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.

Type
Small Molecule
Groups
Approved
Structure
Thumb
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
AMolybdopterin synthase catalytic subunit
substrate
Humans
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

Hover over products below to view reaction partners

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
Adverseeffects
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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.
DrugInteraction
Porfimer sodiumFosdenopterin may increase the photosensitizing activities of Porfimer sodium.
TretinoinThe risk or severity of adverse effects can be increased when Tretinoin is combined with Fosdenopterin.
VerteporfinFosdenopterin may increase the photosensitizing activities of Verteporfin.
Interactions
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Food Interactions
No interactions found.

Products

Products2
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Product Ingredients
IngredientUNIICASInChI Key
Fosdenopterin hydrobromideX41B5W735T2301083-34-9GGLKTKQOHMCQHF-UNHNTEMGSA-N
International/Other Brands
Nulibry (BridgeBio Pharma, Inc.)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
NulibryInjection, powder, for solution9.5 mg/1IntravenousOrigin Biosciences, Inc.2021-03-30Not applicableUS flag

Categories

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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. FDA News Release: FDA Approves First Treatment for Molybdenum Cofactor Deficiency Type A [Link]
  6. OMIM: MOLYBDENUM COFACTOR DEFICIENCY, COMPLEMENTATION GROUP A (# 252150) [Link]
  7. FDA Approved Drug Products: Nulibry (fosdenopterin) for intravenous injection [Link]
  8. Health Canada: Sun safety tips for parents [Link]
Human Metabolome Database
HMDB0059639
KEGG Compound
C18239
ChemSpider
17221217
RxNav
2531288
ChEBI
60210
ChEMBL
CHEMBL2338675
ZINC
ZINC000034962340
Wikipedia
Fosdenopterin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Active Not RecruitingTreatmentMolybdenum Cofactor Deficiency, Type A1
2, 3RecruitingTreatmentMolybdenum Cofactor Deficiency, Type A1
1CompletedTreatmentDeficiency of Activity of Molybdenum-dependent Enzymes (Sulfite Oxidase [SOX], Xanthine Dehydrogenase, and Aldehyde Oxidase) / Molybdenum Cofactor Deficiency (MoCD) / Rare Autosomal Recessive Disorder1
1, 2WithdrawnTreatmentMolybdenum Cofactor Deficiency, Type A1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous9.5 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US7504095No2005-01-312025-01-31US flag

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
logP-2.9ChemAxon
pKa (Strongest Acidic)1.8ChemAxon
pKa (Strongest Basic)5.03ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count7ChemAxon
Polar Surface Area196.99 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity82.02 m3·mol-1ChemAxon
Polarizability29.93 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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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
  1. 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]
  2. 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]
  3. 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
  1. 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
  1. 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
  1. FDA Approved Drug Products: Nulibry (fosdenopterin) for intravenous injection [Link]

Drug created on February 28, 2021 23:47 / Updated on July 28, 2021 15:01