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10:43 PM

'Game-Changer': Former Diet Drug Used To Treat Rare Genetic Epilepsy Syndromes

Cook Children's leader in groundbreaking research

While most of us know Fenfluramine as one of two components in a notorious weight loss drug, researchers are finding it has remarkable potential for the treatment of rare genetic epilepsy syndromes.

Cook Children’s recently participated in multicenter studies of the drug in treatment of patients with Dravet syndrome and is currently enrolling patients in a study for Lennox Gastaut Syndrome.

The research trials sponsored by Zogenix focus on a low-dose, liquid solution of fenfluramine, which was previously used in “fen-phen” for obesity and ultimately taken off the market following evidence it was related to adverse effects on heart valves.

Dravet syndrome affects an estimated 20,000 patients in the United States. Dravet results in a severe epilepsy with seizures typically resistant to treatment with currently available therapies.

The trial found that fenfluramine reduced the frequency of convulsive seizures by a median 62.7 percent, compared with a 1.2 percent median reduction in patients taking placebo, meeting the main goal of the trial.

Dr. M. Scott Perry, medical director of Neurology and Director of the Genetic Epilepsy Clinic at Cook Children’s said, “This drug is a game-changer for patients suffering from Dravet Syndrome. Rarely do we get a treatment for epilepsy which reduces seizures so significantly, especially in an epilepsy syndrome that is this refractory to therapy. I can’t wait to see if the results are as remarkable for Lennox Gastaut Syndrome.”

Thus far, no significant cardiac valvulopathy or pulmonary hypertension has been noted in trials for epilepsy, possibly due to the lower dosing used in these trials.

Zogenix will now focus on submitting applications for a marketing approval of its drug in the U.S. and Europe in the fourth quarter of 2018.

Treating Glucose transporter type 1 deficiency syndrome (GLUT1DS)

Cook Children's hosts the only open-label investigator-sponsored trial (IST) available in the U.S., which allows access to triheptanoin, an experimental dietary supplement, free of charge to patients with clinically diagnosed GLUT1DS, not requiring genetically proven mutation for participation.

This trial, under the research leadership of Adrian Lacy, M.D., a neurologist, is open to any GLUT1 spectrum disorder patient above age 1 year, not obtaining satisfactory benefit or who are unable to continue with ketogenic diet therapy, have never been on a diet, and do not meet inclusion criteria for other available triheptanoin trials currently open to patients in the U.S. To date 14 patients have enrolled from throughout Texas and 10 other states. This trial remains open for participation for at least five years until FDA approval for prescribed use occurs.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a genetically inherited disorder that impairs metabolism in the brain, by causing impairment in transport of glucose from the blood into brain cells which require the sugar as their primary energy source.

Without a sufficient source of energy to fuel important cellular functions, regulatory activities and growth, individuals with classic features of GLUT1DS display varying degrees of global delay in early development, early-onset epilepsy with multiple seizure types, dystonia, and other chronic and paroxysmal disorders of movement.

While a significant portion of patients may develop microcephaly after initial normal head size at birth, there are no other syndromic features. Because of the complexity of the syndrome, and difficulty in making the diagnosis, this disease is considered very rare, with only a few hundred known patients worldwide. However, it is suspected there may be several thousand unidentified patients and conservative reports have estimated incidence at 1 in 90,000. Fortunately, Cook Children's has an answer.

Antiepileptic drugs are poorly effective for seizure control in most patients, and some are even known to be detrimental in GLUT1DS. Seizures are typically medically refractory and the ketogenic diet is most often the mainstay of treatment. A highly restrictive diet requiring drastic restriction of sugar (carbohydrates) and protein relying primarily on dietary fat for calories, the ketogenic diet forces the body to secrete molecules called ketones, which are used by cells in the brain to partially obtain energy to perform their functions. While the diet can be very effective in this condition, the restrictive nature makes it difficult to maintain in many patients.

Triheptanoin is a molecule which can be digested by the body like other dietary fat molecules, called triglycerides. However, unlike naturally occurring dietary trigylcerides, digestion of triheptanoin releases a unique molecule, which is absorbed by the digestive system, transported from the blood into cells in the brain, and metabolized to supply energy to the brain in the same manner as ketones but without requiring patients to endure the restrictive ketogenic diet.

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