Dojolvi
triheptanoin
Species
RatPig
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
Minipig (GLP); published rat dietary study
“A 9-month repeat dose oral toxicity study in juvenile minipigs was submitted in support of the safety of long-term administration of triheptanoin in adult and pediatric patients. In addition, a published 9-month dietary toxicity study of triheptanoin in rats was submitted in support of the safety in rodents.”
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
“The chronic (9-month) dietary toxicity of triheptanoin was assessed in juvenile male and female minipigs (the equivalent human age of >2 years) at doses of 10%, 30%, or 50% DCI following dosing (study UX007-PC002).”
Species: general tox
Juvenile minipig (9-month GLP); published 9-month rat dietary study
“A 9-month repeat dose oral toxicity study in juvenile minipigs was submitted in support of the safety of long-term administration of triheptanoin in adult and pediatric patients. In addition, a published 9-month dietary toxicity study of triheptanoin in rats was submitted in support of the safety in rodents.”
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“reproductive toxicity studies in rats (fertility and early embryonic development study, embryofetal development study, and pre- and postnatal development study) and rabbits (an embryofetal development study) was submitted in the NDA”
Species: carcinogenicity
Not conducted
“Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug.”
Surrogate used in
No surrogate used; triheptanoin itself tested
“Triheptanoin was well tolerated without any treatment-related toxicity or deaths.”
Study lengthopen answer page →
Longest pivotal study
39 (9-month juvenile minipig)
“The no observed adverse effect level (NOAEL) for daily administration of triheptanoin for 9 months in minipigs was 50% DCI.”
Pivotal GLP studies
9-month GLP dietary study in juvenile minipigs with 3-month interim sacrifice and 4-week recovery
“In the dietary administration of UX007 to male and female juvenile minipigs at doses of 0%, 10%, 30%, or 50% DCI for 9 months with a 4-week recovery and a 3-month interim sacrifice”
Route in tox
Oral (dietary admixture)
“In the dietary administration of UX007 to male and female juvenile minipigs at doses of 0%, 10%, 30%, or 50% DCI for 9 months”
Skipped studiesopen answer page →
Genotoxicity
Negative in Ames, in vitro chromosome aberration (human lymphocytes) and in vivo rat micronucleus assays
“Triheptanoin was not mutagenic in the Ames assay up to 4800 µg/plate, did not induce chromosomal aberration in vitro in human peripheral blood lymphocytes up to 409 µg/ml, and it was negative in the in vivo rat micronucleus assay at up to 2000 mg/kg/day.”
Carcinogenicity
Not conducted
“Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug.”
Reproductive & developmental
Rat and rabbit EFD: increased skeletal malformations and decreased litter weights at high dietary doses
“Administration of dietary triheptanoin to pregnant rats at doses approximately 2 times above, and pregnant rabbits approximately equal to the targeted clinical dose of 35% DCI resulted in increased incidence of skeletal malformations and decreased litter weights in both species and reduced number of viable litters in rabbits.”
Safety pharmacology
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.
Genotox: Ames
Negative (up to 4800 µg/plate)
“Triheptanoin was not mutagenic in the Ames assay up to 4800 µg/plate”
Genotox: in vitro mammalian
Chromosomal aberration in human peripheral blood lymphocytes: negative (up to 409 µg/ml)
“did not induce chromosomal aberration in vitro in human peripheral blood lymphocytes up to 409 µg/ml”
Genotox: in vivo
Rat micronucleus: negative (up to 2000 mg/kg/day)
“it was negative in the in vivo rat micronucleus assay at up to 2000 mg/kg/day”
Carcinogenicity model
Not conducted
“Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug.”
Carcinogenicity timing
No carcinogenicity studies conducted
“Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug.”
hERG / QT
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 doseopen answer page →
First-in-human starting dose
Not stated in public reviews
Why it's blank
The public FDA and EMA reviews of Dojolvi 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: Minipig NOAEL 50% DCI, the highest dose tested; no target organs (FDA integrated review, p. 82)
NOAEL / key findings
Minipig NOAEL 50% DCI, the highest dose tested; no target organs
“The NOAEL for systemic toxicity was the highest administered dose of 50% DCI in minipigs.”
Risksopen answer page →
Immune & cytokine safety
Not a dermal sensitizer in guinea pigs
“Triheptanoin was not a dermal sensitizing agent in male albino guinea pigs.”
Biodistribution & persistence
Dose-related exposure to heptanoate and C5 ketone metabolites without accumulation over 9 months in minipigs
“The dose-related increase in the primary metabolites (heptanoic acid and C5 ketone bodies) showed systemic exposure to UX007, but no accumulation after 9 months of treatment.”
Modality-specific risk
Possible rodent intestinal tumorigenicity; taste-aversion-driven developmental effects
“The proliferative changes observed in the rat intestine may suggest that oral administration of triheptanoin has a potential for causing tumors in rodents.”
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.
Label warnings
- Feeding Tube Dysfunction
- Intestinal Malabsorption in Patients with Pancreatic Insufficiency
Gastrointestinal
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 Dojolvi 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: Minipig NOAEL 50% DCI, the highest dose tested; no target organs (FDA integrated review, p. 82)
Longest repeat-dose systemic studies
Longest repeat-dose study and recovery
9-month (39-week) dietary juvenile minipig study with 4-week recovery; a published 9-month rat dietary study also submitted
“In the dietary administration of UX007 to male and female juvenile minipigs at doses of 0%, 10%, 30%, or 50% DCI for 9 months with a 4-week recovery and a 3-month interim sacrifice”
Pivotal GLP studies
9-month GLP dietary study in juvenile minipigs with 3-month interim sacrifice and 4-week recovery
“In the dietary administration of UX007 to male and female juvenile minipigs at doses of 0%, 10%, 30%, or 50% DCI for 9 months with a 4-week recovery and a 3-month interim sacrifice”
DART package
Species: DART
Rat (fertility, EFD, pre/postnatal) and rabbit (EFD)
“reproductive toxicity studies in rats (fertility and early embryonic development study, embryofetal development study, and pre- and postnatal development study) and rabbits (an embryofetal development study) was submitted in the NDA”
Reproductive & developmental
Rat and rabbit EFD: increased skeletal malformations and decreased litter weights at high dietary doses
“Administration of dietary triheptanoin to pregnant rats at doses approximately 2 times above, and pregnant rabbits approximately equal to the targeted clinical dose of 35% DCI resulted in increased incidence of skeletal malformations and decreased litter weights in both species and reduced number of viable litters in rabbits.”
PPND / ePPND: when
PPND in rat completed before the marketing application
“In the pre- and postnatal development study, the effects of oral dietary administration of triheptanoin (10%, 30%, and 50% DCI) to female rats and their offspring were studied.”
Carcinogenicity
Species: carcinogenicity
Not conducted
“Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug.”
Carcinogenicity model
Not conducted
“Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug.”
Carcinogenicity timing
No carcinogenicity studies conducted
“Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug.”
Safety marginopen answer page →
Safety margin at NOAEL
Minipig NOAEL ~4x human heptanoate AUC at 1.25 g/kg/day (30% DCI)
“The safety margin for clinical dose is approximately 4X, and is based on the area under the concentration time curve (AUC) of heptanoate at the NOAEL in the minipig study and the mean AUC in the clinical study (UX007-CL101) at a dose of 1.25 g/kg/day or 30% DCI.”
NOAEL / key findings
Minipig NOAEL 50% DCI, the highest dose tested; no target organs
“The NOAEL for systemic toxicity was the highest administered dose of 50% DCI in minipigs.”
Efficacy evidenceopen answer page →
Efficacy evidence
Published studies: VLCAD-/- knockout mice fed triheptanoin diet (cardiac function), plus GLUT-1 KO and seizure mouse models
“were compared in wildtype mice and in very long-chain acyl-CoA dehydrogenase deficient (VLCAD-/-) or KO mice”
Why that model
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.
Reviewer's view of the efficacy data
KO mouse pathology may not predict clinical VLCAD deficiency; triheptanoin stabilized but did not significantly improve cardiac function
“Thus, the progressive pathology observed in KO mice fed long-chain triglyceride and MCT diet may not be predictive of the clinical VLCAD enzyme deficiency. Although triheptanoin diet did not significantly improve cardiac function in mice”
Flexibilityopen answer page →
Flexibility accepted
OtherAcceptedBeyond the letter
No nonclinical toxicology studies submitted to the IND; only published pharmacology studies
Why: Prior agreement with FDA
“As per previous agreements, no nonclinical toxicology studies were submitted in the IND (IND 117053). Only published pharmacology studies were submitted in the IND.”
GLPQuestioned
Chronic rat toxicity data came only from a published non-GLP dietary study with limited histopathology
“This was not a good laboratory practice (GLP)-compliant toxicology study, and only a limited number of tissues were examined histologically. The proliferative changes observed in the rat intestine may suggest that oral administration of triheptanoin has a potential for causing tumors in rodents.”
CarcinogenicityVerdict not stated
No carcinogenicity studies for a chronic, lifelong dietary therapy
“Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug.”
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