Long Chain Fatty Acid Oxidation Disorder (LCFAOD)


Dojolvi® is the brand name for triheptanoin, a drug that bypasses the long-chain fatty acid oxidation disorder (LC-FAOD) enzyme deficiencies for energy production and replacement. It consists of 3 odd-chain 7-carbon length fatty acids (heptanoate) that provide a source of calories to affected patients. According to the US Food and Drug Administration (FDA), no formal pharmacodynamic studies were conducted with Dojolvi. The drug is extensively hydrolyzed to heptanoate and glycerol by pancreatic lipases in the intestines. Exposure to triheptanoin in human plasma is minimal. The pharmacokinetics of Dojolvi show high interpatient variability. Exposure to heptanoate increases more than dose-proportional in the dose range for Dojolvi of 0.3 to 0.4 g/kg. Before calculating the dose of Dojolvi, the metabolic requirements of the patient can be determined by daily caloric intake (DCI). Patients should discontinue other medium-chain triglyceride (MCT) products before initiation of Dojolvi. Dojolvi is administered with food, and the recommended dose is divided into 4 doses and is up to 35% of the total prescribed DCI of the patient. Neonatal patients with LC-FAOD may need a higher dose of Dojolvi with increased fat intake.1 

Safety Information and Side Effects

Dojolvi is the first and only prescription drug approved by the FDA for the treatment of patients with LC-FAOD. It should be taken under the supervision of specialists with clinical knowledge of diseases related to diet and nutrition, such as metabolic geneticists and dietitians. Healthcare professionals should start Dojolvi at a low dose and gradually increase the dosage to avoid side effects. Feeding tubes made of polyvinyl chloride (PVC) are contraindicated with Dojolvi, as they are made of a solid plastic material and Dojolvi may not work or may stop working over time with feeding tubes. Patients may have intestinal absorption problems as a possible side effect of pancreatic insufficiency. They may also experience diarrhea, abdominal pain, vomiting, and nausea. It is recommended that patients should stop taking other MCT products before taking Dojolvi. The prescribed dose of Dojolvi should be measured using a cup or oral syringe that is not made of PVC or polystyrene. Dojolvi can be taken using containers made of glass, stainless steel, polypropylene high-density polyethylene (HDPE), or low-density polyethylene (LDPE).2    

Get detailed prescribing information on the Dojolvi monograph page at MPR.

triheptanoin
In clinical trials, patients with long chain fatty acid oxidation disorders (lc-FAODs) treated with triheptanoin are less likely to develop hypoglycemia, cardiomyopathy, rhabdomyolysis, and hepatomegaly. Complications in lc-FAOD patients are reduced from approximately 60% to approximately 10% with the addition of triheptanoin. Triheptanoin was granted FDA approval on 30 June 2020.
Credit: PubChem

Pharmacology

Dojolvi is used as an anaplerotic compound because it acts as a source of calories and fatty acids to bypass deficiencies in the LC-FAOD enzyme. It is an MCT consisting of 3 odd-chain 7-carbon (heptanoate) fatty acids on a glycerol backbone. It is a synthetic drug that undergoes hydrolysis by pancreatic lipases upon oral administration and subsequently releases heptanoate molecules. Dojolvi dosing leads to multiple peak concentrations of heptanoate. It exhibits a high level of variability between patients and a transverse double mitochondrial membrane independent of the carnitine carrier or active transport system. Oxidation of heptanoate within the mitochondria yields an anaplerotic substrate, 1 molecule of propionyl-coenzyme A (CoA), and 2 molecules of acetyl-CoA. It is metabolized to 4-carbon (C4) and 5-carbon (C5) ketone bodies in the liver. Patients with LC-FAOD may experience pharmacological effects of Dojolvi, including improved cardiac function. Clinical studies show that Dojolvi is beneficial in improving brain energy metabolism, reducing the frequency of focal seizures, improving motor function, and increasing glucose tolerance and insulin sensitivity.3

Efficacy and Regulatory Insights

The efficacy of Dojolvi was evaluated in a 4-month, double-blind, randomized controlled study that evaluated Dojolvi as a source of calories and fatty acids. The randomized study compared Dojolvi (7-carbon chain fatty acids) to trioctanoin (8-carbon chain fatty acids) at a dose equivalent to 20% of DCI. The study enrolled 32 pediatric and adult patients with a confirmed diagnosis of LC-FAOD. It involved patients who experienced 1 significant episode of rhabdomyolysis with 2 of the following diagnostic criteria: 1 or more known pathogenic mutations in HADHB, HADHA, CPT2, or ACADVL, a disease-specific elevation of acylcarnitines on a newborn blood spot or in plasma, and low enzyme activity in cultured fibroblasts. Patients with LC-FAOD in the study ranged from 7 to 64 years of age; the median age was 24 years. The dosage for each drug in the study was titrated according to a protocol-specified target of 20% DCI. The actual mean daily dose achieved was 14% for trioctanoin and 16% for Dojolvi.4

How Dojolvi Works in Patients With LC-FAOD

The systemic absorption of Dojolvi is minimal because it is hydrolyzed extensively to glycerol and heptanoate by pancreatic lipases in the intestines upon oral administration. Heptanoate is metabolized by small- and medium-chain beta-oxidation enzymes, as it freely diffuses in the mitochondria. It can undergo 1 or 2 cycles of beta-oxidation, producing 1 unit of 3-carbon propionyl-CoA, 2 units of 2-carbon acetyl-CoA, or 1 unit each of 5-carbon pentanoyl-CoA and acetyl-CoA.  Acetyl-CoA can enter the citric acid cycle (TCA) to produce adenosine triphosphate (ATP), which can be utilized for the synthesis of C4 ketone bodies. Propionyl-CoA is metabolized to succinate and succinyl-CoA to support gluconeogenesis through increased ATP production by resupplying TCA cycle intermediates. It also supports mitochondrial energy production. In the liver, pentanoyl-CoA generates C5 ketone bodies, beta-ketopentanoate and beta-hydroxypentanoate, which serve as anaplerotic substrates that can be used by peripheral tissues in patients with LC-FAOD.5 

Patient Presentation and Treatment of LC-FAOD

Dojolvi, known as UX007 in clinical trials, was approved by the FDA for the treatment of patients with LC-FAOD. The treatment of LC-FAOD is based on the action of anaplerotic molecules that correct the secondary depletion of intermediates in the TCA cycle that occur in this disorder. According to previous studies, some patients aged 2 to 9 years presented with hepatomegaly before initiation of Dojolvi therapy. A 5-year-old patient presented with cardiomyopathy at the time of enrollment. Following initiation of Dojavi in patients with LC-FAOD, most showed marked improvement in endurance, strength, and activity. The patient with cardiomyopathy improved, and the hepatomegaly resolved for other patients. The family of a 2-year-old patient decided to discontinue Dojolvi and return to an MCT diet, which led to a subsequent recurrence of rhabdomyolysis episodes. Dojolvi treatment substantially increased 5C ketone bodies, beta-ketopentanoate and beta-hydroxypentanoate, and 4C ketone bodies, beta-hydroxybutyrate and acetoacetate, in patients with LC-FAOD.6

References

  1. Dojolvi (triheptanoin). Package insert. Ultragenyx Pharmaceutical Inc.; 2020. Accessed August 19, 2021.
  2. Dojolvi (triheptanoin) oral liquid: dosing guide. Ultragenyx Pharmaceutical Inc. Accessed August 19, 2021.
  3. Shirley M. Triheptanoin: first approval. Drugs. 2020;80(15):1595-1600. doi:10.1007/s40265-020-01399-5
  4. Zand D, Doan J, Yi S, et al. Regulatory news: Dojolvi (triheptanoin) as a source of calories and fatty acids in long-chain fatty acid oxidation disorders: FDA approval summary. J Inherit Metab Dis. 2021;44(3):515-517. doi:10.1002/jimd.12377
  5. Kim ES, Keam SJ. Triheptanoin in the management of long-chain fatty acid oxidation disorders: a profile of its use. Drugs Ther Perspect. 2021;37:187-193. doi:10.1007/s40267-021-00816-3
  6. Sklirou E, Alodaib AN, Dobrowolski SF, Mohsen AWA, Vockley J. Physiological perspectives on the use of triheptanoin as anaplerotic therapy for long chain fatty acid oxidation disorders. Front Genet. 2021;11:598760. doi:10.3389/fgene.2020.598760

Reviewed by Harshi Dhingra, MD, on 8/30/2021.