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Melflufen – Investigational Drug

Melphalan flufenamide, also known as melflufen, is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly releases alkylating agents inside cancer cells. Aminopeptidases are overexpressed in multiple myeloma cells and are associated with advanced disease and tumor mutational burden. Targeting aminopeptidases causes selective activity in cancer cells, sparing healthy cells.

Melflufen in Multiple Myeloma

Melflufen is rapidly taken up by myeloma cells due to its high lipophilicity and is immediately hydrolyzed by peptidases to release an entrapped hydrophilic alkylator payload. Aminopeptidases are overexpressed in tumor cells and are even more pronounced in advanced cancers and tumors with a high mutational burden.

In vitro, melflufen is 50-fold more potent in myeloma cells than the alkylator payload itself due to the increased intracellular concentration. Melflufen displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, and has also demonstrated inhibition of DNA repair induction and angiogenesis in preclinical studies.

The melflufen molecule
Melflufen molecule

FDA approval and withdrawal

On February 26, 2021, PEPAXTO (melphalan flufenamide) in combination with dexamethasone was granted accelerated approval by the U.S. Food and Drug Administration, FDA, for the treatment of 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 CD38-directed monoclonal antibody.

On October 22, 2021, the company decided to withdraw PEPAXTO from the market in the US following data from the phase 3 OCEAN study which showed an overall survival in the ITT population with a HR of 1.104.

HORIZON study basis for FDA approval

The FDA approval was based on the results from the pivotal phase 2 HORIZON study, in which melflufen plus dexamethasone demonstrated encouraging efficacy and a clinically manageable safety profile in heavily pretreated patients with relapsed refractory multiple myeloma, primarily hematologic adverse events and a low incidence of non-hematologic adverse events.

Multiple Myeloma is classified as a rare disease in the US and in Europe, and melflufen has been granted orphan designation by the Food and Drug Administration, FDA, and the European Medicines Agency, EMA.

* National Cancer Institute, SEER Cancer Statistics Review 1975-2013 (2016) for patients in USA and GlobalData (2015).