cell micronucleus: negative
“Therefore, CuHis lyophilized powder was considered negative for inducing micronuclei in TK6 cells in the 4-hour treatments with and without metabolic activation and in the 27-hour treatment without metabolic activation under the conditions of the test system.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Therefore, under the experimental conditions used, CuHis was negative in the micronucleus study.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not required; limited life expectancy in Menkes disease meets ICH S1A waiver criteria
“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.”
hERG / QT
Not conducted (no safety pharmacology studies)
“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).”
Anti-drug antibodies: animals
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.
Anti-drug antibodies: patients
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.
Label warnings
- Copper Accumulation and Risk of Toxicity
US prescribing information, Warnings and PrecautionsDailyMed ↗
Tox packageopen answer page →
Before first-in-human
First-in-human: where
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.
Repeat-dose tox before first-in-human
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.
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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
13-week GLP subcutaneous juvenile rat study; recovery not stated
“A 14-day non-good laboratory practice dose-range-finding toxicity study in juvenile rats and a 13-week good laboratory practice toxicity study in juvenile rats using CuHis have been conducted by the Applicant.”
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.”
DART package
Species: DART
Not conducted (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.”
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.”
PPND / ePPND: when
Not conducted; DART 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.”
Carcinogenicity
Species: carcinogenicity
Not conducted (limited life expectancy in Menkes disease)
“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.”
Carcinogenicity model
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.”
Carcinogenicity timing
Not required; limited life expectancy in Menkes disease meets ICH S1A waiver criteria
“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.”
Safety marginopen answer page →
Safety margin at NOAEL
No NOAEL: juvenile rat kidney, liver, spleen findings at 1 mg/kg/day, equivalent to human Cmax at recommended dose
“renal, hepatic, and splenic histopathologic and clinical pathology changes occurred mainly at 5 mg/kg/day, but as low as 1 mg/kg/day (equivalent to the human plasma concentration at the recommended dose of CuHis [based on Cmax])”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Published Menkes mouse model only (CuHis with AAV9-ATP7A); CuHis alone gave no survival benefit
“CuHis administered alone did not provide a survival benefit in a mouse model of MD.”
Why that model
Mouse studies did not mimic clinical dosing; gene therapy may mask CuHis benefit; SC distribution may differ in mice
“Some possibilities include: 1) the study designs did not mimic clinical administration of the drug; 2) gene therapy may have superseded any benefit of CuHis; 3) subcutaneous CuHis may not be readily distributed in mice compared to humans;”
Reviewer's view of the efficacy data
FDA: efficacy not determined in MD mouse models; nonclinical data cannot serve as confirmatory evidence
“Therefore, from a nonclinical perspective, the efficacy of CuHis was not determined in mouse models of MD, and the nonclinical data cannot serve as CE.”
Flexibilityopen answer page →
Flexibility accepted
Study lengthAcceptedBeyond the letter
No chronic repeat-dose toxicity studies in rodents or nonrodents, and no safety pharmacology studies
Why: Short life expectancy of patients; studies unlikely to add information beyond what can be monitored clinically · Serious disease · Human data
“Repeat-dose chronic toxicity studies in rodents and nonrodents have not been conducted with CuHis. PMRs for conducting additional nonclinical studies have not been issued as nonclinical studies to evaluate safety of CuHis are unlikely to provide information beyond what is already known and can be monitored clinically.”
“The short life expectancy of patients with MD negates the need for toxicity studies including safety pharmacology and chronic toxicology studies in animals.”
CarcinogenicityAccepted
No rodent carcinogenicity studies
Why: Limited life expectancy meets ICH S1A waiver criteria · Within the guideline · Serious disease
“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.”
DARTAcceptedBeyond the letter
No fertility, embryo-fetal or pre- and postnatal development studies
Why: Disease manifests predominantly in male infants; limited life expectancy · Serious disease · Other reason
“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. Further, the limited life expectancy of patients with MD negates the need for DART studies in animals to support its use in the clinic.”
Efficacy modelQuestioned
No pharmacology studies in Menkes disease models; only published literature with combination gene therapy
“The Applicant has not conducted pharmacology studies using CuHis in animal models of MD. Instead, the Applicant has submitted published literature to support its efficacy in which CuHis was administered SC in combination with recombinant adeno-associated virus serotype 9-ATP7A delivered to the cerebrospinal fluid (CSF) in a mouse model of MD”
“Therefore, from a nonclinical perspective, the efficacy of CuHis was not determined in mouse models of MD, and the nonclinical data cannot serve as CE.”
Safety marginVerdict not stated
No NOAEL in juvenile rats: kidney, liver and spleen changes as low as 1 mg/kg/day, equivalent to human Cmax
“renal, hepatic, and splenic histopathologic and clinical pathology changes occurred mainly at 5 mg/kg/day, but as low as 1 mg/kg/day (equivalent to the human plasma concentration at the recommended dose of CuHis [based on Cmax])”
Similar precedents
AgamreeSmall molecules · vamorolone · Glucocorticoid receptor (dissociative)Rodent + dog or minipig · 39 wkAlyftrekSmall molecules · vanzacaftor, tezacaftor and deutivacaftor · CFTRRodent + dog or minipig · 39 wkAqneursaSmall molecules · levacetylleucine · Neuronal metabolism (proposed)Rodent + dog or minipig · 39 wkDaybueSmall molecules · trofinetide · IGF-1 tripeptide analogueRodent + dog or minipig · 39 wkDojolviSmall molecules · triheptanoin · Anaplerotic energy substrateRodent + dog or minipig · 39 wkDuvyzatSmall molecules · givinostat · Histone deacetylase (class I/II)Monkey + rodent · 39 wk