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 It has since been withdrawn from the market in the wake of the phase 3 OCEAN trial which showed a decrease in overall survival in comparison to standard treatment with pomalidomide and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- Approved, Withdrawn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
- 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
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to at least one proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody.9 The FDA has withdrawn the drug from the market for this indication following phase 3 trial data showing decreased overall survival.11
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 Used in combination to treat Relapsed or refractory multiple myeloma Regimen 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
Target Actions Organism ADNA cross-linking/alkylationHumans - 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
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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
Ingredient UNII CAS InChI Key Melphalan flufenamide hydrochloride 3412470A0V 380449-54-7 Not applicable - Active Moieties
Name Kind UNII CAS InChI Key Melphalan prodrug Q41OR9510P 148-82-3 SGDBTWWWUNNDEQ-LBPRGKRZSA-N - International/Other Brands
- Pepaxto (Oncopeptides AB)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Pepaxti Injection, powder, for solution 20 mg Intravenous Oncopeptides Ab 2022-08-24 Not applicable EU Pepaxto Injection, powder, lyophilized, for solution 20 mg/50mL Intravenous Oncopeptides, AB 2021-02-26 2022-08-13 US
Categories
- ATC Codes
- L01AA10 — Melphalan flufenamide
- Drug Categories
- Alkylating Activity
- Alkylating Drugs
- Amino Acids
- Amino Acids, Aromatic
- Amino Acids, Cyclic
- Amino Acids, Peptides, and Proteins
- Antineoplastic Agents
- Antineoplastic Agents, Alkylating
- Antineoplastic and Immunomodulating Agents
- Hydrocarbons, Halogenated
- Mustard Compounds
- Narrow Therapeutic Index Drugs
- Nitrogen Mustard Analogues
- Nitrogen Mustard Compounds
- Prodrugs
- 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
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- 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]
- FDA Approved Drug Products: Pepaxto (Melphalan Flufenamide) Intravenous Injection [Link]
- Cancer Network: FDA Has Requested a Partial Clinical Hold on All Trials With Melflufen in Following Study in R/R Myeloma [Link]
- BioSpace: Oncopeptides withdraws Pepaxto® in US, scale down organization and focus on R&D [Link]
- External Links
- Human Metabolome Database
- HMDB0304840
- ChemSpider
- 8111267
- 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);">
Phase Status Purpose Conditions Count 3 Terminated Treatment Multiple Myeloma (MM) 1 3 Terminated Treatment Relapsed Multiple Myeloma / Relapsed/Refractory Multiple Myeloma (RRMM) 1 2 Completed Treatment Multiple Myeloma (MM) 1 2 Terminated Treatment Impaired Renal Function / Multiple Myeloma (MM) 1 2 Terminated Treatment RrMM 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, powder, for solution Intravenous 20 mg Injection, powder, lyophilized, for solution Intravenous 20 mg/50mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US6992207 No 2006-01-31 2022-06-25 US US10543274 No 2020-01-28 2032-04-25 US US10322182 No 2019-06-18 2032-04-25 US US10869928 No 2020-12-22 2032-04-25 US US10285946 No 2019-05-14 2032-04-25 US US11344622 No 2012-04-25 2032-04-25 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source logP 4.04 Wickstrom et al, 2017 pKa 7.13 FDA Label - Predicted Properties
Property Value Source logP 4.28 Chemaxon pKa (Strongest Acidic) 12.11 Chemaxon pKa (Strongest Basic) 8.07 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 2 Chemaxon Polar Surface Area 84.66 Å2 Chemaxon Rotatable Bond Count 14 Chemaxon Refractivity 129.88 m3·mol-1 Chemaxon Polarizability 52.16 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes 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 splash10-0f72-0041900000-293065ca57a9a957b974 Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9000600000-ac9b114733711ec72493 Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9000000000-d4f2675afc6fdccde692 Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS splash10-000i-0930500000-0c27e8990579d40d3582 Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS splash10-001i-9002000000-656e2ca35b89369ab02f Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS splash10-01rg-2590100000-924b96290529737be19c Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
References
- 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]
- 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]
- 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]
- FDA Approved Drug Products: Pepaxto (Melphalan Flufenamide) Intravenous Injection [Link]
Enzymes
- 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
- 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