Chemistry:Melphalan flufenamide

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Short description: Chemical compound
Melphalan flufenamide
Melphalan flufenamide.svg
Clinical data
Trade namesPepaxto, Pepaxti
Other namesMelflufen, 4-[Bis-(2-chloroethyl)amino]-L-phenylalanine-4-fluoro-L-phenylalanine ethyl ester, J1[1][2]
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismAminopeptidase hydrolysis, Spontaneous hydrolyisis on N-mustard
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC24H30Cl2FN3O3
Molar mass498.42 g·mol−1
3D model (JSmol)

Melphalan flufenamide, sold under the brand names Pepaxto and Pepaxti, is an anticancer medication used to treat multiple myeloma.[4][6]

The most common adverse reactions include fatigue, nausea, diarrhea, pyrexia and respiratory tract infection.[4][7]

Melphalan flufenamide was approved for medical use in the United States in February 2021,[6][8][7] and in the European Union in August 2022.[5]

Medical uses

In the United States, 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][6][7]

In the European Union, melphalan flufenamide is indicated, in combination with dexamethasone, for the treatment of adults with multiple myeloma who have received at least three prior lines of therapies, whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one anti-CD38 monoclonal antibody, and who have demonstrated disease progression on or after the last therapy.[5]

Metabolism

Melphalan flufenamide is metabolized by aminopeptidase hydrolysis and by spontaneous hydrolysis on N-mustard.[9]

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.[10] Melphalan flufenamide was synthesized, partly due to previous experience of an alkylating peptide cocktail named Peptichemio[11] 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.[1][2][12][13][14][11][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).[15] 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.[17]

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.[1]

This rapid disappearance from plasma is likely due to hydrolytic enzymes.[18] 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.[19]

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.[1] 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.[20][15]

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.[1][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.[21]

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 U.S. Food and Drug Administration (FDA) approved melphalan flufenamide based on evidence from a clinical trial of 157 adults with multiple myeloma.[7] The trial was conducted at 17 sites in four countries in Spain, France, Italy and the US.[7]

The FDA granted the application for melphalan flufenamide priority review and orphan drug designations.[4][22]

In October 2021, Oncopeptides AB announced the withdrawal of Pepaxto from the US market after the OCEAN trial's data showed no improvement in terms of overall survival versus pomalidomide in the ITT group (19.8 months in the melphalan flufenamide group versus 25.0 months in the pomalidomide group, HR 1.10, 95% CI 0.85–1.44, p = 0,47).[23][24]

Society and culture

Legal status

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.[25] The applicant for this medicinal product is Oncopeptides AB.[25] Melphalan flufenamide was approved for medical use in the European Union in August 2022.[5][26]

Names

Melphalan flufenamide is the international nonproprietary name (INN).[27]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "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): 1232–1241. December 2015. doi:10.1007/s10637-015-0299-2. PMID 26553306. 
  2. ↑ 2.0 2.1 "The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo". Biochemical Pharmacology 86 (7): 888–895. October 2013. doi:10.1016/j.bcp.2013.07.026. PMID 23933387. 
  3. ↑ "Pepaxto- melphalan flufenamide injection, powder, lyophilized, for solution". https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=321f455b-1de8-45bd-96f8-1bf14337f4e9. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 "FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma". 26 February 2021. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple-myeloma.  This article incorporates text from this source, which is in the public domain.
  5. ↑ 5.0 5.1 5.2 5.3 "Pepaxti EPAR". 21 June 2022. https://www.ema.europa.eu/en/medicines/human/EPAR/pepaxti.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. ↑ 6.0 6.1 6.2 "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.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "Drug Trial Snapshot: Pepaxto". 13 December 2022. https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-pepaxto. 
  8. ↑ "Drug Approval Package: Pepaxto". 22 March 2021. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214383Orig1s000TOC.cfm. 
  9. ↑ "Structure-activity relationship for alkylating dipeptide nitrogen mustard derivatives". Oncology Research 14 (3): 113–132. 2003. doi:10.3727/000000003771013071. PMID 14760861. 
  10. ↑ "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. 2006. doi:10.2174/157018006778631893. 
  11. ↑ 11.0 11.1 "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): 617–624. September 2003. doi:10.1097/00001813-200309000-00006. PMID 14501383. 
  12. ↑ "The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo". Molecular Cancer Therapeutics 6 (9): 2409–2417. September 2007. doi:10.1158/1535-7163.MCT-07-0156. PMID 17876040. 
  13. ↑ "Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo". Investigational New Drugs 22 (4): 411–420. November 2004. doi:10.1023/B:DRUG.0000036683.10945.bb. PMID 15292711. 
  14. ↑ "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): 355–363. July 2003. doi:10.1080/10611860310001647140. PMID 14668056. 
  15. ↑ 15.0 15.1 15.2 "In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells". Clinical Cancer Research 19 (11): 3019–3031. June 2013. doi:10.1158/1078-0432.CCR-12-3752. PMID 23584492. 
  16. ↑ 16.0 16.1 "Melphalan-flufenamide is cytotoxic and potentiates treatment with chemotherapy and the Src inhibitor dasatinib in urothelial carcinoma". Molecular Oncology 10 (5): 719–734. May 2016. doi:10.1016/j.molonc.2015.12.013. PMID 26827254. 
  17. ↑ "Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy". Blood 120 (2): 376–385. July 2012. doi:10.1182/blood-2012-02-412783. PMID 22451422. 
  18. ↑ "The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan". Biochemical Pharmacology 79 (9): 1281–1290. May 2010. doi:10.1016/j.bcp.2009.12.022. PMID 20067771. 
  19. ↑ "Aminopeptidase N (CD13) as a target for cancer chemotherapy". Cancer Science 102 (3): 501–508. March 2011. doi:10.1111/j.1349-7006.2010.01826.x. PMID 21205077. 
  20. ↑ "The novel alkylating prodrug J1: diagnosis directed activity profile ex vivo and combination analyses in vitro". Investigational New Drugs 26 (3): 195–204. June 2008. doi:10.1007/s10637-007-9092-1. PMID 17922077. 
  21. ↑ "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". https://ash.confex.com/ash/2015/webprogram/Paper85666.html. 
  22. ↑ (PDF) Advancing Health Through Innovation: New Drug Therapy Approvals 2021 (Report). 13 May 2022. https://www.fda.gov/media/155227/download. Retrieved 22 January 2023.  This article incorporates text from this source, which is in the public domain.
  23. ↑ "Oncopeptides withdraws Pepaxto in US, scale down organization and focus on R&D". 22 October 2021. https://www.oncopeptides.com/en/media/press-releases/oncopeptides-withdraws-pepaxto-in-us-scale-down-organization-and-focus-on-rd. 
  24. ↑ "Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study". The Lancet. Haematology 9 (2): e98-e110. February 2022. doi:10.1016/S2352-3026(21)00381-1. PMID 35032434. 
  25. ↑ 25.0 25.1 "Pepaxti: Pending EC decision". 23 June 2022. https://www.ema.europa.eu/en/medicines/human/summaries-opinion/pepaxti.  Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  26. ↑ "Pepaxti Product information". https://ec.europa.eu/health/documents/community-register/html/h1669.htm. 
  27. ↑ "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 67". WHO Drug Information 26 (1): 72. 2012. 

External links



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