Regular ArticleEnzyme replacement therapy with alglucosidase alfa in Pompe disease: Clinical experience with rate escalation
Introduction
Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the enzyme acid alpha-glucosidase (GAA) [1]. GAA degrades lysosomal glycogen and its deficiency leads to accumulation of glycogen in multiple tissues, particularly in skeletal, smooth, and cardiac muscle [2]. Classic infantile-onset Pompe disease (IOPD) is the most severe phenotype with onset of symptoms within the first few days to weeks of life. Patients with classic IOPD present with hypotonia, hypertrophic cardiomyopathy, myopathic facies, enlarged tongue, and without treatment, rarely survive beyond two years of age [2].
Enzyme replacement therapy (ERT) with alglucosidase alfa has led to significant improvement in clinical outcomes in patients with Pompe disease [3], [4], [5], [6]. However, response to ERT is variable and dependent on a number of factors including phenotype, age at ERT initiation, extent of preexisting pathology, cross-reactive immunologic material (CRIM) status, and rhGAA IgG antibody titers [7], [8], [9], [10]. While the benefits of ERT are considerable, patients often have residual physical impairments including muscle weakness, hearing loss, risk for arrhythmias, hypernasal speech, and dysphagia with risk for aspiration, ptosis, and osteopenia [11].
One strategy to minimize residual physical impairments is to administer ERT at a higher dose and frequency than 20 mg/kg every other week (EOW) as recommended in the Lumizyme® package insert [12], [13], [14], [15]. Prior clinical trials and published case reports have demonstrated that patients with IOPD can safely tolerate up to 40 mg/kg (referred to as higher dose ERT) every week [12], [13], [14], [16]. A recent study of CRIM-positive IOPD patients receiving higher dose ERT demonstrated respiratory and motor improvements compared with patients treated with 20 mg/kg/EOW [14]. Consequently, ERT at doses > 20 mg/kg is increasingly utilized in clinical practice [12], [14], [16].
As the dose of ERT increases, so does the total infusion duration. However, little is known about the effect of longer infusions on the psychosocial wellbeing of patients and their families. Increased infusion duration may compound the psychosocial burden and potentially further disrupt family activities and obligations. A study examining the impact of ERT on patients with LSDs found that while families were generally positive in regards to the health benefits of ERT, time spent getting infusions led to a feeling of “missing out” [17].
For the standard dose of 20 mg/kg, the recommended infusion rates are 1 mg/kg/h (30 min), 3 mg/kg/h (30 min), 5 mg/kg/h (30 min), and 7 mg/kg/h (remainder of the infusion) [15]. Therefore, the infusion duration for 20 mg/kg is 3 h 45 min and 40 mg/kg is 6 h 36 min. This can be a burdensome weekly time commitment for patients and their families. To administer higher dose ERT while reducing infusion duration, safe infusion rate escalation is needed. We developed an infusion rate escalation protocol with the goal of increasing the maximum infusion rate higher than the recommended 7 mg/kg/h and to safely reduce infusion duration. This infusion rate escalation protocol has been implemented successfully in 15 patients with either IOPD or late-onset Pompe disease (LOPD). Details on five patients with IOPD who were receiving higher dose ERT and who completed the infusion rate escalation protocol at Duke University are presented, along with guidelines for safely implementing rate escalation. In two of the five patients, the maximum infusion rate administered was increased to 11 mg/kg/h and the duration of initial rates (1, 3, 5, 7, 9, and 10 mg/kg/h) was shortened further reducing infusion time to 4 h 45 min (data not presented), whereas the other three patients have been infused at a maximum rate of 10 mg/kg/h.
Section snippets
Methods
Patients were selected for infusion rate escalation based on the following criteria; 1) a confirmed diagnosis of Pompe disease as described previously [2], [18], 2) treatment with higher dose ERT for at least six months, 3) low rhGAA IgG antibody titers (defined as antibody titers of < 12,800) [19], and 4) no history of severe IARs. Stepwise infusion rate escalation was performed clinically, not as a research protocol, at Duke University. Clinical data including demographics, GAA variants,
Results
Fifteen patients met the inclusion criteria for infusion rate escalation. Ten patients completed rate escalation at other institutions with guidance from PSK. Five IOPD patients who completed the infusion rate escalation protocol at Duke University are presented. Patient demographics, GAA variant data, age at diagnosis, age at ERT initiation, rhGAA IgG antibody titers prior to rate escalation, and history of IARs are shown in Table 2.
Discussion
Enzyme replacement therapy with alglucosidase alfa for IOPD has been available for over a decade, effectively transforming a formerly fatal disease into a treatable, though not yet curable, disorder. While ERT has revolutionized treatment for patients with IOPD and significantly improved clinical outcomes, quality of life remains reduced due to residual physical impairments. Immune modulation and earlier initiation of treatment through newborn screening initiatives have mitigated some of these
Authors' contributions
AKD, CKW, ZBK, SMD, and PSK participated in the design of the study. CKW, SMD, and PSK were involved in the clinical care of the patients at Duke University. Acquisition, analysis and interpretation of data were performed by AKD and CKW. All authors helped to draft the manuscript, and approved the final manuscript.
Conflict of interest disclosures
AKD, CKW, HLC, ZBK, and SMD have no financial or proprietary interest in the materials presented herein. PSK has received research/grant support and honoraria from Genzyme Corporation and Amicus Therapeutics. PSK is a member of the Pompe and Gaucher Disease Registry Advisory Board for Genzyme Corporation.
Funding
This research was supported by a grant from Genzyme Corporation, a Sanofi Company (Cambridge, MA), and in part by the Lysosomal Disease Network, a part of National Institutes of Health Rare Diseases Clinical Research Network (RDCRN) – Grant number (5U54NS065768-05) (Subaward number is N004689101). The Lysosomal Disease Network (U54NS065768) is a part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), and NCATS. This consortium
Ethics approval and consent to participate
Written informed consent was obtained from a parent or guardian for all individuals as part of Duke Institutional Review Board approved Pompe long-term follow-up study (Pro00010830) and/or Determination of CRIM status in Pompe disease (Pro00001562).
Acknowledgement
The authors thank the patients who participated in this study and their families. We thank Jennifer Coker, BSN, RN, CPN for her help with data acquisition. We thank Dr. Joan Keutzer, PhD for her critical review of the manuscript.
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