Kygevvi
doxecitine and doxribtimine
Species
RatMouseDog
Longest study
26 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog (plus 4-week mouse)
“The nonclinical safety program supporting the clinical development and approval of doxecitine and doxribtimine included repeat-dose oral toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and dogs (up to 3 months)”
Why that species
Shared mitochondrial TK2 and cytosolic nucleoside pathways and conserved mitochondrial genomes analogous to humans
“The studies, conducted in alignment with ICH guidelines, utilized mouse, rat, rabbit, and dog models, leveraging shared mitochondrial TK2 nucleoside phosphorylation and cytosolic nucleoside pathways, as well as conserved mitochondrial genomes and incorporation pathways analogous to those in humans.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In dogs, doxecitine and doxribtimine up to 100 mg/kg/day (doxecitine 50 mg/kg/day and doxribtimine 50 mg/kg/day) for 13 weeks.”
Species: general tox
Mouse (4 weeks), rat (6 months) and dog (3 months)
“The nonclinical safety program supporting the clinical development and approval of doxecitine and doxribtimine included repeat-dose oral toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and dogs (up to 3 months)”
Species: DART
Rat (fertility, EFD, juvenile) and rabbit (EFD)
“reproductive and developmental toxicity assessment including a fertility and early embryonic development study in rats, embryofetal development studies in both rats and rabbits, and a juvenile animal study in rats”
Species: carcinogenicity
Not conducted; 26-week Tg-rasH2 mouse study to be done postapproval
“To address the remaining nonclinical data gaps, the Applicant will conduct the following postapproval studies: a 9-month dog study and a 26-week carcinogenicity study in Tg-rasH2 mice with doxecitine and doxribtimine”
Surrogate used in
No surrogate used; the clinical nucleosides were tested in species sharing human TK2 and nucleoside pathways
“The studies, conducted in alignment with ICH guidelines, utilized mouse, rat, rabbit, and dog models, leveraging shared mitochondrial TK2 nucleoside phosphorylation and cytosolic nucleoside pathways, as well as conserved mitochondrial genomes and incorporation pathways analogous to those in humans.”
Study lengthopen answer page →
Longest pivotal study
26 (6-month juvenile rat)
“The nonclinical safety program supporting the clinical development and approval of doxecitine and doxribtimine included repeat-dose oral toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and dogs (up to 3 months)”
Pivotal GLP studies
6-month rat, 3-month dog and 4-week mouse oral repeat-dose studies
“The nonclinical safety program supporting the clinical development and approval of doxecitine and doxribtimine included repeat-dose oral toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and dogs (up to 3 months)”
Route in tox
Oral
“The nonclinical safety program supporting the clinical development and approval of doxecitine and doxribtimine included repeat-dose oral toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and dogs (up to 3 months)”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames and rat micronucleus; positive in vitro chromosome aberration assay in human lymphocytes
“Doxecitine and doxribtimine were not mutagenic in the in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vivo rat micronucleus assay. However, doxecitine and doxribtimine induced a statistically significant, dose-dependent increase in chromosomal aberrations in human peripheral blood lymphocytes in the absence of metabolic activation.”
Carcinogenicity
Not conducted; 26-week Tg-rasH2 mouse study required postapproval
“To address the remaining nonclinical data gaps, the Applicant will conduct the following postapproval studies: a 9-month dog study and a 26-week carcinogenicity study in Tg-rasH2 mice with doxecitine and doxribtimine”
Reproductive & developmental
Rat and rabbit EFD: maternal toxicity and fetal malformations (dilated aorta, narrow pulmonary trunk) in rabbits at 2000 mg/kg/day
“In embryofetal development studies, oral administration of doxecitine and doxribtimine to pregnant rats and rabbits during organogenesis resulted in maternal toxicity (decreased body weight gain and food consumption) and fetal malformations (dilated aorta with narrow pulmonary trunk) in the rabbit at 2000 mg/kg/day.”
Safety pharmacology
Not conducted as stand-alone studies (endogenous nucleosides); cardiovascular endpoints assessed in 13-week dog study
“No dedicated in vitro and in vivo safety pharmacology studies were conducted due to the endogenous nature of doxecitine and doxribtimine. In the 13-week toxicity study in dogs, cardiovascular endpoints were evaluated.”
Genotox: Ames
Negative
“Doxecitine and doxribtimine were not mutagenic or clastogenic in an in vitro bacterial reverse mutation (Ames) and an in vivo rat micronucleus assay.”
Genotox: in vitro mammalian
Positive: chromosomal aberrations in human lymphocytes without metabolic activation
“Doxecitine and doxribtimine induced chromosomal aberrations in the absence of metabolic activation in an in vitro cytogenetic study in human lymphocytes.”
Genotox: in vivo
Negative rat micronucleus
“Doxecitine and doxribtimine were not mutagenic or clastogenic in an in vitro bacterial reverse mutation (Ames) and an in vivo rat micronucleus assay.”
Carcinogenicity model
Not conducted; 26-week Tg-rasH2 mouse study planned postapproval
“To address the remaining nonclinical data gaps, the Applicant will conduct the following postapproval studies: a 9-month dog study and a 26-week carcinogenicity study in Tg-rasH2 mice with doxecitine and doxribtimine”
Carcinogenicity timing
26-week Tg-rasH2 mouse study is a postmarketing requirement; draft protocol due 11/2026, not started at approval
“Postmarketing Requirement #1 Conduct a 26-week carcinogenicity study in Tg-rasH2 mice to identify and evaluate the carcinogenic risk of dC/dT. Draft Protocol Submission: 11/2026”
hERG / QT
No dedicated safety pharmacology (endogenous nucleosides); cardiovascular endpoints in 13-week dog study
“No dedicated in vitro and in vivo safety pharmacology studies were conducted due to the endogenous nature of doxecitine and doxribtimine. In the 13-week toxicity study in dogs, cardiovascular endpoints were evaluated.”
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 Kygevvi 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: No target organ toxicity; NOAELs at highest doses: 400 (mouse), 2000 (rat), 100 (dog) mg/kg/day (FDA integrated review, p. 81)
NOAEL / key findings
No target organ toxicity; NOAELs at highest doses: 400 (mouse), 2000 (rat), 100 (dog) mg/kg/day
“In repeat-dose toxicity studies conducted in mice, rats, and dogs, no target organ toxicity or other toxicologically significant findings were identified. The no observed adverse effect level (NOAEL) corresponded to the highest dose level evaluated in each species: 400 mg/kg/day in mice, 2000 mg/kg/day in rats, and 100 mg/kg/day in dogs.”
Risksopen answer page →
Immune & cytokine safety
No hormonal or immune modulation in 26-week juvenile rat and 13-week dog studies
“In 26-week juvenile rat and 13-week dog studies, no evidence of tumorigenicity, hyperplasia, preneoplastic lesions, neoplasia, or hormonal/immune modulation was observed.”
Biodistribution & persistence
Not studied by the applicant; deoxynucleosides distribute extensively, highest in spleen, liver, kidney and intestine
“No pharmacokinetic studies on organ distribution were performed with exogenous doxecitine and doxribtimine, since sufficient data was available from literature. Exogenous deoxycytidine and deoxythymidine are distributed extensively in the body, with the highest levels in spleen, liver, kidney, and intestine.”
Modality-specific risk
Genotoxic impurity alpha-hydroxythymidine in the doxribtimine drug substance
“A significant safety concern was identified with respect to alpha-hydroxythymidine, a genotoxic impurity present in the doxribtimine drug substance starting material.”
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
- Elevated Liver Transaminase Levels
- Gastrointestinal Adverse Reactions
HepatotoxicityGastrointestinal
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 Kygevvi 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: No target organ toxicity; NOAELs at highest doses: 400 (mouse), 2000 (rat), 100 (dog) mg/kg/day (FDA integrated review, p. 81)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
6-month (26-week) oral rat study; recovery phase not stated
“The nonclinical safety program supporting the clinical development and approval of doxecitine and doxribtimine included repeat-dose oral toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and dogs (up to 3 months)”
Pivotal GLP studies
6-month rat, 3-month dog and 4-week mouse oral repeat-dose studies
“The nonclinical safety program supporting the clinical development and approval of doxecitine and doxribtimine included repeat-dose oral toxicity studies in mice (up to 4 weeks), rats (up to 6 months), and dogs (up to 3 months)”
DART package
Species: DART
Rat (fertility, EFD, juvenile) and rabbit (EFD)
“reproductive and developmental toxicity assessment including a fertility and early embryonic development study in rats, embryofetal development studies in both rats and rabbits, and a juvenile animal study in rats”
Reproductive & developmental
Rat and rabbit EFD: maternal toxicity and fetal malformations (dilated aorta, narrow pulmonary trunk) in rabbits at 2000 mg/kg/day
“In embryofetal development studies, oral administration of doxecitine and doxribtimine to pregnant rats and rabbits during organogenesis resulted in maternal toxicity (decreased body weight gain and food consumption) and fetal malformations (dilated aorta with narrow pulmonary trunk) in the rabbit at 2000 mg/kg/day.”
PPND / ePPND: when
No PPND study in rat: unwarranted given negative EFD and juvenile rat findings at high exposure margins
“Based on the negative findings in the EFD and juvenile toxicity studies in rats at high exposure margins, a rat PPND study is considered unwarranted.”
Carcinogenicity
Species: carcinogenicity
Not conducted; 26-week Tg-rasH2 mouse study to be done postapproval
“To address the remaining nonclinical data gaps, the Applicant will conduct the following postapproval studies: a 9-month dog study and a 26-week carcinogenicity study in Tg-rasH2 mice with doxecitine and doxribtimine”
Carcinogenicity model
Not conducted; 26-week Tg-rasH2 mouse study planned postapproval
“To address the remaining nonclinical data gaps, the Applicant will conduct the following postapproval studies: a 9-month dog study and a 26-week carcinogenicity study in Tg-rasH2 mice with doxecitine and doxribtimine”
Carcinogenicity timing
26-week Tg-rasH2 mouse study is a postmarketing requirement; draft protocol due 11/2026, not started at approval
“Postmarketing Requirement #1 Conduct a 26-week carcinogenicity study in Tg-rasH2 mice to identify and evaluate the carcinogenic risk of dC/dT. Draft Protocol Submission: 11/2026”
Safety marginopen answer page →
Safety margin at NOAEL
NOAELs in 26-week rat and 13-week dog studies at least 25-fold human baseline-adjusted AUC
“The exposure margin of these toxicology studies were at least 25-fold higher than human exposure based on baseline-adjusted AUC0-24.”
NOAEL / key findings
No target organ toxicity; NOAELs at highest doses: 400 (mouse), 2000 (rat), 100 (dog) mg/kg/day
“In repeat-dose toxicity studies conducted in mice, rats, and dogs, no target organ toxicity or other toxicologically significant findings were identified. The no observed adverse effect level (NOAEL) corresponded to the highest dose level evaluated in each species: 400 mg/kg/day in mice, 2000 mg/kg/day in rats, and 100 mg/kg/day in dogs.”
Efficacy evidenceopen answer page →
Efficacy evidence
Tk2 knock-in (Tk2KI) and knockout (Tk2KO) mouse models of TK2 deficiency
“Primary pharmacodynamics A total of five non-GLP primary pharmacodynamic studies, including three literature studies, were conducted using wild-type (WT), Tk2KO, and Tk2KI mouse models to evaluate the effects of nucleoside and nucleotide therapies on TK2 deficiency (TK2d).”
Why that model
TK2-deficient mouse models reproduce mtDNA depletion resembling human infantile encephalomyopathy
“Both models exhibit mitochondrial dysfunction and respiratory chain defects, mimicking the severe mitochondrial DNA (mtDNA) depletion caused by thymidine kinase 2 deficiency, which closely resembles human infantile encephalomyopathy.”
Reviewer's view of the efficacy data
FDA: TK2-deficient animal models gave mechanistic support and evidence of survival benefit, contributing confirmatory evidence
“the targeted mechanism of action of doxecitine and doxribtimine, and treatment of TK2 deficient animal models that provides additional mechanistic support and evidence of a survival benefit.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
No 2-year rat carcinogenicity study; weight-of-evidence assessment instead, with 26-week Tg-rasH2 mouse study postapproval
Why: Endogenous compounds, years of clinical experience, no tumorigenicity in 26-week rat and 13-week dog studies · Weight of evidence · Human data · Pharmacology or kinetics
“The Applicant submitted a weight-of-evidence assessment in lieu of a 2-year rat carcinogenicity study. The Agency agreed with the Applicant’s weight-of-evidence assessment that a 2-year rat carcinogenicity study would not add value”
“Provided the endogenous nature of the compounds, up to 10 years clinical experience of the use of the compounds, and that no evidence of tumorigenicity observed in the 26-week toxicity study in juvenile rats and in the 13-week toxicity study in dogs, it is agreed that the potential for doxecitine and doxribtimine to cause carcinogenicity is low and a two-year carcinogenicity study can be waived.”
Study lengthAccepted with a conditionBeyond the letter
No 9-month chronic dog study before approval (dog studies up to 13 weeks); deferred to postmarketing
“The Applicant did not conduct a 9-month dog toxicity study, carcinogenicity studies, and a rat PPND study with doxecitine and doxribtimine.”
“The Agency also confirmed that the 39-week repeat-dose toxicity study in dogs could be conducted as a PMR.”
DARTAcceptedBeyond the letter
No rat pre- and postnatal development study
Why: Negative embryofetal and juvenile rat studies at high exposure margins · Weight of evidence
“Based on the negative findings in the EFD and juvenile toxicity studies in rats at high exposure margins, a rat PPND study is considered unwarranted.”
Safety pharmacologyAcceptedBeyond the letter
No dedicated safety pharmacology studies; cardiovascular endpoints in 13-week dog study and functional assessments in toxicity studies
Why: Endogenous nature of the nucleosides; no findings in toxicity studies at 25-fold or higher exposure · Pharmacology or kinetics · Weight of evidence
“No dedicated in vitro and in vivo safety pharmacology studies were conducted due to the endogenous nature of doxecitine and doxribtimine.”
“The exposure margin of these toxicology studies were at least 25-fold higher than human exposure based on baseline-adjusted AUC0-24. The safety pharmacology is considered sufficiently addressed.”
Impurity or metaboliteAccepted with a conditionBeyond the letter
Genotoxic impurity alpha-hydroxythymidine above the ICH M7 TTC; mutagenic/clastogenic characterization required postmarketing
“This exposure level represents approximately -fold exceedance of the 1.5 μg TTC for genotoxic impurities established in ICH M7(R2) guidance.”
“Postmarket assessments will be required to characterize the mutagenic and clastogenic potential of alpha-hydroxythymidine in the presence of doxecitine and doxribtimine.”
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