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.”
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.”
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.”