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”
Species: general tox
Rat (Sprague-Dawley) 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.”
Species: DART
Rat and rabbit (embryo-fetal development)
“In the embryo-fetal development studies of E4 in the rat and rabbit, E4 caused maternal toxicity (reduced body weight and food consumption) and was embryotoxic at 3 mg/kg in the rat”
Species: carcinogenicity
CD-1 mouse and Wistar rat (two-year)
“Two long-term (two-year) carcinogenicity studies with E4 have been performed, one using CD-1 mice and one with Wistar rats.”
Surrogate used in
No surrogate used; estetrol tested alone and with drospirenone in monkeys
“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.”
Genotox: Ames
Equivocal: TA102 mutagenic activity not fully reproducible across Ames tests
“Therefore, and overall, the Ames test studies suggest a not fully reproducible mutagenic activity in the strain TA102 perhaps via a cross-linking mode of action.”
Genotox: in vitro mammalian
Mouse lymphoma assay (L5178Y): negative with and without metabolic activation
“E4 did not display mutagenic activity in the mouse lymphoma assay, either in the presence or in the absence of a rat metabolizing system.”
Genotox: in vivo
Rat bone marrow micronucleus: negative up to 2000 mg/kg
“E4 did not induce damage to the chromosomes or the mitotic apparatus of rat bone marrow cells after a single oral administration up to 2000 mg/kg.”
Carcinogenicity model
Two-year rat and mouse studies; estetrol carcinogenic in both
“Two-year carcinogenicity studies in rats and mice showed that estetrol is carcinogenic.”
Carcinogenicity timing
Rat and mouse carcinogenicity studies completed before the marketing application
“The tumor findings from the rat and mouse final carcinogenicity studies were reviewed and agreed upon by the Division and ECAC on November 24, 2020.”
hERG / QT
No hERG inhibition at 480x the E4 Cmax at the MRHD
“E4 did not interfere with the hERG channel conduction in in vitro patch-clamp experiments using concentrations of E4 that were 480 times the Cmax of E4 at the MRHD.”
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.”
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 applicable: immunogenicity studies not performed or needed for this hormonal contraceptive
“Immunogenicity studies were not performed and not necessary for this hormonal contraceptive product.”
Label warnings
Boxed warning: Cigarette smoking and serious cardiovascular events
- Thromboembolic Disorders and Other Vascular Problems
- Hyperkalemia
- Hypertension
- Migraine
- Malignant Neoplasms
- Liver Disease
- Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment
- Glucose Tolerance and Hypertriglyceridemia
- Gallbladder Disease and Cholestasis
- Effect on Binding Globulins
- Bleeding Irregularities and Amenorrhea
- Depression
- Hereditary Angioedema
- Chloasma
CardiovascularThrombosis & embolismMetabolic & endocrineSecondary malignancyHepatotoxicityBleedingPsychiatric
US prescribing information, Boxed Warning and 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
39-week monkey (oral, GLP) with 6-week recovery
“39-week toxicity study by the oral route (gavage) in adult female cynomolgus monkeys followed by a 6-week treatment-free period (Study ES-T20, GLP)”
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.”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“In the embryo-fetal development studies of E4 in the rat and rabbit, E4 caused maternal toxicity (reduced body weight and food consumption) and was embryotoxic at 3 mg/kg in the rat”
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.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a pre- and post-natal development study in rats, E4 caused maternal toxicity (reduced body weight and food consumption), parturition difficulties or absence of delivery”
Carcinogenicity
Species: carcinogenicity
CD-1 mouse and Wistar rat (two-year)
“Two long-term (two-year) carcinogenicity studies with E4 have been performed, one using CD-1 mice and one with Wistar rats.”
Carcinogenicity model
Two-year rat and mouse studies; estetrol carcinogenic in both
“Two-year carcinogenicity studies in rats and mice showed that estetrol is carcinogenic.”
Carcinogenicity timing
Rat and mouse carcinogenicity studies completed before the marketing application
“The tumor findings from the rat and mouse final carcinogenicity studies were reviewed and agreed upon by the Division and ECAC on November 24, 2020.”
Safety marginopen answer page →
Safety margin at NOAEL
Estetrol NOAEL 3.3x (chronic rat) and 2.1x (chronic monkey) the MRHD by AUC
“The safety margins for E4 at the NOAEL in the chronic rat and monkey studies were 3.3x and 2.1x the MRHD, respectively, on an AUC basis.”
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.”
Efficacy evidenceopen answer page →
Efficacy evidence
Ovulation and implantation inhibition in normal rabbits
“In New Zealand White rabbits, E4 inhibited ovulation and implantation with respective oral ED50s of 0.7 mg/kg bid and 0.06 mg/kg bid.”
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: anticipated anti-ovulatory and anti-implantation effects shown in animal models; no off-target or safety pharmacology signals
“E4 had the anticipated pharmacological effects of inhibiting ovulation and preventing implantation in animal models.”
Flexibilityopen answer page →
Flexibility accepted
OtherAcceptedBeyond the letter
No new nonclinical program for drospirenone; relies on FDA's previous findings of safety for the listed drug YAZ
Why: Adequate scientific bridge to the listed drug YAZ established · Class precedent
“The Applicant refers to the Agency’s previous findings of safety for the nonclinical pharmacology, pharmacokinetics, and toxicology of the DRSP component of the approved product YAZ® (NDA 021676, approved March 16, 2006) to support the nonclinical safety of drospirenone in Nextstellis.”
“An adequate scientific bridge has been established to the Listed Drug YAZ®; therefore, the Applicant may rely on the nonclinical sections of the YAZ approved labeling to support Nextstellis labeling.”
GenotoxicityAcceptedBeyond the letter
Estetrol positive in Ames strain TA102; in vivo assays did not suggest genotoxicity
Why: In vivo studies do not suggest that E4 is a genotoxicant · Weight of evidence
“The genotoxicity testing of E4 was not straight-forward. In the first Ames test, E4 was positive, as increased revertants were seen in the TA102 strain.”
“Collectively, the in vivo studies do not suggest that E4 is a genotoxicant.”
Safety marginCriticised but acceptedBeyond the letter
Low toxicity margins for estetrol and drospirenone in the repeat-dose program
Why: Toxicities identified are clinically well known from other combined oral contraceptives · Class precedent · Human data
“Margins of toxicity are considered to be low, but they are acceptable, considering that the toxicities identified in the programme are clinically well-known from other COC products.”
Impurity or metaboliteAcceptedBeyond the letter
Estetrol metabolism not studied in monkey; no animal plasma data on the two major human glucuronide metabolites
Why: Glucuronides have low pharmacological activity and form via direct conjugation; no toxicological concern · Pharmacology or kinetics
“In vivo metabolic pathways have not been studied in monkeys. No data on the levels of the two major human metabolites in plasma, the E4-3- and E4-16-glucuronide, is thus available.”
“Since the two glucuronides have low pharmacological activity and glucuronidation and sulfation seem to be formed via direct reactions they are considered to be of no toxicological concern.”
Similar precedents
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