Triheptanoin for Pyruvate Dehydrogenase Deficiency

Overseen By Danielle Black, MPH

Age: < 18

Sex: Any

Trial Phase: Phase 1

Sponsor: Jirair Krikor Bedoyan

Disqualifiers: Mcad, Liver disease, Alcohol, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

Duration: 24 months

6 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a medical research study to test a medication in patients with a disease called Pyruvate Dehydrogenase Complex (PDC) Deficiency. The medication is triheptanoin, which is currently FDA approved for the treatment of Long-Chain Fatty Acid Oxidation Disorders. Previous research suggests that triheptanoin may also be effective in the treatment PDC Deficiency. This study will investigate the safety and efficacy (how well it works) of triheptanoin in patients with PDC Deficiency.

Will I have to stop taking my current medications?

The trial requires a 30-day washout period (time without taking certain medications) if you are currently on any investigational drugs or therapies. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug Triheptanoin for Pyruvate Dehydrogenase Deficiency?

Triheptanoin has been shown to reduce the frequency and severity of muscle breakdown episodes in patients with long-chain fatty acid oxidation disorders and improve motor skills in other metabolic conditions, suggesting it may help with energy-related issues in Pyruvate Dehydrogenase Deficiency. ^{1 2 3 4 5}

How is the drug Triheptanoin unique in treating Pyruvate Dehydrogenase Deficiency?

Triheptanoin is unique because it provides an alternative energy source for the body by supplying medium-chain fatty acids, which can bypass the blocked metabolic pathway in Pyruvate Dehydrogenase Deficiency, unlike other treatments that may not address this specific energy deficit. ^{6 7 8 9 10}

Research Team

Jirair Bedoyan, MD, PhD

Principal Investigator

UPMC Children's Hospital of Pittsburgh

Eligibility Criteria

This trial is for children with a condition called Pyruvate Dehydrogenase Complex (PDC) Deficiency. Specific eligibility criteria are not provided, but typically participants must meet certain health standards and may be required to have a confirmed diagnosis of PDC Deficiency.

Inclusion Criteria

I am between 1 and 17 years old.

I have PDCD and a metabolic physician is overseeing my care.

I have not had gene therapy, organ, or bone-marrow transplants.

Exclusion Criteria

Use of alcohol or drugs of abuse

Pregnant, breastfeeding, or lactating females

I am not currently in a research study or haven't waited 30 days after one. I haven't had gene therapy or a transplant.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive triheptanoin added to their diet, administered at least 4 times per day, with a target dose of 1.2-3.9 g/kg body weight

24 months

10 visits (5 in-person at UPMC Children's Hospital of Pittsburgh, others can be remote)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Triheptanoin

Trial Overview The study is testing the safety and effectiveness of triheptanoin, a medication approved for Long-Chain Fatty Acid Oxidation Disorders, in treating PDC Deficiency in children.

Participant Groups

Group I: Triheptanoin Experimental Treatment 1 Intervention

Open label study

Triheptanoin is already approved in United States for the following indications:

Approved in United States as Dojolvi for:

• Long-chain fatty acid oxidation disorders (LC-FAOD)

Who Is Running the Clinical Trial?

Jirair Krikor Bedoyan

Lead Sponsor

Trials

1

Recruited

6+

Ultragenyx Pharmaceutical Inc

Industry Sponsor

Trials

94

Recruited

104,000+

Dr. Emil D. Kakkis

Ultragenyx Pharmaceutical Inc

Chief Executive Officer since 2010

MD/PhD in Biological Chemistry from UCLA

Dr. Eric Crombez

Ultragenyx Pharmaceutical Inc

Chief Medical Officer since 2023

MD from Wayne State University School of Medicine

Findings from Research

Triheptanoin (Dojolvi™) is a synthetic medium-chain triglyceride that received regulatory approval in June 2020 in the USA for treating long-chain fatty acid oxidation disorders (LC-FAOD) in both pediatric and adult patients.

This compound is being explored for its potential benefits in other metabolic disorders and conditions associated with energy deficiency, highlighting its versatility as an anaplerotic treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triheptanoin: First Approval. Shirley, M.[2021]

Triheptanoin treatment significantly reduced the frequency and severity of rhabdomyolysis episodes in a 6-year-old patient with early-onset LCHAD deficiency, decreasing episodes from 13 in 6 months to only 3 after starting the treatment.

Despite the improvement in rhabdomyolysis, triheptanoin did not alter the progression of retinopathy, indicating that while it is effective for certain symptoms, it may not address all complications of the disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful management of rhabdomyolysis with triheptanoin in a child with severe long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency. Kahraman, AB., Yildiz, Y., Gokmen-Ozel, H., et al.[2023]

Triheptanoin, a triglyceride derived from the odd-chain fatty acid heptanoate, has shown promise in treating various neurological and metabolic diseases by providing alternative energy sources when traditional pathways are impaired.

Clinical reports indicate that triheptanoin supplementation can be beneficial for conditions like GLUT1 deficiency epilepsy and long-chain fatty acid oxidation disorders, highlighting its potential as a therapeutic option in clinical nutrition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic potential of triheptanoin in metabolic and neurodegenerative diseases. Wehbe, Z., Tucci, S.[2021]

In a study involving 75 patients with long-chain fatty acid oxidation disorders (LC-FAOD), triheptanoin significantly reduced the annual rate of major clinical events (MCEs) from 1.76 to 0.96 events per year in patients who had previously been treated, and from 2.33 to 0.71 events per year in treatment-naïve patients, indicating its efficacy in managing the condition.

The safety profile of triheptanoin was consistent with previous studies, with most adverse events being mild to moderate, although there were serious adverse events in a few patients, none of which were directly related to the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study. Vockley, J., Burton, B., Berry, G., et al.[2021]

A child with severe Short Chain Enoyl Co-A Hydratase (SCEH) deficiency showed modest improvements in motor skills, attention, muscle bulk, and strength after 37 months of treatment with triheptanoin, an odd chain oil with anapleurotic properties.

The treatment was well-tolerated, with no significant adverse effects reported, suggesting that triheptanoin could be a safe and effective option for managing SCEH deficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency. Engelstad, K., Salazar, R., Koenigsberger, D., et al.[2022]

The study successfully produced a highly purified and functional form of the human dihydrolipoyl acetyltransferase (E2) component of the pyruvate dehydrogenase complex (PDC), demonstrating significant acetyltransferase activity and proper assembly into a pentagonal dodecahedron structure.

While the recombinant E2 enhanced regulatory enzyme activities, it only supported low overall PDC activity without the E3-binding protein (E3BP), indicating that E3BP is crucial for achieving high PDC activity and efficient channeling of reducing equivalents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Assembly and full functionality of recombinantly expressed dihydrolipoyl acetyltransferase component of the human pyruvate dehydrogenase complex. Yang, D., Song, J., Wagenknecht, T., et al.[2021]

A study of 22 participants with confirmed pyruvate dehydrogenase complex (PDHc) deficiency identified four distinct clinical groups, highlighting the diverse neurological impacts of the condition, including neonatal encephalopathy and Leigh syndrome.

Genetic analysis revealed that mutations in the PDHA1 gene were common, particularly in those with Leigh syndrome, while mutations in the PDHX gene were associated with non-progressive encephalopathy, suggesting different underlying mechanisms and potential for long-term survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. Barnerias, C., Saudubray, JM., Touati, G., et al.[2013]

An improved method for reconstituting the pyruvate dehydrogenase complex (PDC) shows that selective cleavage of the protein X component significantly reduces its activity, but adding a large excess of E3 can restore function, highlighting the importance of E3 in maintaining PDC activity.

The study reveals that the N-terminal region of protein X is crucial for E3 binding, and differences in interactions with various E3 sources can explain previous challenges in restoring PDC function after protein X cleavage.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reconstitution of mammalian pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes: analysis of protein X involvement and interaction of homologous and heterologous dihydrolipoamide dehydrogenases. Sanderson, SJ., Khan, SS., McCartney, RG., et al.[2019]

The pyruvate dehydrogenase multienzyme complex (PDC), crucial for converting pyruvate to acetyl-CoA, shows reduced activity in diabetes, which could impact energy metabolism.

Introducing an exogenous E2 subdomain to PDC can inhibit its inactivation by kinases, and specific amino acids (Ile229 and Phe231) in this subdomain are key to enhancing this protective effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heterologously expressed inner lipoyl domain of dihydrolipoyl acetyltransferase inhibits ATP-dependent inactivation of pyruvate dehydrogenase complex. Identification of important amino acid residues. Jackson, JC., Vinluan, CC., Dragland, CJ., et al.[2019]

This case report presents the anesthetic management of a patient with pyruvate dehydrogenase complex deficiency (PDCD), a rare X-linked disorder affecting glucose metabolism.

The patient was successfully managed with a combination of dexmedetomidine and ketamine while requiring spontaneous ventilation, highlighting a potential anesthetic approach for similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anesthesia management for ENT surgery in a child with X-linked pyruvate kinase deficiency. Hau, V., Bonilla-Velez, J., Low, D.[2021]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Triheptanoin: First Approval. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Successful management of rhabdomyolysis with triheptanoin in a child with severe long-chain 3-hydroxyacyl-coenzyme A dehydrogenase (LCHAD) deficiency. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Therapeutic potential of triheptanoin in metabolic and neurodegenerative diseases. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Effects of triheptanoin (UX007) in patients with long-chain fatty acid oxidation disorders: Results from an open-label, long-term extension study. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Exploring triheptanoin as treatment for short chain enoyl CoA hydratase deficiency. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Assembly and full functionality of recombinantly expressed dihydrolipoyl acetyltransferase component of the human pyruvate dehydrogenase complex. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Pyruvate dehydrogenase complex deficiency: four neurological phenotypes with differing pathogenesis. [2013]

8. England pubmed.ncbi.nlm.nih.gov

Reconstitution of mammalian pyruvate dehydrogenase and 2-oxoglutarate dehydrogenase complexes: analysis of protein X involvement and interaction of homologous and heterologous dihydrolipoamide dehydrogenases. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Heterologously expressed inner lipoyl domain of dihydrolipoyl acetyltransferase inhibits ATP-dependent inactivation of pyruvate dehydrogenase complex. Identification of important amino acid residues. [2019]

10. France pubmed.ncbi.nlm.nih.gov

Anesthesia management for ENT surgery in a child with X-linked pyruvate kinase deficiency. [2021]