Olaratumab

Olaratumab
Monoclonal antibody
Type Whole antibody
Source Human
Target PDGF-R α
Clinical data
Trade names Lartruvo
Synonyms IMC-3G3, LY-3012207
AHFS/Drugs.com Monograph
License data
Routes of
administration		 Intravenous infusion
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding None
Metabolism Proteolytic enzymes
Elimination half-life 11 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • None
UNII
KEGG
Chemical and physical data
Formula C6554H10076N1736O2048S40
Molar mass 147.2 kg/mol
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Olaratumab (trade name Lartruvo) is a monoclonal antibody developed by Eli Lilly and Company for the treatment of solid tumors. It is directed against the platelet-derived growth factor receptor alpha.[1]

Medical uses

Olaratumab is used in combination with doxorubicin for the treatment of adults with advanced soft-tissue sarcoma (STS) who cannot be cured by cancer surgery or radiation therapy, and who have not been previously treated with doxorubicin.[2][3]

In a randomised controlled trial with 133 STS patients, olaratumab plus doxorubicin improved the median of progression-free survival from 4.1 to 6.6 months as compared to doxorubicin alone (p = 0.0615, narrowly missing statistical significance), and overall survival from 14.7 to 26.5 months (p = 0.0003, highly significant).[2][4]

Contraindications

The drug has no contraindications apart from hypersensitivity reactions.[2]

Side effects

In studies, the most serious side effects of the combination olaratumab/doxorubicin were neutropenia (low count of neutrophil white blood cells) with a severity of grade 3 or 4 in 55% of patients, and musculoskeletal pain grade 3 or 4 in 8% of patients. Common milder side effects were lymphopenia, headache, diarrhoea, nausea and vomiting, mucositis, and reactions at the infusion site;[2] all typical effects of cancer therapies.

Interactions

No pharmacokinetic interactions with doxorubicin were observed in studies. Being a monoclonal antibody, olaratumab is neither metabolised by cytochrome P450 liver enzymes nor transported by transmembrane pumps, and is thus not expected to interact relevantly with other drugs.[2]

Pharmacology

Mechanism of action

Olaratumab inhibits growth of tumour cells by blocking subunit alpha of the platelet-derived growth factor receptor, a type of tyrosine kinase.[2]

Pharmacokinetics

After intravenous infusion, olaratumab has a volume of distribution of 7.7 litres in steady state and a biological half-life of 11 days.[2]

History

Olaratumab was originally developed by ImClone Systems, which was acquired by Eli Lilly in 2008.[5] A Phase I clinical trial was conducted in Japanese patients in September 2010,[6] followed by a Phase II trial in 133 patients, starting in October 2010.[7]

In February 2015, the European Medicines Agency assigned olaratumab orphan drug status for the treatment of soft-tissue sarcoma.[8] The European Commission granted a conditional marketing authorisation, based on the mentioned Phase II study, valid throughout the European Union on 9 November 2016.[9]

Considered a promising drug, the FDA granted olaratumab fast track designation, breakthrough therapy designation and priority review status. In October 2016, the US FDA issued an accelerated approval notice for use of olaratumab with doxorubicin to treat adults with certain types of soft-tissue sarcoma, based on the same study.[3][10]

A Phase III trial started in September 2015 and is expected to complete in September 2020.[10][11]

References

  1. ↑ Statement on a Nonproprietary name adopted by the USAN Council: Olaratumab
  2. 1 2 3 4 5 6 7 "EPAR – Product information for Lartruvo" (PDF). European Medicines Agency. 23 November 2016.
  3. 1 2 "FDA grants accelerated approval to new treatment for advanced soft tissue sarcoma". US FDA. 19 October 2016.
  4. ↑ Tap, W. D.; Jones, R. L.; Van Tine, B. A.; Chmielowski, B; Elias, A. D.; Adkins, D; Agulnik, M; Cooney, M. M.; Livingston, M. B.; Pennock, G; Hameed, M. R.; Shah, G. D.; Qin, A; Shahir, A; Cronier, D. M.; Ilaria Jr, R; Conti, I; Cosaert, J; Schwartz, G. K. (2016). "Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial". Lancet. 388 (10043): 488–97. doi:10.1016/S0140-6736(16)30587-6. PMC 5647653. PMID 27291997.
  5. ↑ "Imclone legacy drug gains green light for Lilly in soft tissue sarcoma". BioWorld.
  6. ↑ Doi, T; Ma, Y; Dontabhaktuni, A; Nippgen, C; Nippgen, J; Ohtsu, A (2014). "Phase I study of olaratumab in Japanese patients with advanced solid tumors". Cancer Science. 105 (7): 862–869. doi:10.1111/cas.12444. PMC 4317910. PMID 24816152.
  7. ↑ Clinical trial number NCT01185964 for "A Study of IMC-3G3 in Soft Tissue Sarcoma" at ClinicalTrials.gov
  8. ↑ "Orphan Designation for olaratumab". European Medicines Agency. 9 April 2015.
  9. ↑ "EPAR summary for the public for Lartruvo" (PDF). European Medicines Agency. 23 November 2016.
  10. 1 2 Shirley, M (2016). "Olaratumab: First Global Approval". Drugs. 77: 107–112. doi:10.1007/s40265-016-0680-2. PMID 27995580.
  11. ↑ Clinical trial number NCT02451943 for "A Study of Doxorubicin Plus Olaratumab (LY3012207) in Participants With Advanced or Metastatic Soft Tissue Sarcoma (ANNOUNCE)" at ClinicalTrials.gov

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