Clinical trial of insulin-like growth factor-1 in Phelan-McDermid syndrome

A Kolevzon, M S Breen, P M Siper, D Halpern, Y Frank, H Rieger, J Weismann, M P Trelles, B Lerman, R Rapaport, J D Buxbaum, A Kolevzon, M S Breen, P M Siper, D Halpern, Y Frank, H Rieger, J Weismann, M P Trelles, B Lerman, R Rapaport, J D Buxbaum

Abstract

Background: Phelan-McDermid syndrome (PMS) is caused by haploinsufficiency of the SHANK3 gene and is characterized by global developmental delays and autism spectrum disorder (ASD). Based on several converging lines of preclinical and clinical evidence supporting the use of insulin-like growth factor-1 (IGF-1) in PMS, this study aims to follow-up a previous pilot study with IGF-1 to further evaluate this novel therapeutic for core symptoms of ASD in children with PMS.

Methods: Ten children aged 5-9 with PMS were enrolled. Participants were randomized to receive IGF-1 or placebo (saline) using a 12-week, double-blind, crossover design. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as secondary outcome measures reflecting core symptoms of ASD. To increase power and sample size, we jointly analyzed the effect of IGF-1 reported here together with results from our previous controlled trail of IGF-1 in children with PMS (combined N = 19).

Results: Results on the ABC-SW did not reach statistical significance, however significant improvements in sensory reactivity symptoms were observed. In our pooled analyses, IGF-1 treatment also led to significant improvements in repetitive behaviors and hyperactivity. There were no other statistically significant effects seen across other clinical outcome measures. IGF-1 was well tolerated and there were no serious adverse events.

Limitations: The small sample size and expectancy bias due to relying on parent reported outcome measures may contribute to limitations in interpreting results.

Conclusion: IGF-1 is efficacious in improving sensory reactivity symptoms, repetitive behaviors, and hyperactivity in children with PMS. Trial registration NCT01525901.

Keywords: ASD; Autism spectrum disorder; IGF-1; Insulin-like growth factor-1; PMS; Phelan-McDermid syndrome; shank3.

Conflict of interest statement

AK receives research support from AMO Pharma and consults to Acadia, Alkermes, Ritrova, Jaguar, Neuren, GW Pharma, and Ovid Therapeutics. JDB has a shared patent with Mount Sinai for IGF-1 in Phelan-McDermid syndrome. No other authors have competing interests to disclose.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Significant outcome measures between baseline and week 12 of drug (IGF-1) or placebo. Mean changes are shown across the second study (left), first study [9] (center) and the combined effect (right) for the following significant outcome scores testing for time × treatment interactions: A ABC-SW, significant effect in the first study only (p = 0.04); B RBS-R Restricted Behavior, significant effect in the first study (p = 0.04) and combined study effect (p = 0.03); C SP Under-responsive/seeks sensation, significant effect in the second study only (p = 0.03); and D SP Modulation of body movement and position, significant effect in the second study only (p = 0.02). E Exploratory analysis applying a Mann Whitney-U test on difference in scores at 12 weeks identified significant reduction in ABC-hyperactivity scores in the first (p = 0.03) and combined study effect (p = 0.01). Mean differences and standard errors are shown for all outcome measures. Abbreviations: ABC-SW = Aberrant Behavior Checklist—Social Withdrawal subscale; RBS = Repetitive Behavior Scale; SP = Sensory Profile; ABC-hyperactivity = Aberrant Behavior Checklist-hyperactivity

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