Aqneursa
levacetylleucine
Species
RatDog
Longest study
39 wk
Genotox
Conducted Conducted
Carcinogenicity
Not conducted Not conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and dog
“Repeat dose oral toxicity 26-week rat and 39-week dog study reviews included below are from PharmTox review by Dr. Miyun Tsai-Turton, dated December 16, 2021, conducted under the IND.”
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 was tested
“Levacetylleucine (0, 100, 200, and 600 mg/kg/day) administered by oral gavage in dogs in a 39-week toxicity study followed by a 4-week treatment-free period was without adverse effects with NOAEL of 600 mg/kg/day.”
Study lengthopen answer page →
Longest pivotal study
39 (39-week dog)
“Levacetylleucine (0, 100, 200, and 600 mg/kg/day) administered by oral gavage in dogs in a 39-week toxicity study followed by a 4-week treatment-free period was without adverse effects with NOAEL of 600 mg/kg/day.”
Pivotal GLP studies
26-week rat and 39-week dog oral gavage studies
“There were no toxicologically significant findings in the 26-week rat and 39-week dog oral gavage toxicology studies conducted with levacetylleucine.”
Route in tox
Oral gavage
“There were no toxicologically significant findings in the 26-week rat and 39-week dog oral gavage toxicology studies conducted with levacetylleucine.”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro human lymphocyte chromosome aberration and in vivo rat bone marrow assays
“Levacetylleucine was non-mutagenic in vitro (in bacterial cells) and non-clastogenic in vitro (in cultured human peripheral lymphocytes) and in vivo (in bone marrow cells of the CD rats).”
Carcinogenicity
Not conducted; postmarketing requirement
“We are requiring juvenile toxicity, fertility, and early embryonic development, pre- and postnatal development, and carcinogenicity studies to be conducted postapproval.”
Reproductive & developmental
Dose-ranging rat EFD: resorptions, post-implantation loss and skeletal malformations at 600 mg/kg/day
“In pregnant rats, increases in resorptions, post-implantation loss, and skeletal malformation were seen due to exposure to levacetylleucine at doses of 600 mg/kg/day and at the human-equivalent dose of 97 mg/kg/day.”
Safety pharmacology
hERG inhibition <30% at 525 µM; IC50 not determinable (solubility-limited)
“At the highest feasible concentration of 525μM, levacetylleucine inhibited hERG tail currents by less than 30%, therefore, half-maximal inhibitory concentration (IC50) could not be determined, as the concentration response curve was limited by solubility.”
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 Aqneursa 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: NOAEL exposure margins 2-3-fold in rats and 6-9-fold in dogs vs human AUC at MRHD (FDA integrated review, p. 88)
NOAEL / key findings
NOAEL exposure margins 2-3-fold in rats and 6-9-fold in dogs vs human AUC at MRHD
“Safety margins achieved at the no-observed-adverse-effect levels were 2- to 3-fold in rats and 6- to 9-fold in dogs compared to the steady-state AUCs in humans at the maximum recommended human dose (MRHD).”
Risksopen answer page →
Immune & cytokine safety
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.
Biodistribution & persistence
No distribution, milk or placental transfer studies conducted
“No studies of distribution, of excretion in milk and placental transfer with levacetylleucine have been carried out, as levacetylleucine is metabolized by deacetylation (a robust and ubiquitous mechanism), giving rise to a single metabolite, L-leucine, which is endogenously present in humans.”
Modality-specific risk
Embryo-fetal toxicity (malformations, embryo-fetal death)
“Embryofetal development toxicity, including malformations and embryofetal death, was observed based on dose-ranging embryofetal developmental toxicology studies that were conducted in rats and rabbits at 1.4- and 6-fold the MRHD based on body surface area.”