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First-in-Human Trial Finds Ketone Formulation Safe in Angelman Syndrome

The treatment was well-tolerated in children with AS, positively affecting constipation, a common symptom of the condition.

Safety and possible efficacy were observed in the first-in-human trial of exogenous ketone formulation from trumarco™ Nutrition in individuals with Angelman syndrome (AS), the Foundation for Angelman Syndrome Therapeutics (FAST) recently announced.1 

A total of 13 patients with AS between the age of 4 and 11 years were included in the double-blind, placebo-controlled crossover trial. The study was conducted over a period of 16 weeks, with patients receiving both the nutritional formulation and the placebo formulation, followed by a washout period between each treatment arm.

Investigators found that the specialized ketone formulation was well-tolerated in participants over the short-term period and positively affected the common symptom of constipation. Measured by the Vineland Adaptive Behavior Scales, investigators observed early trends toward improvements in fine motor skills. In addition, patients recorded a decrease in delta power on electroencephalography and auditory event-related potentials, which may suggest an improvement in memory and cognition.

“This was the first clinical trial in this age range, and the baseline data collected has offered insights into outcome measures in many phase 1/2 trials planned or currently underway in Angelman syndrome,” Jessica Duis, MD, assistant professor of pediatrics at University of Colorado School of Medicine, said in a statement.1 “While more studies are needed, we are excited about the prospect of use of this formulation to improve the quality of life of individuals with Angelman syndrome, as it may offer the opportunity to safely liberalize very restrictive low carbohydrate diets to ensure the same benefit even with the introduction of preferred foods.”

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While the results demonstrated safety, due to the small study population and heterogenicity, investigators noted that efficacy will need to be further evaluated in a larger, long-term study of this patient population. The trial follows preclinical work that suggested an exogenous ketone improved motor development, seizure activity, and learning in a mouse model of AS. The ketone formulation used in the study was a combination of beta-hydroxybutyrate, 2 grams of carbohydrate, 1 gram of protein, and 9 grams of fat, in addition to minerals, per 100 kcal. Patients took the supplement orally as a food or beverage 3 times daily. 

Patients began the study with a 2-week baseline period, continuing their existing dietary regimen—the ketogenic diet, the low glycemic index diet, or the standard American diet (regular diet). This was followed by a 4-week intervention period where patients consumed either placebo of the nutritional formulation, while continuing their current diet, then by a 4-week washout period where patients continued their dietary regiment with no study regimens. The study concluded with another 4-week intervention period and an abbreviated 2-week washout period. Data were collected by investigators at baseline, intervention, and washout periods, and then recorded by the parent/caregiver on a daily basis via apps on a provided tablet. At the end of the trial, patients also had a follow-up phone call with study personnel. 

“The results from this early safety and tolerability study are promising for individuals living with Angelman syndrome,” Allyson Berent, DVM, DACVIM, chief science officer for FAST, said in a statement.1 “There is robust data showing the benefit of modified ketogenic diets positively impacting individuals with seizures and other neurodevelopmental delays, and finding a medical food that would manage the metabolic aspects of these symptoms, while not having to be on prohibitively restrictive diets, would dramatically improve the quality of life of those living with Angelman syndrome.”

In April 2021, FAST announced funding for the Emergency Care Consortium grant, which would establish a global emergency and urgent care hotline. Free of charge, the hotline is available 24 hours a day and 7 days a week for provider-to-provider consultations, free of charge, helping to manage urgent issues related to AS, namely seizures. The hotline was made available in July 2021.2

REFERENCES
1. FAST-funded nutritional trial shows safety and possible efficacy. News release. FAST. December 10, 2021. Accessed December 20, 2021. https://cureangelman.org/new-results-available-on-fast-funded-exogenous-ketone-trial
2. FAST funds emergency care consortium grant for seizure hotline. News release. FAST. April 26, 2021. Accessed December 20, 2021. https://cureangelman.org/emergency-care-consortium-grant-for-seizure-hotline