Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome
| Autor: | Nicole G. Cantwell, Charles A. Nelson, Vanessa Vogel-Farley, Yaron Finkelstein, Raina N. Fichorova, Heather M. O’Leary, Deirdre M. Finnegan, Matt Gregas, Walter E. Kaufmann, Geneva DeGregorio, Alexandra C. Walco, Mark E. Alexander, Omar Khwaja, Eugenia Ho, Ingrid A. Holm, Kush Kapur, Katherine Barnes, Michael W. Shannon, Mriganka Sur, Leonard Rappaport, Umakanth Khatwa, Luis M. Pereira |
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| Rok vydání: | 2014 |
| Předmět: |
Oncology
congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Rett syndrome Hypoglycemia Neurodevelopmental disorder Internal medicine Rett Syndrome medicine Humans Insulin-Like Growth Factor I Child Adverse effect Mecasermin Multidisciplinary business.industry Biological Sciences medicine.disease Recombinant Proteins Mood Endocrinology Tolerability Child Preschool Intercellular Signaling Peptides and Proteins Anxiety Female medicine.symptom business medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 111:4596-4601 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1311141111 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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