Low-dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial

Robert K Naviaux, Brooke Curtis, Kefeng Li, Jane C Naviaux, A Taylor Bright, Gail E Reiner, Marissa Westerfield, Suzanne Goh, William A Alaynick, Lin Wang, Edmund V Capparelli, Cynthia Adams, Ji Sun, Sonia Jain, Feng He, Deyna A Arellano, Lisa E Mash, Leanne Chukoskie, Alan Lincoln, Jeanne Townsend, Robert K Naviaux, Brooke Curtis, Kefeng Li, Jane C Naviaux, A Taylor Bright, Gail E Reiner, Marissa Westerfield, Suzanne Goh, William A Alaynick, Lin Wang, Edmund V Capparelli, Cynthia Adams, Ji Sun, Sonia Jain, Feng He, Deyna A Arellano, Lisa E Mash, Leanne Chukoskie, Alan Lincoln, Jeanne Townsend

Abstract

Objective: No drug is yet approved to treat the core symptoms of autism spectrum disorder (ASD). Low-dose suramin was effective in the maternal immune activation and Fragile X mouse models of ASD. The Suramin Autism Treatment-1 (SAT-1) trial was a double-blind, placebo-controlled, translational pilot study to examine the safety and activity of low-dose suramin in children with ASD.

Methods: Ten male subjects with ASD, ages 5-14 years, were matched by age, IQ, and autism severity into five pairs, then randomized to receive a single, intravenous infusion of suramin (20 mg/kg) or saline. The primary outcomes were ADOS-2 comparison scores and Expressive One-Word Picture Vocabulary Test (EOWPVT). Secondary outcomes were the aberrant behavior checklist, autism treatment evaluation checklist, repetitive behavior questionnaire, and clinical global impression questionnaire.

Results: Blood levels of suramin were 12 ± 1.5 μmol/L (mean ± SD) at 2 days and 1.5 ± 0.5 μmol/L after 6 weeks. The terminal half-life was 14.7 ± 0.7 days. A self-limited, asymptomatic rash was seen, but there were no serious adverse events. ADOS-2 comparison scores improved by -1.6 ± 0.55 points (n = 5; 95% CI = -2.3 to -0.9; Cohen's d = 2.9; P = 0.0028) in the suramin group and did not change in the placebo group. EOWPVT scores did not change. Secondary outcomes also showed improvements in language, social interaction, and decreased restricted or repetitive behaviors.

Interpretation: The safety and activity of low-dose suramin showed promise as a novel approach to treatment of ASD in this small study.

Figures

Figure 1
Figure 1
Trial profile.
Figure 2
Figure 2
Safety monitoring. (A) Free cortisol, (B) proteinuria, (C) creatinine, (D) hemoglobin, (E) white blood cells (WBC), (F) platelets, (G) aspartate aminotransferase (AST), (H) rash – antecubital fossa, (I) chest. Data were analyzed by two‐way ANOVA to test for treatment, time, and treatment × time interaction effects. P and F values reflect the treatment effect. Only the rash was significantly different between suramin and placebo groups.
Figure 3
Figure 3
Pharmacokinetics of single‐dose suramin in children with autism spectrum disorders. (A) Two‐compartment model of suramin blood concentrations. The first 48 h were dominated by the distribution phase. Over 90% of the model is described by the elimination phase. (B) Plasma suramin concentrations. (C) A two‐compartment model correlated well with measured values. (D) Pediatric PK parameters of suramin.
Figure 4
Figure 4
Suramin pharmacometabolomics. Rank order of metabolites and pathways that were changed by suramin at 6 weeks after treatment.
Figure 5
Figure 5
Shared biochemical pathways. 75% of the pathways that were altered by suramin in children with ASD were also altered in the mouse models. Asterisks (*) indicate pathways that were changed at 2 days, but not at 6 weeks after treatment.

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