Alyftrek
vanzacaftor, tezacaftor and deutivacaftor
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 GLP-compliant definitive repeat dose VNZ single agent studies were carried out for durations up to 28-days in mouse, 6 months in rat and 9 months in dog.”
Why that species
Metabolism comparable between animal species and humans
“Metabolism was comparable between animal species and humans.”
Surrogate molecule
No surrogate; vanzacaftor tested directly; deutivacaftor relied on bridged ivacaftor data
“The nonclinical program for NDA 218730 primarily focused on evaluation of the safety of the new molecular entity VNZ. The Applicant established a scientific bridge to leverage the nonclinical toxicity data from the IVA program (NDA 203188, Trade name: KALYDECO [tablet]) to characterize the safety profile of D-IVA.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog, vanzacaftor)
“In a GLP study, Beagle dogs (4 animals/sex/group) were administered VNZ by oral gavage once daily at 0 (vehicle), 1.5, 4, or 10 mg/kg for 39 weeks”
Pivotal GLP studies
Vanzacaftor 6-month rat and 9-month dog studies; 28-day mouse study
“The GLP-compliant definitive repeat dose VNZ single agent studies were carried out for durations up to 28-days in mouse, 6 months in rat and 9 months in dog.”
Route in tox
Oral (gavage)
“In a GLP study, Beagle dogs (4 animals/sex/group) were administered VNZ by oral gavage once daily at 0 (vehicle), 1.5, 4, or 10 mg/kg for 39 weeks”
Skipped studiesopen answer page →
Genotoxicity
Vanzacaftor negative in Ames, in vitro TK6 micronucleus and in vivo rat micronucleus assays
“Vanzacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene variant, in vitro micronucleus assay in TK6 cells, and in vivo rat micronucleus assay.”
Carcinogenicity
Vanzacaftor: 6-month rasH2 mouse negative up to 30 mg/kg/day; 2-year rat study also conducted
“In the case of VNZ, the studies consisted of a 6-month Tg.rasH2 transgenic mouse carcinogenicity study and a 2-year rat carcinogenicity study. VNZ did not demonstrate a carcinogenic potential at the doses evaluated in the Tg.rasH2 mouse up to 30mg/kg/day.”
Reproductive & developmental
Vanzacaftor rat and rabbit EFD: no adverse developmental effects up to 30x (rat) and 22x (rabbit) MRHD exposure
“In animal embryo fetal development (EFD) studies, oral administration of vanzacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 30 times the exposure at the maximum recommended human dose (MRHD) in rats and 22 times the MRHD in rabbits.”
Safety pharmacology
Vanzacaftor hERG IC50 0.7 µM (~3800-fold free Cmax margin); cardiovascular effects assessed in telemetered dogs
“VNZ inhibited hERG current with an IC50 of 0.7 μM, which provides a ~3800-fold margin of exposure over the clinical concentration (free Cmax). Effects of VNZ on the cardiovascular system was assessed in telemetered male dogs.”
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 Alyftrek 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: Vanzacaftor rat target organs: stomach (erosion/ulcers) and liver at >20x (male) and >60x (female) MRHD exposure (FDA integrated review, p. 97)
NOAEL / key findings
Vanzacaftor rat target organs: stomach (erosion/ulcers) and liver at >20x (male) and >60x (female) MRHD exposure
“In the general toxicology program for VNZ in rats, the major target organs of toxicity were the stomach (erosion/ulcers) and liver (hepatocellular vacuolar degeneration, multifocal hepatocellular necrosis) at exposures greater than 20 times (males) and 60 times (females) the exposure at the maximum recommended human dose (MRHD) of 20 mg VNZ.”
Risksopen answer page →
Immune & cytokine safety
26-week rat: decreased lymphocytes in spleen, thymus and lymph nodes
“decreases in lymphocytes in the spleen, thymus, and lymph nodes for males ≥25 mg/kg/day and females ≥12.5 mg/kg/day.”
Biodistribution & persistence
Highest in GI tract, liver and kidneys in rats; no substantial melanin binding
“Distribution was highest in the GI-tract, liver and kidneys for all three compounds in rats. No substantial binding to melanin-containing tissues was observed.”
Modality-specific risk
Potential QTc prolongation signalled by hERG, not seen in dog repeat-dose studies
“The good laboratory practice human ether-a-go-go related gene assay indicated a potential QTc prolongation risk, which was not observed upon follow-up in the dog repeat dose toxicology studies.”