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.

Long-term exposure to Myozyme results in a decrease of anti-drug antibodies in late-onset Pompe disease patients

“…This finding, which possibly reflects a worsening of the disease despite ERT in a subset of patients, will need to be confirmed in larger studies. Notably, a recently published meta-analysis of clinical trials involving LOPD patients undergoing ERT also showed a marked improvement in 6MWT and FVC in the first year of treatment, followed by a subsequent stabilization or decline in performance11.…”

“…The approval of recombinant human GAA (rhGAA) (Myozyme) for the treatment of Pompe disease resulted in a significant improvement of both life expectancy and quality of life of infantile PD patients7, although long-term follow up of children treated with enzyme replacement therapy (ERT) revealed occurrence of symptoms resulting from the incomplete correction of the enzyme deficiency in certain tissues8. Approval of ERT for LOPD patients followed that of pediatric subjects few years later, and long-term benefit of ERT in this population is still being assessed91011.…”

Acute respiratory failure as presentation of late-onset Pompe disease complicating the diagnostic process as a labyrinth: a case report

“…Replacement therapy with alglucosidase alfa (Myozyme®, Genzyme), a recombinant lysosomal glycogen-cleaving enzyme, is at present the only specific pharmacological approach for LOPD. A recent systematic literature review evaluated 22 publications and 438 patients [12]. Treatment with alglucosidase alfa had a mortality rate nearly five-fold lower compared to untreated patients.…”

Headache: A Presentation of Pompe Disease; A Case Report

“…Specific treatment with enzyme replacement (human recombinant GAA) is available [17], which highlights the importance of early diagnosis. In addition, appropriate management of respiratory disturbances with non-invasive positive pressure ventilation (NIPPV) and assisted coughing is able to improve the prognosis [7,8].…”

“…The patient has also received enzyme replacement. A systemic review showed that enzyme replacement therapy was associated an increase of 1.4 % FVC after 2 months [17]. Because of such effective treatments, physicians are advised to be informed about various presentation of Pompe disease, especially respiratory insufficiency as an essentially fatal condition [18].…”