Vadimezan Explained

Vadimezan (also known as or ASA404[1] and dimethylxanthenone acetic acid or DMXAA) is a tumor-vascular disrupting agent (tumor-VDA) that attacks the blood supply of a cancerous tumor to cause tumor regression.[2]

Clinical trials

Non-small cell lung cancer

Despite positive results at the preclinical stage, vadimezan failed in human clinical trials. Studies have demonstrated the reason for the inefficacy. Vadimezan was shown to target the STING pathway,[3] however, this effect is mouse specific; it has no effect on human STING.[4] A single amino acid difference at position 162 (S162A) of the cyclic-dinucleotide-binding site of STING makes mouse STING sensitive to the drug, whereas human STING remains insensitive.

Vadimezan had been studied in combination with chemotherapy in at least two Phase II trials for advanced non-small cell lung cancer (NSCLC) and showed survival extensions of around 5 months when compared to chemotherapy alone (14.0 months compared to 8.8 months).[5] [6] In April 2008, a Phase III trial started. In March 2010, the phase III trial of use as a first line therapy for NSCLC gave poor results.[7] Interim results on another phase III trial as second-line therapy for NSCLC were completed in 2011. In November 2010, the second trial also gave poor interim results.[8]

Other cancers

Vadimezan has also been studied for the treatment of prostate cancer[6] and HER2-negative metastatic breast cancer.[1] [9]

History

Vadimezan was discovered by Bruce Baguley and William Denny and their teams at the Auckland Cancer Society Research Centre at the University of Auckland in New Zealand.[9] It was licensed to Antisoma in 2001. Novartis acquired the worldwide rights for it in 2007 and it underwent development by Antisoma and Novartis.[6] [9] In 2020 CRM Therapeutics, a Dutch drug-development company, initiated research for re-developing Vadimezan in combination with its proprietary targeted delivery platform. Since January 2021, Vadimezan is a registered trademark of CRM Therapeutics B.V., Rotterdam.

Notes and References

  1. News: New Zealand drug tested for breast-cancer fight . 2009-02-13 . 14 February 2009 . The New Zealand Herald .
  2. http://www.medicalnewstoday.com/articles/103734.php ASA404, A Novel Cancer Agent, Begins Pivotal Trial To Explore New Approach In Treating Lung Cancer, The Leading Cause Of Cancer Death
  3. Prantner D, Perkins DJ, Lai W, Williams MS, Sharma S, Fitzgerald KA, Vogel SN . 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential . The Journal of Biological Chemistry . 287 . 47 . 39776–88 . November 2012 . 23027866 . 3501038 . 10.1074/jbc.M112.382986 . free .
  4. Conlon J, Burdette DL, Sharma S, Bhat N, Thompson M, Jiang Z, Rathinam VA, Monks B, Jin T, Xiao TS, Vogel SN, Vance RE, Fitzgerald KA . 6 . Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid . Journal of Immunology . 190 . 10 . 5216–25 . May 2013 . 23585680 . 3647383 . 10.4049/jimmunol.1300097 .
  5. McKeage MJ, Von Pawel J, Reck M, Jameson MB, Rosenthal MA, Sullivan R, Gibbs D, Mainwaring PN, Serke M, Lafitte JJ, Chouaid C, Freitag L, Quoix E . 6 . Randomised phase II study of ASA404 combined with carboplatin and paclitaxel in previously untreated advanced non-small cell lung cancer . British Journal of Cancer . 99 . 12 . 2006–12 . December 2008 . 19078952 . 2607218 . 10.1038/sj.bjc.6604808 .
  6. http://www.drugdevelopment-technology.com/projects/antisomas/ ASA404 Vascular Disrupting Agent for Solid Tumours
  7. Web site: Antisoma's Shares Plummet 70% as Cancer Candidate Bombs in Phase III NSCLC Trial. https://web.archive.org/web/20160304062009/http://www.genengnews.com/gen-news-highlights/antisoma-39-s-shares-plummet-70-as-cancer-candidate-bombs-in-phase/78565237/ . 4 March 2016 . Genetic Engineering & Biotechnology News. GEN Publishing, Inc.. 20 August 2013 . 29 March 2010 .
  8. News: Antisoma and Novartis Ditch ASA404 After Second Phase III NSCLC Trial Bombs . 11 November 2010 .
  9. Web site: ASA404 to be developed in breast cancer . https://web.archive.org/web/20120220100350/http://www.antisoma.com/asm/media/press/pr2009/2009-02-12/ . 20 February 2012 . 2009-02-13 . 12 February 2009 . Antisoma .

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