The following is an excerpt from Effect of L1-79 on Core Symptoms of Autism Spectrum Disorder A Case Series.
The prevalence of autism spectrum disorder (ASD) has increased substantially since the 1990s and currently affects approximately 3.5 million individuals in the United States, although recent estimates suggest a leveling off (which may be attributable to changes in epidemiologic methods). The estimated cost of care is $2.4 million per individual during the lifetime, including education, special housing, medical care, and caregiver productivity loss. In the United States, no medications have been approved for the core symptoms of ASD, and only aripiprazole and risperidone are approved for the management of irritability or agitation. These agents have potentially serious adverse effects, including tardive dyskinesia and weight gain; the latter increases patients’ risk of metabolic syndrome and other metabolic
The core symptoms of ASD include communication difficulties; trouble understanding relationships; restricted and repetitive behavior, interests, or activities; and difficulties in social interactions. These impairments appear to be mediated by catecholaminergic neurotransmission in the sympathetic nervous system, limbic system, hypothalamus, and brainstem via nutrient-sensing mechanisms that reticulate throughout the central nervous system (CNS) to the cortex, basal ganglia, and other structures. The conversion of tyrosine to dihydroxyphenylalanine by tyrosine hydroxylase is the first and rate-limiting step in the biosynthesis of catecholamines, including dopamine, norepinephrine, and epinephrine. The tyrosine hydroxylase inhibitor L1-79, a racemic formulation of amethylparatyrosine, is currently under evaluation as a treatment for the core symptoms of ASD (NCT02947048). The L-isomer of amethylparatyrosine, metyrosine (Trademark: Demser® (Bausch Health, Bridgewater, New Jersey)), is approved for the management of patients with pheochromocytoma. Because metyrosine is an approved agent, and the US Food and Drug Administration 505(b)(2) guidance states that any stereoisomer of an approved agent can be considered to be the same agent, this investigator-initiated trial was predicated on using the D,L-isomer as an unapproved use of an approved agent. At approved doses of 1000 to 4000 mg/d, metyrosine is associated with sedation, gastrointestinal effects, tremor, and, at higher doses, trismus, extrapyramidal signs, and other motor disturbances. L1-79, which is administered at a fraction of the metyrosine dosage, is currently used in a polytherapeutic regimen under clinical development for the treatment of various tumor types (NCT03512756; Tyme Technologies Inc, New York, New York). Hyperpigmentation and rash were the most common drug-related adverse events observed with this polytherapy regimen that included L1-79; all adverse events in the trial were mild to moderate in intensity. No serious adverse events or deaths were attributed to study drug, and no adverse events led to discontinued use of the study drug.
In light of the tolerability of L1-79 when used in a polytherapeutic regimen in heavily pretreated patients with stage 4 cancer, we believed this agent would be tolerable to use in otherwise healthy individuals with ASD. Given the potential effects on ASD pathophysiology, we designed a prospective case series to examine the effects of low doses of L1-79 on ASD.
The full article can be accessed here: Effect of L1-79 on Core Symptoms of Autism Spectrum Disorder A Case Series