Background Pompe’s disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompe’s disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompe’s disease. Methods Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). Results At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1±13.1 m on the 6-minute walk test and an absolute increase of 3.4±1.2 percentage points in FVC; P = 0.03 and P = 0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). Conclusions In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa0909859

A Randomized Study of Alglucosidase Alfa in Late-Onset Pompe's Disease

Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants.

In a previous 52-wk trial, treatment with alglucosidase alfa markedly improved cardiomyopathy, ventilatory function, and overall survival among 18 children <7 mo old with infantile-onset Pompe disease. Sixteen of the 18 patients enrolled in an extension study, where they continued to receive alglucosidase alfa at either 20 mg/kg biweekly (n = 8) or 40 mg/kg biweekly (n = 8), for up to a total of 3 y. These children continued to exhibit the benefits of alglucosidase alfa at the age of 36 mo. Cox regression analyses showed that over the entire study period, alglucosidase alfa treatment reduced the risk of death by 95%, reduced the risk of invasive ventilation or death by 91%, and reduced the risk of any type of ventilation or death by 87%, compared with an untreated historical control group. Cardiomyopathy continued to improve and 11 patients learned and sustained substantial motor skills. No significant differences in either safety or efficacy parameters were observed between the 20 and 40 mg/kg biweekly doses. Overall, long-term alglucosidase alfa treatment markedly extended survival as well as ventilation-free survival and improved cardiomyopathy.

/pdf/early-treatment-with-alglucosidase-alfa-prolongs-long-term-8dth6fjc2k.pdf

Early Treatment with Alglucosidase Alfa Prolongs Long Term Survival of Infants with Pompe Disease

In 1964, Christian de Duve first suggested that enzyme replacement might prove therapeutic for lysosomal storage diseases (LSDs). Early efforts identified the major obstacles, including the inability to produce large quantities of the normal enzymes, the lack of animal models for proof-of-concept studies, and the potentially harmful immune responses to the "foreign" normal enzymes. Subsequently, the identification of receptor-mediated targeting of lysosomal enzymes, the cloning and overexpression of human lysosomal genes, and the generation of murine models markedly facilitated the development of enzyme replacement therapy (ERT). However, ERT did not become a reality until the early 1990s, when its safety and effectiveness were demonstrated for the treatment of type 1 Gaucher disease. Today, ERT is approved for six LSDs, and clinical trials with recombinant human enzymes are ongoing in several others. Here, we review the lessons learned from 20 years of experience, with an emphasis on the general principles for effective ERT and the remaining challenges.

/pdf/enzyme-replacement-therapy-for-lysosomal-diseases-lessons-3q6qn461ku.pdf

Enzyme replacement therapy for lysosomal diseases: lessons from 20 years of experience and remaining challenges.

The complexity of central breathing disturbances during sleep has become increasingly obvious. They present as central sleep apnoeas (CSAs) and hypopnoeas, periodic breathing with apnoeas, or irregular breathing in patients with cardiovascular, other internal or neurological disorders, and can emerge under positive airway pressure treatment or opioid use, or at high altitude. As yet, there is insufficient knowledge on the clinical features, pathophysiological background and consecutive algorithms for stepped-care treatment. Most recently, it has been discussed intensively if CSA in heart failure is a "marker" of disease severity or a "mediator" of disease progression, and if and which type of positive airway pressure therapy is indicated. In addition, disturbances of respiratory drive or the translation of central impulses may result in hypoventilation, associated with cerebral or neuromuscular diseases, or severe diseases of lung or thorax. These statements report the results of an European Respiratory Society Task Force addressing actual diagnostic and therapeutic standards. The statements are based on a systematic review of the literature and a systematic two-step decision process. Although the Task Force does not make recommendations, it describes its current practice of treatment of CSA in heart failure and hypoventilation.

https://erj.ersjournals.com/content/erj/49/1/1600959.full.pdf

John Charles A Loo

Papers

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