Fosdenopterin
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
- Weight
- Average: 363.223
Monoisotopic: 363.057999429 - Chemical Formula
- C10H14N5O8P
- Synonyms
- C(PMP)
- CPMP
- Cyclic pyranopterin monophosphate
- Fosdenopterin
- External IDs
- ALXN-1101
- WHO 11150
Pharmacology
- Indication
Fosdenopterin is indicated to reduce the risk of mortality in patients with molybdenum cofactor deficiency (MoCD) type A.7
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- 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 AMolybdopterin synthase catalytic subunit substrateHumans - 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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- Toxicity
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. Identify potential medication risksEasily compare up to 40 drugs with our drug interaction checker.Get severity rating, description, and management advice.Learn more - 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 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 Nulibry Injection, powder, lyophilized, for solution 9.5 mg/1 Intravenous Sentynl Therapeutics, Inc. 2021-03-30 Not applicable US
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
Phase Status Purpose Conditions Count 2 Completed Treatment Molybdenum Cofactor Deficiency, Type A 1 2, 3 Completed Treatment Molybdenum Cofactor Deficiency, Type A 1 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 1, 2 Withdrawn Treatment Molybdenum Cofactor Deficiency, Type A 1
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
- Not Available
Targets

- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Substrate
- General Function
- Catalytic subunit of the molybdopterin synthase complex, a complex that catalyzes the conversion of precursor Z into molybdopterin. Acts by mediating the incorporation of 2 sulfur atoms from thiocarboxylated MOCS2A into precursor Z to generate a dithiolene group.
- Specific Function
- Molybdopterin synthase activity
- Gene Name
- MOCS2
- Uniprot ID
- O96007
- Uniprot Name
- Molybdopterin synthase catalytic subunit
- Molecular Weight
- 20943.735 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]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Inhibitor
- General Function
- Drug transmembrane transporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide, metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acy...
- 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
- Sodium-independent organic anion transmembrane transporter activity
- Specific Function
- Involved in the renal elimination of endogenous and exogenous organic anions. Functions as organic anion exchanger when the uptake of one molecule of organic anion is coupled with an efflux of one ...
- 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
- Monovalent cation:proton antiporter activity
- Specific Function
- Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
- 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 December 01, 2022 11:30