Nexletol
bempedoic acid
Species
MonkeyRat
Longest study
52 wk
Genotox
Conducted Conducted
Carcinogenicity
Conducted Conducted
Repro
Conducted Conducted
First dose
Not conducted Not stated publicly
Speciesopen answer page →
Species
Rat and monkey
“In conclusion, safety margins established from the 26-week rat and 52-week monkey studies support the proposed 180 mg/day dose of bempedoic acid”
Why that species
Rat and monkey most relevant species on PK grounds; monkey more predictive than rodents for PPARα-mediated effects
“From the pharmacokinetic point of view, the rats and monkeys were the most relevant species for non-clinical efficacy and safety studies.”
Surrogate molecule
No surrogate; the clinical compound was tested
“Bempedoic acid produced mild increases (up to 62%) in creatinine in both sexes treated at ≥20 mg/kg/day without any correlating histological kidney changes.”
Study lengthopen answer page →
Longest pivotal study
52 (52-week monkey)
“0 (vehicle), 6, 20 and 60 mg/kg/day, once daily for 52 weeks”
Pivotal GLP studies
26-week rat and 52-week monkey studies
“In conclusion, safety margins established from the 26-week rat and 52-week monkey studies support the proposed 180 mg/day dose of bempedoic acid”
Route in tox
Skipped studiesopen answer page →
Genotoxicity
Ames negative; chromosome aberrations in human lymphocytes only with S9 at cytotoxic concentration
“Bempedoic acid was not mutagenic in the Ames test. Increases in chromosome aberration were observed in human peripheral blood lymphocytes in vitro, but only in the presence of S9 and at a concentration associated with a level of cytotoxicity that approached or exceeded the maximum permissible.”
Carcinogenicity
2-year rat: hepatocellular, thyroid follicular and pancreatic islet cell tumors in males at 30 mg/kg/day
“In the 2-year rat carcinogenicity study, the incidences of hepatocellular adenomas, hepatocellular adenomas combined with carcinomas, thyroid follicular cell adenomas, follicular cell adenomas combined with carcinomas, and pancreas islet cell adenomas combined with carcinomas were statistical increased in male rats at 30 mg/kg/day.”
Reproductive & developmental
Rat fertility, EFD and PPND: adverse effects only at maternally toxic doses
“The low safety margins identified from fertility, embryo-fetal and pre-and postnatal development studies conducted in rat (Table 47) are considered acceptable, because the adverse effects were only observed at maternally toxic doses.”
Safety pharmacology
No adverse CNS, pulmonary or cardiovascular effects in safety pharmacology studies
“In safety pharmacology studies, bempedoic acid administration was not associated with adverse effects on CNS, pulmonary, or cardiovascular function.”
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 Nexletol 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 exposures <1x (26-week rat) and 13x (52-week monkey) human AUC at 180 mg/day (FDA integrated review, p. 72)
NOAEL / key findings
NOAEL exposures <1x (26-week rat) and 13x (52-week monkey) human AUC at 180 mg/day
“safety margins established from the 26-week rat and 52-week monkey studies support the proposed 180 mg/day dose of bempedoic acid and correspond to at least <1 and 13 times the clinical exposure at the human dose of 180 mg, respectively, based on AUC exposures at the nonclinical no observed adverse effect levels (NOAELs).”
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
Highest concentrations in liver, kidney and lung; no retention in melanin-containing tissue
“The highest concentrations were found in liver, kidney and lung and contents of the GI tract. The liver is the main target organ of toxicity in rats (see section 4.2). There was no retention in melanin-containing tissue.”
Modality-specific risk
Hypoglycemia and lactic acidosis deaths at high doses; synergistic toxicity with atorvastatin; rodent PPARα liver effects
“Safety issues identified in animals included unexpected mortalities secondary to hypoglycemia (in rats and monkeys) and lactic acidosis (in rats) as well as synergistic toxicologic interaction between bempedoic acid and atorvastatin in monkeys.”