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.”
Species: general tox
Rat (up to 6 months) and dog (up to 9 months)
“single and repeated dose toxicity studies in rats (up to 6-month) and dogs (up to 9-month)”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“reproductive and developmental toxicity studies including fertility studies in male and female rats, embryo-fetal developmental studies in rats and rabbits, and a peri- and post-natal developmental study in rats”
Species: carcinogenicity
Rat (2-year) and CByB6F1/Tg rasH2 mouse (6-month)
“The carcinogenic potential of orally administered FTR was assessed in a 2-year study in rats as well as in a 6-month study in CByB6F1/Tg rasH2 hemizygous mice.”
Surrogate used in
No surrogate used; fostemsavir tested directly
“single and repeated dose toxicity studies in rats (up to 6-month) and dogs (up to 9-month)”
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”
Genotox: Ames
Negative (Ames, Salmonella and E. coli)
“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.”
Genotox: in vitro mammalian
Chromosome aberration test in human lymphocytes: negative
“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.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“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 model
2-year rat; 6-month CByB6F1/Tg rasH2 mouse
“The carcinogenic potential of orally administered FTR was assessed in a 2-year study in rats as well as in a 6-month study in CByB6F1/Tg rasH2 hemizygous mice.”
Carcinogenicity timing
2-year rat and 26-week transgenic mouse completed before the marketing application; no significant tumor increases
“Fostemsavir produced no statistically significant increases in tumors over controls in a 2-year carcinogenicity study conducted in rats and a 26-week carcinogenicity study conducted in trnnsgenic mice.”
hERG / QT
Temsavir hERG inhibition 53% at 30 µM; Purkinje fiber APD prolongation; QT lengthened in conscious dogs
“BMS-626529 inhibited potassium channels in hERG assay (15, 30, 53% at 3, 10, 30µM, respectively), prolonged action potential duration in rabbit Purkinje fibers (12% at 30µM), and lengthened electrocardiogram (ECG) QT in conscious dogs (QT80, for ~8 to 18 msec, ~2.2 µg/ml).”
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.”
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
- Immune Reconstitution Syndrome
- QTc Prolongation with Higher than Recommended Dosages
- Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-Infection
- Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
CardiovascularHepatotoxicityInfections
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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) dog (oral) with 2-month recovery
“BMS-663068: A 9-Month Oral Toxicity Study in Dogs Followed by a 2-Month Recovery”
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)”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“reproductive and developmental toxicity studies including fertility studies in male and female rats, embryo-fetal developmental studies in rats and rabbits, and a peri- and post-natal developmental study in rats”
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).”
PPND / ePPND: when
Rat PPND completed before the marketing application
“This pre- and postnatal development study in rats showed no significant maternal toxicity at 300 mg/kg (maternal NOAEL AUC =2,550 μg.h/mL)”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and CByB6F1/Tg rasH2 mouse (6-month)
“The carcinogenic potential of orally administered FTR was assessed in a 2-year study in rats as well as in a 6-month study in CByB6F1/Tg rasH2 hemizygous mice.”
Carcinogenicity model
2-year rat; 6-month CByB6F1/Tg rasH2 mouse
“The carcinogenic potential of orally administered FTR was assessed in a 2-year study in rats as well as in a 6-month study in CByB6F1/Tg rasH2 hemizygous mice.”
Carcinogenicity timing
2-year rat and 26-week transgenic mouse completed before the marketing application; no significant tumor increases
“Fostemsavir produced no statistically significant increases in tumors over controls in a 2-year carcinogenicity study conducted in rats and a 26-week carcinogenicity study conducted in trnnsgenic mice.”
Safety marginopen answer page →
Safety margin at NOAEL
9-month dog NOAEL (liver findings) 10 mg/kg/day, ~2.6x human AUC
“Increased bilirubin and multifocal canalicular pigment deposits in 9-month dog study (not fully reversible, for females at ≥10 mg/kg and males at 30 mg/kg) with the NOAEL at 10 mg/kg/day (Day 1 AUC =51 µg.h/ml, SF =2.6).”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Cell-culture antiviral activity of temsavir against HIV-1 clinical isolates in PBMCs
“Temsavir IC50 value ranged from 0.01 to >2000 nM against clinical isolates of subtypes A, B, B', C, D, F, G and CRF01_AE in PBMCs.”
Why that model
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.
Reviewer's view of the efficacy data
FDA: temsavir antiviral activity variable across and within HIV-1 subtypes; no activity against subtype AE in cell culture or clinically
“TMR antiviral activity was variable and displayed a wide range of EC50 values across and within all HIV-1 subtypes. • TMR does not show activity in cell culture or clinically against subtype AE isolates (also known as subtype E).”
Flexibilityopen answer page →
Flexibility accepted
Safety pharmacologyAccepted
No stand-alone CNS or respiratory safety pharmacology studies; assessed within toxicity studies
Why: Per ICH M3(R2); CNS findings only at doses not tolerated in mice and dogs, well above human exposure · Within the guideline · Weight of evidence
“Effects on the central nervous system: Based on ICH M3(R2) guidance, no independent central nervous system (CNS) safety pharmacology studies were conducted for FTR.”
“In conclusion, CNS effects are not expected in humans treated with FTR as the CNS related findings only occurred at doses that were not tolerated in mice and dogs at exposures well above those at the RHD.”
Similar precedents
ArtesunateSmall molecules · artesunate · Plasmodium (antimalarial)Rodent + dog or minipig · 4 wkBlujepaSmall molecules · gepotidacin · Bacterial topoisomerases (gyrase/topo IV)Rodent + dog or minipig · 13 wkBrexafemmeSmall molecules · ibrexafungerp · Fungal glucan synthaseRodent + dog or minipig · 26 wkEgatenSmall molecules · triclabendazole · Fasciola (tubulin)Rodent + dog or minipig · 13 wkExblifepSmall molecules · cefepime and enmetazobactam · PBPs; beta-lactamase (enmetazobactam)Rodent + dog or minipig · 13 wkFexinidazoleSmall molecules · fexinidazole · Trypanosoma bruceiRodent + dog or minipig · 4 wk