Sapropterin As a Treatment for Autistic Disorder: Results of A Randomized, Double-Blind, Placebo-Controlled Trial and An Open Label Extension

Background: Most studies of biological interventions for autism have focused on symptom reduction, emphasizing behaviors that are thought to be secondary to autism—e.g., self-injurious behavior, aggression, hyperactivity, and OCD components—as opposed to core features. Sapropterin, used to treat tetrahydrobiopterin (BH4)-responsive phenylketonuria, is of interest as a possible treatment of autism. Fernell et al. reported on a pilot study in 6 children ages 3-5 years with autism using 3 mg/kg/day for 3 months. In an open-label design, they found improved social functioning in all subjects. A subsequent report described a double-blind placebo-controlled crossover trial with 12 boys, ages 4-7. The investigators found only small, nonsignificant changes at both 3 and 6 months in total scores on the CARS, but post-hoc analyses revealed significant improvements in social interactions at 6 months. As noted, these and other studies suggested that sapropterin might ameliorate core symptoms of autism at least in younger subjects. However, the studies had notable limitations. We therefore conducted a double-blind study of sapropterin at higher dosage levels that are now feasible with the formulation currently available in the United States.

Objectives: The purpose of this study was to evaluate the efficacy of the approved formulation of sapropterin on the core symptoms of autism in young children.

Methods: This was a double-blind, placebo-controlled, 16-week trial followed by an open-label extension. In the placebo-controlled study, participants were 46 children (3-6 years old) with ASD. The primary outcome measure was the CGI-I Scale; secondary measures assessed social interactions, language, and odd behaviors, as well as side effects. Participants were randomized to 20 mg/kg/day of sapropterin or placebo. Behavioral and safety measures were collected at baseline, 8, and 16 weeks. In the open-label study, participants were 30 children who successfully completed the double-blind placebo-controlled arm of the study. Primary and secondary outcome measures were the same as those used in the placebo-controlled study.

Results: Participants were 83% male, 46% white, and an average age of 60 months; 76% received at least one concurrent complementary medication. At 16-weeks, the placebo (n=23) and sapropterin  (n=23) groups showed similar proportions with a CGI-I of 1 (Very Much Improved) (4.5% vs. 0.0%) and 2 (Much Improved) (9.1% vs. 25.0%). Compared to placebo, sapropterin subjects had significant improvement, with moderate effect sizes, in social interaction and expressive language. BH4 was well-tolerated with few side effects. Open-label data is still being collected.

Conclusions: At 16 week, the primary outcome measure of global clinical improvement was not different for active treatment vs. placebo; however, analyses of secondary measures yielded statistically significant differences suggesting that BH4 may enhance development in social interaction and in language in young individuals with an autism spectrum disorder and that it is generally well tolerated even at the relatively high dose used in this study. The open-label extension will help us to determine extended safety profiles as some children will have been on the medication for 8 months. It will also help us discern patterns of improvement and if they plateau with regard to change.