title: Survival and long-term outcomes in late-onset Pompe disease following alglucosidase alfa treatment: a systematic review and meta-analysis.
abstract: A number of studies have assessed the efficacy of alglucosidase alfa as an enzyme replacement therapy (ERT) on motor and respiratory endpoints in patients with late-onset Pompe disease (LOPD). A previous review evaluated the clinical efficacy and safety of alglucosidase alfa; however, it is difficult to draw inferences from individual studies due to small patient populations, particularly in evaluating the benefit on survival. To evaluate the current evidence on the long-term efficacy of alglucosidase alfa with regard to survival, motor, and respiratory function in patients with LOPD in relation to the natural progression of the disease, a new systematic literature review was performed identifying studies that assessed either mortality, percent predicted forced vital capacity (% FVC), or the 6-min walk test (6MWT) among treated and untreated LOPD patients. Patient overlap was avoided by removing smaller studies or ensuring the use of only one conflicting study per outcome. Mortality was modeled using Poisson models for each treatment group. Outcomes were modeled using first- and second-order fractional polynomial meta-analysis with fixed- and random-effects. Meta-regression was used to explore sources of heterogeneity. Twenty-two publications pertaining to 19 studies/trials were selected, including 438 patients when accounting for overlaps, with the average study duration being 45.7 months. Patients treated with alglucosidase alfa in these studies had a nearly five-fold lower mortality rate than untreated patients (rate ratio: 0.21; 95 % credible interval: 0.11, 0.41). On average, % FVC declined consistently among untreated patients, including a 2.3 % decline after 12 months follow-up and 6.2 % decline after 48 months. This is in contrast to alglucosidase alfa-treated patients, who, on average, improved rapidly, with an increase of 1.4 % FVC after 2 months, followed by a slow regression back to baseline over a three-year period. Nonetheless, the relative difference between those treated and not grew over time, from 4.5 % FVC after 12 months to 6 % FVC after 48 months. In the 6MWT, alglucosidase alfa-treated patients on average had the largest improvement over the first 20 months of treatment of approximately 50 meters increase over baseline, with its substantial stabilization in the following years. By comparison, untreated patients do not show 6MWT improvement over time. Alglucosidase alfa has a beneficial effect in LOPD patients as demonstrated by improvements in survival and ambulation maintained over time, as well as prevention of deterioration in respiratory function.
authors.affiliation: Friedrich-Baur-Institut, Neurologische Klinik, Klinikum der Universität München, Munich, Germany. bschoser@med.uni-muenchen.de.
authors.forename: Benedikt
authors.identifier: http://orcid.org/0000-0002-2757-8131
authors.initials: B
authors.lastname: Schoser
authors.affiliation: Sanofi Genzyme, Patient Outcomes and Medical Economics, Cambridge, MA, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stewart
authors.affiliation: School of Population and Public Health, University of British Columbia, Vancouver, Canada.|Redwood Outcomes, Vancouver, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Kanters
authors.affiliation: Sanofi Genzyme, Patient Outcomes and Medical Economics, Cambridge, MA, USA.
authors.forename: Alaa
authors.initials: A
authors.lastname: Hamed
authors.affiliation: Redwood Outcomes, Vancouver, Canada.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Jansen
authors.affiliation: Redwood Outcomes, Vancouver, Canada.
authors.forename: Keith
authors.initials: K
authors.lastname: Chan
authors.affiliation: School of Population and Public Health, University of British Columbia, Vancouver, Canada.|Redwood Outcomes, Vancouver, Canada.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Karamouzian
authors.affiliation: Department of Clinical and Experimental Medicine, Reference Center for Rare Neuromuscular Disorders, University of Messina, Messina, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Toscano
mesh_terms: D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000401:mortality*; D006801:Humans; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000627:therapeutic use*
chemical_list: C509951:GAA protein, human; D000520:alpha-Glucosidases
keywords: Alglucosidase alfa; Enzyme replacement therapy; Glycogen storage disease type 2; Late-onset Pompe disease (LOPD); Systematic review