Lynkuet
elinzanetant
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
“Pivotal GLP-compliant repeated dose studies were conducted in Sprague Dawley (SD) rats and Cynomolgus monkeys and comprised studies of 4, 13 (two studies), and 26 weeks duration in rats and 4, 13 (two studies) and 39 weeks duration in monkeys.”
Why that species
Pharmacological responsiveness (potency, NK receptor sequence homology) plus PK and metabolic profile
“SD rats and Cynomolgus monkeys were selected as species for the investigation of systemic toxicological effects based on pharmacological responsiveness (potency, sequence homology, and pharmacologic effects on the NK receptors) as well as based on the pharmacokinetic and metabolic profile.”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the pivotal chronic toxicity studies conducted by the Applicant, including a 26-week study in SD rats (Study R-13894) and a 39-week study in monkeys (Study R-13895), elinzanetant increased levels of the liver-associated enzymes ALT, AST, and ALP.”
Species: general tox
Rat (up to 26 weeks) and cynomolgus monkey (up to 39 weeks)
“Pivotal GLP-compliant repeated dose studies were conducted in Sprague Dawley (SD) rats and Cynomolgus monkeys and comprised studies of 4, 13 (two studies), and 26 weeks duration in rats and 4, 13 (two studies) and 39 weeks duration in monkeys.”
Species: DART
Rat and rabbit (full reproductive and developmental battery)
“A full battery of reproductive and developmental toxicity studies was conducted in rats and rabbits.”
Species: carcinogenicity
Tg rasH2 mouse (6-month) and rat (2-year)
“Elinzanetant’s potential for carcinogenicity was assessed in a six-month carcinogenicity transgenic mouse model (tg RasH2) study in addition to one long-term two-year rat study.”
Surrogate used in
No surrogate used; rat and monkey selected for pharmacological responsiveness to elinzanetant
“SD rats and Cynomolgus monkeys were selected as species for the investigation of systemic toxicological effects based on pharmacological responsiveness (potency, sequence homology, and pharmacologic effects on the NK receptors) as well as based on the pharmacokinetic and metabolic profile.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“Pivotal GLP-compliant repeated dose studies were conducted in Sprague Dawley (SD) rats and Cynomolgus monkeys and comprised studies of 4, 13 (two studies), and 26 weeks duration in rats and 4, 13 (two studies) and 39 weeks duration in monkeys.”
Pivotal GLP studies
26-week SD rat and 39-week cynomolgus monkey chronic studies
“In the pivotal chronic toxicity studies conducted by the Applicant, including a 26-week study in SD rats (Study R-13894) and a 39-week study in monkeys (Study R-13895), elinzanetant increased levels of the liver-associated enzymes ALT, AST, and ALP.”
Route in tox
Oral
“The in vivo PK/TK studies with elinzanetant (BAY 3427080) were conducted via oral administration, which is the intended route of administration in humans, in rats and Cynomolgus monkeys which were used for toxicology studies.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and rat bone marrow micronucleus assays
“Elinzanetant showed no genotoxic potential in bacterial mutation assay (Ames test), mouse lymphoma assay, and in vivo bone marrow micronucleus test in rats.”
Carcinogenicity
2-year rat: uterine (endometrial) tumors and hematolymphoid lymphomas at ≥60 mg/kg/day (29-fold human AUC)
“In a 2-year carcinogenicity study in female rats, oral doses of elinzanetant ≥60 mg/kg/day (29-fold the total AUC(0-24) at the human therapeutic dose) increased the incidence of endometrial adenocarcinoma, the combination of malignant and benign endometrial tumors and squamous cell carcinoma of the uterus, and lymphomas of the hematolymphoid system.”
Reproductive & developmental
Pregnancy loss and stillbirth in animal reproduction studies; no fetal malformations
“Based on findings from animal reproduction studies, elinzanetant may cause pregnancy loss or stillbirth when administered during pregnancy. Fetal malformations were not observed in these animal studies.”
Safety pharmacology
No major signals in cardiovascular, respiratory and CNS battery; hERG IC50 ~31 µM (14x Cmax)
“Elinzanetant did not generate major safety signals in a complete battery of safety pharmacology studies (cardiovascular, respiratory, and CNS). Elinzanetant inhibited the activity of hERG channels with an IC50 of approximately 31μM that provides multiples of exposure of 14X and 4,820X, based on the maximum plasma concentration (Cmax) and Cmax, unbound at the maximal recommended human dose, respectively.”
Genotox: Ames
Negative
“Elinzanetant showed no genotoxic potential in bacterial mutation assay (Ames test), mouse lymphoma assay, and in vivo bone marrow micronucleus test in rats.”
Genotox: in vitro mammalian
Mouse lymphoma assay: negative
“Elinzanetant showed no genotoxic potential in bacterial mutation assay (Ames test), mouse lymphoma assay, and in vivo bone marrow micronucleus test in rats.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Elinzanetant showed no genotoxic potential in bacterial mutation assay (Ames test), mouse lymphoma assay, and in vivo bone marrow micronucleus test in rats.”
Carcinogenicity model
6-month Tg rasH2 mouse and 2-year rat
“Elinzanetant’s potential for carcinogenicity was assessed in a six-month carcinogenicity transgenic mouse model (tg RasH2) study in addition to one long-term two-year rat study.”
Carcinogenicity timing
Six-month rasH2 mouse and two-year rat completed before the marketing application
“Elinzanetant’s potential for carcinogenicity was assessed in a six-month carcinogenicity transgenic mouse model (tg RasH2) study in addition to one long-term two-year rat study.”
hERG / QT
hERG IC50 ~31 µM: 14x Cmax and 4,820x unbound Cmax at MRHD
“Elinzanetant inhibited the activity of hERG channels with an IC50 of approximately 31μM that provides multiples of exposure of 14X and 4,820X, based on the maximum plasma concentration (Cmax) and Cmax, unbound at the maximal recommended human dose, respectively.”
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 Lynkuet 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: PD-related reproductive findings: none adverse up to 25 mg/kg (rat) and 30 mg/kg (monkey), margins 10 and 0.3 (EMA assessment report, p. 32)
NOAEL / key findings
PD-related reproductive findings: none adverse up to 25 mg/kg (rat) and 30 mg/kg (monkey), margins 10 and 0.3
“No adverse PD related reproductive findings were observed in rats up to 25 mg/kg and in monkeys up to 30 mg/kg, corresponding to a safety margin of 10 and 0.3, respectively, based on total exposure (AUC0-24).”
Risksopen answer page →
Immune & cytokine safety
Thymus atrophy and lymphoid depletion, attributed to treatment-induced stress
“In addition, thymus atrophy, reduced thymus weight or lymphoid depletion of the thymus were noted. The effects observed in adrenal glands and thymus were discussed to be related to treatment-induced stress and non-adverse.”
Biodistribution & persistence
Distributes to liver and pigmented tissues (uveal tract, retina); crosses the blood-brain barrier
“Autoradiographic studies revealed that, following the oral administration of radiolabeled elinzanetant to different species, radioactivity distributed to major organs, including the liver and pigmented tissues (e.g., the uveal tract and the retina). In typical PK studies, elinzanetant was also found to cross the blood brain barrier.”
Modality-specific risk
CNS-related clinical signs, including convulsions
“Elinzanetant exerted CNS-related clinical signs including convulsions and has a known CNS activity.”
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
- Central Nervous System (CNS) Depressant Effect and Daytime Impairment
- Hepatic Transaminase Elevations
- Risk of Pregnancy Loss
- Risk of Seizure
NeurotoxicityPsychiatricHepatotoxicityEmbryo-fetal toxicity
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 Lynkuet 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: PD-related reproductive findings: none adverse up to 25 mg/kg (rat) and 30 mg/kg (monkey), margins 10 and 0.3 (EMA assessment report, p. 32)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week cynomolgus monkey (oral); no recovery groups in monkey studies
“Recovery groups were included in one of the 13- week rat studies but unfortunately not in Cynomolgus monkeys.”
Pivotal GLP studies
26-week SD rat and 39-week cynomolgus monkey chronic studies
“In the pivotal chronic toxicity studies conducted by the Applicant, including a 26-week study in SD rats (Study R-13894) and a 39-week study in monkeys (Study R-13895), elinzanetant increased levels of the liver-associated enzymes ALT, AST, and ALP.”
DART package
Species: DART
Rat and rabbit (full reproductive and developmental battery)
“A full battery of reproductive and developmental toxicity studies was conducted in rats and rabbits.”
Reproductive & developmental
Pregnancy loss and stillbirth in animal reproduction studies; no fetal malformations
“Based on findings from animal reproduction studies, elinzanetant may cause pregnancy loss or stillbirth when administered during pregnancy. Fetal malformations were not observed in these animal studies.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“A pre- and postnatal developmental study was conducted in the rat.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (6-month) and rat (2-year)
“Elinzanetant’s potential for carcinogenicity was assessed in a six-month carcinogenicity transgenic mouse model (tg RasH2) study in addition to one long-term two-year rat study.”
Carcinogenicity model
6-month Tg rasH2 mouse and 2-year rat
“Elinzanetant’s potential for carcinogenicity was assessed in a six-month carcinogenicity transgenic mouse model (tg RasH2) study in addition to one long-term two-year rat study.”
Carcinogenicity timing
Six-month rasH2 mouse and two-year rat completed before the marketing application
“Elinzanetant’s potential for carcinogenicity was assessed in a six-month carcinogenicity transgenic mouse model (tg RasH2) study in addition to one long-term two-year rat study.”
Safety marginopen answer page →
Safety margin at NOAEL
39-week monkey NOAEL: 0.35x (females, 30 mg/kg/day) and 1x (males, 80 mg/kg/day) MRHD AUC
“39-week repeat dose study in monkeys Female 30 3000 0.35X Male 80 8370 1X”
NOAEL / key findings
PD-related reproductive findings: none adverse up to 25 mg/kg (rat) and 30 mg/kg (monkey), margins 10 and 0.3
“No adverse PD related reproductive findings were observed in rats up to 25 mg/kg and in monkeys up to 30 mg/kg, corresponding to a safety margin of 10 and 0.3, respectively, based on total exposure (AUC0-24).”
Efficacy evidenceopen answer page →
Efficacy evidence
Mongolian gerbil model: elinzanetant reduced NK-1 agonist (GR-73632)-induced foot tapping
“In a Mongolian gerbil foot tapping model, elinzanetant at intracerebroventricular doses of 1, 3 and 10 mg/kg reduced GR-73632 (NK-1 receptor agonist) induced foot tapping, a behaviour associated with NK-1 receptor agonists.”
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
EMA: mechanism of action sufficiently described; insurmountable high-affinity NK-1/NK-3 antagonist, NK-1 preferring
“In summary, the mechanism of action of elinzanetant has been sufficiently described. Elinzanetant is shown to act as an insurmountable antagonist with high affinity for NK-1 and NK-3 receptors, with a preference for the NK-1 receptor.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginVerdict not stated
No margin at 39-week monkey NOAEL: females below 1x and males 1x MRHD AUC
“The NOAEL for females was the low-dose of 30 mg/kg/day, with AUC(0-24) = 3000 µg.h/L (<1 X MRHD) and the NOAEL for males was the high-dose of 80 mg/kg/day, with AUC(0-24) = 8370 µg.h/L (1 X MRHD).”
Safety marginVerdict not stated
No margin at the rat pre- and postnatal developmental NOAEL (0.23x MRHD AUC)
“2) At the NOAEL of 1.5 mg/kg/day for developmental toxicity there is no safety margin (0.23 X) based on AUC0-24h of 8572 ng•h/mL (Elinzanetant) obtained from clinical study B002427.”
Impurity or metaboliteAcceptedBeyond the letter
2-year rat carcinogenicity study gave very low exposure margins to main metabolites M27 and M18/21
Why: Executive CAC agreed metabolite coverage in the rat carcinogenicity study is adequate · Other reason
“While the carcinogenicity study generated adequate clinical exposure margins for the parent drug and its primary metabolite (M30/34) in rats, it provided very low exposure margins to the other two main metabolites (M27 and M18/21).”
“1. The Exec CAC agreed metabolite coverage in rat carcinogenicity study is adequate.”
RecoveryQuestioned
No recovery groups in cynomolgus monkey repeat-dose studies; recovery only in one 13-week rat study
“Recovery groups were included in one of the 13- week rat studies but unfortunately not in Cynomolgus monkeys.”
DARTAcceptedBeyond the letter
No dedicated male fertility study; male reproductive organs assessed in repeat-dose toxicity study
Why: Repeat-dose reproductive organ findings only at high exposure (margin 80; safety factor 56 at NOAEL), indicating low male fertility risk · Weight of evidence
“No dedicated male fertility study was conducted. Instead, male reproductive organs were assessed in a repeated dose toxicity study, which is acceptable.”
“These effects occurred at a dose resulting in an exposure margin of 80, with a safety factor of 56 at the NOAEL, when unbound exposure is compared to human exposure.”
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