Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome

Omar S. Khwaja, Eugenia Ho, Katherine V. Barnes, Heather M. O'Leary, Luis M. Pereira, Yaron Finkelstein, Charles A. Nelson, Vanessa Vogel-Farley, Geneva DeGregorio, Ingrid A. Holm, Umakanth Khatwa, Kush Kapur, Mark E. Alexander, Deirdre M. Finnegan, Nicole G. Cantwell, Alexandra C. Walco, Leonard Rappaport, Matt Gregas, Raina N. Fichorova, Michael W. ShannonMriganka Sur, Walter E. Kaufmann

Research output: Contribution to journalArticlepeer-review

112 Scopus citations


Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulinlike growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40-120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Original languageEnglish (US)
Pages (from-to)4596-4601
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number12
StatePublished - Mar 25 2014
Externally publishedYes

ASJC Scopus subject areas

  • General


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