Melphalan flufenamide (Pepaxto)

Note: this drug has been withdrawn from the US market.

Mechanism of action

From the NCI Drug Dictionary: 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.

Diseases for which it is used

Multiple myeloma

History of changes in FDA indication

Multiple myeloma - WITHDRAWN

• 2021-02-26: Granted accelerated approval to in combination with dexamethasone for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD-38 directed monoclonal antibody. (Based on HORIZON_RRMM)
  • 2021-10-22: Approval withdrawn. (Based on OCEAN)

History of changes in EMA indication

• 2022-08-17: Initial authorization as Pepaxti

Also known as

• Code name: J1
• Generic name: melflufen
• Brand named: Pepaxti, Pepaxto, Ygalo