Chinese hamster ovary cell-derived recombinant human acid α-glucosidase in infantile-onset Pompe disease

Abstract

Objective-To conduct an open-label, multinational, multicenter study examining the safety and efficacy of recombinant human acid α-glucosidase (rhGAA) in treatment of infantile-onset Pompe disease.Study design-We enrolled 8 infant patients who had Pompe disease with GAA activity <1% of normal, cardiomyopathy, and hypotonia. In the 52-week initial phase, rhGAA was infused intravenously at 10 mg/kg weekly; an extension phase continued survivors' treatment with 10 to 20 mg/kg of rhGAA weekly or 20 mg/kg every 2 weeks for as long as 153 weeks. Safety measurements included adverse events, laboratory tests, and anti-rhGAA antibody titers. Efficacy evaluations included survival, ventilator use, echo-cardiograms, growth, and motor and cognitive function.Result-After 52 weeks of treatment, 6 of 8 patients were alive, and 5 patients were free of invasive ventilator support. Clinical improvements included ameliorated cardiomyopathy and improved growth and cognition. Five patients acquired new motor milestones; 3 patients walked independently. Four patients died after the initial study phase; the median age at death or treatment withdrawal for all patients was 21.7 months, significantly later than expected for patients who were not treated. Treatment was safe and well tolerated; no death was drug-related. Patients with infantile-onset Pompe disease typically present before 12 months of age with progressive, hypertrophic cardiomyopathy that may obstruct left ventricular outflow; profound muscle weakness and hypotonia; non-attainment or loss of motor milestones; difficulty feeding; and failure to thrive. These patients have a dramatically shortened life span. In patients who are not treated, the median age of death ranges from 6.0 to 8.7 months. 4,7 In the most rapidly progressive form, also termed "classic" infantile Pompe disease, the mortality rate is as high as 92% to 95% in the first year of life. 7 In an historical cohort of patients manifesting Pompe disease in the first year of life, irrespective of phenotype, 74% died by 1 year of age, 91% by 2 years of age, and 93% by 3 years of age. 7 Death generally results from cardiac and respiratory failure. 1,3,7No approved specific treatment for Pompe disease currently exists. However, recombinant human GAA (rhGAA) has shown physiological activity both in animal disease models and in early clinical trials. 8-15 In 3 pilot studies in severely affected infants, rhGAA (purified from transgenic rabbit milk 11-14 or from Chinese hamster ovary [CHO] cell cultures 8 ) markedly ameliorated cardiomyopathy and prolonged all patients' survival beyond 1 year. One of 6 patients given rhGAA from rabbit milk (a preparation that is no longer available) and 1 of 3 patients given CHO cell-derived rhGAA walked independently and remained ventilator-free. The remaining 7 patients from these 3 studies showed lesser degrees of motor improvement and eventually required ventilation. As of January 2006, 3 of the 9 patients in these pilot studies had died and 6 remained alive (unpublished data)...

CRIM‐negative infantile Pompe disease: 42‐month treatment outcome

“…Furthermore, there are only a few reports on brain imaging in infants with classic Pompe disease. This may be attributed to the early mortality usually observed in untreated patients, the lack of close monitoring OF CNS parameters due to the historical endpoints chosen to prove the efficacy of ERT (Amalfitano et al 2001;Kishnani et al 2006bKishnani et al , 2007Klinge et al 2005; Van den Hout et al 2001, or to difficulties of cognitive testing and the risk of sedation for MRI in patients on ERT who may still have significant respiratory muscle weakness and/or cardiomyopathy. Furthermore, it also became evident that not all patients responded equally well to ERT regarding motor development, and it has been shown that this is dependent on CRIM status and hypothesized to be directly mediated by antibody response to ERT (Kishnani et al 2010).…”

“…Kishnani et al reported that CRIM-negative status predicted reduced overall survival and invasive ventilator-free survival and poorer motor development in ERT-treated infants with Pompe disease (Kishnani et al 2010). The effect of CRIM status was hypothesized to be mediated by antibody response to exogenous protein (Kishnani et al 2007;Kishnani et al 2010;Kishnani et al 2006b). Induction of immune modulation to eliminate antibodies in a CRIM-negative patient was first reported through intravenous administration of gamma globulin, anti-CD20 monoclonal antibody (rituximab), and methotrexate (Mendelsohn et al 2009) and proved to be a promising approach to overcome poor prognosis in CRIM-negative patients (Kishnani et al 2010).…”

Postmortem Findings and Clinical Correlates in Individuals with Infantile-Onset Pompe Disease

“…Infantile-onset Pompe disease (IPD) presents in the first few days to weeks of life with hypotonia, developmental delay, and cardiomyopathy. Enzyme replacement therapy (ERT) with recombinant acid alpha-glucosidase (rhGAA) improves survival in IPD (van den Hout et al 2000;Kishnani et al 2006). While the disorder was described decades ago, our understanding of disease complications continues to evolve, particularly as ERT has improved survival.…”

Response to Reuser

“…[3][4][5][6][7][8] In fact, dosing for acid alpha glucosidase is now clinically indicated at essentially an equivalent dosing for all Pompe patients, albeit now being given as a total dose of 20-mg/kg-every-other-week infusion, to reduce the need for frequent intravenous infusions. 9 The problems of lack of sustained improvement in motor status in CRIM-negative patients with high-titer antibody have also been verified, indeed new clinical trials attempting to address this concern are ongoing.…”