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.”
Species: general tox
Rat (26-week) and monkey (52-week)
“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”
Species: DART
Rat and rabbit (embryo-fetal development)
“Bempedoic acid was not teratogenic when given orally at doses of 60 and 80 mg/kg/day, resulting in 11 and 12 times the systemic exposure in humans at the maximum recommended human dose (MRHD) of 180 mg to pregnant rats and rabbits, respectively.”
Species: carcinogenicity
Mouse and rat (2-year)
“The carcinogenic potential of bempedoic acid was evaluated in a 2-year study in mice and rats.”
Surrogate used in
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.
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.”
Genotox: Ames
Negative
“Bempedoic acid was negative for mutagenicity in an in vitro Ames assay and negative for clastogenicity in the vitro human lymphocyte chromosome aberration assay.”
Genotox: in vitro mammalian
Human lymphocyte chromosome aberration: clastogenic only with S9 at cytotoxic concentration; considered not biologically relevant
“Positive: Clastogenic response was observed with metabolic activation at the highest concentration tested (1,000 μg/mL). However, this response was considered not biologically relevant since 1,000 μg/mL concentration cytotoxic (relative mitotic index = 58%).”
Genotox: in vivo
Negative: mouse micronucleus and rat bone marrow micronucleus/liver comet
“Bempedoic acid was negative in both in vivo mouse micronucleus and in vivo rat bone marrow micronucleus/liver comet assay.”
Carcinogenicity model
2-year mouse and 2-year rat
“The carcinogenic potential of bempedoic acid was evaluated in a 2-year study in mice and rats.”
Carcinogenicity timing
2-year rat and mouse completed during development; reports required before clinical studies over 6 months
“the IND was put on Partial Clinical Hold on November 19, 2009, for clinical studies in excess of 6 months until draft repo1ts from completed 2-year rat and mouse carcinogenicity studies were submitted.”
hERG / QT
5.4% inhibition at 1000 μM; IC50 >1000 μM, ≥15x human Cmax at 180 mg
“A statistically significant 5.4% inhibition of the hERG current was noted at 1,000μM, the highest concentration tested. IC50 was not calculated but was estimated to be >1,000μM (345 μg/mL), at least 15 times the human Cmax at the clinical dose of 180 mg.”
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.”
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 (small molecule)
“Immunogenicity (for Biologics) Bioanalysis (Not applicable) Incidence (Not applicable)”
Label warnings
- Hyperuricemia
- Tendon Rupture
Metabolic & endocrineMusculoskeletal
US prescribing information, 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 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)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
52-week cynomolgus monkey (oral gavage); recovery phase not stated
“In the 52-week monkey toxicity study, histological change in liver was limited to periportal or diffuse vacuolation consistent with positive staining Oil Red O (lipids) at ≥20 mg/kg/day.”
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”
DART package
Species: DART
Rat and rabbit (embryo-fetal development)
“Bempedoic acid was not teratogenic when given orally at doses of 60 and 80 mg/kg/day, resulting in 11 and 12 times the systemic exposure in humans at the maximum recommended human dose (MRHD) of 180 mg to pregnant rats and rabbits, respectively.”
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.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In a rat pre- and postnatal development study, treatment with bempedoic acid was associated with adverse delivery outcomes, including increases in stillborn pup and reductions in numbers of live pups, pup survival, pup growth, and slight delays in learning and memory at ≥10 mg/kg/day (below the clinical exposure at human dose of 180 mg, based on AUC).”
Carcinogenicity
Species: carcinogenicity
Mouse and rat (2-year)
“The carcinogenic potential of bempedoic acid was evaluated in a 2-year study in mice and rats.”
Carcinogenicity model
2-year mouse and 2-year rat
“The carcinogenic potential of bempedoic acid was evaluated in a 2-year study in mice and rats.”
Carcinogenicity timing
2-year rat and mouse completed during development; reports required before clinical studies over 6 months
“the IND was put on Partial Clinical Hold on November 19, 2009, for clinical studies in excess of 6 months until draft repo1ts from completed 2-year rat and mouse carcinogenicity studies were submitted.”
Safety marginopen answer page →
Safety margin at NOAEL
26-week rat NOAEL <1x and 52-week monkey NOAEL 13x human AUC at 180 mg
“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).”
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).”
Efficacy evidenceopen answer page →
Efficacy evidence
LDLR+/- and LDLR-/- Yucatan miniature pigs (160 days): LDL-C lowered vs vehicle
“Long-term treatment (160 days) with bempedoic acid at 120 and 240 mg/kg resulted in significant decreases in LDL-C levels (54% to 63%) in LDLR+/- pigs; modest decreases (27% to 29%) in LDL-C were noted in LDLR-/- pigs as compared to vehicle control.”
Why that model
Rat and monkey most relevant species on pharmacokinetic grounds
“From the pharmacokinetic point of view, the rats and monkeys were the most relevant species for non-clinical efficacy and safety studies.”
Reviewer's view of the efficacy data
EMA: adequate evidence of ACL-dependent inhibition of cholesterol synthesis
“Overall, the primary pharmacodynamic studies provided adequate evidence that bempedoic acid mediates its effects on cholesterol metabolism via ACL-dependent inhibition of cholesterol synthesis.”
Flexibilityopen answer page →
Flexibility accepted
Safety marginAcceptedBeyond the letter
26-week rat NOAEL below clinical exposure (<1x AUC); 52-week monkey NOAEL 13x
Why: Rodent margin limited by rodent-specific PPAR-related effects; monkey more representative of human responses · Pharmacology or kinetics
“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 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).”
“The low safety margin in rodent studies is due to dose-limiting, rodent-specific PPARD-related effects that occurred at low multiples of clinical exposures. The monkey is considered more representative of the potential human responses than rodents for PPARD-mediated effects.”
Juvenile toxAcceptedBeyond the letter
Juvenile rat NOAEL at exposure below clinical exposure (no safety margin)
Why: Juvenile toxicity profile comparable to adult rats; findings were rodent-specific PPAR effects not relevant to humans · Pharmacology or kinetics · Weight of evidence
“The NOAEL is established as 10 mg/kg/day (at doses resulting in exposures below the clinical exposure, based on AUC) considering the absence of effect on growth and neurobehavior in juvenile rats treated at the high dose (10 mg/kg/day) tested.”
“However, the absence of a safety margin is not of clinical concern, because the toxicological profile of bempedoic acid in juvenile rats was comparable to that observed in adult rats.”
DARTAcceptedBeyond the letter
Low safety margins in rat fertility, embryo-fetal and pre- and postnatal development studies
Why: Adverse effects only at maternally toxic doses · Other reason
“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.”
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