Pralatrexate

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Pralatrexate
Pralatrexate.png
Pralatrexate ball-and-stick.png
Clinical data
Trade names Folotyn
AHFS/Drugs.com Monograph
License data
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Identifiers
  • N-(4-{{#parsoidfragment:6}}{1-[(2,4-diaminopteridin-6-yl)methyl]but-3-yn-1-yl}benzoyl)-L-glutamic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.205.791 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C23H23N7O5
Molar mass 477.481 g·mol−1
3D model (JSmol)
  • O=C(O)[C@@H](NC(=O)c1ccc(cc1)C(CC#C)Cc2nc3c(nc2)nc(nc3N)N)CCC(=O)O
  • InChI=1S/C23H23N7O5/c1-2-3-14(10-15-11-26-20-18(27-15)19(24)29-23(25)30-20)12-4-6-13(7-5-12)21(33)28-16(22(34)35)8-9-17(31)32/h1,4-7,11,14,16H,3,8-10H2,(H,28,33)(H,31,32)(H,34,35)(H4,24,25,26,29,30)/t14?,16-/m0/s1 Yes check.svgY
  • Key:OGSBUKJUDHAQEA-WMCAAGNKSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Pralatrexate, sold under the brand name Folotyn, is a medication used for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). [3] [4]

Contents

Pralatrexate was approved for medical use in the United States in September 2009, as the first treatment for Peripheral T-cell Lymphoma (PTCL), an often aggressive type of non-Hodgkins lymphoma. [4] [5]

Medical uses

Pralatrexate is indicated for the treatment of people with relapsed or refractory peripheral T-cell lymphoma (PTCL). [3]

Available forms

It is administered intravenously weekly for 6 weeks in 7-week cycles, with mandatory folic acid and vitamin B12 supplementation to mitigate toxicities like mucositis. [3]

Side effects

Pralatrexate is associated with several notable side effects, most prominently mucositis, which is considered the most frequently observed adverse event during treatment for relapsed or refractory peripheral T-cell lymphoma. Mucositis risk can be reduced through supplementation with leucovorin, cyanocobalamin, and folic acid. Other adverse effects described include myelosuppression, anemia, thrombocytopenia, neutropenia, and gastrointestinal symptoms, which require monitoring and supportive care to mitigate toxicity. [6]

Mechanism of action

Pralatrexate is a folate analog metabolic inhibitor designed to selectively enter cancer cells that overexpress the reduced folate carrier (RFC-1). Once inside the cell, pralatrexate competitively inhibits dihydrofolate reductase (DHFR), disrupting folate-dependent processes crucial for DNA synthesis, RNA production, and cell division, ultimately leading to apoptosis. Its enhanced cellular uptake and polyglutamylation contribute to prolonged intracellular retention and potent cytotoxicity, distinguishing it from other antifolate agents. [7]

Discovery

Research on this class of drugs began in the 1950s at SRI International, where scientists were focused on developing new chemotherapies and antifolates that would be effective against tumor cells. [8]

In the late 1970s, researchers at Memorial Sloan Kettering Cancer Center discovered, that cancerous cells take in natural folate through a protein identified as plasma membrane transporter (now referred to as "reduced folate carrier type 1" or "RFC-1"). Further research showed that when normal cells evolve into cancerous cells they often overproduce RFC-1 to ensure they get enough folate. [9]

A subsequent scientific collaboration was ultimately formed among SRI International, Memorial Sloan Kettering Cancer Center, and the Southern Research Institute with the intention of developing an antifolate with greater therapeutic selectivity – an agent that could be more effectively internalized into tumors (transported into the cells through RFC-1) and would be more toxic to cancer cells than normal cells. [9]

This collaboration, supported by the National Cancer Institute, [10] led to the identification of pralatrexate in the mid-1990s. Pralatrexate was later licensed to Allos Therapeutics in 2002 for further development. [11] Allos Therapeutics, Inc. was acquired by Spectrum Pharmaceuticals, Inc. on September 5, 2012. Allos is a wholly owned subsidiary of Spectrum. [12]

Society and culture

US approval

Pralatrexate (Folotyn®) is a folate analogue metabolic inhibitor approved by the U.S. Food and Drug Administration (FDA) in September 2009 as a single-agent therapy for relapsed or refractory (R/R) PTCL, a rare and aggressive subtype of non-Hodgkin lymphoma comprising about 10-15% of cases. It was the first drug specifically approved for this indication, based on accelerated approval criteria emphasizing overall response rate (ORR) as a surrogate for clinical benefit in a disease with limited treatment options and poor prognosis (median overall survival [OS] of 5-11 months post-relapse). [5] [4]

EU rejection

The European Medicines Agency (EMA) rejected pralatrexate (Folotyn) due to a lack of sufficient clinical evidence of the drug's benefits, which it deemed did not outweigh the risks. The EMA's Committee for Medicinal Products for Human Use (CHMP) highlighted key concerns regarding the study design and the lack of comparative data. This differed from the U.S. Food and Drug Administration (FDA), which granted accelerated approval based on a single-arm trial, which lacked the rigor required for a traditional approval, which was demanded by the EMA. [13]

Economics

Some oncologists, patient groups, and insurance companies criticized the cost of $30,000 a month or more, which could reach a total of $126,000 during a course of treatment. [14] This is especially troublesome, considering that the development cost of this small molecule pharmaceutical is significantly lower than the development cost of similarly-priced biopharmaceuticals. [15] [16] [17]

References

  1. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  2. ↑ "Summary Basis of Decision (SBD) for Folotyn". Health Canada . 23 October 2014. Retrieved 29 May 2022.
  3. 1 2 3 "Folotyn- pralatrexate injection". DailyMed. 28 May 2020. Retrieved 21 October 2020.
  4. 1 2 3 "FDA Approves First Drug for Treatment of Peripheral T-cell Lymphoma". U.S. Food and Drug Administration (FDA) (Press release). 25 September 2009. Archived from the original on 1 October 2009. Retrieved 21 October 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  5. 1 2 "Drug Approval Package: Folotyn (Pralatrexate) Injection NDA #022468". U.S. Food and Drug Administration (FDA). 23 November 2009. Archived from the original on April 4, 2021. Retrieved 21 October 2020.
  6. ↑ O'Connor OA, Amengual J, Colbourn D, Deng C, Sawas A (November 2017). "Pralatrexate: a comprehensive update on pharmacology, clinical activity and strategies to optimize use". Leukemia & Lymphoma. 58 (11): 2548–2557. doi:10.1080/10428194.2017.1306642. PMID   28738754.
  7. ↑ Zhao JC, Jaszczur SM, Afifi S, Foss F (June 2020). "Pralatrexate injection for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma". Expert Review of Hematology. 13 (6): 577–583. doi:10.1080/17474086.2020.1756257. PMID   32293930.
  8. ↑ "Allos Therapeutics: News". Archived from the original on 2013-01-17. Retrieved 2010-09-20., Allos Therapeutics Press Release, "Allos Therapeutics' Pralatrexate Demonstrates Anticancer Activity in Multiple Cancer Cell Lines".
  9. 1 2 , Memorial Sloan Kettering Cancer Center Press Release, "FDA Approves Lymphoma Drug Developed at Memorial Sloan Kettering".
  10. ↑ "The NExT Steps in Drug Development at NCI". NCI Cancer Bulletin. 20 October 2009. Archived from the original on 5 October 2014. Retrieved 21 October 2020.
  11. ↑ "FDA Approves Pralatrexate for Treatment of Peripheral T-Cell Lymphoma" (Press release). SRI International. 2009-09-25. Archived from the original on 2013-07-03. Retrieved 2013-07-10.
  12. ↑ Avery G (2012-09-07). "Purchase of Allos Therapeutics is completed". Denver Business Journal . Retrieved 2013-07-10.
  13. ↑ "Folotyn | European Medicines Agency (EMA)". www.ema.europa.eu. 2012-01-20. Retrieved 2025-10-14.
  14. ↑ Pollack A (December 4, 2009). "Questioning a Cancer Drug That Costs $30,000 a Month". New York Times . Retrieved 2009-12-05. The price of the new drug, called Folotyn, is at least triple that of other drugs that critics have said are too expensive for the benefits they offer to patients.
  15. ↑ "Questioning a $30,000-a-Month Cancer Drug (Published 2009)". 2009-12-05. Retrieved 2025-10-14.
  16. ↑ "$30K per month: Too much for a cancer drug? | Fierce Pharma". www.fiercepharma.com. 2009-12-07. Retrieved 2025-10-14.
  17. ↑ Kansteiner F, Becker Z, Liu A, Sagonowsky E, Dunleavy K (2023-05-22). "Most expensive drugs in the US in 2023". www.fiercepharma.com. Retrieved 2025-10-14.
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