Fosdenopterin: a First-in-class Synthetic Cyclic Pyranopterin Monophosphate for the Treatment of Molybdenum Cofactor Deficiency Type A

Schwahn, Bernd

doi:10.17925/usn.2021.17.2.85

Cited by 3 publications

(12 citation statements)

References 59 publications

(82 reference statements)

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“…The pharmacodynamic biomarkers S-sulfocysteine, xanthine, hypoxanthine and urate respond within 24-48 h and return to normal or near-normal concentrations within 1 week. 16,25,65,80,125 No biochemical effect has been observed in patients with MoCD type B upon cPMP substitution. 25 Since the first treatment in 2008, no decrease in biochemical efficacy over time was observed, suggesting no requirement for frequent biochemical monitoring once a child is reliably established on treatment.…”

Section: Ongoing Surveillance For Specific Complicationsmentioning

confidence: 99%

“…127 No pharmacodynamic data have been published to demonstrate a dose-response relationship or the benefits of higher doses. 16 The starting dose for the licensed preparation fosdenopterin (as free base) has been determined by the license holder as 400 μg/kg in pre-term infants and 550 μg/kg in term infants, administered once daily as slow intravenous infusion. A dose of 900 μg/kg once daily is suggested after the first 2 months of treatment and for any child that is over 1 year old at the start of treatment.…”

Section: Ongoing Surveillance For Specific Complicationsmentioning

confidence: 99%

“…The overall survival of a cohort of children with MoCD-A treated with cPMP substitution was improved over a comparable cohort of untreated children. 16,24,25,124,127 The long-term neurological outcome of children with MoCD-A treated with cPMP has been variable, depending on the extent of irreversible brain injury prior to treatment. A small number of neonates with MoCD-A that were treated with cPMP substitution prior to showing signs of severe acute sulfite encephalopathy have not developed cystic encephalomalacia and severe cerebral palsy, as opposed to their untreated affected siblings who displayed the typical phenotype of MoCD.…”

Section: Ongoing Surveillance For Specific Complicationsmentioning

confidence: 99%

“…Since 2008, cPMP has been available in clinical trials and in compassionate use programs for a small number of individual patients. 16 Treatment with synthetic cPMP (fosdenopterin) has been granted market authorization for the treatment of MoCD type A by FDA in February 2021, by the Israeli Ministry of Health in July 2022 and by EMA in September 2022. The evidence base for the rational use of cPMP is very limited.…”

Section: Introductionmentioning

confidence: 99%

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Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies

Schwahn,

van Spronsen,

Misko

et al. 2024

J of Inher Metab Disea

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Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD‐A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search.

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Section: Ongoing Surveillance For Specific Complicationsmentioning

confidence: 99%

Section: Ongoing Surveillance For Specific Complicationsmentioning

confidence: 99%

Section: Ongoing Surveillance For Specific Complicationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies

Schwahn,

van Spronsen,

Misko

et al. 2024

J of Inher Metab Disea

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“…Finally, in 2021, chemically synthesized cPMP (named ‘Fosdenopterin’) was approved by the FDA and received marketing authorization as a Nulibry product [ 90 ]. It is administered via daily intravenous injections at a concentration of 400 µg/kg in pre-term infants and 550 µg/kg in term infants until it is increased to 900 µg/kg after the first three months of treatment or directly for children starting the therapy at the age of one year or later (Nulibry prescribing information [ 91 ]).…”

Section: Therapies To Treat Mocdmentioning

confidence: 99%

Molybdenum Cofactor Deficiency in Humans

Johannes

Schwarz

2022

Molecules

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Molybdenum cofactor (Moco) deficiency (MoCD) is characterized by neonatal-onset myoclonic epileptic encephalopathy and dystonia with cerebral MRI changes similar to hypoxic–ischemic lesions. The molecular cause of the disease is the loss of sulfite oxidase (SOX) activity, one of four Moco-dependent enzymes in men. Accumulating toxic sulfite causes a secondary increase of metabolites such as S-sulfocysteine and thiosulfate as well as a decrease in cysteine and its oxidized form, cystine. Moco is synthesized by a three-step biosynthetic pathway that involves the gene products of MOCS1, MOCS2, MOCS3, and GPHN. Depending on which synthetic step is impaired, MoCD is classified as type A, B, or C. This distinction is relevant for patient management because the metabolic block in MoCD type A can be circumvented by administering cyclic pyranopterin monophosphate (cPMP). Substitution therapy with cPMP is highly effective in reducing sulfite toxicity and restoring biochemical homeostasis, while the clinical outcome critically depends on the degree of brain injury prior to the start of treatment. In the absence of a specific treatment for MoCD type B/C and SOX deficiency, we summarize recent progress in our understanding of the underlying metabolic changes in cysteine homeostasis and propose novel therapeutic interventions to circumvent those pathological changes.

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N-Heterocycles as Privileged Scaffolds in FDA Approved Different NMEs of 2021: A Review

Chaudhry

Munir

Malik

2023

LOC

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Presence of N-heterocyclic ring systems as promising features in the molecular skeleton of FDA approved drugs, underlie the remarkable contributions of these heterocyclic nuclei in the field of medicine. Despite instability risks associated with COVID pandemic, the US FDA approved 50 drugs (36 NMEs and 14 biological products) in the year 2021. The active ingredients of 32 drugs out of these 36 NMEs (almost 89%) contain saturated, partially unsaturated and/or aromatic N-heterocyclic moieties in their molecular assemblies, hence dominating the medicinal approvals. While 27 molecules (75% of these NMEs drugs) are prominent small NMEs. Herein, we have considered profiling of those FDA approved 27 small-molecule drugs which are decorated with N-heterocycles as privileged scaffolds. These drugs are grouped on the basis of a number of N-heterocycles present in their structural framework. The spectrum of these drugs in terms of their structural features and medicinal importance is summarized in this review. Also, the pertinent analyses of their drug-likeliness conferring some general pharmacokinetic principles is highlighted.

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Fosdenopterin: a First-in-class Synthetic Cyclic Pyranopterin Monophosphate for the Treatment of Molybdenum Cofactor Deficiency Type A

Cited by 3 publications

References 59 publications

Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies

Consensus guidelines for the diagnosis and management of isolated sulfite oxidase deficiency and molybdenum cofactor deficiencies

Molybdenum Cofactor Deficiency in Humans

N-Heterocycles as Privileged Scaffolds in FDA Approved Different NMEs of 2021: A Review

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