Baxfendy
baxdrostat
Species
MonkeyRat
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 cynomolgus monkey
“A comprehensive toxicology program was conducted in both rats and cynomolgus monkeys.”
Why that species
Monkey RAAS closely resembles human, making it pharmacologically relevant; rat is a low-potency responder species
“The cynomolgus monkey renin-angiotensin system closely resembles the human system, making it a relevant species for assessing pharmacodynamic efficacy and toxicity.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Baxdrostat was evaluated in repeat-dose oral toxicology studies of up to 6 months in rats and 9 months in monkeys.”
Species: general tox
Rat and cynomolgus monkey
“A comprehensive toxicology program was conducted in both rats and cynomolgus monkeys.”
Species: DART
Rat and rabbit (embryo-fetal development)
“While baxdrostat had no effects on embryo-fetal development in rats or rabbits dosed through organogenesis at exposures up to 54‑fold (rat) and 29-fold (rabbit) the human dose of 2 mg, baxdrostat showed greatly reduced potency in rats compared to humans, which limits the interpretability of the rodent data.”
Species: carcinogenicity
Rat (2-year) and transgenic mouse (6-month)
“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies.”
Surrogate used in
No surrogate used; baxdrostat itself tested in rats and monkeys
“A comprehensive toxicology program was conducted in both rats and cynomolgus monkeys.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month monkey)
“In a 39-week oral gavage toxicity study in cynomolgus monkeys with a 4-week recovery phase, baxdrostat was administered at doses of 0, 1, 3, or 6 mg/kg/day.”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey oral studies
“Baxdrostat was evaluated in repeat-dose oral toxicology studies of up to 6 months in rats and 9 months in monkeys.”
Route in tox
Oral gavage
“In 13-week and 26-week oral gavage toxicity study in Wistar Han rats with a 4-week recovery phase, baxdrostat was administered at doses of 0, 1, 3, or 10 mg/kg/day.”
Skipped studiesopen answer page →
Genotoxicity
Not genotoxic in a battery of in vitro and in vivo assays
“Baxdrostat was not genotoxic when tested in a battery of in vitro and in vivo assays.”
Carcinogenicity
2-year rat and 6-month transgenic mouse: no evidence of carcinogenicity
“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies. There was no evidence of carcinogenicity with oral doses up to 45 mg/kg/day in mice (264-fold), and up to 10 mg/kg/day in male rats (105-fold) and up to 3 mg/kg/day in female rats (62-fold).”
Reproductive & developmental
Rat and rabbit EFD: rat skull malformations and rabbit reduced fetal weight at >54- and >29-fold clinical exposure
“In embryofetal development studies, reduced maternal body weight gain and fetal toxicities were observed in rats (adverse skeletal malformations of skull: mandible/zygomatic arch fusion) and rabbits (decrease in fetal body weight) at exposures >54-fold and >29-fold relative to the clinical exposures at the MRHD.”
Safety pharmacology
hERG IC50 360 μM (~15,000-fold over free Cmax); trend to QTc prolongation (+7%) in monkey telemetry at 50 mg/kg
“Baxdrostat inhibited the hERG tail current with an IC50 of 360 μM, approximately 15,000-fold above the free Cmax at the clinical dose of 2 mg. A trend toward persistent QTc prolongation (+7%) was observed at 6 hours post-dose in single-dose telemetry study in monkeys at 50 mg/kg.”
Genotox: Ames
Negative up to 5000 μg/plate, with and without S9
“Conclusion: Baxdrostat demonstrated no mutagenic activity in bacterial test systems up to the maximum recommended concentration of 5000 μg/plate, in the absence and presence of a rat liver metabolic activation system (S9).”
Genotox: in vitro mammalian
L5178Y in vitro micronucleus: weak statistical positive with 24-hour exposure (low vehicle control); negative with 3-hour exposure
“Conclusion: The 24-hour continuous exposure protocol yielded statistically positive results, which were slightly outside the historical control range with statistical significance partly due to an unusually low concurrent vehicle control. No increase in micronuclei formation was observed with the 3-hour exposure protocol.”
Genotox: in vivo
Rat bone marrow micronucleus and liver comet: negative
“Conclusion: Baxdrostat demonstrated no genotoxic potential in vivo, showing no clastogenic activity in bone marrow or DNA strand breaks in liver.”
Carcinogenicity model
2-year rat and 6-month rasH2 transgenic mouse; negative
“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies. There was no evidence of carcinogenicity with oral doses up to 45 mg/kg/day in mice (264-fold), and up to 10 mg/kg/day in male rats (105-fold) and up to 3 mg/kg/day in female rats (62-fold).”
Carcinogenicity timing
6-month rasH2 transgenic mouse and 2-year rat completed before the marketing application
“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies.”
hERG / QT
hERG IC50 360 μM, ~15,000-fold above free Cmax at 2 mg
“Baxdrostat inhibited the hERG tail current with an IC50 of 360 μM, approximately 15,000-fold above the free Cmax at the clinical dose of 2 mg.”
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 Baxfendy 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: Dehydration; adrenal zona glomerulosa hypertrophy and renal juxtaglomerular hyperplasia in monkeys, pharmacology-related (FDA pharmacology/toxicology review, p. 20)
NOAEL / key findings
Dehydration; adrenal zona glomerulosa hypertrophy and renal juxtaglomerular hyperplasia in monkeys, pharmacology-related
“Frequently observed findings were primarily related to the primary pharmacology of baxdrostat, including dehydration (rats and monkeys) and microscopic findings in adrenal glands (zona glomerulosa hypertrophy) and kidneys (juxtaglomerular cell hyperplasia) in monkeys.”
Risksopen answer page →
Immune & cytokine safety
Decreased lymphocytes in spleen, thymus and mesenteric lymph nodes in 39-week monkey study (non-adverse)
“Baxdrostat was well tolerated despite dehydration (increased incidence of thinness and skin tenting), reduced body weight gain, and histological changes in adrenals, kidneys, spleen, thymus, and mesenteric lymph nodes (decreased lymphocytes).”
Biodistribution & persistence
Wide distribution, highest in adrenal, liver, cecum and kidney; low brain/spinal cord; melanin binding
“Tissue distribution studies revealed widespread tissue distribution with highest exposures in adrenal gland, liver, cecum, and kidney (tissue-to-plasma ratios up to 17.3 for adrenal gland). Brain and spinal cord showed substantially lower concentrations, while pigmented tissues demonstrated selective melanin binding in Long Evans rats.”
Modality-specific risk
Electrolyte/fluid imbalance and adrenal effects; adrenal insufficiency risk negligible at therapeutic doses
“Based on nonclinical data, the risk of adrenal insufficiency appears to be negligible at therapeutic doses and would be a potential concern at very high, supra-therapeutic exposures where the drug's selectivity for aldosterone synthase may be overcome.”
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
- Hyperkalemia
- Hyponatremia
Metabolic & endocrine
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 Baxfendy 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: Dehydration; adrenal zona glomerulosa hypertrophy and renal juxtaglomerular hyperplasia in monkeys, pharmacology-related (FDA pharmacology/toxicology review, p. 20)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (oral gavage) with 4-week recovery
“Monkey Studies: In a 39-week oral gavage toxicity study in cynomolgus monkeys with a 4-week recovery phase, baxdrostat was administered at doses of 0, 1, 3, or 6 mg/kg/day.”
Pivotal GLP studies
26-week rat and 39-week cynomolgus monkey oral studies
“Baxdrostat was evaluated in repeat-dose oral toxicology studies of up to 6 months in rats and 9 months in monkeys.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“While baxdrostat had no effects on embryo-fetal development in rats or rabbits dosed through organogenesis at exposures up to 54‑fold (rat) and 29-fold (rabbit) the human dose of 2 mg, baxdrostat showed greatly reduced potency in rats compared to humans, which limits the interpretability of the rodent data.”
Reproductive & developmental
Rat and rabbit EFD: rat skull malformations and rabbit reduced fetal weight at >54- and >29-fold clinical exposure
“In embryofetal development studies, reduced maternal body weight gain and fetal toxicities were observed in rats (adverse skeletal malformations of skull: mandible/zygomatic arch fusion) and rabbits (decrease in fetal body weight) at exposures >54-fold and >29-fold relative to the clinical exposures at the MRHD.”
PPND / ePPND: when
PPND in Wistar Han rat completed before the marketing application
“Prenatal and Postnatal Development (PPND) Study Eighty F0 generation time-mated female Wistar-Han rats were assigned to 4 groups (20 animals each).”
Carcinogenicity
Species: carcinogenicity
Rat (2-year) and transgenic mouse (6-month)
“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies.”
Carcinogenicity model
2-year rat and 6-month rasH2 transgenic mouse; negative
“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies. There was no evidence of carcinogenicity with oral doses up to 45 mg/kg/day in mice (264-fold), and up to 10 mg/kg/day in male rats (105-fold) and up to 3 mg/kg/day in female rats (62-fold).”
Carcinogenicity timing
6-month rasH2 transgenic mouse and 2-year rat completed before the marketing application
“The carcinogenic potential of baxdrostat was evaluated in 6-month transgenic mouse and 2-year rat studies.”
Safety marginopen answer page →
Safety margin at NOAEL
Monkey 39-week NOAEL: 11-fold (males) and 8.5-fold (females) vs 2 mg human dose
“11-fold (males) and 8.5-fold (females) compared to the 2 mg human dose.”
NOAEL / key findings
Dehydration; adrenal zona glomerulosa hypertrophy and renal juxtaglomerular hyperplasia in monkeys, pharmacology-related
“Frequently observed findings were primarily related to the primary pharmacology of baxdrostat, including dehydration (rats and monkeys) and microscopic findings in adrenal glands (zona glomerulosa hypertrophy) and kidneys (juxtaglomerular cell hyperplasia) in monkeys.”
Efficacy evidenceopen answer page →
Efficacy evidence
Telemetered cynomolgus monkeys on low-sodium diet plus furosemide (maximal RAAS activation)
“Sodium-Depleted Telemetry Studies: To evaluate pharmacodynamic effects under conditions of maximal RAAS activation, telemetered cynomolgus monkeys were maintained on a low-sodium diet and treated with the diuretic furosemide, which models a common clinical scenario.”
Why that model
Cynomolgus monkey renin-angiotensin system closely resembles human, making it the relevant species
“The cynomolgus monkey renin-angiotensin system closely resembles the human system, making it a relevant species for assessing pharmacodynamic efficacy and toxicity.”
Reviewer's view of the efficacy data
FDA: BP reductions in sodium-depleted monkeys provide proof-of-concept for antihypertensive efficacy
“The observed blood pressure reductions and compensatory heart rate increases in sodium-depleted monkeys provide proof-of-concept for antihypertensive efficacy.”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAcceptedBeyond the letter
Rat and transgenic mouse carcinogenicity studies likely did not achieve aldosterone synthase inhibition; treated as off-target assessment only
Why: Low aldosterone is not identified in the published literature as an independent carcinogenicity risk factor · Weight of evidence
“As aldosterone synthase inhibition was not likely achieved at the doses tested in these rodent studies, the findings are considered an off-target assessment; notably, low aldosterone has not been identified in the published literature as an independent risk factor for carcinogenicity.”
SpeciesVerdict not stated
Chronic rat study not pharmacologically active; on-target chronic toxicity assessed in cynomolgus monkey only
“Notably, baxdrostat was not considered pharmacologically active at these doses in the chronic rat study and therefore the results of that evaluation primarily represent an off-target assessment.”
DARTVerdict not stated
Rat developmental studies of limited interpretability because of greatly reduced baxdrostat potency in rats
“While baxdrostat had no effects on embryo-fetal development in rats or rabbits dosed through organogenesis at exposures up to 54‑fold (rat) and 29-fold (rabbit) the human dose of 2 mg, baxdrostat showed greatly reduced potency in rats compared to humans, which limits the interpretability of the rodent data.”
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