Genetics in Medicine - Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease

Genetics in Medicine - Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease

Genetics in Medicine (2009) 11, 210–219; doi:10.1097/GIM.0b013e31819d0996

Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease

Marc Nicolino¹, Barry Byrne², J Edmund Wraith³, Nancy Leslie⁴, Hanna Mandel⁵, David R Freyer⁶, Georgianne L Arnold⁷, Eniko K Pivnick⁸, C J Ottinger⁹, Peter H Robinson¹⁰, John-Charles A Loo¹¹, Martin Smitka¹², Philip Jardine¹³, Luciano Tatò¹⁴, Brigitte Chabrol¹⁵, Shawn McCandless¹⁶, Shigemi Kimura¹⁷, L Mehta¹⁸, Deeksha Bali¹⁹, Alison Skrinar²⁰, Claire Morgan²⁰, Lakshmi Rangachari²⁰, Deya Corzo²¹ and Priya S Kishnani¹⁹

1. ¹Division of Pediatric Endocrinology, Diabetology and Metabolism, Hôpital Debrousse, University Lyon, Lyon, France
2. ²Shands Hospital, University of Florida, Gainesville, Florida
3. ³Royal Manchester Children's Hospital, Manchester, United Kingdom
4. ⁴Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
5. ⁵Rambam Medical Center, Haifa, Israel
6. ⁶DeVos Children's Hospital, Grand Rapids, Michigan
7. ⁷University of Rochester Medical Center, Rochester, New York
8. ⁸University of Tennessee Health Science Center, Memphis, Tennessee
9. ⁹Fort Wayne Neurological Center, Fort Wayne, Indiana
10. ¹⁰Royal Hospital for Sick Children, Edinburgh, United Kingdom
11. ¹¹Long Beach Memorial Medical Center, Long Beach, California
12. ¹²Technical University, Dresden, Germany
13. ¹³Bristol Royal Hospital for Children, Bristol, United Kingdom
14. ¹⁴University of Verona, Verona, Italy
15. ¹⁵Hopital Timone Enfants, Marseille, France
16. ¹⁶University Hospitals of Cleveland, Cleveland, Ohio
17. ¹⁷Kumamoto University Graduate School, Kumamoto, Japan
18. ¹⁸Mount Sinai Medical Center, New York, New York
19. ¹⁹Duke University Medical Center, Durham, North Carolina
20. ²⁰Genzyme Corporation, Cambridge, MA
21. ²¹Millennium Pharmaceuticals Inc., Cambridge MA

Correspondence: Priya S. Kishnani, MD, Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC 27710. E-mail: kishn001@mc.duke.edu.

Received 4 January 2008; Accepted 13 October 2008

Disclosure: P.S. Kishnani, M. Nicolino, and B. Byrne are members of the Pompe Disease Advisory Board for Genzyme Corporation. D. Bali and P. Kishnani have served as consultants for Genzyme Corporation. The clinical trials of Myozyme were supported by grants from Genzyme Corporation at the various sites at which patients were treated. Duke University and inventors of the method of treatment and predecessors of the cell lines used to generate the enzyme used in this clinical trial will benefit financially pursuant to Duke University's Policy on Inventions, Patents, and Technology Transfer, even if those cell lines are not used in the commercialized therapy.

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Abstract

Purpose: A clinical trial was conducted to evaluate the safety and efficacy of alglucosidase alfa in infants and children with advanced Pompe disease.

Methods: Open-label, multicenter study of IV alglucosidase alfa treatment in 21 infants 3–43 months old (median 13 months) with minimal acid α-glucosidase activity and abnormal left ventricular mass index by echocardiography. Patients received IV alglucosidase alfa every 2 weeks for up to 168 weeks (median 120 weeks). Survival results were compared with an untreated reference cohort.

Results: At study end, 71% (15/21) of patients were alive and 44% (7/16) of invasive-ventilator free patients remained so. Compared with the untreated reference cohort, alglucosidase alfa reduced the risk of death by 79% (P < 0.001) and the risk of invasive ventilation by 58% (P = 0.02). Left ventricular mass index improved or remained normal in all patients evaluated beyond 12 weeks; 62% (13/21) achieved new motor milestones. Five patients were walking independently at the end of the study and 86% (18/21) gained functional independence skills. Overall, 52% (11/21) of patients experienced infusion-associated reactions; 95% (19/20) developed IgG antibodies to recombinant human lysosomal acid α-glucosidase; no patients withdrew from the study because of safety concerns.

Conclusions: In this population of infants with advanced disease, biweekly infusions with alglucosidase alfa prolonged survival and invasive ventilation-free survival. Treatment also improved indices of cardiomyopathy, motor skills, and functional independence.

Keywords: 

Pompe disease; glycogen storage disease type II; acid maltase deficiency; Myozyme; alglucosidase alfa; lysosomal acid α-glucosidase; recombinant human GAA; enzyme replacement therapy; cardiomyopathy; motor development