Triheptanoin

DOJOLVI is indicated as a source of calories and fatty acids for the treatment of adult and pediatric patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD). DOJOLVI is a medium-chain triglyceride indicated as a source of calories and fatty acids for the treatment of adult and pediatric patients with molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAOD).

Oral liquid: clear, colorless to light yellow liquid supplied in a 500 mL bottle containing 100% w/w of triheptanoin. Oral Liquid, 100% w/w of triheptanoin. ( 3 )

None. None.

5 WARNINGS AND PRECAUTIONS Feeding Tube Dysfunction : Regularly monitor the feeding tube to ensure proper functioning and integrity. ( 5.1 ) Intestinal Malabsorption in Patients with Pancreatic Insufficiency : Low or absent pancreatic enzymes may reduce absorption of DOJOLVI. Avoid administration of DOJOLVI in patients with pancreatic insufficiency. ( 5.2 )

5.1 Feeding Tube Dysfunction Feeding tube performance and functionality can degrade over time depending on usage and environmental conditions. In clinical trials, feeding tube dysfunction was reported in patients receiving triheptanoin. The contribution of DOJOLVI cannot be ruled out. Do not administer DOJOLVI in feeding tubes manufactured of polyvinyl chloride (PVC) [see Dosage and Administration (2.4 ] . Regularly monitor the feeding tube to ensure proper functioning and integrity.

5.2 Intestinal Malabsorption in Patients with Pancreatic Insufficiency Pancreatic enzymes hydrolyze triheptanoin and release heptanoate as medium-chain fatty acids in the small intestine. Low or absent pancreatic enzymes may result in reduced absorption of heptanoate subsequently leading to insufficient supplementation of medium-chain fatty acids. Avoid administration of DOJOLVI in patients with pancreatic insufficiency.

Pancreatic Lipase Inhibitors : Avoid co-administration due to potential for reduced clinical effect of DOJOLVI. ( 7.1 )

7.1 Pancreatic Lipase Inhibitors Co-administration of triheptanoin with a pancreatic lipase inhibitor (e.g., orlistat) may reduce exposure to the triheptanoin metabolite, heptanoate, and reduce the clinical effect of triheptanoin [see Clinical Pharmacology (12.3) ] . Avoid co-administration of DOJOLVI with pancreatic lipase inhibitors.

Most common adverse reactions are (≥10%): abdominal pain, diarrhea, vomiting, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ultragenyx Pharmaceutical Inc. at 1-888-756-8657 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety population included 79 patients with LC-FAOD exposed to DOJOLVI in two studies: one open-label 78-week study of DOJOLVI in 29 patients (Study 1) followed by an open-label extension study (Study 2). Twenty-four patients from Study 1 continued into Study 2. Patients ranged from 4 months to 63 years of age and the population was 52% male. Of the 79 patients, 87% were White, 5% were Black or African-American, 4% were Asian, and 4% other. The daily dosage of DOJOLVI ranged between 12% and 41% DCI (which corresponds to 0.7 g/kg/day to 6.0 g/kg/day for pediatric patients and 0.5 g/kg/day to 1.3 g/kg/day for adult patients) for a mean duration of 23 months. The most common adverse reactions to DOJOLVI reported in the pooled safety population of Study 1 and Study 2 were gastrointestinal (GI)-related, and included abdominal pain (abdominal discomfort, abdominal distension, abdominal pain, abdominal pain upper, GI pain) [60%], diarrhea [44%], vomiting [44%], and nausea [14%]. Gastrointestinal (GI) Adverse Reactions In Study 1 and Study 2, median time to onset of a first occurrence of a GI adverse reaction was 7.3 weeks. GI adverse reactions led to dose reductions in 35% and 12% of patients in Study 1 and Study 2, respectively. In Study 3, a 4-month double-blind randomized controlled study, commonly reported adverse reactions with triheptanoin were similar to those reported in Study 1 and Study 2.

8.1 Pregnancy Risk Summary There are no available data on triheptanoin use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies conducted in pregnant rats and rabbits administered triheptanoin during the period of organogenesis, the primary toxicological effect (reduced body weight gain) was considered to be specific to decreased food consumption related to taste aversion in animals, and therefore is not relevant to clinical use in the intended populations. There is a pregnancy safety study for DOJOLVI. If a patient becomes pregnant while receiving DOJOLVI, healthcare providers should report DOJOLVI exposure by calling Ultragenyx Pharmaceutical Inc. at 1-888-756-8657. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Embryofetal developmental studies have been conducted with triheptanoin in rats and rabbits following oral administration of 10% (3.2 g/kg), 30% (9.7 g/kg) and 50% (16 g/kg) DCI in rats and 10% (1.2 g/kg), 20% (2.3 g/kg) and 30% (3.5 g/kg) DCI in rabbits during the period of organogenesis. Reduced body weight gain, associated with decreased food consumption, was observed in pregnant rats and rabbits following administration of triheptanoin food mixture and was attributed to taste aversion. The NOAEL for this maternal toxicity (lack of body weight gain) was 10% DCI for both rats and rabbits. 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. The adverse effects on rat and rabbit embryofetal development were associated with the reduced body weight gain observed in pregnant animals. The NOAEL for embryofetal development toxicity was 30% and 20% DCI for rats and rabbits, respectively. In a pre- 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.

8.2 Lactation Risk Summary There are no data on the presence of triheptanoin or its metabolites in human or animal milk, the effects on the breastfed infant, or the effects on milk production. Medium-chain triglycerides and other fatty acids are normal components of breastmilk and the composition of breastmilk varies within feedings, over stages of lactation, and between mothers and populations due to maternal factors including genetics, environment, and diet. The developmental and health benefits of breastfeeding should be considered along with the clinical need for DOJOLVI and any potential adverse effect on the breastfed infant from DOJOLVI or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of DOJOLVI have been established in pediatric patients [see Adverse Reactions (6.1) , Clinical Studies (14) ].

8.5 Geriatric Use Clinical studies of DOJOLVI did not include patients 65 years of age and older to determine if they respond differently from younger adult patients.

Risk Summary There are no available data on triheptanoin use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies conducted in pregnant rats and rabbits administered triheptanoin during the period of organogenesis, the primary toxicological effect (reduced body weight gain) was considered to be specific to decreased food consumption related to taste aversion in animals, and therefore is not relevant to clinical use in the intended populations. There is a pregnancy safety study for DOJOLVI. If a patient becomes pregnant while receiving DOJOLVI, healthcare providers should report DOJOLVI exposure by calling Ultragenyx Pharmaceutical Inc. at 1-888-756-8657. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Embryofetal developmental studies have been conducted with triheptanoin in rats and rabbits following oral administration of 10% (3.2 g/kg), 30% (9.7 g/kg) and 50% (16 g/kg) DCI in rats and 10% (1.2 g/kg), 20% (2.3 g/kg) and 30% (3.5 g/kg) DCI in rabbits during the period of organogenesis. Reduced body weight gain, associated with decreased food consumption, was observed in pregnant rats and rabbits following administration of triheptanoin food mixture and was attributed to taste aversion. The NOAEL for this maternal toxicity (lack of body weight gain) was 10% DCI for both rats and rabbits. 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. The adverse effects on rat and rabbit embryofetal development were associated with the reduced body weight gain observed in pregnant animals. The NOAEL for embryofetal development toxicity was 30% and 20% DCI for rats and rabbits, respectively. In a pre- 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 safety and effectiveness of DOJOLVI have been established in pediatric patients [see Adverse Reactions (6.1) , Clinical Studies (14) ].

Clinical studies of DOJOLVI did not include patients 65 years of age and older to determine if they respond differently from younger adult patients.

DOJOLVI (triheptanoin) is a synthetic medium odd-chain (C7) triglyceride supplied as a colorless to light yellow clear oral liquid. The chemical name of triheptanoin is heptanoic acid, 1,1',1''-(1,2,3-propanetriyl) ester. The empirical formula is C 24 H 44 O 6 and its molecular weight is 428.6 g/mol. The chemical structure is: The caloric value of triheptanoin is 8.3 kcal/mL. The fat content is 0.96 g/mL. Chemical Structure

12.1 Mechanism of Action Triheptanoin is a medium-chain triglyceride consisting of three odd-chain 7-carbon length fatty acids (heptanoate) that provide a source of calories and fatty acids to bypass the long-chain FAOD enzyme deficiencies for energy production and replacement.

12.2 Pharmacodynamics No formal pharmacodynamic studies have been conducted with DOJOLVI.

12.3 Pharmacokinetics Following oral administration, triheptanoin is extensively hydrolyzed to heptanoate and glycerol by pancreatic lipases in the intestines. The exposure of triheptanoin in the human plasma is minimal. Pharmacokinetics of heptanoate exhibits high inter-patient variability. Heptanoate exposure increases greater than dose-proportional in the dose range between triheptanoin 0.3 and 0.4 g/kg. Absorption The pharmacokinetics of heptanoate in healthy adult subjects following an oral administration of DOJOLVI mixed with food are summarized in Table 1. Table 1: Summary of Pharmacokinetic Parameters of Heptanoate after Single and Multiple Oral Administration of DOJOLVI to Healthy Adults (N = 13) DOJOLVI Dose Mean (SD) C max (µmol/L) Mean (SD) AUC 0-8h (µmol*hr/L) Time to First Peak Concentration After oral administration of DOJOLVI, more than one peak concentration of heptanoate is observed. Median (range) (hours) Single Dose 0.3 g/kg 178.9 (145) 336.5 (223) 0.5 (0.4 to 1.0) 0.4 g/kg 259.1 (134) 569.1 (189) 0.8 (0.4 to 6.4) Multiple Doses 0.3 g/kg administered 4 times a day for 2 days (total daily dosage of 1.3 g/kg/day) 319.9 (164) 789.8 (346) 1.2 (0.0 to 2.4) Distribution The plasma protein binding of heptanoate is approximately 80% and is independent of total concentration. Elimination After a single dose of either 0.3 g/kg or 0.4 g/kg triheptanoin to healthy subjects, the mean apparent clearance (CL/F) of heptanoate was 6.05 and 4.31 L/hr/kg, respectively. Half-life (t 1/2 ) of heptanoate could not be determined due to multiple peak concentrations of heptanoate observed. Metabolism Heptanoate, formed by hydrolysis of triheptanoin, can be metabolized to beta-hydroxypentanoate (BHP) and beta-hydroxybutyrate (BHB) in the liver. Excretion After single or multiple repeat doses of triheptanoin to healthy subjects, triheptanoin and its metabolites were minimally excreted in urine. Drug Interaction Studies In Vitro Studies Heptanoate is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Heptanoate and BHP are not CYP substrates nor UGT substrates. Heptanoate increases the unbound fraction of valproic acid by approximately 2-fold.

Triheptanoin is a medium-chain triglyceride consisting of three odd-chain 7-carbon length fatty acids (heptanoate) that provide a source of calories and fatty acids to bypass the long-chain FAOD enzyme deficiencies for energy production and replacement.

No formal pharmacodynamic studies have been conducted with DOJOLVI.

Following oral administration, triheptanoin is extensively hydrolyzed to heptanoate and glycerol by pancreatic lipases in the intestines. The exposure of triheptanoin in the human plasma is minimal. Pharmacokinetics of heptanoate exhibits high inter-patient variability. Heptanoate exposure increases greater than dose-proportional in the dose range between triheptanoin 0.3 and 0.4 g/kg. Absorption The pharmacokinetics of heptanoate in healthy adult subjects following an oral administration of DOJOLVI mixed with food are summarized in Table 1. Table 1: Summary of Pharmacokinetic Parameters of Heptanoate after Single and Multiple Oral Administration of DOJOLVI to Healthy Adults (N = 13) DOJOLVI Dose Mean (SD) C max (µmol/L) Mean (SD) AUC 0-8h (µmol*hr/L) Time to First Peak Concentration After oral administration of DOJOLVI, more than one peak concentration of heptanoate is observed. Median (range) (hours) Single Dose 0.3 g/kg 178.9 (145) 336.5 (223) 0.5 (0.4 to 1.0) 0.4 g/kg 259.1 (134) 569.1 (189) 0.8 (0.4 to 6.4) Multiple Doses 0.3 g/kg administered 4 times a day for 2 days (total daily dosage of 1.3 g/kg/day) 319.9 (164) 789.8 (346) 1.2 (0.0 to 2.4) Distribution The plasma protein binding of heptanoate is approximately 80% and is independent of total concentration. Elimination After a single dose of either 0.3 g/kg or 0.4 g/kg triheptanoin to healthy subjects, the mean apparent clearance (CL/F) of heptanoate was 6.05 and 4.31 L/hr/kg, respectively. Half-life (t 1/2 ) of heptanoate could not be determined due to multiple peak concentrations of heptanoate observed. Metabolism Heptanoate, formed by hydrolysis of triheptanoin, can be metabolized to beta-hydroxypentanoate (BHP) and beta-hydroxybutyrate (BHB) in the liver. Excretion After single or multiple repeat doses of triheptanoin to healthy subjects, triheptanoin and its metabolites were minimally excreted in urine. Drug Interaction Studies In Vitro Studies Heptanoate is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Heptanoate and BHP are not CYP substrates nor UGT substrates. Heptanoate increases the unbound fraction of valproic acid by approximately 2-fold.

, Mutagenesis, Impairment of Fertility Carcinogenesis Nonclinical animal studies evaluating long-term administration of triheptanoin have not been conducted to assess the carcinogenic potential of the drug. In a published chronic 9-month dietary study conducted in rats, daily administration of triheptanoin at dose levels up to 1.14 g/kg was associated with atrophy or hyperplasia of the intestinal villa. In a chronic 9-month dietary study conducted in juvenile minipigs, treatment with triheptanoin at dose levels up to 10 g/kg was well tolerated with no changes in histopathology suggestive of any carcinogenic potential. Published studies with structurally similar triglycerides (i.e., MCTs) were also evaluated. In a 2-year dietary study of rats fed tricaprylin (C8 MCT) at dose levels up to 9.5 g/kg (approximately 1.2 times the anticipated maximum clinical dose), there were increased incidences of pancreatic and forestomach hyperplasia and adenomas but not carcinomas. Chronic administration of a diet containing approximately 17% MCT was not shown to promote effects on colon tumor incidence in an azomethane-induced colon tumorigenicity rat model. Mutagenesis Triheptanoin was not genotoxic in a battery of genotoxicity tests including the in vitro bacterial reverse mutation in S. typhimurium and E. coli , in vitro mammalian chromosomal aberration test in human peripheral blood lymphocytes and the in vivo mammalian erythrocyte micronucleus test in rat bone marrow. Impairment of Fertility Triheptanoin had no effect on fertility or any other parameters of mating performance in rats exposed to repeat dietary administration at dose levels equivalent to up to 50% daily caloric intake (16 g/kg) that resulted in systemic drug exposure (AUC) of heptanoate approximately equal to the maximum recommended human dose.

17 PATIENT COUNSELING INFORMATION Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Preparation and Administration Instruct the patient or caregiver: To read the Instructions for Use for appropriate preparation and administration instructions on oral versus feeding tube administration. Before administration, to mix DOJOLVI thoroughly into semi-solid food/liquid (oral) or medical food/formula (feeding tube) at mealtimes or with snacks. To not prepare or administer DOJOLVI using containers, oral syringes, or measuring cups made of polystyrene or polyvinyl chloride (PVC) plastics. That if a dose is missed, to take the next dose as soon as possible with subsequent doses taken at 3 to 4-hour intervals. Skip the missed dose if it will not be possible to take all doses in a day [see Dosage and Administration (2.2) ] . Storage Instruct the patient or caregiver to store DOJOLVI at room temperature in the bottle in which it was dispensed [see How Supplied/Storage and Handling (16) ] . Feeding Tube Dysfunction Advise the patient or caregiver to regularly monitor the feeding tube for proper functioning and integrity and report to the healthcare provider if any issues are identified [see Warnings and Precautions (5.1) ]. Intestinal Malabsorption in Patients with Pancreatic Insufficiency Inform the patient or caregiver that pancreatic insufficiency may reduce the clinical effect of DOJOLVI. Any known pancreatic insufficiency should be reported to the healthcare provider [see Warnings and Precautions (5.2) ]. Pregnancy Advise a patient who is exposed to DOJOLVI during pregnancy that there is a pregnancy safety study that monitors pregnancy outcomes. Encourage the patient to report the pregnancy to Ultragenyx Pharmaceutical Inc. at 1-888-756-8657 [see Use in Specific Populations (8.1) ] .

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) (see USP Controlled Room Temperature). Do not freeze. DOJOLVI can be used for up to 9 months after opening but not beyond the expiration date on the bottle. Do not dose or store using materials made of polystyrene or polyvinyl chloride (PVC) containers [see Dosage and Administration (2.4) ] . Pharmacist : Dispense only in glass or HDPE bottles.