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

Bernd C Schwahn, Francjan van Spronsen, Abdel Ali Belaidi, Stephen Bowhay, John Christodoulou, Terry G J Derks, Julia B Hennermann, Elisabeth Jameson, Kai Konig, Tracy McGregor, Esperanza Font-Montgomery, Jose Angel Santamaria-Araujo, Saikat Santra, Mamta Vaidya, Anne Vierzig, Evangeline Wassmer, Ilona Weis, Flora Yuen-Wait Wong, Alex Veldman, Guenter Schwarz

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 mug/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.
Original languageEnglish
Pages (from-to)1955 - 1963
Number of pages9
JournalThe Lancet
Volume386
DOIs
Publication statusPublished - 2015

Cite this

Schwahn, B. C., van Spronsen, F., Belaidi, A. A., Bowhay, S., Christodoulou, J., Derks, T. G. J., ... Schwarz, G. (2015). Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. The Lancet, 386, 1955 - 1963. https://doi.org/10.1016/S0140-6736(15)00124-5
Schwahn, Bernd C ; van Spronsen, Francjan ; Belaidi, Abdel Ali ; Bowhay, Stephen ; Christodoulou, John ; Derks, Terry G J ; Hennermann, Julia B ; Jameson, Elisabeth ; Konig, Kai ; McGregor, Tracy ; Font-Montgomery, Esperanza ; Santamaria-Araujo, Jose Angel ; Santra, Saikat ; Vaidya, Mamta ; Vierzig, Anne ; Wassmer, Evangeline ; Weis, Ilona ; Wong, Flora Yuen-Wait ; Veldman, Alex ; Schwarz, Guenter. / Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. In: The Lancet. 2015 ; Vol. 386. pp. 1955 - 1963.
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title = "Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study",
abstract = "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 mug/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.",
author = "Schwahn, {Bernd C} and {van Spronsen}, Francjan and Belaidi, {Abdel Ali} and Stephen Bowhay and John Christodoulou and Derks, {Terry G J} and Hennermann, {Julia B} and Elisabeth Jameson and Kai Konig and Tracy McGregor and Esperanza Font-Montgomery and Santamaria-Araujo, {Jose Angel} and Saikat Santra and Mamta Vaidya and Anne Vierzig and Evangeline Wassmer and Ilona Weis and Wong, {Flora Yuen-Wait} and Alex Veldman and Guenter Schwarz",
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Schwahn, BC, van Spronsen, F, Belaidi, AA, Bowhay, S, Christodoulou, J, Derks, TGJ, Hennermann, JB, Jameson, E, Konig, K, McGregor, T, Font-Montgomery, E, Santamaria-Araujo, JA, Santra, S, Vaidya, M, Vierzig, A, Wassmer, E, Weis, I, Wong, FY-W, Veldman, A & Schwarz, G 2015, 'Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study', The Lancet, vol. 386, pp. 1955 - 1963. https://doi.org/10.1016/S0140-6736(15)00124-5

Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. / Schwahn, Bernd C; van Spronsen, Francjan; Belaidi, Abdel Ali; Bowhay, Stephen; Christodoulou, John; Derks, Terry G J; Hennermann, Julia B; Jameson, Elisabeth; Konig, Kai; McGregor, Tracy; Font-Montgomery, Esperanza; Santamaria-Araujo, Jose Angel; Santra, Saikat; Vaidya, Mamta; Vierzig, Anne; Wassmer, Evangeline; Weis, Ilona; Wong, Flora Yuen-Wait; Veldman, Alex; Schwarz, Guenter.

In: The Lancet, Vol. 386, 2015, p. 1955 - 1963.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study

AU - Schwahn, Bernd C

AU - van Spronsen, Francjan

AU - Belaidi, Abdel Ali

AU - Bowhay, Stephen

AU - Christodoulou, John

AU - Derks, Terry G J

AU - Hennermann, Julia B

AU - Jameson, Elisabeth

AU - Konig, Kai

AU - McGregor, Tracy

AU - Font-Montgomery, Esperanza

AU - Santamaria-Araujo, Jose Angel

AU - Santra, Saikat

AU - Vaidya, Mamta

AU - Vierzig, Anne

AU - Wassmer, Evangeline

AU - Weis, Ilona

AU - Wong, Flora Yuen-Wait

AU - Veldman, Alex

AU - Schwarz, Guenter

PY - 2015

Y1 - 2015

N2 - 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 mug/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.

AB - 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 mug/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.

UR - http://www.sciencedirect.com/science/article/pii/S0140673615001245

U2 - 10.1016/S0140-6736(15)00124-5

DO - 10.1016/S0140-6736(15)00124-5

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EP - 1963

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JF - The Lancet

SN - 0140-6736

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