Patient registries for rare diseases enable systematic data collection and can also be used to facilitate postauthorization safety studies (PASS) for orphan drugs. This study evaluates the PASS for betaine anhydrous (Cystadane), conducted as public private partnership (PPP) between the European network and registry for homocystinurias and methylation defects and the marketing authorization holder (MAH). Data were prospectively collected, 2013-2016, in a noninterventional, international, multicenter, registry study. Putative adverse and severe adverse events were reported to the MAH's pharmacovigilance. In total, 130 individuals with vitamin B6 nonresponsive (N = 54) and partially responsive (N = 7) cystathionine beta-synthase (CBS) deficiency, as well as 5,10-methylenetetrahydrofolate reductase (MTHFR; N = 21) deficiency and cobalamin C (N = 48) disease were included. Median (range) duration of treatment with betaine anhydrous was 6.8 (0-9.8) years. The prescribed betaine dose exceeded the recommended maximum (6 g/day) in 49% of individuals older than 10 years because of continued dose adaptation to weight; however, with disease-specific differences (minimum: 31% in B6 nonresponsive CBS deficiency, maximum: 67% in MTHFR deficiency). Despite dose escalation no new or potential risk was identified. Combined disease-specific treatment decreased mean ± SD total plasma homocysteine concentrations from 203 ± 116 to 81 ± 51 μmol/L (p < 0.0001), except in MTHFR deficiency. Recommendations for betaine anhydrous dosage were revised for individuals ≥ 10 years. PPPs between MAH and international scientific consortia can be considered a reliable model for implementing a PASS, reutilizing well-established structures and avoiding data duplication and fragmentation.

Alder Hey Children's NHS Foundation Trust Liverpool UK

Ap HP Sorbonne University Reference Center for Adult Neurometabolic Diseases La Pitié Salpêtrière University Hospital Paris France

Centre de Référence des Maladies Héréditaires du Métabolisme CHU La Timone Enfants Marseille France

Centre de Référence des Maladies Héréditaires du Métabolisme Hôpital Jeanne de Flandre Lille France

Department of Clinical Genetics Center for Lysosomal and Metabolic Diseases Erasmus Medical Center Rotterdam Netherlands

Department of Clinical Inherited Metabolic Disorders Birmingham Women's and Children's NHS Foundation Trust Birmingham UK

Department of Pediatrics and Inherited Metabolic Disorders Charles University 1st Faculty of Medicine and General University Hospital Prague Czech Republic

Department of Pediatrics Landeskrankenhaus Bregenz Bregenz Austria

Department of Pediatrics University Hospital Centre Zagreb and University of Zagreb School of Medicine Zagreb Croatia

Division of Child Neurology and Metabolic Medicine Centre for Child and Adolescent Medicine University Hospital Heidelberg Germany

Division of Metabolism and Children's Research Center University Children's Hospital University of Zurich Zurich Switzerland

Division of Metabolism Bambino Gesù Children's Hospital IRCCS Rome Italy

Endocrinology and Nutrition Metabolic Congenital Disease H U Ramon y Cajal Madrid Spain

Endocrinology Nutrition and Metabolic Diseases Haut Lévêque Hospital Bordeaux University Bordeaux France

Evelina London Children's Hospital London UK

Inserm UMR_S1163 Institut Imagine Paris France

Instituto de Investigación Santiago de Compostela Spain

Manchester Centre for Genomic Medicine Manchester University Hospitals NHS Trust Manchester UK

Metabolic Department University Children Miguel Servet Hospital Aragon Spain

Necker Hospital APHP Reference Center for Inborn Error of Metabolism and Filière G2M Pediatrics Department University of Paris Paris France

Nephrology and Transplantation MAMEA Reference Center Necker hospital APHP Paris France

Pediatric Unit for Metabolic Diseases Woman Mother Child Department Lausanne University Hospital Lausanne Switzerland

Pediatrics Gastroenterology Hepatology and Nutrition Hospital Sant Joan de Déu Barcelona Spain

Recordati Rare Diseases Puteaux France

Unit of Diagnosis and Treatment of Congenital Metabolic Diseases Service of Neonatology Department of Pediatrics Hospital Clínico Universitario de Santiago CIBERER Health Research Institute of Santiago de Compostela Santiago de Compostela Spain

Unit of Metabolic Disorders Universitary Hospital La Fe Valencia Spain

See more in PubMed

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Cystathionine β-Synthase Deficiency in the E-HOD Registry-Part II: Dietary and Pharmacological Treatment

Recent therapeutic approaches to cystathionine beta-synthase-deficient homocystinuria