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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 III, 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. Shannon, Mriganka Sur, and Walter E. Kaufmann
PNAS published ahead of print March 12, 2014 https://doi.org/10.1073/pnas.1311141111
Omar S. Khwaja
aDepartment of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;bNeurosciences Translational Medicine, Pharma Research and Early Development, F. Hoffmann–La Roche AG, 4070 Basel, Switzerland;
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Eugenia Ho
aDepartment of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;cDivision of Neurology, Children’s Hospital Los Angeles, University of Southern California, Los Angeles, CA 90027;
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Katherine V. Barnes
aDepartment of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Heather M. O’Leary
aDepartment of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Luis M. Pereira
dDepartment of Anesthesia, Perioperative and Pain Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Yaron Finkelstein
eDivisions of Emergency Medicine and Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, ON, Canada M5G 1X8;fDivision of Emergency Medicine, Boston Children’s Hospital, Boston, MA 02115;
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Charles A. Nelson
gDivision of Development Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Vanessa Vogel-Farley
gDivision of Development Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Geneva DeGregorio
gDivision of Development Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Ingrid A. Holm
hDivision of Genetics and Genomics, and The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA 02115;iDepartment of Pediatrics, Harvard Medical School, Boston, MA 02115;
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Umakanth Khatwa
jDivision of Respiratory Diseases, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Kush Kapur
aDepartment of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;kClinical Research Center, Boston Children’s Hospital, Boston, MA 02115;
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Mark E. Alexander
iDepartment of Pediatrics, Harvard Medical School, Boston, MA 02115;lDepartment of Cardiology, Boston Children’s Hospital, Boston, MA 02115;
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Deirdre M. Finnegan
aDepartment of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Nicole G. Cantwell
aDepartment of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Alexandra C. Walco
aDepartment of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Leonard Rappaport
gDivision of Development Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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Matt Gregas
aDepartment of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;kClinical Research Center, Boston Children’s Hospital, Boston, MA 02115;
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Raina N. Fichorova
mDepartment of Obstetrics, Gynecology and Reproductive Biology, Laboratory of Genital Tract Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215; and
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Michael W. Shannon
fDivision of Emergency Medicine, Boston Children’s Hospital, Boston, MA 02115;iDepartment of Pediatrics, Harvard Medical School, Boston, MA 02115;
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Mriganka Sur
nDepartment of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139
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Walter E. Kaufmann
aDepartment of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115;
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  • For correspondence: walter.kaufmann@childrens.harvard.edu
  1. Edited* by Michael Merzenich, Brain Plasticity Institute, San Francisco, CA, and approved February 13, 2014 (received for review June 24, 2013)

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Significance

This paper provides unique insights into mechanism-based therapeutics for Rett syndrome (RTT), a devastating neurodevelopmental disorder. This clinical trial was based on pioneer preclinical work from the laboratory of M.S. Outcome measures include clinical instruments, standardized behavioral measures, and biomarkers, the latter being not only objective but also applicable to experimental studies. We believe this work will a have major impact on the understanding and treatment of RTT, as well as other neurodevelopmental disorders.

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.

Footnotes

  • ↵1O.S.K. and E.H. contributed equally to this work.

  • ↵2Deceased March 10, 2009.

  • ↵3To whom correspondence should be addressed. E-mail: walter.kaufmann{at}childrens.harvard.edu.
  • Author contributions: O.S.K., C.A.N., M.W.S., M.S., and W.E.K. designed research; O.S.K., E.H., K.V.B., H.M.O., V.V.-F., G.D., I.A.H., M.E.A., D.M.F., N.G.C., A.C.W., L.R., R.N.F., and W.E.K. performed research; R.N.F. contributed new reagents/analytic tools; K.V.B., H.M.O., L.M.P., Y.F., C.A.N., U.K., K.K., N.G.C., A.C.W., M.G., R.N.F., and W.E.K. analyzed data; and W.E.K. wrote the paper.

  • The authors declare no conflict of interest.

  • ↵*This Direct Submission article had a prearranged editor.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1311141111/-/DCSupplemental.

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Treatment of Rett syndrome with rhIGF1
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. Shannon, Mriganka Sur, Walter E. Kaufmann
Proceedings of the National Academy of Sciences Mar 2014, 201311141; DOI: 10.1073/pnas.1311141111

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Treatment of Rett syndrome with rhIGF1
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. Shannon, Mriganka Sur, Walter E. Kaufmann
Proceedings of the National Academy of Sciences Mar 2014, 201311141; DOI: 10.1073/pnas.1311141111
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