Verquvo
vericiguat
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”
Why that species
Mouse, rat and dog most relevant species on pharmacokinetic grounds
“From the pharmacokinetic point of view, mouse, rat and dog were the most relevant species for non-clinical efficacy and safety studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Repeated dose toxicity studies were conducted up to 13 weeks in mice, up to 6 months in rats, and 39 weeks in dogs.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”
Pivotal GLP studies
6-month rat and 39-week dog oral GLP studies
“The portfolio of toxicology includes repeat dose toxicology studies up to 6 months duration in rats, up to 39 weeks in dogs, 2-year rodent carcinogenicity studies, a standard battery of genetic toxicology assays, developmental and reproductive toxicology and juvenile animal studies.”
Route in tox
Oral
“The pivotal studies were conducted in accordance with GLP guidelines and used the oral route of administration, consistent with the clinical route of administration.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and rat and mouse micronucleus assays
“Vericiguat was not genotoxic in the in vitro microbial mutagenicity (Ames) assay, the in vitro mouse lymphoma assay and the in vivo rat and mouse micronucleus assay.”
Carcinogenicity
2-year CD1 mouse and Wistar rat: not carcinogenic
“Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Wistar rats. Vericiguat did not show a carcinogenic effect in mice dosed up to 150 mg/kg/day (males) or up to 250 mg/kg/day (females).”
Reproductive & developmental
Rabbit EFD: cardiac ventricular septal defect and truncus arteriosus at ≥2.5 mg/kg/day (≥4x MRHD exposure)
“An increased incidence of cardiac ventricular septal defect along with truncus arteriosus communis was observed at ≥2.5 mg/kg/day, which is ≥4 times the human exposure at the MRHD.”
Safety pharmacology
Dog telemetry: PR interval effect with heart-rate change, possible QRS effect, no QT/QTc effect
“The cardiovascular safety pharmacology in telemetered dogs indicated an effect on the PR interval concurrent with a change in heart rate, possibly an effect on the QRS complex but no effect on QT/QTc intervals.”
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 Verquvo 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: Consistent target organs: liver, kidney and adrenals (FDA integrated review, p. 146)
NOAEL / key findings
Consistent target organs: liver, kidney and adrenals
“Consistent target organs of toxicity were the liver, kidney, and adrenals.”
Risksopen answer page →
Immune & cytokine safety
No indicators of immune-system effects; no further immunotoxicity evaluation
“As there were no indicators of effects on the immune system, no further specific evaluation was conducted.”
Biodistribution & persistence
Melanin binding, including substantia nigra, with longer half-lives in melanin-containing tissues
“Melanin binding of vericiguat and/or its metabolites was also observed for the substantia nigra. Elimination occurred with longer terminal half-lives in melanin-containing tissues”
Modality-specific risk
Embryo-fetal toxicity, possibly a sGC-stimulator class effect
“An additional risk of embryo-fetal toxicity was identified based on findings in rats and rabbits. This risk may be related to the pharmacologic class, as similar findings have been observed with another soluble guanylate cyclase (sGC) stimulator”