Safety and efficacy of alternative alglucosidase alfa regimens in Pompe disease

Laura E. Case; Carl Bjartmar; Claire Morgan; Robin Casey; Joel Charrow; John P. Clancy; Majed Dasouki; Stephanie DeArmey; Khan Nedd; Mary Nevins; Heidi Peters; Dawn Phillips; Zachary Spigelman; Cynthia Tifft; Priya S. Kishnani

doi:10.1016/j.nmd.2014.12.004

Safety and efficacy of alternative alglucosidase alfa regimens in Pompe disease

Laura E. Case, Carl Bjartmar, Claire Morgan, Robin Casey, Joel Charrow, John P. Clancy, Majed Dasouki, Stephanie DeArmey, Khan Nedd, Mary Nevins, Heidi Peters, Dawn Phillips, Zachary Spigelman, Cynthia Tifft, Priya S. Kishnani^*

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

44 Scopus citations

Abstract

Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20mg/kg/week or 40mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n=4), infantile-onset (n=9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy.

Original language	English (US)
Pages (from-to)	321-332
Number of pages	12
Journal	Neuromuscular Disorders
Volume	25
Issue number	4
DOIs	https://doi.org/10.1016/j.nmd.2014.12.004
State	Published - Apr 1 2015

Funding

LEC has received honoraria from Genzyme Corporation of Sanofi, has participated in research supported by Genzyme Corporation of Sanofi, PTC Therapeutics, the Leal Foundation, Families of SMA, Enobia Pharma Inc./Alexion, the Robertson Foundation, GlaxoSmithKline, Eli Lilly, and CINRG, has been awarded grant support from the National Skeletal Muscle Research Center, and is a member of the Pompe Registry Board of Advisors for Genzyme Corporation of Sanofi. PSK has received research/grant support and honoraria from Genzyme Corporation. Priya S. Kishnani is a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Corporation. Duke University and the inventors of the method of treatment and precursors of the cell lines used to generate the enzyme (rhGAA) used commercially have received royalties pursuant to the University's policy on inventions, patents, and technology transfer. This potential conflict for Duke University has been resolved through monetization.

Keywords

Alglucosidase alfa
Clinical decline
Dose
Enzyme replacement therapy
Infantile onset
Late onset
Pompe disease

ASJC Scopus subject areas

Pediatrics, Perinatology, and Child Health
Neurology
Clinical Neurology
Genetics(clinical)

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10.1016/j.nmd.2014.12.004

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title = "Safety and efficacy of alternative alglucosidase alfa regimens in Pompe disease",

abstract = "Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20mg/kg/week or 40mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n=4), infantile-onset (n=9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy.",

keywords = "Alglucosidase alfa, Clinical decline, Dose, Enzyme replacement therapy, Infantile onset, Late onset, Pompe disease",

author = "Case, {Laura E.} and Carl Bjartmar and Claire Morgan and Robin Casey and Joel Charrow and Clancy, {John P.} and Majed Dasouki and Stephanie DeArmey and Khan Nedd and Mary Nevins and Heidi Peters and Dawn Phillips and Zachary Spigelman and Cynthia Tifft and Kishnani, {Priya S.}",

note = "Funding Information: LEC has received honoraria from Genzyme Corporation of Sanofi, has participated in research supported by Genzyme Corporation of Sanofi, PTC Therapeutics, the Leal Foundation, Families of SMA, Enobia Pharma Inc./Alexion, the Robertson Foundation, GlaxoSmithKline, Eli Lilly, and CINRG, has been awarded grant support from the National Skeletal Muscle Research Center, and is a member of the Pompe Registry Board of Advisors for Genzyme Corporation of Sanofi. PSK has received research/grant support and honoraria from Genzyme Corporation. Priya S. Kishnani is a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Corporation. Duke University and the inventors of the method of treatment and precursors of the cell lines used to generate the enzyme (rhGAA) used commercially have received royalties pursuant to the University's policy on inventions, patents, and technology transfer. This potential conflict for Duke University has been resolved through monetization. Publisher Copyright: {\textcopyright} 2014 The Authors.",

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doi = "10.1016/j.nmd.2014.12.004",

language = "English (US)",

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AU - Case, Laura E.

AU - Bjartmar, Carl

AU - Morgan, Claire

AU - Casey, Robin

AU - Charrow, Joel

AU - Clancy, John P.

AU - Dasouki, Majed

AU - DeArmey, Stephanie

AU - Nedd, Khan

AU - Nevins, Mary

AU - Peters, Heidi

AU - Phillips, Dawn

AU - Spigelman, Zachary

AU - Tifft, Cynthia

AU - Kishnani, Priya S.

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PY - 2015/4/1

Y1 - 2015/4/1

N2 - Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20mg/kg/week or 40mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n=4), infantile-onset (n=9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy.

AB - Emerging phenotypes in long-term survivors with Pompe disease on standard enzyme replacement therapy (ERT) (alglucosidase alfa 20mg/kg/2 weeks) can include patients with worsening motor function. Whether higher doses of ERT improve skeletal function in these patients has not been systematically studied. This exploratory, randomized, open-label, 52-week study examined the safety and efficacy of 2 ERT regimens of alglucosidase alfa (20mg/kg/week or 40mg/kg/2 weeks) in 13 patients with Pompe disease and clinical decline or a lack of improvement on standard ERT: late-onset (n=4), infantile-onset (n=9). Cross-reactive immunologic material assay-negative patients were excluded. Eleven of 13 patients completed the study. Trends for improvement were seen in total gross motor function, but not mobility; however, 6 (late-onset, 2; infantile-onset, 4) of 11 patients (55%) who met the entry criteria of motor decline (late-onset, 4; infantile-onset, 7) showed improvement in motor and/or mobility skills. No between-regimen differences in efficacy emerged. Two case studies highlight the benefits of increased ERT dose in patients with Pompe disease experiencing clinical decline. Both alternative regimens were generally well tolerated. This study was limited by the small sample size, which is not uncommon for small clinical studies of rare diseases. Additionally, the study did not include direct assessment of muscle pathology, which may have identified potential causes of decreased response to ERT. Results were inconclusive but suggest that increased ERT dose may be beneficial in some patients with Pompe disease experiencing motor decline. Controlled studies are needed to clarify the benefits and risks of this strategy.

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KW - Clinical decline

KW - Dose

KW - Enzyme replacement therapy

KW - Infantile onset

KW - Late onset

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Safety and efficacy of alternative alglucosidase alfa regimens in Pompe disease

Abstract

Funding

Keywords

ASJC Scopus subject areas

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