title: Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome.
abstract: 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.
authors.affiliation: Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115.
authors.forename: Omar S
authors.initials: OS
authors.lastname: Khwaja
authors.forename: Eugenia
authors.initials: E
authors.lastname: Ho
authors.forename: Katherine V
authors.initials: KV
authors.lastname: Barnes
authors.forename: Heather M
authors.initials: HM
authors.lastname: O'Leary
authors.forename: Luis M
authors.initials: LM
authors.lastname: Pereira
authors.forename: Yaron
authors.initials: Y
authors.lastname: Finkelstein
authors.forename: Charles A
authors.initials: CA
authors.lastname: Nelson
authors.forename: Vanessa
authors.initials: V
authors.lastname: Vogel-Farley
authors.forename: Geneva
authors.initials: G
authors.lastname: DeGregorio
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Holm
authors.forename: Umakanth
authors.initials: U
authors.lastname: Khatwa
authors.forename: Kush
authors.initials: K
authors.lastname: Kapur
authors.forename: Mark E
authors.initials: ME
authors.lastname: Alexander
authors.forename: Deirdre M
authors.initials: DM
authors.lastname: Finnegan
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Cantwell
authors.forename: Alexandra C
authors.initials: AC
authors.lastname: Walco
authors.forename: Leonard
authors.initials: L
authors.lastname: Rappaport
authors.forename: Matt
authors.initials: M
authors.lastname: Gregas
authors.forename: Raina N
authors.initials: RN
authors.lastname: Fichorova
authors.forename: Michael W
authors.initials: MW
authors.lastname: Shannon
authors.forename: Mriganka
authors.initials: M
authors.lastname: Sur
authors.forename: Walter E
authors.initials: WE
authors.lastname: Kaufmann
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D036341:Intercellular Signaling Peptides and Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D015518:Rett Syndrome / Q000188:drug therapy*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; C065700:myotrophin; D007334:Insulin-Like Growth Factor I