Nextstellis
drospirenone and estetrol
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
“Repeated-dose toxicity has been evaluated in Sprague-Dawley (SD) rat and Cynomolgus monkey in studies of up to 6 and 9 months respectively.”
Why that species
Not stated in public reviews
The reviews list the species but not why. For small molecules, ICH M3(R2) expects one rodent and one non-rodent species, chosen with in vitro metabolism, protein binding and exposure data compared with human.
“In vitro metabolic and plasma protein binding data for animals and humans and systemic exposure data (ICH S3A, Ref. 7) in the species used for repeated-dose toxicity studies generally should be evaluated before initiating human clinical trials.”
✓ VerifiedICH 2009: ICH M3(R2): Guidance on Nonclinical Safety Studies for the Conduct…, p. 11Source ↗
Surrogate molecule
No surrogate; the clinical compound estetrol was tested, alone and with drospirenone
“E4 given in combination with DRSP in the female cynomolgus monkey for 13-weeks produced treatment-related effects consistent with anticipated hormonal changes of a progestin/estrogen drug combination”
Study lengthopen answer page →
Longest pivotal study
39 (39-week monkey)
“The toxicity profile of estetrol has been characterised in the toxicology programme performed in mice, rats and monkey in doses up to 39 weeks duration.”
Pivotal GLP studies
Estetrol: 6-month (26-week) rat and 9-month (39-week) cynomolgus monkey studies
“Repeated-dose toxicity has been evaluated in Sprague-Dawley (SD) rat and Cynomolgus monkey in studies of up to 6 and 9 months respectively.”
Route in tox
Oral (gavage)
“A 26-Week Toxicity Study by the Oral Route (Gavage) in Rats Followed by an 8-Week Treatment-Free Period (Study ES-T18)”
Skipped studiesopen answer page →
Genotoxicity
Estetrol negative in Ames, mouse lymphoma, rat micronucleus and rat Comet assays (weight of evidence)
“Weight of evidence indicates that E4 is not considered genotoxic in a full battery of in vitro and in vivo assays (Ames assay, in vitro mouse lymphoma assay, an in vivo rat micronucleus assay, and in vivo rat Comet assay).”
Carcinogenicity
Estetrol 104-week female rat: increased mammary neoplasms at 0.7x MRHD
“E4 doses of up to 0.8 mg/kg/day were administered orally to female rats for 104 weeks. At the high-dose of 0.8 mg/kg/day E4 (0.7x the MRHD on an AUC basis), there was an increased incidence of mammary neoplasms”
Reproductive & developmental
Rat and rabbit EFD: fetal growth retardation and developmental effects secondary to maternal toxicity; no intrinsic teratogenicity
“The observed fetal growth retardation and developmental effects were likely consequences of maternal toxicity in the pregnant female rat and rabbit. There are no indications for intrinsic teratogenic properties of E4 or DRSP in either rat or rabbit.”
Safety pharmacology
No cardiovascular effects in telemetered monkeys and no respiratory effects in rats at ≥115x MRHD
“E4 did not alter the cardiovascular function of telemetered monkeys and did not affect the respiratory functions of rats up to the highest dose tested (100 mg/kg in monkeys and 150 mg/kg in rats), with safety margins of approximately 115 times and 830 times the MRHD on an AUC basis, 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 Nextstellis 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: Exaggerated estrogenic effects: mammary/uterine epithelial proliferation, estrous inhibition, depressed erythropoiesis, cholestasis (FDA multi-discipline review, p. 36)
NOAEL / key findings
Exaggerated estrogenic effects: mammary/uterine epithelial proliferation, estrous inhibition, depressed erythropoiesis, cholestasis
“E4 demonstrated an ability to stimulate mammary and uterine epithelium proliferation, inhibit estrous cyclicity, depress erythropoiesis, and cause cholestasis in both rats and monkeys.”
Risksopen answer page →
Immune & cytokine safety
Thymus weight reduction with minimal to severe lymphoid atrophy in all species
“Lymphoid atrophy was noted in all species evaluated. Thymus weight was reduced in all species, associated with minimal to severe lymphoid atrophy.”
Biodistribution & persistence
Wide tissue distribution with rapid elimination; no retention, including in melanin-containing tissues
“E4 and its metabolites were widely distributed in rat tissues after a single oral dose of [14C]-E4 and are rapidly eliminated with no evidence of retention in any organ or tissues, including melanin-containing tissues.”
Modality-specific risk
Estrogen/progestin class effects, including cholestasis and hyperglycemia
“Adverse effects observed in the nonclinical chronic studies, including cholestasis and hyperglycemia, are known to be associated risks of CHCs.”