Melphalan flufenamide

DCTPepD ID  DCTPepD0108

Active Ingredients   Melphalan flufenamide

Description  A peptide-drug conjugate composed of a peptide conjugated, via an aminopeptidase-targeting linkage, to the alkylating agent melphalan, with potential antineoplastic and anti-angiogenic activities. Upon administration, the highly lipophilic melphalan flufenamide penetrates cell membranes and enters cells. In aminopeptidase-positive tumor cells, melphalan flufenamide is hydrolyzed by peptidases to release the hydrophilic alkylating agent melphalan. This results in the specific release and accumulation of melphalan in aminopeptidase-positive tumor cells. Melphalan alkylates DNA at the N7 position of guanine residues and induces DNA intra- and inter-strand cross-linkages. This results in the inhibition of DNA and RNA synthesis and the induction of apoptosis, thereby inhibiting tumor cell proliferation. Peptidases are overexpressed by certain cancer cells. The administration of melphalan flufenamide allows for enhanced efficacy and reduced toxicity compared to melphalan.

Synonyms  J-1; J1; L-melphalanyl-p-L-fluorophenylalanine Ethyl Ester; Melflufen; Prodrug J1; Ygalo

Disease  Relapsed/Refractory Multiple Myeloma (RRMM)

Classification

  

Peptide and derivative

Structure Information


Molecular Formula  C24H30Cl2FN3O3

Molecular Weight  498.4

Active Sequence  Not available

Sequence Length  Not available

Modification  Not available

Structure

 

Show IUPAC/InChI/SMILES

IUPAC Name  ethyl (2S)-2-[[(2S)-2-amino-3-[4-[bis(2-chloroethyl)amino]phenyl]propanoyl]amino]-3-(4-fluorophenyl)propanoate

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

InChI_Key YQZNKYXGZSVEHI-VXKWHMMOSA-N

SMILES  O=C(OCC)[C@@H](NC([C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1)=O)CC2=CC=C(F)C=C2

External Codes


PubChem CID  9935639

DrugBank Accession Number  DB16627

NCI Thesaurus Code  C107680  

UNII  F70C5K4786   GSRS

CAS  380449-51-4



Drug approval


Drug 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. The FDA has withdrawn the drug from the market for this indication following phase 3 trial data showing decreased overall survival.

Drug Name Strength Dosage Form/Route Company Marketing Status Drug ID Approval year
PEPAXTO EQ 20MG BASE/VIAL POWDER;INTRAVENOUS ONCOPEPTIDES AB Discontinued NDA: 214383 2021
Pepaxti Depends on body weight Infusion (drip) Oncopeptides AB Prescription EMEA/H/C/005681 2022

ClinicalTrials.gov Identifier Title Condition or disease Phase Purpose
NCT04534322 An Expanded Access Program Protocol for Melphalan Flufenamide in Combination With Dexamethasone in Patients With Triple Class Refractory Multiple Myeloma Relapsed and/or Refractory Multiple Myeloma Expanded Access Program (Approved for marketing) Treatment
NCT03151811 A Randomized, Controlled, Open-label, Phase 3 Study of Melflufen/Dexamethasone Compared With Pomalidomide/Dexamethasone for Patients With Relapsed Refractory Multiple Myeloma Who Are Refractory to Lenalidomide Multiple Myeloma Phase 3 Treatment
NCT03481556 An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen and Dexamethasone in Combination With Either Bortezomib or Daratumumab in Patients With Relapsed or Relapsed-Refractory Multiple Myeloma Multiple Myeloma Phase 1/2 Treatment
NCT03639610 A Study of the Pharmacokinetics of Melphalan During Treatment With Melflufen and Dexamethasone in Patients With Relapsed Refractory Multiple Myeloma and Impaired Renal Function Renal Impairment; Multiple Myeloma Phase 2 Treatment
NCT04649060 A Randomized, Controlled, Open-Label Phase 3 Study of Melflufen in Combination With Daratumumab Compared With Daratumumab in Patients With Relapsed or Relapsed-Refractory Multiple Myeloma Relapsed Multiple Myeloma; Relapsed-Refractory Multiple Myeloma Phase 3 Treatment

    More clinical information is obtained from ClinicalTrials.gov.





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