NAV

Melphalan flufenamide

Identification

Summary

Melphalan flufenamide is a melphalan prodrug used to treat relapsed or refractory multiple myeloma.

Generic Name
Melphalan flufenamide
DrugBank Accession Number
DB16627
Background

Melphalan flufenamide, also known as melflufen or J1, is a prodrug of melphalan.1,9 Melphalan flufenamide is more readily uptaken by cells than melphalan, and is cleaved to the active metabolite by aminopeptidases.1 In vitro models show that melphalan is 10 to hundreds of times more potent than melphalan.1 The increased potency makes melphalan flufenamide a treatment option for patients with relapsed or refractory multiple myeloma who have attempted at least 4 lines of therapy already.2,9

Melphalan flufenamide was granted FDA approval on 26 February 2021.9. It has since been withdrawn from the market in the wake of the phase 3 OCEAN trial which showed a decrease in overall survival in comparison to standard treatment with pomalidomide and dexamethasone despite superior progression-free survival.10,11

Type
Small Molecule
Groups
Approved, Withdrawn
Structure
3D
Similar Structures
Weight
Average: 498.42
Monoisotopic: 497.1648254
Chemical Formula
C24H30Cl2FN3O3
Synonyms
  • Melflufen
  • Melphalan flufenamide
  • MFF
External IDs
  • J 1
  • J-1
  • J1
  • Prodrug J 1
  • Prodrug J-1
  • WHO 9493
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Pharmacology

Indication

Melphalan flufenamide is indicated in combination with dexamethasone to treat adults with relapsed or refractory multiple myeloma who have received ≥4 therapies and are refractory to at least one proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody.9 The FDA has withdrawn the drug from the market for this indication following phase 3 trial data showing decreased overall survival.11

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Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to treatRelapsed or refractory multiple myelomaRegimen in combination with: Dexamethasone (DB01234)••••••••••••••••••••••••••• •• •• ••••• • ••••••••• •••••••••• ••••••••• •••••••••• •• •• ••••• • •••••••••• •••••••••• •••••••••• •• •• ••••• • •••••••••••••••• •••••• •• ••••• • ••••• ••••••••• ••••••••••••••••••
Contraindications & Blackbox Warnings
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Pharmacodynamics

Melphalan flufenamide is an alkylating agent indicated to treat relapsed or refractory multiple myeloma in Melphalan flufenamide has a long duration of action as it is given every 28 days.1 Patients should be counselled regarding risks of thrombocytopenia, neutropenia, anemia, infections, secondary malignancies, embryo-fetal toxicity.9

Mechanism of action

Melphalan flufenamide is a more lipophilic prodrug of melphalan, which allows it to be more readily uptaken by cells.1,2 It is likely taken up into malignant cells by passive diffusion, where it is hydrolyzed by aminopeptidase N.1 The expression of aminopeptidases, along with other hydrolytic enzymes, is upregulated in many malignant cells, making the hydrolysis reaction to melphalan more favourable in a malignant cell.1 Increased concentrations of free melphalan in malignant cells leads to rapid irreversible DNA damage and apoptosis, reducing the potential for the development of resistance.1

Free melphalan is an nitrogen mustard derivative alkylating agent.2,4 Melphalan attaches alkyl groups to the N-7 position of guanine and N-3 position of adenine, leading to the formation of monoadducts, and DNA fragmenting when repair enzymes attempt to correct the error.5,6 It can also cause DNA cross-linking from the N-7 position of one guanine to the N-7 position of another, preventing DNA strands from separating for synthesis or transcription.5,6 Finally, melphalan can induce a number of different mutations.5 While melphalan induces phosphorylation of the DNA damage marker γ-H2AX in melphalan sensitive cells at 6 hours, melphalan flufenamide induces γ-H2AX at 2 hours.3 Melphalan flufenamide is also able to induce γ-H2AX in melphalan-resistant cells.3

TargetActionsOrganism
ADNA
cross-linking/alkylation
Humans
Absorption

For a 40 mg intravenous infusion, the active metabolite reaches a Cmax of 432 ng/mL, with a Tmax of 4-15 minutes, and an AUC of 3143 h*µg/mL.1,9

Volume of distribution

The mean volume of distribution of melphalan flufenamide is 35 L and of melphalan is 76 L.9

Protein binding

Data regarding the protein binding of melphalan flufenamide are not readily available.9 However, free melphalan is 60% bound to albumin, 20% bound to alpha-1-acid glycoprotein, and 10% bound to other proteins in plasma.8

Metabolism

Melphalan flufenamide is metabolised to desethyl-melphalan and melphalan.9 Melphalan is spontaneously hydrolyzed to monohydroxy-melphalan and dihydroxy-melphalan.9

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Route of elimination

Data regarding the route of elimination of melphalan flufenamide are not readily available.9 Free melphalan undergoes rapid and spontaneous decomposition, complicating studies on the route of elimination.7 However, it is expected to be mainly renally excreted.7

Half-life

The mean elimination half life of melphalan flufenamide is 2.1 minutes and of melphalan is 70 minutes.9

Clearance

The mean clearance of melphalan flufenamide is 692 L/h and of melphalan is 23 L/h.9

Adverse Effects
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Toxicity

Data regarding overdoses of melphalan flufenamide are not readily available.9 However, nonclinical safety studies in dogs have shown an increased risk of mortality in subjects receiving higher than recommended doses.9 Patients should be treated with symptomatic and supportive measures.

Pathways
Not Available
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Not Available

Interactions

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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.
Not Available
Food Interactions
No interactions found.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Melphalan flufenamide hydrochloride3412470A0V380449-54-7Not applicable
Active Moieties
NameKindUNIICASInChI Key
MelphalanprodrugQ41OR9510P148-82-3SGDBTWWWUNNDEQ-LBPRGKRZSA-N
International/Other Brands
Pepaxto (Oncopeptides AB)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
PepaxtiInjection, powder, for solution20 mgIntravenousOncopeptides Ab2022-08-24Not applicableEU flag
PepaxtoInjection, powder, lyophilized, for solution20 mg/50mLIntravenousOncopeptides, AB2021-02-262022-08-13US flag

Categories

ATC Codes
L01AA10 — Melphalan flufenamide
Drug Categories
Classification
Not classified
Affected organisms
Not Available

Chemical Identifiers

UNII
F70C5K4786
CAS number
380449-51-4
InChI Key
YQZNKYXGZSVEHI-VXKWHMMOSA-N
InChI
InChI=1S/C24H30Cl2FN3O3/c1-2-33-24(32)22(16-18-3-7-19(27)8-4-18)29-23(31)21(28)15-17-5-9-20(10-6-17)30(13-11-25)14-12-26/h3-10,21-22H,2,11-16,28H2,1H3,(H,29,31)/t21-,22-/m0/s1
IUPAC Name
ethyl (2S)-2-[(2S)-2-amino-3-{4-[bis(2-chloroethyl)amino]phenyl}propanamido]-3-(4-fluorophenyl)propanoate
SMILES
CCOC(=O)[C@H](CC1=CC=C(F)C=C1)NC(=O)[C@@H](N)CC1=CC=C(C=C1)N(CCCl)CCCl

References

General References
  1. Wickstrom M, Nygren P, Larsson R, Harmenberg J, Lindberg J, Sjoberg P, Jerling M, Lehmann F, Richardson P, Anderson K, Chauhan D, Gullbo J: Melflufen - a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017 Jun 8;8(39):66641-66655. doi: 10.18632/oncotarget.18420. eCollection 2017 Sep 12. [Article]
  2. Mateos MV, Blade J, Bringhen S, Ocio EM, Efebera Y, Pour L, Gay F, Sonneveld P, Gullbo J, Richardson PG: Melflufen: A Peptide-Drug Conjugate for the Treatment of Multiple Myeloma. J Clin Med. 2020 Sep 27;9(10). pii: jcm9103120. doi: 10.3390/jcm9103120. [Article]
  3. Ray A, Ravillah D, Das DS, Song Y, Nordstrom E, Gullbo J, Richardson PG, Chauhan D, Anderson KC: A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol. 2016 Aug;174(3):397-409. doi: 10.1111/bjh.14065. Epub 2016 Apr 20. [Article]
  4. Osborne MR, Lawley PD, Crofton-Sleigh C, Warren W: Products from alkylation of DNA in cells by melphalan: human soft tissue sarcoma cell line RD and Escherichia coli WP2. Chem Biol Interact. 1995 Aug 18;97(3):287-96. doi: 10.1016/0009-2797(95)03623-t. [Article]
  5. Povirk LF, Shuker DE: DNA damage and mutagenesis induced by nitrogen mustards. Mutat Res. 1994 Dec;318(3):205-26. doi: 10.1016/0165-1110(94)90015-9. [Article]
  6. Lawley PD, Phillips DH: DNA adducts from chemotherapeutic agents. Mutat Res. 1996 Aug 17;355(1-2):13-40. doi: 10.1016/0027-5107(96)00020-6. [Article]
  7. Nath CE, Shaw PJ, Trotman J, Zeng L, Duffull SB, Hegarty G, McLachlan AJ, Gurney H, Kerridge I, Kwan YL, Presgrave P, Tiley C, Joshua D, Earl J: Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. Br J Clin Pharmacol. 2010 May;69(5):484-97. doi: 10.1111/j.1365-2125.2010.03638.x. [Article]
  8. Gera S, Musch E, Osterheld HK, Loos U: Relevance of the hydrolysis and protein binding of melphalan to the treatment of multiple myeloma. Cancer Chemother Pharmacol. 1989;23(2):76-80. doi: 10.1007/BF00273521. [Article]
  9. FDA Approved Drug Products: Pepaxto (Melphalan Flufenamide) Intravenous Injection [Link]
  10. Cancer Network: FDA Has Requested a Partial Clinical Hold on All Trials With Melflufen in Following Study in R/R Myeloma [Link]
  11. BioSpace: Oncopeptides withdraws Pepaxto® in US, scale down organization and focus on R&D [Link]
Human Metabolome Database
HMDB0304840
ChemSpider
8111267
RxNav
2531369
ChEMBL
CHEMBL4303060
Wikipedia
Melphalan_flufenamide

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
PhaseStatusPurposeConditionsCount
3TerminatedTreatmentMultiple Myeloma (MM)1
3TerminatedTreatmentRelapsed Multiple Myeloma / Relapsed/Refractory Multiple Myeloma (RRMM)1
2CompletedTreatmentMultiple Myeloma (MM)1
2TerminatedTreatmentImpaired Renal Function / Multiple Myeloma (MM)1
2TerminatedTreatmentRrMM1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, powder, for solutionIntravenous20 mg
Injection, powder, lyophilized, for solutionIntravenous20 mg/50mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6992207No2006-01-312022-06-25US flag
US10543274No2020-01-282032-04-25US flag
US10322182No2019-06-182032-04-25US flag
US10869928No2020-12-222032-04-25US flag
US10285946No2019-05-142032-04-25US flag
US11344622No2012-04-252032-04-25US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
logP4.04Wickstrom et al, 2017
pKa7.13FDA Label
Predicted Properties
PropertyValueSource
logP4.28Chemaxon
pKa (Strongest Acidic)12.11Chemaxon
pKa (Strongest Basic)8.07Chemaxon
Physiological Charge1Chemaxon
Hydrogen Acceptor Count4Chemaxon
Hydrogen Donor Count2Chemaxon
Polar Surface Area84.66 Å2Chemaxon
Rotatable Bond Count14Chemaxon
Refractivity129.88 m3·mol-1Chemaxon
Polarizability52.16 Å3Chemaxon
Number of Rings2Chemaxon
Bioavailability1Chemaxon
Rule of FiveYesChemaxon
Ghose FilterNoChemaxon
Veber's RuleNoChemaxon
MDDR-like RuleNoChemaxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0f72-0041900000-293065ca57a9a957b974
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9000600000-ac9b114733711ec72493
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9000000000-d4f2675afc6fdccde692
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-0930500000-0c27e8990579d40d3582
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-001i-9002000000-656e2ca35b89369ab02f
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-01rg-2590100000-924b96290529737be19c
Predicted 1H NMR Spectrum1D NMRNot Applicable
Predicted 13C NMR Spectrum1D NMRNot Applicable
Chromatographic Properties
Collision Cross Sections (CCS)
Not Available

Targets

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Details1. DNA
Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Cross-linking/alkylation
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
References
  1. Wickstrom M, Nygren P, Larsson R, Harmenberg J, Lindberg J, Sjoberg P, Jerling M, Lehmann F, Richardson P, Anderson K, Chauhan D, Gullbo J: Melflufen - a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017 Jun 8;8(39):66641-66655. doi: 10.18632/oncotarget.18420. eCollection 2017 Sep 12. [Article]
  2. Mateos MV, Blade J, Bringhen S, Ocio EM, Efebera Y, Pour L, Gay F, Sonneveld P, Gullbo J, Richardson PG: Melflufen: A Peptide-Drug Conjugate for the Treatment of Multiple Myeloma. J Clin Med. 2020 Sep 27;9(10). pii: jcm9103120. doi: 10.3390/jcm9103120. [Article]
  3. Ray A, Ravillah D, Das DS, Song Y, Nordstrom E, Gullbo J, Richardson PG, Chauhan D, Anderson KC: A novel alkylating agent Melflufen induces irreversible DNA damage and cytotoxicity in multiple myeloma cells. Br J Haematol. 2016 Aug;174(3):397-409. doi: 10.1111/bjh.14065. Epub 2016 Apr 20. [Article]
  4. FDA Approved Drug Products: Pepaxto (Melphalan Flufenamide) Intravenous Injection [Link]

Enzymes

Details1. Aminopeptidase N
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Zinc ion binding
Specific Function
Broad specificity aminopeptidase. Plays a role in the final digestion of peptides generated from hydrolysis of proteins by gastric and pancreatic proteases. May play a critical role in the pathogen...
Gene Name
ANPEP
Uniprot ID
P15144
Uniprot Name
Aminopeptidase N
Molecular Weight
109538.68 Da
References
  1. Wickstrom M, Nygren P, Larsson R, Harmenberg J, Lindberg J, Sjoberg P, Jerling M, Lehmann F, Richardson P, Anderson K, Chauhan D, Gullbo J: Melflufen - a peptidase-potentiated alkylating agent in clinical trials. Oncotarget. 2017 Jun 8;8(39):66641-66655. doi: 10.18632/oncotarget.18420. eCollection 2017 Sep 12. [Article]

Drug created at February 28, 2021 23:40 / Updated at December 13, 2022 10:46