Novel Triglyceride Oil May Treat Huntington's

January 14, 2015

A French research team has identified a possible biomarker of Huntington's disease characterized by deficits in the mitochondrial energy production process. They have further shown that a novel synthetic triglyceride oil may be able to correct these deficits and may be a potential treatment of the condition.

"This treatment — known as triheptanoin — is targeting something that is different at the cellular level in Huntington's patients," senior researcher, Fanny Mochel, MD, Pitié-Salpêtrière University Hospital, Paris, France, commented to Medscape Medical News.

"We believe certain intermediates necessary in the energy production process are missing in Huntington's patients and this triglyceride compound replaces these intermediates, allowing normalization of the metabolism process in the brain."

The study was published online in Neurology on January 7.

Energy Profile

For this analysis, the researchers used MRI spectroscopy to analyze the energy profile before, during, and after the brain was visually stimulated in 9 people in the early stages of Huntington's disease and 13 people without the disease. In people without the disease, the brain's metabolism increased during visual stimulation, then returned to the normal level. In the patients with Huntington's, however, metabolism did not change during visual stimulation.

For the next part of the study, 10 patients with Huntington's were then treated with triheptanoin for 1 month, and the metabolism tests were repeated. Results showed that the metabolism increased with visual stimulation by about 10%, similar to the previous observations in healthy volunteers. Movement and motor skills also improved somewhat in the patients with Huntington's disease.

Dr Mochel holds a use patent for triheptanoin in Huntington's disease that has been licensed to the company Ultragenyx. The agent is also being studied in some other rare metabolic diseases.

Commenting on the study for Medscape Medical News, Edward Wild, MD, University College London, United Kingdom, said the research represented "an interesting and inventive approach" to drug development for Huntington's in that it has established "a potentially relevant metabolic difference between Huntington's patients and controls and then shows that treatment with a drug candidate is associated with a restoration of that difference towards control levels."

He explained that because the disease develops so slowly, it is difficult and very expensive to detect clinical effects of a potential new drug. "We really need ways to assess whether a drug is hitting its target and achieving a meaningful biological effect, before deciding whether to spend big money on full-scale clinical trials."

But he pointed out some caveats, namely that this was an open-label study, with patients aware of which treatment they were receiving. "This could influence both the functional MRI spectroscopy and clinical measures, so it's difficult to conclude anything firm about this treatment, other than a randomized, double-blinded trial would still be needed to assess both the treatment and the proposed biomarker," Dr Wild said.

Another limitation was that the treated and untreated groups did not appear to have been directly compared. "Comparing groups sets a higher hurdle, but an important one to clear before a treatment can be declared a success," Dr Wild noted. But he added: "I do look forward to hearing more about this treatment and means of assessing its effect."

Energy Deficiency

Dr Mochel explained to Medscape Medical News that she started to investigate energy deficiency as part of weight loss seen in Huntington's disease about 10 years ago. "There appears to be a metabolic dysfunction and the body tries to compensate so that the principal organs sacrifice energy to the brain. But the body is running in a constant state of energy deficiency," she said.

Dr Mochel believes that patients with Huntington's have a problem in generating adenosine triphosphate in the Krebs cycle. They found that patients with the disease had decreased circulating levels of certain amino acids, which could reflect their mitochondrial oxidation in order to provide two key intermediates for the Krebs cycle: acetyl-CoA and succinyl-CoA.

"Based on that, we used a synthetic triglyceride compound with specific properties not found in food which provides these key intermediates needed for the Krebs cycle."

The group first tested their hypothesis in muscle tissue in patients with Huntington's disease. "We measured the concentration of various metabolites in specific areas and identified the inorganic phosphate (Pi)/phosphocreatine (PCr) ratio as an outcome measure of brain metabolic dysfunction in patients with Huntington's. We found that in one third of patients the muscle shows energy deficiency, which was corrected with triheptanoin. In the current study we did the same thing in the brain using the visual cortex as our area of interest. So we have now shown that the proof of concept demonstrated previously in muscle is also happening in the brain."

She noted that in three patients who weren't fully adherent there was not a clear effect, but the other seven patients did show a response to triheptanoin.

In terms of clinical effects, the researchers report a decrease in the Unified Huntington's Disease Rating Scale motor score of patients treated with triheptanoin. "But we have to be very cautious here as this was not a randomized controlled trial and we may just be seeing a placebo effect," Dr Mochel stated.

"We believe this problem in the Krebs cycle is there in Huntington's patients right from the start in early life but that the body compensates, but as the patients age the body can no longer compensate adequately and symptoms appear," Dr Mochel said.

She explained that the novel property of the agent is that it contains an odd number (three) of carbon molecules. "This means it is broken down to two different metabolites which are both key intermediates of the Krebs cycle. This is very synergistic as it gives two different entry points into the Krebs cycle."

The researchers are now starting a randomized trial in which patients with Huntington's disease will receive triheptanoin or placebo for 6 months, after which all patients will receive the active drug for the following 6 months. Endpoints will include spectroscopy markers, clinical scores, and brain striatum atrophy measures.

The study was supported by Ipsen and the French National Institute of Health and Research. Ultragenyx Pharmaceutical Inc provided the investigational drug triheptanoin for the study. Dr Mochel holds a use patent for triheptanoin in Huntington's disease that has been licensed to the company Ultragenyx.

Neurology. Published online January 7, 2015. Abstract

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