Recombinant human acid -glucosidase Major clinical benefits in infantile-onset Pompe disease

Background: Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid -glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. Methods: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n 9) or 40 mg/kg (n 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. Results: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. Conclusions: Recombinant human acid -glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid -glucosidase in which patients were older. NEUROLOGY 2007;68:99–109 Editorial, see page 88. See also page 110. This article was previously published in electronic format as an Expedited E-pub at www.neurology.com From the Department of Pediatrics (P.S.K., M.M., J.L., D.B.), Duke University Medical Center, Durham, NC; Genzyme Corporation (D.C., B.T., S.R., M.A.W.), Cambridge, MA; Division of Pediatric Endocrinology (M.N., J.D.), Diabetology and Metabolism, Hôpital Debrousse, Lyon, France; Division of Pediatrics (B.B., C.S.), Shands Hospital at University of Florida, Gainesville, FL; Metabolic Unit (H.M., M.H.), Rambam Medical Centre, Haifa, Israel; Department of Pediatrics and Medical Genetics (W.L.H., Y.H.C.), National Taiwan University Hospital, Taipei, Taiwan; Department of Pediatrics and Medical Genetics (N.L., R.H.), Cincinnati Children’s Hospital Medical Center, Cincinnati, OH; Department of Cardiology (J.L.), Children’s Hospital, Boston, MA; Willink Biochemical Genetics Unit (S.V., J.E.W.), Royal Manchester Children’s Hospital, Manchester, UK; Department of Genetics (D.G.), Emory University Medical Center, Atlanta, GA; Department of Molecular and Human Genetics (D.B.), Columbus Children’s Hospital, Columbus, OH; Division of Metabolic Diseases and Genetics (A.V.D.P.), Department of Pediatrics, Erasmus Medical Center/Sofia Children’s Hospital, Rotterdam, The Netherlands; Department of Pediatrics (J.P.C.), University of Alabama at Birmingham, University of Alabama, Birmingham, AL; Centro Fondazione Mariani per le malattie metaboliche dell’Infanzia (R.P.), Department of Pediatrics, University Milano-Bicocca, San Gerardo Hospital, Monza, Italy; Département de Pédiatrie (G.M.), CHU Amiens, Amiens, France; Metabolic Unit (M.B.), Universitäts-Kinderklinik Mainz, Mainz, Germany; Pediatric Intensive Care Unit (G.S.D.l.G., M.J.), University Hospital Center Côte de Nacre, Caen, France; Genzyme Corporation (M.D.), Naarden, The Netherlands; Institute of Biomedical Sciences (Y.T.C.), Academica Sinica, Taipei, Taiwan. *These authors contributed equally to this study. Disclosure: D. Bali, B. Byrne, Y.T. Chen, R. Hopkin, P.S. Kishnani, H. Mandel, M. McDonald, M. Nicolino, C. Spencer, and A. van der Ploeg have received research/grant support from Genzyme Corporation for other research or activities not reported in this article. P.S. Kishnani, M. Nicolino, B. Byrne, and A. van der Ploeg are members of the Pompe Disease Advisory Board for Genzyme Corporation. Y.T. Chen and J. Levine have served as consultants for Genzyme. J. Levine, J.E. Wraith, C. Spencer, M. McDonald, Y.T. Chen, R. Hopkin, P.S. Kishnani, M. Nicolino, and H. Mandel have received honoraria from Genzyme Corporation. The clinical trials with rhGAA have been supported by a grant from Genzyme Corporation at the various sites at which patients were treated. rhGAA, in the form of Genzyme’s product Myozyme has now been approved in the United States, Canada, and the European Union as therapy for Pompe disease. Erasmus Medical Center/Sofia Children’s Hospital, Duke University, and inventors of the method of treatment and predecessors of the cell lines used to generate the enzyme (rhGAA) used in this clinical trial may benefit financially pursuant to their respective Policy on Inventions, Patents, and Technology Transfer, even if those cell lines are not used in the commercialized therapy. Received May 17, 2006. Accepted in final form October 10, 2006. Address correspondence and reprint requests to Dr. Priya Sunil Kishnani, Division of Medical Genetics, Department of Pediatrics, Box 3528, Duke University Medical Center, Durham, NC 27710; e-mail: [email protected] Copyright © 2007 by AAN Enterprises, Inc. 99 Pompe disease, also known as glycogen storage disease type II or acid maltase deficiency, is a rare, progressively debilitating, and often fatal lysosomal storage disorder. Patients with Pompe disease have an autosomal-recessively inherited deficiency of the enzyme acid -glucosidase (GAA), which hydrolyzes glycogen to glucose. This GAA deficiency causes glycogen to accumulate in multiple tissues, especially skeletal and cardiac muscle. Glycogen deposits disrupt muscle cytoarchitecture and function, causing progressive motor, respiratory, and cardiac dysfunction.1 Patient age at the onset of Pompe disease symptoms and the rate of deterioration can vary considerably.1 Patients with infantile-onset Pompe disease experience symptoms within the first year of life and progress rapidly to death. In other patients, symptoms are exhibited later and the disease progresses more slowly, but it is still associated with significant morbidity. Patients with early onset of symptoms typically manifest hypotonia, muscle weakness, and cardiomyopathy within the first months of life. The outlook for these patients is grim; they fail to acquire or lose motor developmental milestones, and cardiorespiratory failure and death usually occur before 1 year of age.2-4 Slonim et al.5 described a subset of infantile-onset patients with less severe cardiac involvement (i.e., less severe cardiomyopathy and a lack of cardiomegaly before the age of 6 months) who survived longer with ventilatory support. However, a recent retrospective chart review found early cardiomegaly even among first-birthday survivors.6 In this historical cohort, early symptom onset was associated with early demise. In early clinical trials, IV enzyme replacement with different forms of recombinant human (rh) GAA has improved survival, cardiac and respiratory function, and motor development in severely affected infants.7-11 A subset of these treated patients achieved independent ambulation. In a recent trial of rhGAA derived from transfected Chinese hamster ovary cells, eight of eight infants showed cardiac improvement, six were alive, and five were free of invasive ventilation after 52 weeks of treatment, and five attained new motor milestones.11 Of the three patients who eventually achieved the ability to walk independently, all had begun treatment prior to the age of 6 months, suggesting that early treatment may be critical for the optimal motor response to treatment.11 In this multicenter, multinational, open-label, dose-ranging study, we examined the safety and efficacy of rhGAA treatment in a larger cohort of severely affected patients with Pompe disease who began treatment prior to 6 months of age. Methods. Study design and treatment. Local institutional review boards or independent ethics committees approved protocols and consent forms at each of 13 primary sites (six centers in the Untied States, five in Europe, one in Taiwan, and one in Israel). Parents or guardians gave written informed consent for patients’ participation. An independent data safety monitoring board reviewed safety; an independent allergic reaction review board was consulted, if required, for issues related to serious infusionassociated reactions (IARs). Eligible patients had documented symptoms of infantile-onset Pompe disease, including skin fibroblast GAA activity 1% of the normal mean and hypertrophic cardiomyopathy (left ventricular mass index 65 g/m by echocardiogram); they were no older than 26 weeks at enrollment. Exclusion criteria included respiratory insufficiency (O2 saturation 90% or CO2 partial pressure 55 mm Hg [venous] or 40 mm Hg [arterial] in room air or any ventilator use), a major congenital anomaly or clinically significant intercurrent illness unrelated to Pompe disease, or any prior GAA treatment. A total of 18 patients were studied. Parents or legal guardians were informed that the protocoldefined stopping rules related to the occurrence of serious adverse events (AEs) and allowed for temporary or permanent patient discontinuation if the investigator, safety review board, and sponsor determined there was a significant risk to patient safety. It was considered unethical to include a placebo group as part of the study design for the following reasons: 1) infantile-onset Pompe disease is a rapidly fatal disorder and 2) early clinical trials have shown that treatment with various forms of rhGAA can improve survival, cardiac and respiratory function, growth, and motor development in severely affected infants.7-11 Thus, a historical control group of 61 severely affected infants 6 months old and younger was identified by applying the study inclusion and exclusion criteria to a group of 168 patients with infantileonset Pompe disease identified through a retrospective chart review.6 The cohort included 168 patients from nine countries, 33 different sites, with birth dates ranging from before 1985 to 2002.6 Drug effects on overall survival (with or without ventilator use) and invasive ventilator-free survival were compared between treated patients and this historical cohort; our group of 18 treated patients provided 98% power to detect a difference between treated and control groups. Table 1 summarizes the screening criteria applied to the original historical patient population in order for patients to be included in the historical control subgroup. Alglucosidase alfa, which contains rhGAA produced in Chinese hamster ovary cells, was supplied by Genzyme Corporation. A simple randomization scheme was used to assign patients to the two dose groups. Upon confirmation that patients met all eligibility criteria and completion of pretreatment screening and baseline assessments, eligible patients were randomized in a 1:1 ratio to receive an IV infusion of either 20 mg/kg or 40 mg/kg of rhGAA every other week. Clinicians and patients were not blinded to the dose of rhGAA used. The total amount of rhGAA administered could be adjusted every 4 weeks to account for changes in body weight. Clinical assessments of safety and efficacy. Patients were observed and their vital signs were monitored during rhGAA infusion and for 2 hours afterward. Safety assessments included evaluating blood and urine chemistry (data not shown), the occurrence and timing of the development of anti-rhGAA IgG antibodies (assayed at first rhGAA infusion and every 4 weeks thereafter), and the incidence and nature of AEs, including IARs. Efficacy was measured by assessing survival, ventilator use, left ventricular mass by echocardiography, growth (weight and length), muscle GAA activity and glycogen levels, motor development (using the Alberta Infant Motor Scale [AIMS]12), and level of disability (using an adaptation of the Pediatric Evaluation of Disability Index [PEDI]13 developed for Pompe disease.14,15 Although not an efficacy endpoint, cognitive development (using Bayley’s Scales of Infant Development, Second Edition [BSID-II]) was also serially evaluated.16 Echocardiograms and glycogen content in muscle biopsy samples were centrally read by a pediatric cardiologist and a pathologist who were blinded to dose, patient, and time point. Motor and cognitive evaluations were centrally scored by a nonblinded central clinician. Survival and ventilation data were analyzed up to 18 months of age, as compared to survival of the historical control group; all other efficacy data were analyzed with respect to changes from baseline after 52 weeks of treatment. The primary efficacy endpoint was the Kaplan-Meier17 proportion of patients alive and free of invasive ventilation at 18 months of age. Safety data were analyzed for the duration of treatment. Because patients were enrolled over a period of 1 year, safety data ranged from 52 weeks for the last patient randomized to treatment to 106 weeks for the first patient treated with rhGAA. 100 NEUROLOGY 68 January 9, 2007 GAA activity assay. Cultured skin fibroblasts and muscle biopsy tissue obtained from patients were assayed for GAA activity against 4-methylumbelliferyl -d-glucoside in an assay similar to the method of Reuser et al.18 and described in detail in Kishnani et al.11 Biochemical glycogen determination. Open quadriceps muscle biopsies were performed at baseline and weeks and week 52. Biopsy samples taken at weeks 12 and 52 were obtained 48 hours after the regularly scheduled rhGAA infusion for that visit. A 0.5 0.5 3-cm sample was taken from alternating sides at each time point under general, regional, or local anesthesia. Methods for glycogen quantification were performed as described in Kishnani et al.11 Briefly, for biochemical analysis, muscle tissues were homogenized, centrifuged, boiled, and treated with amyloglucosidase to digest the glycogen. The glucose produced was quantified with a Glucose Trinder Kit (Sigma, St. Louis, MO). Biochemical measurements of glycogen levels in skeletal muscle of normal children are not available. Therefore, changes in glycogen content were compared between baseline and week 52 within individual patients. Anti-rhGAA antibody testing. Serum samples were taken prior to each infusion from initiation of therapy through week 24, and subsequently at weeks 38, 52, 64, 78, 90, and 104. As discussed above, different patients received different durations of rhGAA treatment, ranging from 52 to 106 weeks, depending on when they enrolled in the study. The presence of IgG antibodies to rhGAA was assessed using enzyme-linked immunosorbent assays and confirmed using radioimmunoprecipitation, as described in Kishnani et al.11 Genotyping. DNA was isolated from the peripheral blood of patients and sequenced. GAA mutation analysis was determined by Genzyme Corporation, as described previously.11 Cross-reacting immunologic material (CRIM) status. CRIM status was determined as described previously.11 Briefly, cell lysates derived from patients’ fibroblasts were subjected to Western blot analysis with a pool of monoclonal antibodies that recognize both native and recombinant GAA. A patient was considered to be CRIM positive if the presence of any of these forms of GAA was detected in samples prepared from patient fibroblasts in the Western blot assay. Results. Disposition of patients. A total of 20 patients were evaluated for eligibility to participate in this study (figure 1). Two patients were excluded from the study; one was determined not to have Pompe disease based on GAA activity levels. The other required ventilation during the baseline period before receiving any treatment. This patient was discontinued from the study because the use of any ventilation at the time of enrollment was an exclusion criterion but went on to receive rhGAA under an expanded