Rukobia
fostemsavir
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 nonclinical safety profile of FTR supporting this NDA has been extensively explored from (1) single and repeated dose toxicity studies in rats (up to 6-month) and dogs (up to 9-month)”
Why that species
Rat and dog formed metabolites BMS-646915 and BMS-930644 at exposures above human
“Both the rat and dog formed BMS-646915 and BMS-930644 at adequate exposure levels (greater than human exposure).”
Surrogate molecule
No surrogate; the clinical compound was tested
“FTR was clinically tolerated by rats for 26 weeks at oral doses of ≤300 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month dog)
“FTR was well tolerated by dogs for 39 weeks at oral doses of ≤60 mg/kg/day.”
Pivotal GLP studies
Repeat-dose oral studies up to 6 months in rats and 9 months in dogs
“The nonclinical safety profile of FTR supporting this NDA has been extensively explored from (1) single and repeated dose toxicity studies in rats (up to 6-month) and dogs (up to 9-month)”
Route in tox
Oral
“FTR was clinically tolerated by rats for 26 weeks at oral doses of ≤300 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, human lymphocyte chromosome aberration and rat bone marrow micronucleus assays
“Fostemsavir was not genotoxic in the bacterial reverse mutation assay (Ames test in Salmonella and E. coli), a chromosome aberration test in human lymphocytes, and rat bone marrow micronucleus test.”
Carcinogenicity
2-year rat and 26-week transgenic mouse: no statistically significant tumor increases
“In a 2-year carcinogenicity study conducted in rats and a 26-week carcinogenicity study conducted in transgenic mice, fostemsavir produced no statistically significant increases in tumors over controls.”
Reproductive & developmental
Rat EFD: cleft palate and other craniofacial malformations at maternally toxic 1,000 mg/kg/day
“Teratogenic effects occurred in rats at the maternally toxic dose of 1,000 mg/kg/day, such as cleft palate, open eyes, shortened snout, microstomia, misaligned mouth/jaw, and protruding tongue (SF =144).”
Safety pharmacology
hERG inhibition (53% at 30 uM temsavir), Purkinje fiber APD prolongation and QT prolongation in conscious dogs
“(2) Cardiac effects: potassium channels inhibition (hERG assay;15, 30, 53% at 3, 10, 30µM TMR, respectively), action potential duration prolongation (rabbit Purkinje fibers; 12% at 30µM TMR), electrocardiogram (ECG) QT prolongation in conscious 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 Rukobia 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: Target organs: testes, kidney and adrenal in rats; liver in dogs (EMA assessment report, p. 23)
NOAEL / key findings
Target organs: testes, kidney and adrenal in rats; liver in dogs
“In repeated-dose toxicity studies, the target organs of toxicity were testes, kidneys, and adrenal gland in rats and liver in dogs.”
Risksopen answer page →
Immune & cytokine safety
No immunotoxicity in TDAR assay within the 26-week rat study
“The potential effects of FTR on the T-cell dependent antibody response (TDAR) to KLH were evaluated in accordance with ICH S8 as part of the pivotal 26-week oral rat toxicity study. From this study there is no indication of an immunotoxic potential for FTR.”
Biodistribution & persistence
Melanin-associated uveal distribution; significant placental transfer with fetal exposure including brain
“These findings suggest a potential association with melanin containing tissues of the eye uveal tract. Distribution studies performed in pregnant rats revealed significant transfer across the placenta with foetal exposure to all tissues examined including the brain.”
Modality-specific risk
QT prolongation and heart rate increase
“QT and heart rate findings may be associated with results observed in the human QT study (Section III.17.3), and tachycardia events reported in clinical trials.”