A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease

Abstract Background Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA. Results Reveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (−0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks. Conclusions Additional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late-onset Pompe disease. Trial registration ISRCTN01435772 and ISRCTN01230801 , registered 27 October 2011

Autopsy findings in late-onset Pompe disease: A case report and systematic review of the literature

Background Late-onset Pompe disease (LOPD) is a rare cause of declining proximal muscle strength and respiratory function that can also affect other organ systems. The development of enzyme replacement therapy has made it one of the few inherited muscle disorders with treatment, but clinical response is difficult to assess due to the variable and often slow progression of illness. A better understanding of the disease\u27s systemic effects can be gleaned through autopsy findings. Purpose The purpose of this study was to: (1) describe the histological findings observed in LOPD, (2) provide correlations between reported histological and clinical findings, and (3) review the literature on autopsy findings in LOPD. Methods Histological evaluation of autopsy tissues from a 62-year-old woman with LOPD was conducted. A clinical history was obtained by review of the medical records. The literature was reviewed for previously reported histological and clinical findings in LOPD. Based on this case report and information from prior publications, histological and clinical findings for the disease were correlated. Results Histologic examination revealed mostly mild vacuolar myopathy typical of glycogen accumulation within skeletal and smooth muscle cells. The most prominent vacuolar myopathy was in quadriceps muscle, which also exhibited chronic myositis with degenerating and regenerating muscle fibers. Transmission electron microscopy disclosed lysosomal glycogen accumulation within skeletal, cardiac, and vascular smooth muscle cells, correlating with published case reports of basilar artery and ascending aortic aneurysms and carotid artery dissection. Organs containing smooth muscle cells (the bladder, intestine, and esophagus) were also affected, explaining reports of symptoms such as urinary incontinence and dysphagia. In addition to glycogen accumulation, there was obvious damage to the contraction apparatus of myofibrils within cardiac and skeletal muscle cells. These histological and ultrastructural findings correlate with the clinical manifestations of LOPD. Conclusions This study is the first to describe histological findings of LOPD utilizing both traditional paraffin-processed tissues and epoxy resin embedded tissues for high-resolution light microscopy. The findings are similar to those seen in previous studies, but with improved morphological detail and glycogen preservation. This patient exhibited histological involvement of multiple organs, correlating with the clinical features of LOPD. With the advent of definitive therapy for Pompe disease, it is important to be aware of these findings and use them to develop methods for tracking therapeutic response. Highlights ► Autopsy studies are important in understanding the systemic effects of LOPD. ► Multiple organ involvement is evident in LOPD, correlating with clinical findings. ► Histologic quantification of glycogen may be a useful biomarker of ERT response

Enhanced efficacy from gene therapy in Pompe disease using coreceptor blockade

International audienceEnzyme replacement therapy (ERT) is the standard-of-care treatment of Pompe disease, a lysosomal storage disorder caused by deficiency of acid alpha-glucosidase (GAA). One limitation of ERT with recombinant human (rh) GAA is antibody formation against GAA. Similarly, in adeno-associated virus (AAV) vector-mediated gene transfer for Pompe disease, development of antibodies against the GAA transgene product and the AAV vector prevents therapeutic efficacy and vector readministration, respectively. Here a nondepleting anti-CD4 monoclonal antibody (mAb) was administrated intravenously prior to administration of an AAV2/9 vector encoding GAA to suppress anti-GAA responses, leading to a substantial reduction of anti-GAA immunoglobulins, including IgG1, IgG2a, IgG2b, IgG2c, and IgG3. Transduction efficiency in liver with a subsequent AAV2/8 vector was massively improved by the administration of anti-CD4 mAb with the initial AAV2/9 vector, indicating a spread of benefit derived from control of the immune response to the first AAV2/9 vector. Anti-CD4 mAb along with AAV2/9-CBhGAApA significantly increased GAA activity in heart and skeletal muscles along with a significant reduction of glycogen accumulation. Taken together, these data demonstrated that the addition of nondepleting anti-CD4 mAb with gene therapy controls humoral immune responses to both vector and transgene, resulting in clear therapeutic benefit in mice with Pompe disease

Algorithm for the Early Diagnosis and Treatment of Patients with Cross Reactive Immunologic Material-Negative Classic Infantile Pompe Disease: A Step towards Improving the Efficacy of ERT

OBJECTIVE: Although enzyme replacement therapy (ERT) is a highly effective therapy, CRIM-negative (CN) infantile Pompe disease (IPD) patients typically mount a strong immune response which abrogates the efficacy of ERT, resulting in clinical decline and death. This study was designed to demonstrate that immune tolerance induction (ITI) prevents or diminishes the development of antibody titers, resulting in a better clinical outcome compared to CN IPD patients treated with ERT monotherapy. METHODS: We evaluated the safety, efficacy and feasibility of a clinical algorithm designed to accurately identify CN IPD patients and minimize delays between CRIM status determination and initiation of an ITI regimen (combination of rituximab, methotrexate and IVIG) concurrent with ERT. Clinical and laboratory data including measures of efficacy analysis for response to ERT were analyzed and compared to CN IPD patients treated with ERT monotherapy. RESULTS: Seven CN IPD patients were identified and started on the ITI regimen concurrent with ERT. Median time from diagnosis of CN status to commencement of ERT and ITI was 0.5 months (range: 0.1–1.6 months). At baseline, all patients had significant cardiomyopathy and all but one required respiratory support. The ITI regimen was safely tolerated in all seven cases. Four patients never seroconverted and remained antibody-free. One patient died from respiratory failure. Two patients required another course of the ITI regimen. In addition to their clinical improvement, the antibody titers observed in these patients were much lower than those seen in ERT monotherapy treated CN patients. CONCLUSIONS: The ITI regimen appears safe and efficacious and holds promise in altering the natural history of CN IPD by increasing ERT efficacy. An algorithm such as this substantiates the benefits of accelerated diagnosis and management of CN IPD patients, thus, further supporting the importance of early identification and treatment initiation with newborn screening for IPD