Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study

TY - JOUR

T1 - Safety and physiological effects of two different doses of elosulfase alfa in patients with morquio a syndrome: A randomized, double-blind, pilot study

AU - Burton, Barbara K

AU - Berger, Kenneth I

AU - Lewis, Gregory D

AU - Tarnopolsky, Mark

AU - Treadwell, Marsha

AU - Mitchell, John J

AU - Muschol, Nicole

AU - Jones, Simon A

AU - Sutton, V Reid

AU - Pastores, Gregory M

AU - Lau, Heather

AU - Sparkes, Rebecca

AU - Genter, Fred

AU - Shaywitz, Adam J

AU - Harmatz, Paul

N1 - © 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

PY - 2015/10

Y1 - 2015/10

N2 - The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain.

AB - The primary treatment outcomes of a phase 2, randomized, double-blind, pilot study evaluating safety, physiological, and pharmacological effects of elosulfase alfa in patients with Morquio A syndrome are herewith presented. Patients aged ≥7 years and able to walk ≥200 m in the 6-min walk test (6MWT) were randomized to elosulfase alfa 2.0 or 4.0 mg/kg/week for 27 weeks. The primary objective was to evaluate the safety of both doses. Secondary objectives were to evaluate effects on endurance (6MWT and 3-min stair climb test [3MSCT]), exercise capacity (cardio-pulmonary exercise test [CPET]), respiratory function, muscle strength, cardiac function, pain, and urine keratan sulfate (uKS) levels, and to determine pharmacokinetic parameters. Twenty-five patients were enrolled (15 randomized to 2.0 mg/kg/week and 10 to 4.0 mg/kg/week). No new or unexpected safety signals were observed. After 24 weeks, there were no improvements versus baseline in the 6MWT, yet numerical improvements were seen in the 3MSCT with 4.0 mg/kg/week. uKS and pharmacokinetic data suggested no linear relationship over the 2.0-4.0 mg/kg dose range. Overall, an abnormal exercise capacity (evaluated in 10 and 5 patients in the 2.0 and 4.0 mg/kg/week groups, respectively), impaired muscle strength, and considerable pain were observed at baseline, and there were trends towards improvements in all domains after treatment. In conclusion, preliminary data of this small study in a Morquio A population with relatively good endurance confirmed the acceptable safety profile of elosulfase alfa and showed a trend of increased exercise capacity and muscle strength and decreased pain.

KW - Adolescent

KW - Adult

KW - Child

KW - Chondroitinsulfatases/genetics

KW - Double-Blind Method

KW - Drug Administration Schedule

KW - Enzyme Replacement Therapy

KW - Exercise Test

KW - Female

KW - Heart Function Tests

KW - Humans

KW - Keratan Sulfate/urine

KW - Male

KW - Mucopolysaccharidosis IV/drug therapy

KW - Muscle Strength

KW - Patient Safety

KW - Pilot Projects

KW - Recombinant Proteins/therapeutic use

KW - Respiratory Function Tests

KW - Treatment Outcome

KW - Walking

U2 - 10.1002/ajmg.a.37172

DO - 10.1002/ajmg.a.37172

M3 - SCORING: Journal article

C2 - 26069231

VL - 167A

SP - 2272

EP - 2281

JO - AM J MED GENET A

JF - AM J MED GENET A

SN - 1552-4825

IS - 10

ER -