melphalan flufenamide
{{Short description|Alkylating type cancer drug}}
{{Update|date=March 2024}}
{{Use dmy dates|date=June 2023}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| image = Melphalan flufenamide.svg
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| pronounce =
| tradename = Pepaxto, Pepaxti
| Drugs.com = {{drugs.com|monograph|melphalan}}
| MedlinePlus =
| DailyMedID = Melphalan flufenamide
| pregnancy_AU =
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| routes_of_administration = Intravenous
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| ATC_prefix = L01
| ATC_suffix = AA10
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| legal_US = Withdrawn from market{{cite web | title=FDA issues final decision to withdraw approval of Pepaxto (melphalan flufenamide) | website=U.S. Food and Drug Administration | date=23 February 2024 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-final-decision-withdraw-approval-pepaxto-melphalan-flufenamide | archive-url=https://web.archive.org/web/20240224002144/https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-final-decision-withdraw-approval-pepaxto-melphalan-flufenamide | url-status=dead | archive-date=24 February 2024 | access-date=12 March 2024}}{{cite journal | vauthors = Olivier T, Prasad V | title = The approval and withdrawal of melphalan flufenamide (melflufen): Implications for the state of the FDA | journal = Translational Oncology | volume = 18 | pages = 101374 | date = April 2022 | pmid = 35196605 | pmc = 8866737 | doi = 10.1016/j.tranon.2022.101374 }}
| legal_EU = Rx-only
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| metabolism = hydrolysis
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| CAS_number_Ref =
| CAS_number = 380449-51-4
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| PubChem = 9935639
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| DrugBank_Ref =
| DrugBank = DB16627
| ChemSpiderID_Ref =
| ChemSpiderID = 8111267
| UNII_Ref =
| UNII = F70C5K4786
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| ChEMBL = 4303060
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| synonyms = Melflufen, 4-[Bis-(2-chloroethyl)amino]-L-phenylalanine-4-fluoro-L-phenylalanine ethyl ester, J1{{cite journal | vauthors = Berglund Å, 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 | title = 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 | journal = Investigational New Drugs | volume = 33 | issue = 6 | pages = 1232–1241 | date = December 2015 | pmid = 26553306 | doi = 10.1007/s10637-015-0299-2 | s2cid = 8207569 }}{{cite journal | vauthors = Strese S, Wickström M, Fuchs PF, Fryknäs M, Gerwins P, Dale T, Larsson R, Gullbo J | title = The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo | journal = Biochemical Pharmacology | volume = 86 | issue = 7 | pages = 888–895 | date = October 2013 | pmid = 23933387 | doi = 10.1016/j.bcp.2013.07.026 }}
| IUPAC_name = Ethyl (2S)-2-
| C=24|H=30|Cl=2|F=1|N=3|O=3
| SMILES = CCOC(=O)[C@H](CC1=CC=C(C=C1)F)NC(=O)[C@H](CC2=CC=C(C=C2)N(CCCl)CCCl)N
| StdInChI = 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
| StdInChI_comment =
| StdInChIKey = YQZNKYXGZSVEHI-VXKWHMMOSA-N
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Melphalan flufenamide, sold under the brand names Pepaxto and Pepaxti, is an anticancer medication used to treat multiple myeloma.{{cite web | title=FDA grants accelerated approval to melphalan flufenamide for relapsed or refractory multiple myeloma | website=U.S. Food and Drug Administration (FDA) | date=26 February 2021 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple-myeloma | access-date=1 March 2021 | archive-date=1 March 2021 | archive-url=https://web.archive.org/web/20210301195353/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-melphalan-flufenamide-relapsed-or-refractory-multiple-myeloma | url-status=dead }} {{PD-notice}}{{cite press release | title=FDA Approves Oncopeptides' Pepaxto (melphalan flufenamide) for Patients with Triple-Class Refractory Multiple Myeloma | publisher=Oncopeptides AB | via=PR Newswire | date=1 March 2021 | url=https://www.prnewswire.com/news-releases/fda-approves-oncopeptides-pepaxto-melphalan-flufenamide-for-patients-with-triple-class-refractory-multiple-myeloma-301237310.html | access-date=1 March 2021 | archive-date=1 March 2021 | archive-url=https://web.archive.org/web/20210301131901/https://www.prnewswire.com/news-releases/fda-approves-oncopeptides-pepaxto-melphalan-flufenamide-for-patients-with-triple-class-refractory-multiple-myeloma-301237310.html | url-status=live }}
The most common adverse reactions include fatigue, nausea, diarrhea, elevated body temperature and respiratory tract infections.
Melphalan flufenamide was approved for medical use in the United States in February 2021,{{cite web | title=Drug Approval Package: Pepaxto | website=U.S. Food and Drug Administration (FDA) | date=22 March 2021 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214383Orig1s000TOC.cfm | access-date=12 September 2021 | archive-date=13 September 2021 | archive-url=https://web.archive.org/web/20210913054048/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/214383Orig1s000TOC.cfm | url-status=live }}{{cite web | title=Drug Trial Snapshot: Pepaxto | website=U.S. Food and Drug Administration (FDA) | date=13 December 2022 | url=https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-pepaxto | archive-url=https://web.archive.org/web/20221214055042/https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trial-snapshot-pepaxto | url-status=dead | archive-date=14 December 2022 | access-date=14 December 2022}} and in the European Union in August 2022.
Medical uses
In the United States before market withdrawal, melphalan flufenamide was 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.
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.
Metabolism
Melphalan flufenamide is metabolized by aminopeptidase hydrolysis and by spontaneous hydrolysis on N-mustard.{{cite journal | vauthors = Gullbo J, Tullberg M, Våbenø J, Ehrsson H, Lewensohn R, Nygren P, Larsson R, Luthman K | title = Structure-activity relationship for alkylating dipeptide nitrogen mustard derivatives | journal = Oncology Research | volume = 14 | issue = 3 | pages = 113–132 | year = 2003 | pmid = 14760861 | doi = 10.3727/000000003771013071 | doi-access = free }}
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.{{cite journal | vauthors = Wickström M, Lövborg H, Gullbo J | doi = 10.2174/157018006778631893| title = Future Prospects for Old Chemotherapeutic Drugs in the Target-Specific Era; Pharmaceutics, Combinations, Co-Drugs and Prodrugs with Melphalan as an Example| journal = Letters in Drug Design & Discovery| volume = 3| issue = 10| pages = 695–703| year = 2006 }} Melphalan flufenamide was synthesized, partly due to previous experience of an alkylating peptide cocktail named Peptichemio{{cite journal | vauthors = Gullbo J, Dhar S, Luthman K, Ehrsson H, Lewensohn R, Nygren P, Larsson R | title = 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 | journal = Anti-Cancer Drugs | volume = 14 | issue = 8 | pages = 617–624 | date = September 2003 | pmid = 14501383 | doi = 10.1097/00001813-200309000-00006 | s2cid = 10282399 }}
Pharmacology
Compared to melphalan, melphalan flufenamide exhibits significantly higher in vitro and in vivo activity in several models of human cancer.{{cite journal | vauthors = Wickström M, Johnsen JI, Ponthan F, Segerström L, Sveinbjörnsson B, Lindskog M, Lövborg H, Viktorsson K, Lewensohn R, Kogner P, Larsson R, Gullbo J | title = The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo | journal = Molecular Cancer Therapeutics | volume = 6 | issue = 9 | pages = 2409–2417 | date = September 2007 | pmid = 17876040 | doi = 10.1158/1535-7163.MCT-07-0156 | s2cid = 22694740 | doi-access = }}{{cite journal | vauthors = Gullbo J, Lindhagen E, Bashir-Hassan S, Tullberg M, Ehrsson H, Lewensohn R, Nygren P, De La Torre M, Luthman K, Larsson R | title = Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo | journal = Investigational New Drugs | volume = 22 | issue = 4 | pages = 411–420 | date = November 2004 | pmid = 15292711 | doi = 10.1023/B:DRUG.0000036683.10945.bb | s2cid = 31613292 }}{{cite journal | vauthors = Gullbo J, Wickström M, Tullberg M, Ehrsson H, Lewensohn R, Nygren P, Luthman K, Larsson R | title = Activity of hydrolytic enzymes in tumour cells is a determinant for anti-tumour efficacy of the melphalan containing prodrug J1 | journal = Journal of Drug Targeting | volume = 11 | issue = 6 | pages = 355–363 | date = July 2003 | pmid = 14668056 | doi = 10.1080/10611860310001647140 | s2cid = 25203458 }}{{cite journal | vauthors = Viktorsson K, Shah CH, Juntti T, Hååg P, Zielinska-Chomej K, Sierakowiak A, Holmsten K, Tu J, Spira J, Kanter L, Lewensohn R, Ullén A | title = Melphalan-flufenamide is cytotoxic and potentiates treatment with chemotherapy and the Src inhibitor dasatinib in urothelial carcinoma | journal = Molecular Oncology | volume = 10 | issue = 5 | pages = 719–734 | date = May 2016 | pmid = 26827254 | pmc = 5423156 | doi = 10.1016/j.molonc.2015.12.013 }}
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).{{cite journal | vauthors = Chauhan D, Ray A, Viktorsson K, Spira J, Paba-Prada C, Munshi N, Richardson P, Lewensohn R, Anderson KC | title = In vitro and in vivo antitumor activity of a novel alkylating agent, melphalan-flufenamide, against multiple myeloma cells | journal = Clinical Cancer Research | volume = 19 | issue = 11 | pages = 3019–3031 | date = June 2013 | pmid = 23584492 | pmc = 4098702 | doi = 10.1158/1078-0432.CCR-12-3752 }} 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.{{cite journal | vauthors = Chesi M, Matthews GM, Garbitt VM, Palmer SE, Shortt J, Lefebure M, Stewart AK, Johnstone RW, Bergsagel PL | title = Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy | journal = Blood | volume = 120 | issue = 2 | pages = 376–385 | date = July 2012 | pmid = 22451422 | pmc = 3398763 | doi = 10.1182/blood-2012-02-412783 }}
Structure
Chemically, the drug is best described as the ethyl ester of a dipeptide consisting of melphalan and the amino acid 4-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.
This rapid disappearance from plasma is likely due to hydrolytic enzymes.{{cite journal | vauthors = Wickström M, Viktorsson K, Lundholm L, Aesoy R, Nygren H, Sooman L, Fryknäs M, Vogel LK, Lewensohn R, Larsson R, Gullbo J | title = The alkylating prodrug J1 can be activated by aminopeptidase N, leading to a possible target directed release of melphalan | journal = Biochemical Pharmacology | volume = 79 | issue = 9 | pages = 1281–1290 | date = May 2010 | pmid = 20067771 | doi = 10.1016/j.bcp.2009.12.022 }}
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.{{cite journal | vauthors = Wickström M, Larsson R, Nygren P, Gullbo J | title = Aminopeptidase N (CD13) as a target for cancer chemotherapy | journal = Cancer Science | volume = 102 | issue = 3 | pages = 501–508 | date = March 2011 | pmid = 21205077 | pmc = 7188354 | doi = 10.1111/j.1349-7006.2010.01826.x }}
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. 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.{{cite journal | vauthors = Wickström M, Haglund C, Lindman H, Nygren P, Larsson R, Gullbo J | title = The novel alkylating prodrug J1: diagnosis directed activity profile ex vivo and combination analyses in vitro | journal = Investigational New Drugs | volume = 26 | issue = 3 | pages = 195–204 | date = June 2008 | pmid = 17922077 | doi = 10.1007/s10637-007-9092-1 | s2cid = 19915448 }}
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. 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.{{Cite web |url=https://ash.confex.com/ash/2015/webprogram/Paper85666.html |title=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 |access-date=3 March 2016 |archive-date=6 March 2016 |archive-url=https://web.archive.org/web/20160306102133/https://ash.confex.com/ash/2015/webprogram/Paper85666.html |url-status=live }}
History
Efficacy was evaluated in HORIZON (NCT02963493), a multicenter, single-arm trial. Eligible patients were required to have relapsed refractory multiple myeloma. 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. 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. The U.S. Food and Drug Administration (FDA) approved melphalan flufenamide based on evidence from a clinical trial of 157 adults with multiple myeloma. The trial was conducted at 17 sites in four countries in Spain, France, Italy and the US.
The FDA granted the application for melphalan flufenamide under the priority review and orphan drug programs.{{cite report | title=Advancing Health Through Innovation: New Drug Therapy Approvals 2021 | website=U.S. Food and Drug Administration (FDA) | date=13 May 2022 | url=https://www.fda.gov/media/155227/download | format=PDF | access-date=22 January 2023 | archive-date=6 December 2022 | archive-url=https://web.archive.org/web/20221206210020/https://www.fda.gov/media/155227/download | url-status=live }} {{PD-notice}}
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).{{Cite web |title=Oncopeptides withdraws Pepaxto in US, scale down organization and focus on R&D |url=https://www.oncopeptides.com/en/media/press-releases/oncopeptides-withdraws-pepaxto-in-us-scale-down-organization-and-focus-on-rd | date=22 October 2021 |access-date=19 June 2023 |website=Oncopeptides }}{{cite journal | vauthors = Schjesvold FH, Dimopoulos MA, Delimpasi S, Robak P, Coriu D, Legiec W, Pour L, Špička I, Masszi T, Doronin V, Minarik J, Salogub G, Alekseeva Y, Lazzaro A, Maisnar V, Mikala G, Rosiñol L, Liberati AM, Symeonidis A, Moody V, Thuresson M, Byrne C, Harmenberg J, Bakker NA, Hájek R, Mateos MV, Richardson PG, Sonneveld P | title = Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study | journal = The Lancet. Haematology | volume = 9 | issue = 2 | pages = e98–e110 | date = February 2022 | pmid = 35032434 | doi = 10.1016/S2352-3026(21)00381-1 | s2cid = 245950577 | doi-access = free }}
Society and culture
= Legal status =
In 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. The applicant for this medicinal product is Oncopeptides AB.{{cite web | title=Pepaxti: Pending EC decision | website=European Medicines Agency | date=23 June 2022 | url=https://www.ema.europa.eu/en/medicines/human/summaries-opinion/pepaxti | access-date=26 June 2022 | archive-date=26 June 2022 | archive-url=https://web.archive.org/web/20220626032005/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/pepaxti | url-status=live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged. Melphalan flufenamide was approved for medical use in the European Union in August 2022.{{cite web | title=Pepaxti EPAR | website=European Medicines Agency (EMA) | date=21 June 2022 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/pepaxti | access-date=14 December 2022}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.{{cite web | title=Pepaxti Product information | website=Union Register of medicinal products | url=https://ec.europa.eu/health/documents/community-register/html/h1669.htm | access-date=3 March 2023}}
= Names =
Melphalan flufenamide is the international nonproprietary name (INN).{{cite journal | vauthors=((World Health Organization)) | year=2012 | title=International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 67 | journal=WHO Drug Information | volume=26 | issue=1 | page=72 | hdl=10665/109416 | hdl-access=free }}
References
{{Reflist}}
External links
- {{ClinicalTrialsGov|NCT02963493|A Study of Melphalan Flufenamide (Melflufen) in Combination With Dexamethasone in Relapsed Refractory Multiple Myeloma Patients (HORIZON)}}
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