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levoleucovorin

Trade name: fusilev

Small moleculeapprovedOrphan Drug FDA

Approved

Mar 7, 2008

Levoleucovorin is the pharmacologically active isomer of leucovorin or 5-formyl tetrahydrofolic acid, a folate analog . Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “onecarbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. Levoleucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme. Fusilev® (levoleucovorin) is approved by FDA for i) rescue after high-dose methotrexate therapy in osteosarcoma, ii) diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists and iii) in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. — NCATS

Clinical trial activity

105 trials · 119 clinical orgs · 21 marketing orgs

Phase 1
28
Phase 2
80
Phase 3
19
Phase 4
1

Earliest trial started Oct 1, 1997 (NCT00005586)

Timeline

1990s

  1. Dec 18, 1990

    Orphan Drug Designation

  2. Jan 1, 1997

    Earliest Phase 3 Sponsor(trial)

2000s

  1. Jan 1, 2005

    Earliest Phase 2 Sponsor(trial)

  2. Mar 7, 2008

    Spectrum Pharmaceuticals — Earliest FDA Approval

  3. Mar 7, 2008

    Aurobindo Pharma — Marketing Organization

  4. Mar 7, 2008

    Spectrum Pharmaceuticals — NDA Organization

  5. Mar 7, 2008

    Acrotech Biopharma LLC — Marketing Organization

  6. Mar 7, 2008

    Acrotech Biopharma LLC — NDA Secondary Org

2010s

  1. Jan 1, 2011

    Earliest Phase 1 Sponsor(trial)

  2. Mar 9, 2015

    Sandoz — Marketing Organization

  3. Mar 9, 2015

    Novartis — Marketing Organization

  4. Oct 20, 2015

    Mylan — Marketing Organization

  5. Oct 20, 2015

    PHARMOBEDIENT — Marketing Organization

  6. Jun 16, 2016

    West-Ward Pharmaceutical — Marketing Organization

  7. Jun 16, 2016

    Hikma — Marketing Organization

  8. Sep 29, 2016

    Actavis — NDA Secondary Org

  9. Sep 29, 2016

    Allergan PLC (2015) — NDA Secondary Org

  10. Feb 13, 2017

    Amneal Pharmaceuticals — Marketing Organization

  11. Feb 13, 2017

    Allergan PLC (2015) — Marketing Organization

  12. May 3, 2018

    Ingenus Pharmaceuticals — Marketing Organization

  13. May 3, 2018

    Novast Labs — Marketing Organization

  14. Sep 14, 2018

    Gland Pharma Ltd — Marketing Organization

  15. Sep 14, 2018

    Fosun — Marketing Organization

  16. Aug 16, 2019

    Nanjing King-Friend — Marketing Organization

  17. Aug 16, 2019

    Meitheal — Marketing Organization

2020s

  1. Nov 2, 2021

    Praxgen Pharma — Marketing Organization

  2. Nov 2, 2021

    Ailex Pharmaceuticals — Marketing Organization

  3. May 22, 2023

    Hainan Poly Pharm — Marketing Organization

Indications

Approved for

Studied for

Mechanism of action

  • Unspecified targetOTHER

    Unknown

    Provides a DHFR-independent source of folate, counteracting methotrexate toxicity. Can enhance toxic effects of fluoropyrimidines in cancer therapy through conversion to 5,10-methylenetetrahydrofolate, stabilising binding of 5-fluoro-2'-deoxyuridine-5'-monophosphate to thymidylate synthase

Approval history

  • approvedMar 7, 2008

Chemistry & pharmacology

Loading structure…

SMILES

Nc1nc(=O)c2c([nH]1)NC[C@H](CNc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)N2C=O
Mol. weight
473.45 g/mol
Lipinski Ro5
1 violation(s)
Rule of 3
No
Chirality
Single Stereoisomer
Inorganic
No
Polymer
No
Delivery
Parenteral
Availability
Prescription Only

Oral

No

Parenteral

Yes

Topical

No

Sources

Also known as

  • (6s)-5-formyl-5,6,7,8-tetrahydrofolic acid
  • (6s)-5-formyl-5,6,7,8-tetrahydrofolic acid
  • (6s)-5-formyltetrahydrofolic acid
  • (6s)-5-formyltetrahydrofolic acid
  • (6s)-folinic acid
  • (6s)-folinic acid
  • (6s)-leucovorin
  • (6s)-leucovorin
  • calcium levofolinate
  • calcium levofolinate
  • calcium levofolinate
  • calcium levofolinate
  • cl-307782
  • cl-307782
  • levofolene
  • levofolene
  • levofolene
  • levofolinate
  • levofolinate
  • levofolinate calcium
  • levofolinate calcium
  • levo-folinic acid
  • levofolinic acid
  • levofolinic acid
  • levofolinic acid
  • levofolinic acid
  • levofolinic acid
  • levoleucovorin
  • levoleucovorin
  • levoleucovorin
  • levoleucovorin
  • levoleucovorin
  • levoleucovorin
  • levoleucovorin
  • levoleucovorin
  • levo-leucovorin
  • levo-leucovorin
  • levoleucovorin calcium
  • levoleucovorin calcium
  • levoleucovorin calcium
  • levoleucovorin calcium
  • levoleucovorin calcium pentahydrate
  • levoleucovorin calcium pentahydrate
  • levoleucovorin calcium pentahydrate
  • levoleucovorin calcium pentahydrate
  • levoleucovorin calcium pentahydrate
  • l-folinic acid
  • l-folinic acid
  • l-folinic acid
  • l-folinic acid
  • l-leucovorin
  • l-leucovorin
  • n-[4-({[(6s)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydropteridin-6-yl]methyl}amino)benzoyl]-l-glutamic acid
  • n-[4-({[(6s)-2-amino-5-formyl-4-oxo-1,4,5,6,7,8-hexahydropteridin-6-yl]methyl}amino)benzoyl]-l-glutamic acid
  • (s)-leucovorin
  • (s)-leucovorin
  • sodium levofolinate
  • sodium levofolinate
  • sodium levofolinate

Clinical trials

NCT IDPhaseStart dateSponsor(s)
NCT07221357Phase 2/Phase 3 (Phase 3)Mar 4, 2026Biontech, Bristol-Myers Squibb
NCT07033689Early Phase 1 (Phase 1)Dec 1, 2025SONIRE Therapeutics Inc., Stanford University
NCT07193862Early Phase 1 (Phase 1)Oct 15, 2025Northwell Health
NCT07011576Phase 2Sep 29, 2025SCRI Development Innovations, Takeda
NCT07106034Phase 2Aug 31, 2025Ningxia Medical University, Shanghai Junshi Bioscience Co.,Ltd.
NCT07021950Phase 2Aug 10, 2025Sun Yat-Sen University
NCT07018570Phase 2Jul 24, 2025Merck, National Cancer Center, Japan
NCT06997497Phase 3Jul 16, 2025Merck
NCT06867822Phase 1/Phase 2 (Phase 2)Jun 30, 2025University of Alabama, Birmingham, V Foundation
NCT06946849Phase 2Jun 1, 2025Fudan University
NCT06855849Phase 2May 31, 2025Yonsei University
NCT06907342Phase 2May 23, 2025Norwegian University of Science and Technology
NCT06936527Phase 1/Phase 2 (Phase 2)May 23, 2025NovaOnco Therapeutics Co., Ltd.
NCT07204574Phase 1/Phase 2 (Phase 2)May 14, 2025Chang Gung University, FBD Biologics
NCT06780111Phase 1/Phase 2 (Phase 2)Apr 23, 2025Daiichi Sankyo, Merck
NCT06793917Phase 3Apr 1, 2025Fujian Medical University
NCT06792695Phase 2Mar 12, 2025AstraZeneca, Parexel
NCT05733689Phase 1Feb 28, 2025Chao Family Comprehensive Cancer Center, Natera, Inc., University of California, Irvine
NCT06501989Phase 2Jan 15, 2025Inova Health System
NCT06747845Phase 2Jan 6, 2025Bristol-Myers Squibb, GlaxoSmithKline, Lustgarten Foundation, University of Pennsylvania
Showing 20 of 105 trials
Page 1 / 6

Organizations

Research & Development (119)

OrganizationOrg typeTrialsAs lead sponsorPhasesEarliest year
Fujian Medical UniversityAcademic/Hospital131342017
MerckFor profit8622020
Cardiff OncologyFor profit4422019
Ono PharmaceuticalsFor profit3312021
RocheFor profit3212011
Sun Yat-Sen UniversityAcademic/Hospital3222013
Zhejiang UniversityAcademic/Hospital3332020
Bristol-Myers SquibbFor profit2122025
EPS CorporationFor profit2222013
Fondazione Giovanni PascaleAcademic/Hospital2222006
Fudan UniversityAcademic/Hospital2212022
Lustgarten FoundationAcademic/Hospital2012022
NovartisFor profit2222019
PfizerFor profit2122007
Pierre FabreFor profit2112021
SONIRE Therapeutics Inc.For profit2222022
Spectrum PharmaceuticalsFor profit2212013
State of New YorkGovernment2012019
State University of New York, BrooklynAcademic/Hospital2012019
Tsukuba UniversityAcademic/Hospital2022013
119 organizations
Page 1 / 6

Marketing (27)

OrganizationOrg typeRelationshipDate
Acrotech Biopharma LLCFor profitMKTGMar 7, 2008
Acrotech Biopharma LLCFor profitNDA2Mar 7, 2008
ActavisFor profitNDA2Sep 29, 2016
Ailex PharmaceuticalsFor profitMKTGNov 2, 2021
Allergan PLC (2015)For profitNDA2Sep 29, 2016
Allergan PLC (2015)For profitMKTGFeb 13, 2017
Amneal PharmaceuticalsFor profitMKTGFeb 13, 2017
Amneal PharmaceuticalsFor profitSYNFeb 13, 2017
Aurobindo PharmaFor profitMKTGMar 7, 2008
FosunFor profitMKTGSep 14, 2018
Gland Pharma LtdFor profitMKTGSep 14, 2018
Gland Pharma LtdFor profitSYNSep 14, 2018
Hainan Poly PharmFor profitMKTGMay 22, 2023
HikmaFor profitSYNJun 16, 2016
HikmaFor profitMKTGJun 16, 2016
Ingenus PharmaceuticalsFor profitMKTGMay 3, 2018
MeithealFor profitMKTGAug 16, 2019
MylanFor profitMKTGOct 20, 2015
Nanjing King-FriendFor profitMKTGAug 16, 2019
NovartisFor profitMKTGMar 9, 2015
Novast LabsFor profitMKTGMay 3, 2018
PHARMOBEDIENTFor profitMKTGOct 20, 2015
Praxgen PharmaFor profitMKTGNov 2, 2021
SandozFor profitMKTGMar 9, 2015
SandozFor profitSYNMar 9, 2015
Spectrum PharmaceuticalsFor profitNDAMar 7, 2008
West-Ward PharmaceuticalFor profitMKTGJun 16, 2016