Summary Basis of Decision for Dojolvi
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Dojolvi is located below.
Recent Activity for Dojolvi
SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.
The following table describes post-authorization activity for Dojolvi, a product which contains the medicinal ingredient triheptanoin. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the 
Management of Drug Submissions and Applications Guidance.
Updated: 2023-07-11
Drug Identification Number (DIN):
DIN 02512556 - 100% w/w triheptanoin, liquid, oral or enteral administration
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| Drug product (DIN 02512556) market notification | Not applicable | Date of first sale: 2021-04-01 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 242196 | 2020-07-28 | Issued NOC 2021-02-15 | NOC issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Dojolvi
Date SBD issued: 2021-05-03
The following information relates to the New Drug Submission for Dojolvi.
Triheptanoin
Drug Identification Number (DIN):
- DIN 02512556 - 100% w/w triheptanoin, liquid, oral or enteral administration
Ultragenyx Pharmaceutical Inc.
New Drug Submission Control Number: 242196
On February 15, 2021, Health Canada issued a Notice of Compliance to Ultragenyx Pharmaceutical Inc. for the drug product Dojolvi.
The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit‑harm-uncertainty profile of Dojolvi is favourable for use as a source of calories and fatty acids for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders.
1 What was approved?
Dojolvi, a medium-chain triglyceride, was authorized as a source of calories and fatty acids for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders.
Clinical studies of Dojolvi did not include sufficient numbers of patients aged 65 years and older to determine whether they respond to Dojolvi differently than younger patients.
Dojolvi is contraindicated in patients who are hypersensitive to this drug or to any component of the container.
Dojolvi was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Dojolvi (triheptanoin, 100% w/w) is presented as a liquid. The liquid does not contain any non-medicinal ingredients.
For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
Additional information may be found in the Dojolvi Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Dojolvi approved?
Health Canada considers that the benefit-harm-uncertainty profile of Dojolvi is favourable for use as a source of calories and fatty acids for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD).
Long-chain fatty acid oxidation disorders constitute a group of rare, life-threatening, autosomal recessive disorders caused by defects in the genes that encode mitochondrial enzymes involved in the conversion of long-chain fatty acids into energy. In patients with LC-FAOD, partial or incomplete oxidation of fatty acids leads to accumulation of potentially toxic fatty acid intermediates, reduced substrates for the tricarboxylic acid cycle (i.e., the citric acid cycle or the Krebs cycle), and impaired gluconeogenesis. During periods of increased energy demand (fasting, infection, or exercise), ketones are not produced effectively and glycogen stores in the liver are depleted. The resulting energy deficiency particularly affects the organs with high-energy requirements and the greatest reliance on fatty acid oxidation for energy (the heart, skeletal muscle, and liver), and leads to acute metabolic crises that present as rhabdomyolysis, hypoglycemia, or cardiomyopathy. These metabolic crises can occur precipitously and lead to hospitalizations or early death. Additionally, the chronic energy deficiency in skeletal muscles leads to muscle function impairment including exercise intolerance.
Newborn screening for LC-FAOD and the early initiation of treatment improve outcomes, but the rate of overall premature mortality, before 1 year of age, is around 50%, and as high as 60% to 90% in some LC-FAOD subtypes, when diagnosed symptomatically. The estimated prevalence in Canada is approximately 200 to 350 patients, with approximately 10 children born with LC-FAOD annually.
There are no approved therapies for the treatment of LC-FAOD in Canada. Standard management includes a low-fat and high-carbohydrate diet based on individual patient energy requirements, avoidance of fasting, and supplementation with medium-chain triglyceride formulations.
Triheptanoin, the medicinal ingredient in Dojolvi, is a medium-chain triglyceride consisting of three odd-chain seven-carbon (C7) fatty acids (heptanoates) that provide a source of odd-chain fatty acids to bypass the enzyme deficiencies in LC-FAOD for energy production and replacement.
The sponsor submitted data from three clinical studies to support the efficacy and safety of triheptanoin in patients with LC-FAOD: study CL201, study CL202, and a study by Gillingham and coauthors (2017) (hereafter referred to as the Gillingham study). Upon review, the Phase II, non-randomized, open-label, single-arm studies, CL201 and CL202, were considered inadequate to be used in the determination of the efficacy of triheptanoin. However, the safety data pooled from 79 patients from studies CL201 and CL202 contributed to the characterization of the safety profile of triheptanoin.
The Gillingham study was a Phase II, double-blind, randomized, controlled trial that compared the effects of food-grade triheptanoin (comparable with the medicinal ingredient in Dojolvi) to that of food-grade, purified trioctanoin (an eight-carbon [C8] medium-chain triglyceride) in patients with mild and stable LC-FAOD following 4 months of treatment. The study enrolled 32 patients aged 7 years and over (median 22.5 years; range 7 years to 64 years).
The primary outcomes of the study included changes in total energy expenditure, cardiac function by echocardiogram, exercise tolerance, and muscle phosphocreatine recovery (an indirect measure of adenosine triphosphate [ATP] synthesis in the muscle) following acute exercise.
Patients consumed approximately 16% of the daily caloric intake from triheptanoin and 14% from trioctanoin during the 4-month period (lower than the study dosage target of 20% of the daily caloric intake).
In both treatment groups, there was no measurable effect on total energy expenditure after 4 months, compared to baseline. The rate of phosphocreatine recovery after acute exercise did not differ between the groups. Patients in both groups had similar mean changes from baseline in left ventricular ejection fraction and wall mass on resting echocardiogram and similar maximal heart rates on treadmill ergometry.
Limitations of the Gillingham study were its short duration, the small number of patients enrolled (all of whom were clinically stable with non-severe disease), the lower dosage of triheptanoin than the proposed triheptanoin dosing, and the lack of prior dietary data for a comparison with the post-randomization dietary data. The study data did not show superiority of triheptanoin over other sources of medium-chain triglycerides. However, the data did demonstrate that triheptanoin is a source of calories and fatty acids that can be used instead of other sources of medium-chain triglycerides in patients with LC-FAOD, without inducing catabolism.
The safety profile of triheptanoin was characterized based on safety data derived from a pooled patient population of 79 patients with LC-FAOD from studies CL201 and CL202. During a mean period of 2.5 years, patients received a mean average daily dose of triheptanoin of 27% (range 8% to 50%) of the daily caloric intake.
In the pooled patient population, treatment-emergent adverse events included rhabdomyolysis (reported in 66% of patients), abdominal pain (60%), upper respiratory tract infection (54%), vomiting (44%), diarrhea (44%), viral upper respiratory tract infection (44%), and nausea (14%). The occurrences of rhabdomyolysis can be due to LC-FAOD, whereas upper respiratory tract infections are common in a pediatric population and may act as a trigger for catabolism, leading to rhabdomyolysis. Therefore, these events have an unclear relationship to triheptanoin.
Across the pooled patient population, the most common treatment-related treatment-emergent adverse events were diarrhea (reported in 34% of patients), abdominal pain (32%), vomiting (9%), and nausea (4%). These gastrointestinal adverse reactions were reported as severe in 1%, moderate in 22%, and mild in 77% of patients.
Four cases of serious adverse events (rhabdomyolysis, gastroenteritis, diverticulitis, and ileus, each reported for one patient [overall 4 patients; 5.1%]), were considered possibly related to triheptanoin by the investigator. In addition, the assessment of causality in these cases may have been confounded by alternative causes or by the underlying disease.
Other potential risks include feeding tube dysfunction with enteral administration of triheptanoin (triheptanoin may degrade polyvinyl chloride and dissolve polystyrene plastics upon contact, particularly if administered undiluted) and intestinal malabsorption in patients with pancreatic insufficiency.
There are no available data on triheptanoin use in pregnant women to evaluate risk of adverse maternal or fetal outcomes.
The studies (CL201 and CL202) did not have a control arm nor did they systematically collect data on adverse events during the retrospective pre-triheptanoin period. Consequently, the rates of adverse events observed in the pooled patient population are difficult to compare with those observed in patients receiving the current standard of care for LC-FAOD.
A Risk Management Plan (RMP) for Dojolvi was submitted by Ultragenyx Pharmaceutical Inc. to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.
The submitted inner and outer labels, package insert and Patient Medication Information section of the Dojolvi Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.
A review of the submitted brand name assessment, including testing for look-alike sound-alike attributes, was conducted and the proposed name Dojolvi was accepted.
Overall, the submitted data support the benefit of triheptanoin as a source of calories and fatty acids for the treatment of pediatric and adult patients with LC-FAOD. However, evidence to support superior efficacy of triheptanoin over the current standard of care with medium-chain triglycerides or evidence to support triheptanoin use to reduce the occurrence of major clinical events in patients with LC-FAOD is lacking. Based on the non-clinical data and clinical studies, Dojolvi has an acceptable safety profile. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Dojolvi Product Monograph to address the identified safety concerns.
This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non‑clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.
3 What steps led to the approval of Dojolvi?
The drug submission for Dojolvi underwent an expedited review process under the Priority Review Policy. The sponsor presented sufficient evidence to demonstrate a favourable benefit-risk profile of Dojolvi as a source of calories and fatty acids for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders, serious and life-threatening diseases for which no drug is presently marketed in Canada.
Submission Milestones: Dojolvi
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2020-02-13 |
| Request for priority status | |
| Filed | 2020-05-01 |
| Approval issued by Director, Bureau of Medical Sciences | 2020-06-04 |
| Submission filed | 2020-07-28 |
| Screening | |
| Screening Acceptance Letter issued | 2020-08-20 |
| Review | |
| Labelling Review complete | 2020-12-24 |
| Quality Evaluation complete | 2021-02-11 |
| Non-Clinical Evaluation complete | 2021-02-11 |
| Clinical/Medical Evaluation complete | 2021-02-11 |
| Review of Risk Management Plan complete | 2021-02-15 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate | 2021-02-15 |
The Canadian regulatory decision on the review of Dojolvi was based on a critical assessment of the data package submitted to Health Canada. The foreign review completed by the United States Food and Drug Administration (FDA) was used as an added reference.
For additional information about the drug submission process, refer to the Management of Drug Submissions and Applications Guidance.
4 What follow-up measures will the company take?
Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada.
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
Triheptanoin, the medicinal ingredient in Dojolvi, is a medium-chain triglyceride consisting of three odd-chain seven-carbon (C7) fatty acids (heptanoates) that provide a source of odd-chain fatty acids to bypass the enzyme deficiencies in the long-chain fatty acid oxidation disorders for energy production and replacement.
Following oral administration, triheptanoin is extensively hydrolyzed to heptanoate and glycerol by pancreatic lipases in the intestines. Consequently, the exposure of triheptanoin in the human plasma is minimal. Heptanoate can be metabolized to beta-hydroxypentanoate (BHP) and beta-hydroxybutyrate (BHB) in the liver. These ketone bodies may be released into the blood and taken up by other tissues to be further processed into acetyl coenzyme A (acetyl-CoA) and propionyl-CoA, which enter the citric acid cycle for energy production.
The pharmacokinetic parameters of triheptanoin were estimated based on a Phase I study in healthy adult subjects using a non-compartmental method.
The median time to maximum observed concentration (Tmax) values ranged from 0.67 hours to 1.4 hours for heptanoate following either single-dose or multiple-dose administrations of triheptanoin, with similar Tmax values for BHB and BHP.
Following oral administration of triheptanoin, multiple peak concentrations were observed for heptanoate, BHB, and BHP in the plasma of most subjects, which made it unfeasible to determine the half-life of triheptanoin metabolites. These findings suggest a complex kinetic nature of the hydrolysis of triheptanoin and the subsequent absorption of heptanoate in the gastrointestinal tract, which may be staged by a food-stimulated secretion of pancreatic lipases in the intestines.
After single-dose administration of triheptanoin, the increase in heptanoate exposure (as measured by the maximum observed plasma concentration [Cmax] and the area under the concentration-time curve [AUC]) was greater than dose proportional in the dose range between triheptanoin 0.3 g/kg and triheptanoin 0.4 g/kg. Apparent accumulations were observed for heptanoate and other triheptanoin metabolites after multiple-dose administration, which may be due to potential time-dependent changes in the clearance of metabolites and/or a diurnal variation caused by the time differences of the pharmacokinetic sampling between single-dose and multiple-dose administrations.
The plasma protein binding of heptanoate was found to be approximately 80% and independent of total concentration. Triheptanoin and its metabolites were minimally excreted in the urine. Due to a narrow dose range tested in the study, dose proportionality for the exposure of triheptanoin metabolites could not be evaluated appropriately.
The analysis of pharmacokinetic data from clinical trials in patients with long-chain fatty acid oxidation disorders was deemed inconclusive due to the sparse collection of samples and other confounding factors, such as dietary management and dose modification/titration, which affected the overall drug exposure throughout the clinical program and confounded the pharmacokinetic results.
Concomitant use of triheptanoin with pancreatic lipase inhibitors (e.g., orlistat) may reduce the systemic exposure of heptanoate and reduce the efficacy of triheptanoin. Therefore, coadministration of triheptanoin with pancreatic lipase inhibitors should be avoided.
For further details, please refer to the Dojolvi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The study by Gillingham and coauthors (Gillingham et al., 2017; hereafter referred to as the Gillingham study) provided data to support the use of Dojolvi (triheptanoin) as a source of calories and fatty acids for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD). It was designed as a proof-of-concept study and hence it was exploratory in nature.
The Gillingham study was a Phase II, double-blind, randomized, controlled trial that compared the effects of food-grade triheptanoin (a seven-carbon[C7] medium-chain triglyceride) to that of food-grade, purified trioctanoin (an eight-carbon [C8] medium-chain triglyceride) in patients with mild and stable LC-FAOD following 4 months of treatment. The study enrolled 32 patients aged 7 years and over (median 22.5 years; range 7 years to 64 years). The diagnosis was confirmed by review of medical records documenting at least one significant episode of rhabdomyolysis and at least two of the following diagnostic criteria: disease-specific elevations of acylcarnitines on a newborn blood spot or in plasma, low enzyme activity in cultured fibroblasts, or one or more known pathogenic mutations in the CPT2, ACADVL, HADHA, or HADHB genes.
The primary outcomes of the study included changes in total energy expenditure, cardiac function by echocardiogram, exercise tolerance, and muscle phosphocreatine recovery (an indirect measure of adenosine triphosphate [ATP] synthesis in the muscle) following acute exercise.
All patients completed the 4-month treatment protocol. No diet-specific information was collected in the medical records. About half of randomized patients completed per-protocol 3-day diet diaries (at the beginning, at week 8, and at the end of the trial). Based on the dietary data, patients consumed approximately 16% of the daily caloric intake from triheptanoin and 14% from trioctanoin during the 4-month period (lower than the study dosage target of 20% of the daily caloric intake).
In both treatment groups, there was no measurable effect on total energy expenditure after 4 months, compared to baseline.
The rate of phosphocreatine recovery after acute exercise did not differ between the groups.
After 4 months, patients in both groups had similar mean changes from baseline in left ventricular ejection fraction (LVEF) and wall mass on resting echocardiogram and similar maximal heart rates on treadmill ergometry. The clinical relevance of non-significant LVEF changes that were within normal range, in a population with normal cardiac function at baseline is unknown.
Secondary outcomes, including body composition, resting energy expenditure, in vivo fatty acid oxidation, and incidence of rhabdomyolysis were similar in both groups after 4 months of treatment.
No differences were observed between the groups in blood markers of metabolism including glucose, insulin, lactate, total serum ketones, acylcarnitines, and serum free fatty acid concentrations.
The limitations of the Gillingham study include short duration, small number of patients enrolled (all of whom were clinically stable with non-severe disease), lower dosage of triheptanoin than the proposed triheptanoin dosing, and lack of prior dietary data to compare with the post-randomization dietary data. Nevertheless, this was the only adequate and well-controlled trial submitted. The study data did not show superiority of triheptanoin over other sources of medium-chain triglycerides. However, the data did demonstrate that triheptanoin is a source of calories and fatty acids that can be used instead of other sources of medium-chain triglycerides in patients with LC-FAOD, without inducing catabolism.
Indication
The New Drug Submission for Dojolvi was filed by the sponsor with the following indication:
- Triheptanoin is indicated for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD).
Following review of the submitted data, Health Canada revised the proposed indication to define the use of Dojolvi as a source of calories and fatty acids for the intended patient population. Accordingly, Health Canada approved the following indication:
- Dojolvi is indicated as a source of calories and fatty acids for the treatment of adult and pediatric patients with long-chain fatty acid oxidation disorders (LC-FAOD).
For more information, refer to the Dojolvi Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The evaluation of the safety profile of triheptanoin was primarily based on safety data derived from a pooled patient population of 79 patients with LC-FAOD from studies CL201 and CL202.
Study CL201 was a Phase II, single-arm, open-label study in 29 patients with severe LC-FAOD. At enrollment, the median age of the patients was 5.3 years (range 10 months to 59 years). The mean duration of exposure to triheptanoin was 483 days, with a mean dose of 31% of the daily caloric intake (range 17% to 68%). Overall, 25 (86%) patients completed 24 weeks of treatment and 24 (83%) patients completed 78 weeks.
Study CL202 is an ongoing Phase II, single-arm, open-label, safety and efficacy extension study of triheptanoin (commercial grade) in 75 LC-FAOD patients. The study enrolled three cohorts of LC-FAOD patients: rollover patients (number of patients [n] = 24) from study CL201, triheptanoin-naïve patients who failed conventional therapy and had no prior exposure to triheptanoin (n = 20), and patients treated with triheptanoin in other prior clinical studies or treatment programs (n = 31). At enrollment, the median age of patients was 9.8 years (range 0.3 to 63 years). The mean duration of treatment at data cut-off was 26 months (range 0.1 to 41 months).
During a mean period of 2.5 years, the pooled 79 patients from studies CL201 and CL202 received a mean average daily dose of triheptanoin of 27% (range 8% to 50%) of the daily caloric intake.
In the pooled patient population, treatment-emergent adverse events included rhabdomyolysis (reported in 66% of patients), abdominal pain (60%), upper respiratory tract infection (54%), vomiting (44%), diarrhea (44%), viral upper respiratory tract infection (44%), and nausea (14%). The occurrences of rhabdomyolysis can be due to LC-FAOD, whereas upper respiratory tract infections are common in a pediatric population and may act as a trigger for catabolism, leading to rhabdomyolysis. Therefore, these events have an unclear relationship to triheptanoin.
Across the pooled patient population, the most common treatment-related treatment-emergent adverse events were diarrhea (reported in 34% of patients), abdominal pain (32%), vomiting (9%), and nausea (4%). These gastrointestinal adverse reactions were reported as severe in 1%, moderate in 22%, and mild in 77% of patients.
Four cases of serious adverse events (rhabdomyolysis, gastroenteritis, diverticulitis, and ileus, each reported for one patient [overall 4 patients; 5.1%]), were considered possibly related to triheptanoin by the investigator. In addition, the assessment of causality in these cases may have been confounded by alternative causes or by the underlying disease.
Treatment discontinuation due to treatment-emergent adverse events (myalgia, gastroesophageal reflux disease, pain, diarrhea, vomiting, and rhabdomyolysis) was reported in 5 (6%) patients. The cases of diarrhea, vomiting, and rhabdomyolysis were considered related to the treatment.
Dose reductions due to treatment-emergent adverse events occurred in 20 subjects (25%). Gastrointestinal adverse reactions, mostly abdominal pain and diarrhea, led to dose reductions in 10 (35%) patients in study CL201 and 9 (12%) patients in study CL202.
Dosing was interrupted due to treatment-emergent adverse events (mostly gastrointestinal drug reactions) in 16 patients (20%).
Other potential risks include feeding tube dysfunction with enteral administration of triheptanoin (triheptanoin may degrade polyvinyl chloride and dissolve polystyrene plastics upon contact, particularly if administered undiluted) and intestinal malabsorption in patients with pancreatic insufficiency.
There are no available data on triheptanoin use in pregnant women to evaluate risk of adverse maternal or fetal outcomes.
The studies did not have a control arm and did not systematically collect data on adverse events during the retrospective pre-triheptanoin period. Consequently, the rates of adverse events observed in the pooled patient population are difficult to compare with those observed in patients receiving the current standard of care for LC-FAOD.
Appropriate warnings and precautions are in place in the Dojolvi Product Monograph to address the identified safety concerns.
For more information, refer to the Dojolvi Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
The non-clinical data support the use of Dojolvi for the specified indication.
The medicinal ingredient in Dojolvi, triheptanoin, was well tolerated at the highest dose level tested in chronic 9-month dietary toxicity studies conducted in rats (with daily oral administration of triheptanoin at dose levels up to 1.14 g/kg) and juvenile minipigs (at doses up to 50% of the daily caloric intake [50% DCI]).
Triheptanoin was not genotoxic in a battery of in vitro and in vivo genotoxicity tests. A 2-year rat carcinogenicity study has not been conducted. Based on the submitted evidence from published studies, the lack of long-term carcinogenicity studies was considered acceptable.
In embryo-fetal development studies conducted in pregnant animals during the period of organogenesis, oral administration of triheptanoin food admixture at dose levels of ≥30% DCI (in rats) and ≥20% DCI (in rabbits) resulted in maternal toxicity that was manifested as reduced maternal body weight and lower corrected total weight gain. These adverse effects were attributed to a reduction in food consumption because of taste aversion to triheptanoin. Based on an increased incidence of skeletal malformations and reduced litter weights following oral administration of triheptanoin at higher dose levels (50% DCI in rats and 30% DCI in rabbits), the no-observed-adverse-effect level for developmental toxicity was 30% DCI in rats and 20% DCI in rabbits. The developmental toxicity was likely secondary to the maternal toxicity.
In a prenatal and postnatal developmental study in rats, reduced birthweights and delayed sexual maturation in pups were observed at 50% DCI and were considered secondary to the reductions in body weight gain in pregnant rats.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Dojolvi Product Monograph. In view of the intended use of Dojolvi, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.
For more information, refer to the Dojolvi Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Dojolvi has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).
Proposed limits of drug-related impurities are considered adequately qualified, i.e., within the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies.
The sites involved in production are compliant with Good Manufacturing Practices.
No raw materials of human or animal origin are used during the drug substance manufacturing process. The drug product does not contain any excipients.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| DOJOLVI | 02512556 | ULTRAGENYX PHARMACEUTICAL INC | TRIHEPTANOIN 100 % / W/W |