Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study.

Esperanza Font-Montgomery, Günter Schwarz, Alex Veldman, Flora Y Wong, Ilona Weis, Evangeline Wassmer, Anne Vierzig, Mamta Vaidya, Saikat Santra, José A Santamaria-Araujo, Bernd C Schwahn, Tracy L McGregor, Kai König, Elisabeth Jameson, Julia B Hennermann, Terry G Derks, John Christodoulou, Stephen Bowhay, Abdel A Belaidi, Francjan J Van Spronsen

Journal: Lancet (London, England) 2016;386(10007):1955-1963

PMID: 26343839

Full Text on Elsevier Science View on PubMed

Abstract

BACKGROUND

Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor.

METHODS

In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80-320 μg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP.

FINDINGS

Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease.

INTERPRETATION

cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit.

FUNDING

German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.

Address: Royal Hospital for Sick Children, NHS Greater Glasgow and Clyde, Glasgow, UK; Willink Biochemical Genetics Unit, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. Electronic address: [email protected].; Beatrix Children's Hospital, University Medical Center of Groningen, University of Groningen, Groningen, Netherlands.; Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne, CECAD Cologne, University of Cologne, Cologne, Germany; Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia.; Royal Hospital for Sick Children, NHS Greater Glasgow and Clyde, Glasgow, UK.; Western Sydney Genetics Program, Children's Hospital at Westmead, and Disciplines of Paediatrics & Child Health and Genetic Medicine, University of Sydney, Sydney, NSW, Australia.; Villa Metabolica, Center for Pediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.; Willink Biochemical Genetics Unit, Saint Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.; Department of Pediatrics, Mercy Hospital for Women, Melbourne, VIC, Australia.; Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr Children's Hospital at Vanderbilt, Nashville, TN, USA.; Children's Hospital of Wisconsin, Milwaukee, WI, USA.; Orphatec/Colbourne Pharmaceuticals, Niederkassel, Germany.; Birmingham Children's Hospital, Birmingham, UK.; Paediatric Intensive Care, Bart's Health NHS Trust, Royal London Hospital, London, UK.; Paediatric Intensive Care, University Children's Hospital, University of Cologne, Cologne, Germany.; Children's Hospital, Gemeinschaftsklinikum Koblenz-Mayen, Kemperhof, Koblenz, Germany.; Monash Newborn, Monash Medical Centre, The Ritchie Centre, Hudson Institute of Medical Research, and The Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Orphatec/Colbourne Pharmaceuticals, Niederkassel, Germany; Monash Newborn, Monash Medical Centre, The Ritchie Centre, Hudson Institute of Medical Research, and The Department of Paediatrics, Monash University, Melbourne, VIC, Australia.; Institute of Biochemistry, Department of Chemistry, Center for Molecular Medicine Cologne, CECAD Cologne, University of Cologne, Cologne, Germany; Orphatec/Colbourne Pharmaceuticals, Niederkassel, Germany.

DOI: 10.1016/S0140-6736(15)00124-5

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MeSH Terms: Cohort Studies, Compassionate Use Trials, Drug Administration Schedule, Female, Humans, Infant, Newborn, Male, Metal Metabolism, Inborn Errors, Organophosphorus Compounds, Pterins, Treatment Outcome