Christian J Hendriksz1, Roberto Giugliani2, Paul Harmatz3, Eugen Mengel4, Nathalie Guffon5, Vassili Valayannopoulos6, Rossella Parini7, Derralynn Hughes8, Gregory M Pastores9, Heather A Lau9, Moeenaldeen D Al-Sayed10, Julian Raiman11, Ke Yang12, Matthew Mealiffe12, Christine Haller12. 1. Salford Royal NHS Foundation Trust, Salford, UK. Electronic address: chris.hendriksz@srft.nhs.uk. 2. Medical Genetics Service/HCPA, Department of Genetics/UFRGS and INAGEMP, Porto Alegre, Brazil. 3. UCSF Benioff Children's Hospital Oakland, Oakland, CA, USA. 4. Villa Metabolica, Centre for Pediatric and Adolescent Medicine, MC University of Mainz, Mainz, Germany. 5. Hôpital Femme Mère Enfant Centre de référence des maladies héréditaires du metabolism, Bron Cedex, France. 6. Reference Center for Inherited Metabolic Disease, Hôpital Necker-Enfants Malades and IMAGINE Institute, Paris, France. 7. Unita Operativa Semplice Malattie Metaboliche Rare, Azienda Ospedaliera San Gerardo, Monza, Italy. 8. Royal Free London NHS Foundation Trust & University College, London, UK. 9. New York University School of Medicine, New York, NY, USA. 10. King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. 11. Hospital for Sick Children, Toronto, ON, Canada. 12. BioMarin Pharmaceutical Inc., Novato, CA, USA.
Abstract
OBJECTIVE: To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA). METHODS:Patients with Morquio A syndromeaged ≥5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.0mg/kg/every other week (qow; N=59), or placebo (N=59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well. RESULTS: The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z-scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group (P=0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group (P=0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant differences between elosulfase alfa qw and placebo favoring elosulfase alfa qw. Differences between elosulfase alfa qow and placebo were not statistically significant. Positive changes were observed in most tertiary variables, demonstrating the efficacy of weekly treatment with elosulfase alfa. CONCLUSIONS: Treatment with weekly elosulfase alfa led to improvements across most efficacy measures, resulting in clinically meaningful benefits in a heterogeneous study population.
RCT Entities:
OBJECTIVE: To report and discuss the multi-domain impact of elosulfase alfa, with focus on tertiary and composite endpoints, in the 24-week, randomized, double-blind, placebo-controlled phase 3 trial in patients with Morquio A syndrome (mucopolysaccharidosis IVA). METHODS:Patients with Morquio A syndrome aged ≥5 years were randomized 1:1:1 to elosulfase alfa 2.0mg/kg/week (qw; N=58), elosulfase alfa 2.0mg/kg/every other week (qow; N=59), or placebo (N=59) for 24 weeks. Primary and secondary efficacy measures were 6-minute walk test (6MWT; primary), 3-minute stair climb test (3-MSCT) and urinary keratan sulfate (KS). Safety was also evaluated. Tertiary efficacy measures included respiratory function measures, activities of daily living (MPS Health Assessment Questionnaire [MPS-HAQ]), anthropometric, echocardiographic and radiographic measures, hearing and corneal clouding assessment. In order to fully characterize treatment impact in this heterogeneous disorder, the effect of elosulfase alfa on composite efficacy measures was evaluated as well. RESULTS: The study was not designed to have sufficient power for any of the tertiary outcomes. For most tertiary endpoints, subjects treated with the weekly dose of elosulfase alfa improved more than those receiving placebo. The largest treatment effects were seen in maximal voluntary ventilation (MVV), MPS-HAQ, height, and growth rate. The qow group appeared similar to placebo. The analysis of a pre-specified composite endpoint (combining changes from baseline in 6MWT, 3MSCT and MVV z-scores equally weighted) showed a modest positive impact of elosulfase alfa qw versus placebo group (P=0.053). As a pre-specified supportive analysis, the O'Brien Rank Sum composite endpoint (changes from baseline in 6MWT, 3MSC, and MVV), analysis also showed that the qw group performed better than the placebo group (P=0.011). In post-hoc analyses, combinations of other endpoints were also explored using the O'Brien Rank Sum test and showed statistically significant differences between elosulfase alfa qw and placebo favoring elosulfase alfa qw. Differences between elosulfase alfa qow and placebo were not statistically significant. Positive changes were observed in most tertiary variables, demonstrating the efficacy of weekly treatment with elosulfase alfa. CONCLUSIONS: Treatment with weekly elosulfase alfa led to improvements across most efficacy measures, resulting in clinically meaningful benefits in a heterogeneous study population.
Authors: Shaukat Khan; Carlos J Alméciga-Díaz; Kazuki Sawamoto; William G Mackenzie; Mary C Theroux; Christian Pizarro; Robert W Mason; Tadao Orii; Shunji Tomatsu Journal: Mol Genet Metab Date: 2016-11-29 Impact factor: 4.797
Authors: Eriko Yasuda; Yasuyuki Suzuki; Tsutomu Shimada; Kazuki Sawamoto; William G Mackenzie; Mary C Theroux; Christian Pizarro; Li Xie; Freeman Miller; Tariq Rahman; Heidi H Kecskemethy; Kyoko Nagao; Thierry Morlet; Thomas H Shaffer; Yasutsugu Chinen; Hiromasa Yabe; Akemi Tanaka; Haruo Shintaku; Kenji E Orii; Koji O Orii; Robert W Mason; Adriana M Montaño; Toshiyuki Fukao; Tadao Orii; Shunji Tomatsu Journal: Mol Genet Metab Date: 2016-04-25 Impact factor: 4.797
Authors: Kazuki Sawamoto; Yasuyuki Suzuki; William G Mackenzie; Mary C Theroux; Christian Pizarro; Hiromasa Yabe; Kenji E Orii; Robert W Mason; Tadao Orii; Shunji Tomatsu Journal: Expert Opin Orphan Drugs Date: 2016-07-28 Impact factor: 0.694
Authors: Shunji Tomatsu; Kazuki Sawamoto; Carlos J Alméciga-Díaz; Tsutomu Shimada; Michael B Bober; Yasutsugu Chinen; Hiromasa Yabe; Adriana M Montaño; Roberto Giugliani; Francyne Kubaski; Eriko Yasuda; Alexander Rodríguez-López; Angela J Espejo-Mojica; Oscar F Sánchez; Robert W Mason; Luis A Barrera; William G Mackenzie; Tadao Orii Journal: Drug Des Devel Ther Date: 2015-04-01 Impact factor: 4.162
Authors: Shunji Tomatsu; Kazuki Sawamoto; Tsutomu Shimada; Michael B Bober; Francyne Kubaski; Eriko Yasuda; Robert W Mason; Shaukat Khan; Carlos J Alméciga-Díaz; Luis A Barrera; William G Mackenzie; Tadao Orii Journal: Expert Opin Orphan Drugs Date: 2015-10-29 Impact factor: 0.694