Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome
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...
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| Format: | Article |
| Language: | en_US |
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National Academy of Sciences (U.S.)
2014
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| Online Access: | http://hdl.handle.net/1721.1/91474 https://orcid.org/0000-0003-2442-5671 |
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| author | Khwaja, Omar S. Ho, Eugenia Barnes, Katherine V. O'Leary, Heather M. Pereira, Luis M. Finkelstein, Yaron Nelson III, Charles A. Vogel-Farley, Vanessa DeGregorio, Geneva Holm, Ingrid A. Khatwa, Umakanth Kapur, Kush Alexander, Mark E. Finnegan, Deidre M. Cantwell, Nicole G. Walco, Alexandra C. Rappaport, Leonard Gregas, Matt Fichorova, Raina N. Shannon, Michael W. Sur, Mriganka Kaufmann, Walter E. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Khwaja, Omar S. Ho, Eugenia Barnes, Katherine V. O'Leary, Heather M. Pereira, Luis M. Finkelstein, Yaron Nelson III, Charles A. Vogel-Farley, Vanessa DeGregorio, Geneva Holm, Ingrid A. Khatwa, Umakanth Kapur, Kush Alexander, Mark E. Finnegan, Deidre M. Cantwell, Nicole G. Walco, Alexandra C. Rappaport, Leonard Gregas, Matt Fichorova, Raina N. Shannon, Michael W. Sur, Mriganka Kaufmann, Walter E. |
| author_sort | Khwaja, Omar S. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:07:09Z |
| format | Article |
| id | mit-1721.1/91474 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T15:07:09Z |
| publishDate | 2014 |
| publisher | National Academy of Sciences (U.S.) |
| record_format | dspace |
| spelling | mit-1721.1/914742022-09-29T12:47:27Z Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome Khwaja, Omar S. Ho, Eugenia Barnes, Katherine V. O'Leary, Heather M. Pereira, Luis M. Finkelstein, Yaron Nelson III, Charles A. Vogel-Farley, Vanessa DeGregorio, Geneva Holm, Ingrid A. Khatwa, Umakanth Kapur, Kush Alexander, Mark E. Finnegan, Deidre M. Cantwell, Nicole G. Walco, Alexandra C. Rappaport, Leonard Gregas, Matt Fichorova, Raina N. Shannon, Michael W. Sur, Mriganka Kaufmann, Walter E. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Sur, Mriganka 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. Rett Syndrome Foundation (Grant 2534) Autism Speaks (Organization) (Grant 5795) National Institutes of Health (U.S.) (Harvard Clinical and Translational Science Center, Grant 1 UL1 RR 025758-01) Boston Children’s Hospital (Translational Research Program) Boston Children’s Hospital (Intellectual and Developmental Disabilities Research Center P30 HD18655) 2014-11-06T18:21:18Z 2014-11-06T18:21:18Z 2014-03 2013-06 Article http://purl.org/eprint/type/JournalArticle 0027-8424 1091-6490 http://hdl.handle.net/1721.1/91474 Khwaja, O. S., E. Ho, K. V. Barnes, H. M. O’Leary, L. M. Pereira, Y. Finkelstein, C. A. Nelson, et al. “Safety, Pharmacokinetics, and Preliminary Assessment of Efficacy of Mecasermin (recombinant Human IGF-1) for the Treatment of Rett Syndrome.” Proceedings of the National Academy of Sciences 111, no. 12 (March 12, 2014): 4596–4601. https://orcid.org/0000-0003-2442-5671 en_US http://dx.doi.org/10.1073/pnas.1311141111 Proceedings of the National Academy of Sciences Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf National Academy of Sciences (U.S.) PNAS |
| spellingShingle | Khwaja, Omar S. Ho, Eugenia Barnes, Katherine V. O'Leary, Heather M. Pereira, Luis M. Finkelstein, Yaron Nelson III, Charles A. Vogel-Farley, Vanessa DeGregorio, Geneva Holm, Ingrid A. Khatwa, Umakanth Kapur, Kush Alexander, Mark E. Finnegan, Deidre M. Cantwell, Nicole G. Walco, Alexandra C. Rappaport, Leonard Gregas, Matt Fichorova, Raina N. Shannon, Michael W. Sur, Mriganka Kaufmann, Walter E. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome |
| title | Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome |
| title_full | Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome |
| title_fullStr | Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome |
| title_full_unstemmed | Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome |
| title_short | Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome |
| title_sort | safety pharmacokinetics and preliminary assessment of efficacy of mecasermin recombinant human igf 1 for the treatment of rett syndrome |
| url | http://hdl.handle.net/1721.1/91474 https://orcid.org/0000-0003-2442-5671 |
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