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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 12; pp. 4596 - 4601
• Main Authors: Khwaja, Omar S., Ho, Eugenia, Barnes, Katherine V., O'Leary, Heather M., Pereira, Luis M., Finkelstein, Yaron, Nelson, Charles A., Vogel-Farley, Vanessa, DeGregorio, Geneva, Holm, Ingrid A., Khatwa, Umakanth, Kapur, Kush, Alexander, Mark E., Finnegan, Deirdre M., Cantwell, Nicole G., Walco, Alexandra C., Rappaport, Leonard, Gregas, Matt, Fichorova, Raina N., Shannon, Michael W., Sur, Mriganka, Kaufmann, Walter E.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 25.03.2014; National Acad Sciences
• Subjects: Anxiety; Anxiety disorders; Apnea; Biological Sciences; Breathing; Child; Child, Preschool; Dosage; Effectiveness studies; Experimentation; Female; Growth hormones; Heart rate; Humans; Insulin-Like Growth Factor I - adverse effects; Insulin-Like Growth Factor I - pharmacokinetics; Insulin-Like Growth Factor I - therapeutic use; Intellectual disability; Intercellular Signaling Peptides and Proteins - adverse effects; Intercellular Signaling Peptides and Proteins - pharmacokinetics; Intercellular Signaling Peptides and Proteins - therapeutic use; Kinetics; Mutation; Neurological disorders; Pharmacokinetics; Pharmacology; Recombinant Proteins - adverse effects; Recombinant Proteins - pharmacokinetics; Recombinant Proteins - therapeutic use; Rett Syndrome - drug therapy; Somatomedins
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1311141111

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 insulin-like 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.