Ekterly
sebetralstat
Species
MonkeyRat
Longest study
26 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
“the Applicant characterized the toxicity profile of sebetralstat with general toxicity studies in dogs (up to 4 weeks), and rats and monkeys (4 weeks, 13 weeks, and long-term dosing at durations up to 6 months).”
Why that species
Pharmacological relevance: plasma kallikrein inhibited in monkey (IC50 5.07 nM) and rat (69.8 nM)
“Pharmacology studies sufficiently justified the choice of species for toxicology investigations. The monkey, mouse and rat turned out to be the most relevant species (IC50 of 5.07 nM, 13.9 nM and 69.8 nM respectively).”
Surrogate molecule
No surrogate; the clinical compound was tested
“In the 26-week study, daily oral gavage administration of 30, 100, or 300 mg/kg/day was clinically well tolerated, with no sebetralstat-related deaths.”
Species: general tox
Wistar Han rat and cynomolgus monkey (up to 26 weeks)
“To support the marketing authorisation, the applicant performed GLP-compliant repeat-dose studies in Crl:WI(Han) rats and in Cynomolgus NHP via oral route for up to 26 weeks.”
Species: DART
Rat and rabbit (full DART set)
“A full set of developmental and reproductive toxicity studies were performed in rats and rabbits.”
Species: carcinogenicity
Tg rasH2 mouse (26-week) and rat (104-week)
“A statement regarding carcinogenicity has been implemented in SmPC in section 5.3. to reflect the lack of carcinogenicity based on a 26-week study in rasH2-Tg transgenic mice and a 104-week study in rats.”
Surrogate used in
No surrogate used; rabbit (EFD species) not pharmacologically active against rabbit plasma kallikrein
“Regarding species selection, rabbits cannot be considered as pharmacologically active species since PD data showed IC50 values higher than 40,000 nM regarding inhibition of rabbit plasma kallikrein enzyme”
Study lengthopen answer page →
Longest pivotal study
26 (6-month rat and monkey)
“the Applicant characterized the toxicity profile of sebetralstat with general toxicity studies in dogs (up to 4 weeks), and rats and monkeys (4 weeks, 13 weeks, and long-term dosing at durations up to 6 months).”
Pivotal GLP studies
Oral repeat-dose studies up to 26 weeks in Wistar Han rats and cynomolgus monkeys
“To support the marketing authorisation, the applicant performed GLP-compliant repeat-dose studies in Crl:WI(Han) rats and in Cynomolgus NHP via oral route for up to 26 weeks.”
Route in tox
Oral gavage (twice weekly in the 26-week monkey study)
“In the 26-week study, NHP were also administered sebetralstat by oral gavage 0, 50, 100, 200 and 300 mg/kg/dose sebetralstat, twice weekly (Mondays and Fridays).”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, mouse lymphoma and in vivo rat micronucleus assays
“Sebetralstat was not mutagenic or clastogenic in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro chromosomal aberration assay in mouse lymphoma cells, and in vivo rat micronucleus assay.”
Carcinogenicity
26-week rasH2 mouse and 104-week rat: no carcinogenicity
“A statement regarding carcinogenicity has been implemented in SmPC in section 5.3. to reflect the lack of carcinogenicity based on a 26-week study in rasH2-Tg transgenic mice and a 104-week study in rats.”
Reproductive & developmental
Rat EFD: cleft palate and interventricular septal defects at 60 times MRHD exposure
“In an embryo-fetal development (EFD) study in pregnant rats, administration of sebetralstat during the period of organogenesis caused increased incidence of malformations in offspring, specifically cleft palate and incomplete interventricular septum of the heart, at 60 times the exposure at the maximum recommended human dose (MRHD) of 1,200 mg sebetralstat.”
Safety pharmacology
hERG inhibition <30% at 30 µM; no heart rate, blood pressure or ECG/QTc effects in monkeys up to 300 mg/kg
“an in vitro study on hERG channels demonstrated the absence of inhibition > 30% of these channels at a concentration of 30 µM. This concentration allows a safety margin > 50. When NHP was exposed to doses up to 300 mg/kg, no effect was observed on heart rate, BP and ECG parameters, QTc prolongation and other waveform morphologies.”
Genotox: Ames
Negative
“Sebetralstat was negative for mutagenic or clastogenic potential in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro L5178Y gene mutation assay, and the in vivo micronucleus assay (bone marrow) in male and female Wistar Han rats.”
Genotox: in vitro mammalian
L5178Y mouse lymphoma gene mutation assay: negative
“Sebetralstat was negative for mutagenic or clastogenic potential in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro L5178Y gene mutation assay, and the in vivo micronucleus assay (bone marrow) in male and female Wistar Han rats.”
Genotox: in vivo
Rat bone marrow micronucleus: negative
“Sebetralstat was negative for mutagenic or clastogenic potential in the following assays: in vitro bacterial reverse mutation assay (Ames test), in vitro L5178Y gene mutation assay, and the in vivo micronucleus assay (bone marrow) in male and female Wistar Han rats.”
Carcinogenicity model
26-week Tg rasH2 mouse and 104-week rat; no carcinogenicity
“A statement regarding carcinogenicity has been implemented in SmPC in section 5.3. to reflect the lack of carcinogenicity based on a 26-week study in rasH2-Tg transgenic mice and a 104-week study in rats.”
Carcinogenicity timing
26-week rasH2 mouse completed; 2-year rat ongoing at approval (postmarketing requirement)
“While the NDA includes appropriate preapproval nonclinical and clinical pharmacology studies, a post-marketing requirement will be issued to complete an ongoing 2-year carcinogenicity study in rats receiving sebetralstat.”
hERG / QT
hERG inhibition <30% at 30 µM (margin >50); no ECG/QTc effects in monkeys up to 300 mg/kg
“With regard to the cardiovascular system, an in vitro study on hERG channels demonstrated the absence of inhibition > 30% of these channels at a concentration of 30 µM. This concentration allows a safety margin > 50. When NHP was exposed to doses up to 300 mg/kg, no effect was observed on heart rate, BP and ECG parameters, QTc prolongation and other waveform morphologies.”
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 Ekterly 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: 26-week rat NOAEL 300 mg/kg/day (highest dose); all findings non-adverse (EMA assessment report, p. 27)
NOAEL / key findings
26-week rat NOAEL 300 mg/kg/day (highest dose); all findings non-adverse
“Therefore, all findings in the 26-week study were considered non-adverse. Thus, the NOAEL was 300 mg/kg/day, the highest dose tested”
Risksopen answer page →
Immune & cytokine safety
Thymus microscopic findings in monkeys at 300 mg/kg/day and above
“Microscopic findings in adrenals, kidneys and thymus were also apparent at sebetralstat 500/300 or 300 mg/kg/day.”
Biodistribution & persistence
Limited placental transfer in rats (QWBA); moderate melanin binding
“The extent of placental transfer of total radioactivity was investigated in rats (study 187593) by QWBA where limited placental transfer was observed. Moreover, data suggest a moderate binding affinity of sebetralstat for melanin.”
Modality-specific risk
Hepatotoxicity, with liver the main target organ in monkeys
“In repeat-dose toxicity studies sebetralstat showed an intrinsic ability to induce hepatotoxicity. In NHPs, the liver was the main affected organ in 35-day daily dosing study”
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.
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 Ekterly 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: 26-week rat NOAEL 300 mg/kg/day (highest dose); all findings non-adverse (EMA assessment report, p. 27)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
26-week intermittent oral cynomolgus monkey study with 8-week recovery; 26-week daily rat study had no recovery group
“KVD900: A 26-Week Intermittent Oral (gavage) Administration Toxicity Study with an 8-Week Recovery Period in Non-Human Primates (Cynomolgus Monkeys)”
Pivotal GLP studies
Oral repeat-dose studies up to 26 weeks in Wistar Han rats and cynomolgus monkeys
“To support the marketing authorisation, the applicant performed GLP-compliant repeat-dose studies in Crl:WI(Han) rats and in Cynomolgus NHP via oral route for up to 26 weeks.”
DART package
Species: DART
Rat and rabbit (full DART set)
“A full set of developmental and reproductive toxicity studies were performed in rats and rabbits.”
Reproductive & developmental
Rat EFD: cleft palate and interventricular septal defects at 60 times MRHD exposure
“In an embryo-fetal development (EFD) study in pregnant rats, administration of sebetralstat during the period of organogenesis caused increased incidence of malformations in offspring, specifically cleft palate and incomplete interventricular septum of the heart, at 60 times the exposure at the maximum recommended human dose (MRHD) of 1,200 mg sebetralstat.”
PPND / ePPND: when
GLP PPND in rat completed before the marketing application
“In a GLP pre- and postnatal development study, Crl:WI(Han) pregnant female rats (20 animals/sex/group) received sebetralstat at daily oral doses 0, 100, 200, 450 mg/kg from GD 6 to Lactation Day 20.”
Carcinogenicity
Species: carcinogenicity
Tg rasH2 mouse (26-week) and rat (104-week)
“A statement regarding carcinogenicity has been implemented in SmPC in section 5.3. to reflect the lack of carcinogenicity based on a 26-week study in rasH2-Tg transgenic mice and a 104-week study in rats.”
Carcinogenicity model
26-week Tg rasH2 mouse and 104-week rat; no carcinogenicity
“A statement regarding carcinogenicity has been implemented in SmPC in section 5.3. to reflect the lack of carcinogenicity based on a 26-week study in rasH2-Tg transgenic mice and a 104-week study in rats.”
Carcinogenicity timing
26-week rasH2 mouse completed; 2-year rat ongoing at approval (postmarketing requirement)
“While the NDA includes appropriate preapproval nonclinical and clinical pharmacology studies, a post-marketing requirement will be issued to complete an ongoing 2-year carcinogenicity study in rats receiving sebetralstat.”
Safety marginopen answer page →
Safety margin at NOAEL
26-week monkey NOAEL (300 mg/kg biweekly) 1.20x human AUC; 26-week rat NOAEL 28.8x
“26-Week Oral Rat, Daily 300 983,000 28.8 26-Week Oral Monkey, Biweekly 300 42,400 1.20x”
NOAEL / key findings
26-week rat NOAEL 300 mg/kg/day (highest dose); all findings non-adverse
“Therefore, all findings in the 26-week study were considered non-adverse. Thus, the NOAEL was 300 mg/kg/day, the highest dose tested”
Efficacy evidenceopen answer page →
Efficacy evidence
Carrageenan-induced paw oedema in Sprague-Dawley rats (non-HAE acute inflammation model)
“No HAE-disease animal model has been established. Therefore, a carrageenan-induced paw edema study in Sprague-Dawley rats (a non-HAE disease model of acute inflammation) was used to evaluate the in vivo anti-inflammatory activity of sebetralstat.”
Why that model
No established animal model of HAE; carrageenan paw oedema used as surrogate for tissue swelling
“Since there is no established animal model of HAE, the CPE model was selected as a surrogate for tissue swelling in HAE attacks.”
Reviewer's view of the efficacy data
EMA: model shows target engagement only, not clinical efficacy; accepted given satisfactory clinical efficacy
“The laboratory clearly states that the objective of its studies is not to serve as a treatment model for a human disease, nor to reflect clinical efficacy or the treatment schedule but that the vivo model serves to demonstrate the pharmacological engagement of the target. Given the clinical efficacy in humans appears satisfactory, no other points are therefore raised”
Flexibilityopen answer page →
Flexibility accepted
CarcinogenicityAccepted with a conditionBeyond the letter
2-year rat carcinogenicity study still ongoing at approval; completion issued as a postmarketing requirement
“While the NDA includes appropriate preapproval nonclinical and clinical pharmacology studies, a post-marketing requirement will be issued to complete an ongoing 2-year carcinogenicity study in rats receiving sebetralstat.”
CarcinogenicityCriticised but accepted
Carcinogenicity high doses did not reach ICH S1 exposure ratios (50-fold rasH2 mouse, 25-fold rat)
Why: No significant increase in malignant tumours; high dose gives margin of 5.7 for malignant tumours · Within the guideline
“According to ICHS1, selection of high dose for carcinogenicity study should be based on a 50-fold exposure ratio (AUC) in TgrasH2 mice and 25-fold for the 2-year rat study. While the dose range chosen in the carcinogenicity studies performed can be acceptable, it cannot be excluded with absolute certainty a lack of carcinogenic potential, as the 50-fold and 25-fold exposure ratio are not met.”
“In the absence of significant increase in the incidence of any malignant tumours, the high dose can be used to calculate safety margins for malignant tumours formation. Safety margins of 5.7 would be obtained based on unbound AUC.”
Study lengthAccepted
Chronic nonrodent toxicity limited to 6 months in monkey
Why: ICH M3(R2): 6-month nonrodent studies acceptable for chronic intermittent treatments such as hereditary angioedema · Within the guideline
“Per ICH guidance for industry M3(R2) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (January 2010), toxicology studies of 6 months’ duration in nonrodents are considered acceptable for products developed as chronic intermittent treatments for indications such as hereditary angioedema.”
SpeciesAccepted
Rabbit used for embryo-fetal development although not a pharmacologically active species for sebetralstat
Why: ICH S5: acceptable since pharmacodynamic effect confirmed in the rat · Within the guideline
“Regarding species selection, rabbits cannot be considered as pharmacologically active species since PD data showed IC50 values higher than 40,000 nM regarding inhibition of rabbit plasma kallikrein enzyme (in other words, fold to human Ki was 12.3 and >6623 for rat and rabbit, respectively). However, according to ICH S5, this can still be accepted since PD effect was clearly confirmed in rats.”
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