Christian J Hendriksz1, Rossella Parini2, Moeenaldeen D AlSayed3, Julian Raiman4, Roberto Giugliani5, John J Mitchell6, Barbara K Burton7, Norberto Guelbert8, Fiona J Stewart9, Derralynn A Hughes10, Robert Matousek11, Sara M Hawley12, Celeste Decker13, Paul R Harmatz14. 1. Salford Royal NHS Foundation Trust, Salford, UK; University of Pretoria, Department of Paediatrics and Child Health, Pretoria, South Africa. Electronic address: chris@fymcamedical.co.uk. 2. Azienda Ospedaliera San Gerardo, Monza, Italy. Electronic address: rossella.parini@unimib.it. 3. King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia. Electronic address: moeen@kfshrc.edu.sa. 4. Birmingham Children's Hospital, Birmingham, UK. Electronic address: julian.raiman@bch.nhs.uk. 5. Med Genet Serv HCPA, Dep Genet UFRGS & INAGEMP, Porto Alegre, Brazil. Electronic address: rgiugliani@hcpa.edu.br. 6. Montreal Children's Hospital, Montreal, QC, Canada. Electronic address: john.mitchell@muhc.mcgill.ca. 7. Lurie Children's Hospital, NWU Feinberg, Chicago, IL, United States. Electronic address: bburton@luriechildrens.org. 8. Hospital de Niños de Cordoba, Cordoba, Argentina. Electronic address: nguelbert@arnet.com.ar. 9. Belfast City Hospital, Belfast, United Kingdom. Electronic address: fiona.stewart@belfasttrust.hscni.net. 10. Royal Free London NHS Foundation Trust & UC, London, United Kingdom. Electronic address: rmgvdah@ucl.ac.uk. 11. BioMarin Pharmaceutical Inc., Novato, CA, United States. Electronic address: robert.matousek@bmrn.com. 12. BioMarin Pharmaceutical Inc., Novato, CA, United States. Electronic address: sara.hawley@bmrn.com. 13. BioMarin Pharmaceutical Inc., Novato, CA, United States. Electronic address: CDecker@bmrn.com. 14. UCSF Benioff Children's Hospital Oakland, Oakland, CA, United States. Electronic address: pharmatz@mail.cho.org.
Abstract
BACKGROUND: Long-term safety and efficacy of elosulfase alfa enzyme replacement therapy (ERT) were assessed in 173 patients with Morquio A syndrome (mucopolysaccharidosis IVA) in a 96-week, open-label, multi-center, phase 3 extension study (MOR-005) of the pivotal 24-week, placebo-controlled study (MOR-004). Changes in efficacy endpoints were evaluated over 120weeks, from MOR-004 baseline to MOR-005 week 96. We report the impact of ERT on activities of daily living (ADL) across three domains (mobility, self-care, and caregiver-assistance), as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ) after 72 and 120weeks or approximately 1 and 2years. RESULTS:Mean baseline MPS-HAQ domain scores showed impairments in mobility, self-care, and independence. The MOR-005 intent-to-treat population (ITT; N=169, including 158 with 2years follow-up) showed sustained significant reductions (representing improvements) in mobility and self-care domainleast square (LS) mean scores vs. baseline at 1 and 2years and a non-significant decrease in the caregiver-assistance domain at 2years. At week 120, LS mean (SE) changes from baseline were -0.5 (0.1) for mobility (P=0.002), -0.4 (0.1) for self-care (P=0.001), and -1.0 (0.5) for caregiver-assistance (P=0.06) (ITT population). Improvements in MPS-HAQ domain scores vs. baseline at 1 and 2years were greater in patients continuously treated with the weekly dosing regimen than in the total MOR-005 population and statistically significant across domains. A comparable untreated cohort of patients from the Morquio A Clinical Assessment Program (MorCAP) natural history study (ITT population, N=94, including 37 with 2years follow-up) showed no improvement over 2years, with two of the three domains worsening (LS mean (SE) changes from baseline: 0.3 (0.3) for mobility, 0.4 (0.2) for self-care, -0.5 (0.8) for caregiver-assistance). Changes in LS mean scores vs. baseline were statistically significantly different between MOR-005 and MorCAP for the mobility domain (-0.7 (SE 0.4), P=0.0490) and the self-care domain (-0.7 (SE 0.3), P=0.0146) at 2years. CONCLUSIONS: Together, these findings suggest that long-term elosulfase alfa ERT is associated with partial recovery of functional abilities, improving Morquio A patients' abilities to perform ADL. TRIAL REGISTRATION: ClinicalTrials.govNCT01415427. Registered 8 August 2011, retrospectively registered.
RCT Entities:
BACKGROUND: Long-term safety and efficacy of elosulfase alfa enzyme replacement therapy (ERT) were assessed in 173 patients with Morquio A syndrome (mucopolysaccharidosis IVA) in a 96-week, open-label, multi-center, phase 3 extension study (MOR-005) of the pivotal 24-week, placebo-controlled study (MOR-004). Changes in efficacy endpoints were evaluated over 120weeks, from MOR-004 baseline to MOR-005 week 96. We report the impact of ERT on activities of daily living (ADL) across three domains (mobility, self-care, and caregiver-assistance), as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ) after 72 and 120weeks or approximately 1 and 2years. RESULTS: Mean baseline MPS-HAQ domain scores showed impairments in mobility, self-care, and independence. The MOR-005 intent-to-treat population (ITT; N=169, including 158 with 2years follow-up) showed sustained significant reductions (representing improvements) in mobility and self-care domain least square (LS) mean scores vs. baseline at 1 and 2years and a non-significant decrease in the caregiver-assistance domain at 2years. At week 120, LS mean (SE) changes from baseline were -0.5 (0.1) for mobility (P=0.002), -0.4 (0.1) for self-care (P=0.001), and -1.0 (0.5) for caregiver-assistance (P=0.06) (ITT population). Improvements in MPS-HAQ domain scores vs. baseline at 1 and 2years were greater in patients continuously treated with the weekly dosing regimen than in the total MOR-005 population and statistically significant across domains. A comparable untreated cohort of patients from the Morquio A Clinical Assessment Program (MorCAP) natural history study (ITT population, N=94, including 37 with 2years follow-up) showed no improvement over 2years, with two of the three domains worsening (LS mean (SE) changes from baseline: 0.3 (0.3) for mobility, 0.4 (0.2) for self-care, -0.5 (0.8) for caregiver-assistance). Changes in LS mean scores vs. baseline were statistically significantly different between MOR-005 and MorCAP for the mobility domain (-0.7 (SE 0.4), P=0.0490) and the self-care domain (-0.7 (SE 0.3), P=0.0146) at 2years. CONCLUSIONS: Together, these findings suggest that long-term elosulfase alfa ERT is associated with partial recovery of functional abilities, improving Morquio A patients' abilities to perform ADL. TRIAL REGISTRATION: ClinicalTrials.govNCT01415427. Registered 8 August 2011, retrospectively registered.
Authors: Mehmet Umut Akyol; Tord D Alden; Hernan Amartino; Jane Ashworth; Kumar Belani; Kenneth I Berger; Andrea Borgo; Elizabeth Braunlin; Yoshikatsu Eto; Jeffrey I Gold; Andrea Jester; Simon A Jones; Cengiz Karsli; William Mackenzie; Diane Ruschel Marinho; Andrew McFadyen; Jim McGill; John J Mitchell; Joseph Muenzer; Torayuki Okuyama; Paul J Orchard; Bob Stevens; Sophie Thomas; Robert Walker; Robert Wynn; Roberto Giugliani; Paul Harmatz; Christian Hendriksz; Maurizio Scarpa Journal: Orphanet J Rare Dis Date: 2019-06-13 Impact factor: 4.123
Authors: Lina Moisan; David Iannuzzi; Bruno Maranda; Philippe M Campeau; John J Mitchell Journal: Orphanet J Rare Dis Date: 2020-09-29 Impact factor: 4.123