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.”
Species: general tox
Rat and dog (vanzacaftor, up to 26 and 39 weeks)
“The nonclinical safety of VNZ was evaluated in safety pharmacology studies in the rat and dog, repeat dose toxicology studies in the rat and dog of up to 26 and 39 weeks duration, respectively;”
Species: DART
Rat and rabbit (vanzacaftor, full DART battery)
“a full battery of developmental and reproductive toxicology studies in the rat and rabbit; genetic toxicology studies (Ames, in vitro micronucleus, and in vivo rat micronucleus assays);”
Species: carcinogenicity
Vanzacaftor: Tg rasH2 mouse (6-month) and rat (2-year)
“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.”
Surrogate used in
No surrogate; deutivacaftor bridged to ivacaftor data via a 13-week rat study
“A scientific bridge was established between D-IVA and IVA in a 13-week repeat dose toxicology study in rats.”
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.”
Genotox: Ames
Vanzacaftor: negative
“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.”
Genotox: in vitro mammalian
Vanzacaftor: in vitro micronucleus in TK6 cells negative
“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.”
Genotox: in vivo
Vanzacaftor: rat micronucleus negative
“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 model
Vanzacaftor: 6-month Tg rasH2 mouse (negative up to 30 mg/kg/day) and 2-year rat
“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.”
Carcinogenicity timing
Vanzacaftor Tg.rasH2 mouse completed; 2-year rat study not yet completed at the marketing application
“However, since the 2-year rat study for VNZ is not yet completed, the carcinogenicity potential cannot be determined at the moment for the VNZ, TEZ, and D-IVA co-administration.”
hERG / QT
Vanzacaftor hERG IC50 0.7 µM, ~3800-fold margin over free Cmax
“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).”
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.”
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
Boxed warning: Drug-induced liver injury and liver failure
- Drug-Induced Liver Injury and Liver Failure
- Hypersensitivity Reactions, Including Anaphylaxis
- Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to Adverse Reactions
- Intracranial Hypertension
- Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors
- Reduced Effectiveness with Concomitant Use with CYP3A Inducers
- Adverse Reactions with Concomitant Use with CYP3A Inhibitors
- Cataracts
HepatotoxicityHypersensitivity & infusion reactionsCardiovascularPsychiatricOcular toxicity
US prescribing information, Boxed Warning and 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week GLP oral dog study (vanzacaftor) with 6-week recovery
“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 with additional animals included in the control and 10 mg/kg/day groups for a 6-week recovery period.”
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.”
DART package
Species: DART
Rat and rabbit (vanzacaftor, full DART battery)
“a full battery of developmental and reproductive toxicology studies in the rat and rabbit; genetic toxicology studies (Ames, in vitro micronucleus, and in vivo rat micronucleus assays);”
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.”
PPND / ePPND: when
GLP PPND in rat (vanzacaftor) completed before the marketing application
“In a GLP pre- and postnatal development study (Study VX-121-TX-017), pregnant rats were administered VNZ at oral doses of 0 (vehicle), 2.5, 5, and 10 mg/kg/day”
Carcinogenicity
Species: carcinogenicity
Vanzacaftor: Tg rasH2 mouse (6-month) and rat (2-year)
“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.”
Carcinogenicity model
Vanzacaftor: 6-month Tg rasH2 mouse (negative up to 30 mg/kg/day) and 2-year rat
“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.”
Carcinogenicity timing
Vanzacaftor Tg.rasH2 mouse completed; 2-year rat study not yet completed at the marketing application
“However, since the 2-year rat study for VNZ is not yet completed, the carcinogenicity potential cannot be determined at the moment for the VNZ, TEZ, and D-IVA co-administration.”
Safety marginopen answer page →
Safety margin at NOAEL
Vanzacaftor 6-month rat NOAEL 21x (male) and 59x (female) clinical exposure
“The NOAELs for VNZ 6-month rat study were 12 mg/kg/day in males and 12.5 mg/kg/day in females. At the NOAELs EMs were 21× in males and 59× in females.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
CF patient-derived HBE cells (F508del/F508del, F508del/MF): increased F508del-CFTR processing and trafficking
“TEZ+D-IVA+VNZ treatment results in increased processing and trafficking of the F508del-CFTR protein in CF-HBE cells with the F508del/F508del and F508del/MF genotype.”
Why that model
No validated animal model of CF that mimics the multi-organ human disease
“As there is no validated animal model for CF that fully mimics the human multi organ affected disease, the use of in vitro systems to study the pharmacology can be accepted.”
Reviewer's view of the efficacy data
EMA: in vitro pharmacology systems acceptable given no validated CF animal model
“As there is no validated animal model for CF that fully mimics the human multi organ affected disease, the use of in vitro systems to study the pharmacology can be accepted.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
Vanzacaftor 2-year rat carcinogenicity study not completed before approval; deferred to postmarketing
Why: 2-year rat study to be conducted as a postmarketing requirement
“A 2-year carcinogenicity study in rats will be conducted as a postmarketing requirement (see Section 24).”
OtherAcceptedBeyond the letter
No full toxicology program for deutivacaftor; bridged to ivacaftor data via a 13-week rat comparison study
Why: No toxicologically significant differences between D-IVA and IVA at the same doses · Class precedent · Weight of evidence
“There were no toxicologically significant differences in findings between the same doses of D-IVA and IVA. Therefore, a bridge to the ivacaftor nonclinical program was justified and no further toxicology studies with D-IVA alone were recommended.”
DARTAcceptedBeyond the letter
No reproductive toxicity studies with deutivacaftor; ivacaftor data used instead
Why: Bridge to ivacaftor established in the 13-week rat toxicity study · Class precedent
“No reproductive toxicity studies have been conducted with D-IVA. A bridge between the toxicity profiles of D-IVA and IVA has been adequately established in the 13-week rat toxicity study.”
OtherAcceptedBeyond the letter
Tezacaftor tested only at one dose in the combination study; exposure multiple 1.2 (males) and 2.7 (females)
Why: Tezacaftor well studied and approved in a previous MAA · Class precedent
“TEZ was only assessed in combination studies with an exposure multiple of 1.2 for males and 2.7 for females at a dose where no toxicity was observed (only 1 dose tested). Since TEZ has been well studied and approved in a previous MAA, this limited amount of data is deemed acceptable.”
Juvenile toxQuestioned
Juvenile rat study (PND 7 to PND 70) too short to exclude liver toxicity with chronic treatment
“While the current juvenile study (PND 7–PND 70) did not identify the liver as a target organ, its limited duration raises uncertainty regarding potential effects with chronic treatment. Thus, the possibility of liver toxicity in juvenile animals cannot be completely ruled out.”
Similar precedents
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