32406
An Open Label and Double Blind Randomized Placebo Controlled Pilot Study of L1-79 [D,L Alpha-Methyl-Para-Tyrosine (DL-AMPT)] for the Treatment of the Core Symptoms of Autism Spectrum Disorder (ASD) in Adolescent and Young Adult Males
Catecholaminergic neurotransmitters play critical roles in many aspects of social, communication and emotional functions, ranging from regulating mood, anxiety, and pleasure to modulating attention, impulse control and response to sensory stimuli. Many of these functions are noted to overlap with behaviors affected in the Social-Communication Interaction (SCI) domain of ASD. L1-79 is a tyrosine hydroxylase inhibitor known to decrease catecholamine biosynthesis by inhibiting the conversion of tyrosine to dihydroxy-phenylalanine (DOPA), the rate limiting reaction in catecholamine synthesis
Objectives:
To determine if 100 or 200 mg of L1-79 given three times per day (TID) can improve deficits within the core symptom domains in adolescents and young adult males with ASD.
Methods:
Two cohorts of males between ages of 13 and 21, with a diagnosis of ASD confirmed by Autism Diagnostic Observation Scale-2 and Autism Diagnostic Interview-Revised were enrolled in either the 100 mg or 200 mg TID dose group. Five participants in each dose group received open label active drug for 28 days for additional safety testing utilizing EKG, urine and blood sampling. Another 15 and 16 subjects, respectively, were randomized in a 2:1 fashion to receive drug or placebo (PBO) for 28 days. Outcome measures included mean change from baseline to day 28 in the Clinical Global Impression of Severity (CGI-S), standard scores on the Vineland Adaptive Behavior Scale – 2 Socialization Domain (VABS-2-SD), Social responsiveness Scale – 2 (SRS-2), and Repetitive Behavior Scale - Revised (RBS-R). Mixed multiple repeated measures analyses were performed for measures that were taken at interim visits.
Results:
The study drug was well tolerated with no serious AEs or significant laboratory abnormalities. Although no results reached statistical significance for comparison against PBO, multiple assessment measures demonstrated improvements in aspects of social functioning for the 200 mg dose group. Mean changes comparing 200mg to PBO were as follows: CGI-S: -.8 vs. -.4, SRS-2 Social Motivation T-score: -10.6 vs. -3.8, VABS-2-SD: 7.6 vs. 1.5, respectively, SRS-2 Total: -7.7 vs -6.4, SRS-2 SCI: -7.6 vs -5.8, respectively. Additionally, trends of improvement in Repetitive Restrictive behaviors (RRBs) were noted in the SRS-2 RRB T-score (-7.6 vs -5.8) and the RBS-R Total Score (-18.1 vs -12.5) for 200mg vs PBO, respectively. Sameness behavior on the RBS-R was the largest contributor to improvement in the RBS-R (-4.7 vs -2.3, 200mg vs PBO, respectively).
Conclusions:
This small, 28-day pilot study of L1-79 demonstrated trends toward improvement in the core domains of SCI and RRB in ASD in adolescent and young adult males. Results suggest that modulation of catecholaminergic neurotransmitters in ASD may be a viable target for therapeutic intervention. A larger study in male and female adolescents and young adults with ASD is planned.