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Identification
- Summary
Fosdenopterin is an exogenous form of cyclic pyranopterin monophosphate (cPMP) used as a replacement substrate in patients with molybdenum cofactor deficiency (MoCD) type A.
- Brand Names
- Nulibry
- Generic Name
- Fosdenopterin
- DrugBank Accession Number
- DB16628
- Background
Molybdenum cofactor deficiency (MoCD) is an exceptionally rare autosomal recessive disorder resulting in a deficiency of three molybdenum-dependent enzymes: sulfite oxidase (SOX), xanthine dehydrogenase, and aldehyde oxidase.1 Signs and symptoms begin shortly after birth and are caused by a build-up of toxic sulfites resulting from a lack of SOX activity.1,5 Patients with MoCD may present with metabolic acidosis, intracranial hemorrhage, feeding difficulties, and significant neurological symptoms such as muscle hyper- and hypotonia, intractable seizures, spastic paraplegia, myoclonus, and opisthotonus. In addition, patients with MoCD are often born with morphologic evidence of the disorder such as microcephaly, cerebral atrophy/hypodensity, dilated ventricles, and ocular abnormalities.1 MoCD is incurable and median survival in untreated patients is approximately 36 months1 - treatment, then, is focused on improving survival and maintaining neurological function.
The most common subtype of MoCD, type A, involves mutations in MOCS1 wherein the first step of molybdenum cofactor synthesis - the conversion of guanosine triphosphate into cyclic pyranopterin monophosphate (cPMP) - is interrupted.1,3 In the past, management strategies for this disorder involved symptomatic and supportive treatment,5 though efforts were made to develop a suitable exogenous replacement for the missing cPMP. In 2009 a recombinant, E. coli-produced cPMP was granted orphan drug designation by the FDA, becoming the first therapeutic option for patients with MoCD type A.1
Fosdenopterin was approved by the FDA on Februrary 26, 2021, for the reduction of mortality in patients with MoCD type A,5 becoming the first and only therapy approved for the treatment of MoCD. By improving the three-year survival rate from 55% to 84%,7 and considering the lack of alternative therapies available, fosdenopterin appears poised to become a standard of therapy in the management of this debilitating disorder.
In July 2022, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended fosdenopterin be granted marketing authorization under exceptional circumstances for the treatment of patients with molybdenum cofactor deficiency (MoCD) Type A.9 In September 2022, the EMA approved the use of fosdenopterin.10,11
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Fosdenopterin (DB16628)
- Weight
- Average: 363.223
Monoisotopic: 363.057999429 - Chemical Formula
- C10H14N5O8P
- Synonyms
- C(PMP)
- CPMP
- Cyclic pyranopterin monophosphate
- Fosdenopterin
- External IDs
- ALXN-1101
- ALXN1101
- ORGN001
- WHO 11150
Pharmacology
- Indication
Fosdenopterin is indicated to reduce the risk of mortality in patients with molybdenum cofactor deficiency (MoCD) type A.7
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Management of Molybdenum cofactor deficiency, type a •••••••••••• ••••••••• - Contraindications & Blackbox Warnings
Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API- Pharmacodynamics
Fosdenopterin replaces an intermediate substrate in the synthesis of molybdenum cofactor, a compound necessary for the activation of several molybdenum-dependent enzymes including sulfite oxidase (SOX).1 Given that SOX is responsible for detoxifying sulfur-containing acids and sulfites such as S-sulfocysteine (SSC), urinary levels of SSC can be used as a surrogate marker of efficacy for fosdenopterin.7 Long-term therapy with fosdenopterin has been shown to result in a sustained reduction in urinary SSC normalized to creatinine.7
Animal studies have identified a potential risk of phototoxicity in patients receiving fosdenopterin - these patients should avoid or minimize exposure to sunlight and/or artificial UV light.7 If sun exposure is necessary, use protective clothing, hats, and sunglasses,7 in addition to seeking shade whenever practical. Consider the use of a broad-spectrum sunscreen in patients 6 months of age or older.8
- Mechanism of action
Molybdenum cofactor deficiency (MoCD) is a rare autosomal-recessive disorder in which patients are deficient in three molybdenum-dependent enzymes: sulfite oxidase (SOX), xanthine dehydrogenase, and aldehyde dehydrogenase.1 The loss of SOX activity appears to be the main driver of MoCD morbidity and mortality, as the build-up of neurotoxic sulfites typically processed by SOX results in rapid and progressive neurological damage. In MoCD type A, the disorder results from a mutation in the MOCS1 gene leading to deficient production of MOCS1A/B,7 a protein that is responsible for the first step in the synthesis of molybdenum cofactor: the conversion of guanosine triphosphate into cyclic pyranopterin monophosphate (cPMP).1,4
Fosdenopterin is an exogenous form of cPMP, replacing endogenous production and allowing for the synthesis of molybdenum cofactor to proceed.7
Target Actions Organism AMolybdenum cofactor biosynthesis protein 1 substrateHumans AXanthine dehydrogenase/oxidase cofactorHumans - Absorption
In healthy adult subjects, the observed Cmax and AUC0-inf following the intravenous administration of 0.68 mg/kg (0.76x the maximum recommended dose) were 2800 ng/mL and 5960 ng*h/mL, respectively.7 Both Cmax and AUC0-inf appear to increase proportionally with increasing doses.
- Volume of distribution
The volume of distribution of fosdenopterin is approximately 300 mL/kg.7
- Protein binding
Plasma protein binding ranges from 6 to 12%,7 though the specific proteins to which fosdenopterin binds have not been elucidated.
- Metabolism
Fosdenopterin metabolism occurs mainly via non-enzymatic degradation into Compound Z, which is a pharmacologically inactive product of endogenous cyclic pyranopterin monophosphate.7
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- Route of elimination
Renal clearance of fosdenopterin accounts for approximately 40% of total clearance.7
- Half-life
The mean half-life of fosdenopterin ranges from 1.2 to 1.7 hours.7
- Clearance
Total body clearance of fosdenopterin ranges from 167 to 195 mL/h/kg.7
- Adverse Effects
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There are no data regarding overdosage of fosdenopterin.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwarePadeliporfin Fosdenopterin may increase the photosensitizing activities of Padeliporfin. Porfimer sodium Fosdenopterin may increase the photosensitizing activities of Porfimer sodium. Tretinoin The risk or severity of adverse effects can be increased when Tretinoin is combined with Fosdenopterin. Verteporfin Fosdenopterin may increase the photosensitizing activities of Verteporfin. - Food Interactions
- No interactions found.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Fosdenopterin hydrobromide X41B5W735T 2301083-34-9 GGLKTKQOHMCQHF-UNHNTEMGSA-N - International/Other Brands
- Nulibry (BridgeBio Pharma, Inc.)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Nulibry Injection, powder, lyophilized, for solution 9.5 mg/1 Intravenous Sentynl Therapeutics, Inc. 2021-03-30 Not applicable US 
Nulibry Injection, powder, lyophilized, for solution 9.5 mg/1 Intravenous Origin Biosciences, Inc. 2021-03-30 Not applicable US Nulibry Injection, powder, for solution 9.5 mg Intravenous Tmc Pharma (Eu) Limited 2022-12-02 Not applicable EU 
Categories
- ATC Codes
- A16AX19 — Fosdenopterin
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Humans and other mammals
Chemical Identifiers
- UNII
- 4X7K2681Y7
- CAS number
- 150829-29-1
- InChI Key
- CZAKJJUNKNPTTO-AJFJRRQVSA-N
- InChI
- InChI=1S/C10H14N5O8P/c11-9-14-6-3(7(16)15-9)12-4-8(13-6)22-2-1-21-24(19,20)23-5(2)10(4,17)18/h2,4-5,8,12,17-18H,1H2,(H,19,20)(H4,11,13,14,15,16)/t2-,4-,5+,8-/m1/s1
- IUPAC Name
- (4aR,5aR,11aR,12aS)-8-amino-2,12,12-trihydroxy-4,4a,5a,6,7,10,11,11a,12,12a-decahydro-2H-1,3,5-trioxa-6,7,9,11-tetraaza-2lambda5-phosphatetracene-2,10-dione
- SMILES
- [H][C@@]12COP(O)(=O)O[C@]1([H])C(O)(O)[C@]1([H])NC3=C(NC(N)=NC3=O)N[C@]1([H])O2
References
- Synthesis Reference
Clinch K, Watt DK, Dixon RA, Baars SM, Gainsford GJ, Tiwari A, Schwarz G, Saotome Y, Storek M, Belaidi AA, Santamaria-Araujo JA: Synthesis of cyclic pyranopterin monophosphate, a biosynthetic intermediate in the molybdenum cofactor pathway. J Med Chem. 2013 Feb 28;56(4):1730-8. doi: 10.1021/jm301855r. Epub 2013 Feb 19.
- General References
- Mechler K, Mountford WK, Hoffmann GF, Ries M: Ultra-orphan diseases: a quantitative analysis of the natural history of molybdenum cofactor deficiency. Genet Med. 2015 Dec;17(12):965-70. doi: 10.1038/gim.2015.12. Epub 2015 Mar 12. [Article]
- Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, Hennermann JB, Jameson E, Konig K, McGregor TL, Font-Montgomery E, Santamaria-Araujo JA, Santra S, Vaidya M, Vierzig A, Wassmer E, Weis I, Wong FY, Veldman A, Schwarz G: Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet. 2015 Nov 14;386(10007):1955-63. doi: 10.1016/S0140-6736(15)00124-5. Epub 2015 Sep 3. [Article]
- Iobbi-Nivol C, Leimkuhler S: Molybdenum enzymes, their maturation and molybdenum cofactor biosynthesis in Escherichia coli. Biochim Biophys Acta. 2013 Aug-Sep;1827(8-9):1086-101. doi: 10.1016/j.bbabio.2012.11.007. Epub 2012 Nov 29. [Article]
- Mendel RR: The molybdenum cofactor. J Biol Chem. 2013 May 10;288(19):13165-72. doi: 10.1074/jbc.R113.455311. Epub 2013 Mar 28. [Article]
- FDA News Release: FDA Approves First Treatment for Molybdenum Cofactor Deficiency Type A [Link]
- OMIM: MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP A (# 252150) [Link]
- FDA Approved Drug Products: Nulibry (fosdenopterin) for intravenous injection [Link]
- Health Canada: Sun safety tips for parents [Link]
- EMA CHMP Positive Opinion: Nulibry (fosdenopterin) [Link]
- Globe Newswire: BridgeBio Pharma and Sentynl Therapeutics Receive Marketing Authorization in the EU for NULIBRY (fosdenopterin) for the Treatment of MoCD Type A [Link]
- EMA Summary of Product Characteristics: NULIBRY (fosdenopterin) solution for injection [Link]
- External Links
- Human Metabolome Database
- HMDB0059639
- KEGG Compound
- C18239
- ChemSpider
- 17221217
- 2531288
- ChEBI
- 60210
- ChEMBL
- CHEMBL2338675
- ZINC
- ZINC000034962340
- Wikipedia
- Fosdenopterin
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample data2 Completed Treatment Molybdenum Cofactor Deficiency, Type A 1 somestatus stop reason just information to hide 2, 3 Completed Treatment Molybdenum Cofactor Deficiency, Type A 1 somestatus stop reason just information to hide 1 Completed Treatment Deficiency of Activity of Molybdenum-dependent Enzymes (Sulfite Oxidase [SOX], Xanthine Dehydrogenase, and Aldehyde Oxidase) / Molybdenum Cofactor Deficiency (MoCD) / Rare Autosomal Recessive Disorder 1 somestatus stop reason just information to hide 1, 2 Withdrawn Treatment Molybdenum Cofactor Deficiency, Type A 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous 9.5 mg Injection, powder, lyophilized, for solution Intravenous 9.5 mg/1 - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US7504095 No 2009-03-17 2025-01-31 US
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source logP -2.9 Chemaxon pKa (Strongest Acidic) 1.8 Chemaxon pKa (Strongest Basic) 5.03 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 11 Chemaxon Hydrogen Donor Count 7 Chemaxon Polar Surface Area 196.99 Å2 Chemaxon Rotatable Bond Count 0 Chemaxon Refractivity 82.02 m3·mol-1 Chemaxon Polarizability 29.93 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS splash10-03di-0009000000-16e8827020246c25244f Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-03di-0009000000-9791eab911b954c83e51 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-03dj-0009000000-4d671848e868d3f2318e Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-03fu-1459000000-3f5f1f57c8354debd983 Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-014i-5910000000-84534e1d0c1cd19d63d5 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-02ps-3912000000-12020f24c85c1980ccec Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 185.1165759 predictedDarkChem Lite v0.1.0 [M-H]- 163.5788 predictedDeepCCS 1.0 (2019) [M+H]+ 181.7867759 predictedDarkChem Lite v0.1.0 [M+H]+ 165.93858 predictedDeepCCS 1.0 (2019) [M+Na]+ 182.4936759 predictedDarkChem Lite v0.1.0 [M+Na]+ 171.82101 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Substrate
- General Function
- Isoform MOCS1A and isoform MOCS1B probably form a complex that catalyzes the conversion of 5'-GTP to cyclic pyranopterin monophosphate (cPMP). MOCS1A catalyzes the cyclization of GTP to (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate and MOCS1B catalyzes the subsequent conversion of (8S)-3',8-cyclo-7,8-dihydroguanosine 5'-triphosphate to cPMP
- Specific Function
- 4 iron, 4 sulfur cluster binding
- Gene Name
- MOCS1
- Uniprot ID
- Q9NZB8
- Uniprot Name
- Molybdenum cofactor biosynthesis protein 1
- Molecular Weight
- 70104.455 Da
References
- Mendel RR: The molybdenum cofactor. J Biol Chem. 2013 May 10;288(19):13165-72. doi: 10.1074/jbc.R113.455311. Epub 2013 Mar 28. [Article]
- Mechler K, Mountford WK, Hoffmann GF, Ries M: Ultra-orphan diseases: a quantitative analysis of the natural history of molybdenum cofactor deficiency. Genet Med. 2015 Dec;17(12):965-70. doi: 10.1038/gim.2015.12. Epub 2015 Mar 12. [Article]
- FDA Approved Drug Products: Nulibry (fosdenopterin) for intravenous injection [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Cofactor
- General Function
- Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Has also low oxidase activity towards aldehydes (in vitro)
- Specific Function
- 2 iron, 2 sulfur cluster binding
- Gene Name
- XDH
- Uniprot ID
- P47989
- Uniprot Name
- Xanthine dehydrogenase/oxidase
- Molecular Weight
- 146422.99 Da
References
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Multidrug efflux pump that functions as a H(+)/organic cation antiporter. Mediates the efflux of cationic compounds, such as the model cations, tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP+), the platinum-based drug oxaliplatin or weak bases that are positively charged at physiological pH, cimetidine, the platinum-based drugs cisplatin and oxaliplatin or the antidiabetic drug metformin. Mediates the efflux of endogenous compounds such as, creatinine, thiamine and estrone-3-sulfate. Plays a physiological role in the excretion of drugs, toxins and endogenous metabolites through the kidney
- Specific Function
- Antiporter activity
- Gene Name
- SLC47A2
- Uniprot ID
- Q86VL8
- Uniprot Name
- Multidrug and toxin extrusion protein 2
- Molecular Weight
- 65083.915 Da
References
- FDA Approved Drug Products: Nulibry (fosdenopterin) for intravenous injection [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Secondary active transporter that functions as a Na(+)-independent organic anion (OA)/dicarboxylate antiporter where the uptake of one molecule of OA into the cell is coupled with an efflux of one molecule of intracellular dicarboxylate such as 2-oxoglutarate or glutarate (PubMed:11669456, PubMed:11907186, PubMed:14675047, PubMed:22108572, PubMed:23832370, PubMed:28534121, PubMed:9950961). Mediates the uptake of OA across the basolateral side of proximal tubule epithelial cells, thereby contributing to the renal elimination of endogenous OA from the systemic circulation into the urine (PubMed:9887087). Functions as a biopterin transporters involved in the uptake and the secretion of coenzymes tetrahydrobiopterin (BH4), dihydrobiopterin (BH2) and sepiapterin to urine, thereby determining baseline levels of blood biopterins (PubMed:28534121). Transports prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) and may contribute to their renal excretion (PubMed:11907186). Also mediates the uptake of cyclic nucleotides such as cAMP and cGMP (PubMed:26377792). Involved in the transport of neuroactive tryptophan metabolites kynurenate (KYNA) and xanthurenate (XA) and may contribute to their secretion from the brain (PubMed:22108572, PubMed:23832370). May transport glutamate (PubMed:26377792). Also involved in the disposition of uremic toxins and potentially toxic xenobiotics by the renal organic anion secretory pathway, helping reduce their undesired toxicological effects on the body (PubMed:11669456, PubMed:14675047). Uremic toxins include the indoxyl sulfate (IS), hippurate/N-benzoylglycine (HA), indole acetate (IA), 3-carboxy-4- methyl-5-propyl-2-furanpropionate (CMPF) and urate (PubMed:14675047, PubMed:26377792). Xenobiotics include the mycotoxin ochratoxin (OTA) (PubMed:11669456). May also contribute to the transport of organic compounds in testes across the blood-testis-barrier (PubMed:35307651)
- Specific Function
- Alpha-ketoglutarate transmembrane transporter activity
- Gene Name
- SLC22A6
- Uniprot ID
- Q4U2R8
- Uniprot Name
- Solute carrier family 22 member 6
- Molecular Weight
- 61815.78 Da
References
- FDA Approved Drug Products: Nulibry (fosdenopterin) for intravenous injection [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Multidrug efflux pump that functions as a H(+)/organic cation antiporter (PubMed:16330770, PubMed:17509534). Plays a physiological role in the excretion of cationic compounds including endogenous metabolites, drugs, toxins through the kidney and liver, into urine and bile respectively (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). Mediates the efflux of endogenous compounds such as creatinine, vitamin B1/thiamine, agmatine and estrone-3-sulfate (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). May also contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- Antiporter activity
- Gene Name
- SLC47A1
- Uniprot ID
- Q96FL8
- Uniprot Name
- Multidrug and toxin extrusion protein 1
- Molecular Weight
- 61921.585 Da
References
- FDA Approved Drug Products: Nulibry (fosdenopterin) for intravenous injection [Link]
Drug created at February 28, 2021 23:47 / Updated at August 26, 2024 19:23