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.”
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.”
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.”