Tripheptanoin (Doljovi®) is a recently approved drug used to treat inborn errors of metabolism, including long chain fatty acid oxidation disorder (LCFAOD). Approval of the drug caused quite a stir because it was the first medication to target LCFAOD at a biological level. The mainstay of LCFAOD treatment remains avoidance of fasting, as well as intake of medium-chain triglyceride (MCT) oil.
However, as is the case with all relatively new medications, patients (and physicians) tend to be jittery about long-term side effects because these are difficult to assess during the clinical trials leading to drug approval. We see the same fear of the unknown at work in people’s reluctance to be inoculated with the Covid-19 vaccines, fearing that some long-term side effects will develop years later, even though currently no shred of clinical evidence supports this view.
Read more about LCFAOD epidemiology
With any new medication, the first step is to gain approval from an established national authority. After that, drug manufacturers will want to encourage that the medication be used as widely as possible so that additional data can be generated, which in turn will generate even more data. Drug manufacturers can then decide whether they want to use the new data to refine their product further.
Because of the extremely stringent regulation of drug approval today, the chance that an unsafe drug will be released onto the market is virtually nil. (Yet, as the classic adage goes, “Never say never.”) It seems that psychologically, people feel more comfortable taking a drug if they see friends and family taking it, and a sort of normalization takes place gradually. However, at the same time, researchers will be busy studying the drug from various angles to validate, challenge, and improve it, and to see if it does what its manufacturers claim it can do.
Mitigating the Course of Disease
A team of Austrian researchers conducted a retrospective study in which they reviewed clinical outcomes and total hospitalization days per year before and after triheptanoin treatment was initiated. They examined the medical records of 12 Austrian patients with a diagnosis of LCFAOD and published their findings in the Orphanet Journal of Rare Diseases.
Here are a few key points regarding the methodology of the study:
- A total of 3 of the 12 patients received triheptanoin shortly after birth.
- The remaining 9 patients received triheptanoin at a mean of 8.1 months after birth.
- One patient discontinued treatment because of side effects.
- Among the other 11 patients, the mean duration of triheptanoin treatment was 5.3 years.
- Of the 12 patients, 10 received triheptanoin continuously.
Some of the results are impressive. After the initiation of triheptanoin treatment, the total number of hospitalization days per year decreased by 82.3%, from 27.1 to 4.8 days. In addition, the total number of hospitalization days decreased from 27.1 in the 1 year before treatment to 8.2 in the year after treatment, a decrease of 69.8%. “All patients were in good clinical condition, showing normal psychomotor development and no impairment in daily life activities,” wrote the authors.
These are astonishing results that confirm what the medical fraternity has long believed about triheptanoin—it dramatically mitigates the disease course and thus improves the quality of life of patients with LCFAOD. Evidence of a drastic reduction in the number of hospital stays bodes well for healthcare systems, which are increasingly struggling to cope with overwhelming numbers of patients.
LCFAOD is a challenging disease to treat. First, reaching a diagnosis is difficult because of the often nonspecific presentation. Secondly, “besides establishing an early diagnosis, the challenge in LCFAOD management is to determine the adequate amount of fat intake, maintain an anabolic state, and temper metabolic crises,” the authors wrote.
Changing the Game
Triheptanoin is touted as a medication that can potentially change the game by directly targeting the cells responsible for LCFAOD. It is certainly clinically promising, although challenges remain in quantifying its effects as a reliable biochemical marker.
Earlier, we mentioned that MCT oil is recommended for patients with LCFAOD. The US Food and Drug Administration has now recommended that MCT oil be replaced with triheptanoin, which would greatly simplify the treatment regime of patients with LCFAOD. However, this study indicates not only that the concurrent intake of MCT oil and triheptanoin is possible, but also that it is likely to be beneficial by lowering the required dose of triheptanoin, thus decreasing the gastrointestinal side effects.
Read more about LCFAOD prognosis
Because of the positive results achieved with triheptanoin, researchers were able to be less stringent about restricting long-chain fat intake, implementing restriction and carbohydrate-based caloric intake only in emergencies. This approach has led to surprising results. “In summary, we assume that together with the beneficial effects of triheptanoin, intake of enough fat leads to greater metabolic stability and better overall outcome,” the authors wrote.
From the data obtained from this study as well as many others, we can safely conclude that triheptanoin works exquisitely to reduce the disease burden of LCFAOD. Just how much of a breakthrough it is depends on much of the research that is currently ongoing. However, triheptanoin certainly seems to be on the right track in offering LCFAOD patients some semblance of a normal life—and that in itself is truly priceless.
Zöggeler T, Stock K, Jörg-Streller M, et al. Long-term experience with triheptanoin in 12 Austrian patients with long-chain fatty acid oxidation disorders. Orphanet J Rare Dis. Published online January 14, 2021. doi:10.1186/s13023-020-01635-x
Roe CR, Brunengraber H. Anaplerotic treatment of long-chain fat oxidation disorders with triheptanoin: review of 15 years experience. Mol Genet Metab. Published online October 24, 2015. doi:10.1016/j.ymgme.2015.10.005