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.”
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.”
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”