Melphalan flufenamide

Melphalan flufenamide, sold under the brand name Pepaxto, is an anticancer medication used to treat multiple myeloma.[4][5]

Melphalan flufenamide
Clinical data
Trade namesPepaxto
Other namesMelflufen, 4-[Bis-(2-chloroethyl)amino]-L-phenylalanine-4-fluoro-L-phenylalanine ethyl ester, J1[1][2]
AHFS/Drugs.comProfessional Drug Facts
License data
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismAminopeptidase hydrolysis, Spontaneous hydrolyisis on N-mustard
Elimination half-life10 min in vitro
Identifiers
IUPAC name
  • Ethyl (2S)-2-[[(2S)-2-amino-3-[4-[bis(2-chloroethyl)amino]phenyl]propanoyl]amino]-3-(4-fluorophenyl)propanoate
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC24H30Cl2FN3O3
Molar mass498.42 g·mol−1
3D model (JSmol)
SMILES
  • CCOC(=O)[C@H](CC1=CC=C(C=C1)F)NC(=O)[C@H](CC2=CC=C(C=C2)N(CCCl)CCCl)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
  • Key:YQZNKYXGZSVEHI-VXKWHMMOSA-N

The most common adverse reactions include fatigue, nausea, diarrhea, pyrexia and respiratory tract infection.[4]

Melphalan flufenamide is a peptidase enhanced cytotoxic (PEnC) that exerts a targeted delivery of melphalan in cells with high expression of aminopeptidases, such as aminopeptidase N, which has been described as over-expressed in human malignancies. Aminopeptidase N plays a functional role in malignant angiogenesis.

Melphalan flufenamide was approved for medical use in the United States in February 2021.[5][6]

Medical uses

Melphalan flufenamide is indicated in combination with dexamethasone for the treatment of adults with relapsed or refractory multiple myeloma, 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.[4][5]

Metabolism

Melphalan flufenamide is metabolized by aminopeptidase hydrolysis and by spontaneous hydrolysis on N-mustard.[7] Its biological half-life is 10 minutes in vitro.

Origin and development

Melphalan flufenamide is a peptidase enhanced cytotoxic (PEnC) with a targeted delivery within tumor cells of melphalan, a widely used classical chemotherapeutic belonging to a group of alkylating agents developed more than 50 years ago. Substantial clinical experience has been accumulated about melphalan since then. Numerous derivatives of melphalan, designed to increase the activity or selectivity, have been developed and investigated in vitro or in animal models.[8] Melphalan flufenamide was synthesized, partly due to previous experience of an alkylating peptide cocktail named Peptichemio[9] and its anti-tumor activity is being investigated.

Pharmacology

Compared to melphalan, melphalan flufenamide exhibits significantly higher in vitro and in vivo activity in several models of human cancer.[10][11][12][13][14][9][15][16] A preclinical study, performed at Dana–Farber Cancer Institute, demonstrated that melphalan flufenamide induced apoptosis in multiple myeloma cell lines, even those resistant to conventional treatment (including melphalan).[17] In vivo effects in xenografted animals were also observed, and the results confirmed by M Chesi and co-workers – in a unique genetically engineered mouse model of multiple myeloma – are believed to be predictive of clinical efficacy.[18]

Structure

Chemically, the drug is best described as the ethyl ester of a dipeptide consisting of melphalan and the amino acid derivative para-fluoro-L-phenylalanine.

Pharmacokinetics

Pharmacokinetic analysis of plasma samples showed a rapid formation of melphalan; concentrations generally exceeded those of melphalan flufenamide during ongoing infusion. Melphalan flufenamide rapidly disappeared from plasma after infusion, while melphalan typically peaked a few minutes after the end of infusion. This suggests that melphalan flufenamide is rapidly and widely distributed to extravasal tissues, in which melphalan is formed and thereafter redistributed to plasma.[19]

This rapid disappearance from plasma is likely due to hydrolytic enzymes.[20] The Zn(2+) dependent ectopeptidase (also known as alanine aminopeptidase), degrades proteins and peptides with a N-terminal neutral amino acid. Aminopeptidase N is frequently overexpressed in tumors and has been associated with the growth of different human cancers suggesting it as a suitable target for anti-cancerous therapy.[21]

Adverse effects

In a human Phase 1 trial, no dose-limiting toxicities (DLTs) were observed at lower doses. At doses above 50 mg, reversible neutropenias and thrombocytopenias were observed, and particularly evident in heavily pretreated patients.[19] These side-effects are shared by most chemotherapies, including alkylating agents in general.

Drug interactions

No drug interaction studies have been reported. Several in vitro studies indicate that melphalan flufenamide may be successfully combined with standard chemotherapy or targeted agents.[22][17]

Therapeutic efficacy

In a Phase 1/2 trial, in solid tumor patients refractory to standard therapy, response evaluation showed disease stabilization in a majority of patients.[19][16] In relapsed and refractory multiple-myeloma (RRMM) patients, promising activity was seen in heavily pre-treated RRMM patients where conventional therapies had failed; the median Progression-Free Survival was 9.4 months and the Duration of Response was 9.6 months.[23] An overall response rate of 41% and a clinical benefit rate of 56% were also shown, with similar results seen across patient populations regardless of their refractory status. Hematologic toxicity was common, but manageable with cycle prolongations, dose modifications and supportive therapy, and non-hematologic treatment-related adverse events were infrequent.

History

Efficacy was evaluated in HORIZON (NCT02963493), a multicenter, single-arm trial.[4] Eligible patients were required to have relapsed refractory multiple myeloma.[4] Patients received melphalan flufenamide 40 mg intravenously on day 1 and dexamethasone 40 mg orally (20 mg for patients ≥75 years of age) on day 1, 8, 15 and 22 of each 28-day cycle until disease progression or unacceptable toxicity.[4] Efficacy was evaluated in a subpopulation of 97 patients who received four or more prior lines of therapy and were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and a CD38-directed antibody.[4]

The application for melphalan flufenamide was granted priority review and orphan drug designations.[4]

Society and culture

On 23 June 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product Pepaxti, intended for the treatment of multiple myeloma.[24] The applicant for this medicinal product is Oncopeptides AB.[24]

Names

Melphalan flufenamide is the international nonproprietary name (INN).[25]

References
  1. Berglund Å, Ullén A, Lisyanskaya A, Orlov S, Hagberg H, Tholander B, et al. (December 2015). "First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies". Investigational New Drugs. 33 (6): 1232–41. doi:10.1007/s10637-015-0299-2. PMID 26553306. S2CID 8207569.
  2. Strese S, Wickström M, Fuchs PF, Fryknäs M, Gerwins P, Dale T, et al. (October 2013). "The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo". Biochemical Pharmacology. 86 (7): 888–95. doi:10.1016/j.bcp.2013.07.026. PMID 23933387.
  3. "Pepaxto- melphalan flufenamide injection, powder, lyophilized, for solution". DailyMed. Archived from the original on 13 September 2021. Retrieved 12 September 2021.
  4. "FDA grants accelerated approval to melphalan flufenamide for relapsed". U.S. Food and Drug Administration (FDA). 26 February 2021. Archived from the original on 1 March 2021. Retrieved 1 March 2021. This article incorporates text from this source, which is in the public domain.
  5. "FDA Approves Oncopeptides' Pepaxto (melphalan flufenamide) for Patients with Triple-Class Refractory Multiple Myeloma" (Press release). Oncopeptides AB. 1 March 2021. Archived from the original on 1 March 2021. Retrieved 1 March 2021 – via PR Newswire.
  6. "Drug Approval Package: Pepaxto". U.S. Food and Drug Administration (FDA). 22 March 2021. Archived from the original on 13 September 2021. Retrieved 12 September 2021.
  7. Gullbo, J; Tullberg, M; Våbenø, J; Ehrsson, H; Lewensohn, R; Nygren, P; Larsson, R; Luthman, K (2003). "Structure-activity relationship for alkylating dipeptide nitrogen mustard derivatives". Oncology Research. 14 (3): 113–32. doi:10.3727/000000003771013071. PMID 14760861.
  8. Wickstrom, M.; Lovborg, H.; Gullbo, J. (2006). "Future Prospects for Old Chemotherapeutic Drugs in the Target-Specific Era; Pharmaceutics, Combinations, Co-Drugs and Prodrugs with Melphalan as an Example". Letters in Drug Design & Discovery. 3 (10): 695. doi:10.2174/157018006778631893.
  9. Gullbo, J; Dhar, S; Luthman, K; Ehrsson, H; Lewensohn, R; Nygren, P; Larsson, R (2003). "Antitumor activity of the alkylating oligopeptides J1 (L-melphalanyl-p-L-fluorophenylalanine ethyl ester) and P2 (L-prolyl-m-L-sarcolysyl-p-L-fluorophenylalanine ethyl ester): Comparison with melphalan". Anti-Cancer Drugs. 14 (8): 617–24. doi:10.1097/00001813-200309000-00006. PMID 14501383. S2CID 10282399.
  10. Berglund, Åke; Ullén, Anders; Lisyanskaya, Alla; Orlov, Sergey; Hagberg, Hans; Tholander, Bengt; Lewensohn, Rolf; Nygren, Peter; Spira, Jack; Harmenberg, Johan; Jerling, Markus; Alvfors, Carina; Ringbom, Magnus; Nordström, Eva; Söderlind, Karin; Gullbo, Joachim (2015). "First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies". Investigational New Drugs. 33 (6): 1232–41. doi:10.1007/s10637-015-0299-2. PMID 26553306. S2CID 8207569.
  11. Strese, Sara; Wickström, Malin; Fuchs, Peder Fredlund; Fryknäs, Mårten; Gerwins, Pär; Dale, Tim; Larsson, Rolf; Gullbo, Joachim (2013). "The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo". Biochemical Pharmacology. 86 (7): 888–95. doi:10.1016/j.bcp.2013.07.026. PMID 23933387.
  12. Wickström, M; Johnsen, J. I.; Ponthan, F; Segerström, L; Sveinbjörnsson, B; Lindskog, M; Lövborg, H; Viktorsson, K; Lewensohn, R; Kogner, P; Larsson, R; Gullbo, J (2007). "The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo". Molecular Cancer Therapeutics. 6 (9): 2409–17. doi:10.1158/1535-7163.MCT-07-0156. PMID 17876040.
  13. Gullbo, J; Lindhagen, E; Bashir-Hassan, S; Tullberg, M; Ehrsson, H; Lewensohn, R; Nygren, P; de la Torre, M; Luthman, K; Larsson, R (2004). "Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo". Investigational New Drugs. 22 (4): 411–20. doi:10.1023/B:DRUG.0000036683.10945.bb. PMID 15292711. S2CID 31613292.
  14. Gullbo, J; Wickström, M; Tullberg, M; Ehrsson, H; Lewensohn, R; Nygren, P; Luthman, K; Larsson, R (2003). "Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour efficacy of the melphalan containing prodrug J1". Journal of Drug Targeting. 11 (6): 355–63. doi:10.1080/10611860310001647140. PMID 14668056. S2CID 25203458.
  15. Chauhan, D.; Ray, A.; Viktorsson, K.; Spira, J.; Paba-Prada, C.; Munshi, N.; Richardson, P.; Lewensohn, R.; Anderson, K. C. (2013). "In Vitro and in Vivo Antitumor Activity of a Novel Alkylating Agent, Melphalan-Flufenamide, against Multiple Myeloma Cells". Clinical Cancer Research. 19 (11): 3019–31. doi:10.1158/1078-0432.CCR-12-3752. PMC 4098702. PMID 23584492.
  16. Viktorsson, K; Shah, C. H.; Juntti, T; Hååg, P; Zielinska-Chomej, K; Sierakowiak, A; Holmsten, K; Tu, J; Spira, J; Kanter, L; Lewensohn, R; Ullén, A (2016). "Melphalan-flufenamide is cytotoxic and potentiates treatment with chemotherapy and the Src inhibitor dasatinib in urothelial carcinoma". Molecular Oncology. 10 (5): 719–34. doi:10.1016/j.molonc.2015.12.013. PMC 5423156. PMID 26827254.
  17. Chauhan, D; Ray, A; Viktorsson, K; Spira, J; Paba-Prada, C; Munshi, N; Richardson, P; Lewensohn, R; Anderson, K. C. (2013). "In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells". Clinical Cancer Research. 19 (11): 3019–31. doi:10.1158/1078-0432.CCR-12-3752. PMC 4098702. PMID 23584492.
  18. Chesi, M; Matthews, G. M.; Garbitt, V. M.; Palmer, S. E.; Shortt, J; Lefebure, M; Stewart, A. K.; Johnstone, R. W.; Bergsagel, P. L. (2012). "Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy". Blood. 120 (2): 376–85. doi:10.1182/blood-2012-02-412783. PMC 3398763. PMID 22451422.
  19. Berglund, Åke; Ullén, A; Lisyanskaya, A; Orlov, S; Hagberg, H; Tholander, B; Lewensohn, R; Nygren, P; Spira, J; Harmenberg, J; Jerling, M; Alvfors, C; Ringbom, M; Nordström, E; Söderlind, K; Gullbo, J (2015). "First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies". Investigational New Drugs. 33 (6): 1232–41. doi:10.1007/s10637-015-0299-2. PMID 26553306. S2CID 8207569.
  20. Wickström, M; Viktorsson, K; Lundholm, L; Aesoy, R; Nygren, H; Sooman, L; Fryknäs, M; Vogel, L. K.; Lewensohn, R; Larsson, R; Gullbo, J (2010). "The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan". Biochemical Pharmacology. 79 (9): 1281–90. doi:10.1016/j.bcp.2009.12.022. PMID 20067771.
  21. Wickström, M; Larsson, R; Nygren, P; Gullbo, J (2011). "Aminopeptidase N (CD13) as a target for cancer chemotherapy". Cancer Science. 102 (3): 501–8. doi:10.1111/j.1349-7006.2010.01826.x. PMC 7188354. PMID 21205077.
  22. Wickström, M; Haglund, C; Lindman, H; Nygren, P; Larsson, R; Gullbo, J (2008). "The novel alkylating prodrug J1: Diagnosis directed activity profile ex vivo and combination analyses in vitro". Investigational New Drugs. 26 (3): 195–204. doi:10.1007/s10637-007-9092-1. PMID 17922077. S2CID 19915448.
  23. "Paper: Efficacy of Melflufen, a Peptidase Targeted Therapy, and Dexamethasone in an Ongoing Open-Label Phase 2a Study in Patients with Relapsed and Relapsed-Refractory Multiple Myeloma (RRMM) Including an Initial Report on Progression Free Survival". Archived from the original on 2016-03-06. Retrieved 2016-03-03.
  24. "Pepaxti: Pending EC decision". European Medicines Agency. 23 June 2022. Archived from the original on 26 June 2022. Retrieved 26 June 2022. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  25. World Health Organization (2012). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 67". WHO Drug Information. 26 (1): 72. hdl:10665/109416.
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