A proof-of-concept study of growth hormone in children with Phelan–McDermid syndrome

Sethuram, Swathi; Levy, Tess; Foss‐Feig, Jennifer H.; Halpern, Danielle; Sandin, Sven; Siper, Paige M.; Walker, Hannah E; Buxbaum, Joseph D.; Rapaport, Robert; Kolevzon, Alexander

doi:10.1186/s13229-022-00485-7

Cited by 7 publications

(3 citation statements)

References 23 publications

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“…Following the available information at the time of initial treatment mentioned above, IGF-1 and human growth hormone (hGH) have been shown to reverse neurobehavioral deficits in PMS. In terms of clinical studies [8] , subsequent investigations included a new short-term pilot study and a randomized controlled trial (RCT) in PMS [17,18] , showing improvements in sensory reactivity, hyperactivity and repetitive behaviors, and good tolerability. Tolerability during long-term treatment has not been studied for indications not associated with low height.…”

Section: Discussionmentioning

confidence: 99%

Long-term treatment with insulin-like growth factor-1 in Phelan-McDermid syndrome: a case report

Parellada,

Burdeus-Olavarrieta,

Fraguas

et al. 2024

Rare Dis Orphan Drugs J

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Phelan-McDermid syndrome (PMS) is a chromosomal microdeletion syndrome generally caused by loss-of-function variants or deletions affecting the SHANK3 gene. We report on a case of a 19-year-old woman with a diagnosis of PMS, autism, and developmental disability. She has been under clinical care since the age of 9 and received treatment with subcutaneous IGF-1 from 11 to 15 years of age. The treatment spanned 2 periods, totaling 35 months, interspersed with a 16-month off-treatment interval. Clinically significant improvement was evident during the treatment periods, particularly in the Social Responsiveness Scale, the Aberrant Behavior Checklist, and clinical assessments, contrasted with a clear deterioration during the off-treatment period. Sleep difficulties worsened during the first period, and EKG repolarization abnormalities emerged during the second period, ultimately leading to definitive treatment discontinuation. In conclusion, an experimental long-term on-off-on treatment with IGF-1 in an adolescent with PMS resulted in mixed results, showcasing positive clinical improvements alongside potentially severe adverse events in the long run.

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Section: Discussionmentioning

confidence: 99%

Long-term treatment with insulin-like growth factor-1 in Phelan-McDermid syndrome: a case report

Parellada,

Burdeus-Olavarrieta,

Fraguas

et al. 2024

Rare Dis Orphan Drugs J

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“…Future efforts should employ larger sample sizes and conduct trials across multiple centers to ensure rigor. Further, other compounds that increase endogenous levels of IGF-1 should be considered and at least two small studies with growth hormone show promise [ 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2022

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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.

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“…Several treatment studies suggest promise but require replication on a larger scale. Both insulin-like growth factor-1 (IGF-1) and the closely related human growth hormone have been shown in small trials to improve symptoms of social withdrawal, sensory sensitivity, and hyperactivity in children with PMS [ 11 – 14 ]. In addition, Neuren Pharmaceuticals recently completed recruitment for a Phase 2 trial of NNZ-2591, an analog of IGF-1, in children with PMS.…”

Section: Introductionmentioning

confidence: 99%

Caregiver perspectives on patient-focused drug development for Phelan-McDermid syndrome

Gizzo,

Bliss,

Palaty

et al. 2024

Orphanet J Rare Dis

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Background Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by SHANK3 haploinsufficiency with clinical manifestations that can be devastating and profoundly affect quality of life. Results The Externally Led Patient-Focused Drug Development (EL-PFDD) meeting was an opportunity for families affected by PMS to share with the Food and Drug Administration (FDA) how symptoms impact their lives and how treatments could be most meaningful. The Voice of the Patient report serves as a summary of this meeting to influence upcoming drug development and clinical trials. The purpose of this report is to provide a clinical perspective on the results of the EL-PFDD meeting to amplify the voice of these caregivers to the scientific community. Conclusions Caregivers prioritize an improved quality of life for their loved ones characterized by improved cognitive function, improved communication, increased independence, and reduced risk of regression. With these caregiver priorities in mind, this report provides the FDA and the scientific community with a clear understanding of which aspects of PMS should influence the development of future therapeutics.

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A proof-of-concept study of growth hormone in children with Phelan–McDermid syndrome

Cited by 7 publications

References 23 publications

Long-term treatment with insulin-like growth factor-1 in Phelan-McDermid syndrome: a case report

Long-term treatment with insulin-like growth factor-1 in Phelan-McDermid syndrome: a case report

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

Caregiver perspectives on patient-focused drug development for Phelan-McDermid syndrome

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