Irofulven Explained

Irofulven or 6-hydroxymethylacylfulvene (also known as HMAF of MGI-114) is an experimental antitumor agent.^{[1] [2]} It belongs to the family of drugs called alkylating agents.

It inhibits the DNA replication of cells deficient in nucleotide excision repair in culture.^{[3] [4]}

Irofulven is an analogue of illudin S, a sesquiterpene toxin found in the Jack 'o' Lantern mushroom (Omphalotus illudens). The compound was originally synthesized by Dr. Trevor McMorris and found to have anticancer properties in mice by Dr. Michael J Kelner.^[5] __TOC__

Licensing and Clinical development

The drug was created and patented by the University of California, San Diego (UCSD), and subsequently licensed to the US biotech company MGI Pharma. Eisai acquired MGI in 2007, and the license was returned to UCSD, which then re-licensed the potential cancer drug to Lantern Pharma in 2015. Soon after, the drug was again sub-licensed to Oncology Venture, now known as Allarty Therapeutics A/S.

The drug has undergone a number of clinical trials, mostly for late-stage tumors as well as ovarian and prostate cancers, usually preceded by treatment with carboplatin and paclitaxel. A multi-center phase 2 trial involving patients with Recurrent or Persistent Ovarian Epithelial or Primary Peritoneal Cancer was well tolerated but irofluven demonstrated modest activity as a single agent.^[6] Previously, a European Phase I study in combination with cisplatin showed substantial evidence for anti-tumor activity. In that study, irofulven showed rapid elimination and high interpatient variability. Platinum and irofulven pharmacokinetics did not suggest drug-drug interactions.^[7]

Despite modest successes demonstrating limited efficacy for late stage tumors that were statistically not significant enough to support broader clinical trials, Allarty decided to stratify patient populations with companion diagnostic tools (biomarkers) to predict outcomes, and thus select that sub-set of patients through DRP (Drug Response Predictors), for whom treatment with irofulven would be most effective. Allarty initiated two Phase 2 drug-screening studies at two Danish University Hospitals for late-stage prostate cancers, wherein 300 patients have been included to be screened, of which only 27 are to be selected for the Phase 2 trial.^[8] In 2021, Lantern Pharma reacquired the rights to the development and commercialization of irofulven. At that time, 9 of the intended 27 patients had been a part of the study which saw an increase of median overall survival from 2.6 to 5.4 months.^[9] The study is estimated to be complete in late 2024.^[10]

Since it was first synthesized, research with irofulven has decreased dramatically over the past decade with only one clinical trial currently being run. A study published in 2021 showed cells with nucleotide excision repair (NER) deficiencies were susceptible to iroflaven while cells without these NER deficiencies were not overly affected. The deficiency of tumors in NER was seen as a potential identifier for patient candidates. Since this discovery, research has increased with researchers calling irofulven a "previously abandoned" anticancer drug.^{[11] [12]}

Synthesis

A synthesis of irofulven has been reported.^[13]

Notes and References

1. Escargueil, A. E. . Poindessous, V. . Soares, D. G. . Sarasin, A. . Cook, P. R. . Larsen, A. K. . Influence of Irofulven, a Transcription-Coupled Repair-Specific Antitumor Agent, on RNA Polymerase Activity, Stability and Dynamics in Living Mammalian Cells . Journal of Cell Science . 121 . Pt 8 . 1275–1283 . April 2008 . 18388315 . 10.1242/jcs.023259 . 9282024 .
2. Kelner, M. J. . McMorris, T. C. . Estes, L. . Wang, W. . Samson, K. M. . Taetle, R. . Efficacy of HMAF (MGI-114) in the MV522 Metastatic Lung Carcinoma Xenograft Model Nonresponsive to Traditional Anticancer Agents . Investigational New Drugs . 14 . 2 . 161–167 . 1996 . 8913837 . 10.1007/BF00210787 . 8439510 .
3. Wang, Y. . Wiltshire, T. . Senft, J. . Reed, E. . Wang, W. . Irofulven Induces Replication-Dependent CHK2 Activation Related to p53 Status . . 73 . 4 . 469–480 . February 2007 . 17118344 . 1800887 . 10.1016/j.bcp.2006.10.023 .
4. Börcsök . Judit . Sztupinszki . Zsofia . Bekele . Raie . Gao . Sizhi P. . Diossy . Miklos . Samant . Amruta S. . Dillon . Kasia M. . Tisza . Viktoria . Spisák . Sándor . Rusz . Orsolya . Csabai . Istvan . Pappot . Helle . Frazier . Zoë J. . Konieczkowski . David J. . Liu . David . 2021-04-01 . Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer . Clinical Cancer Research. 27 . 7 . 2011–2022 . 10.1158/1078-0432.CCR-20-3316 . 1557-3265 . 8026514 . 33208343.
5. MacDonald, J. R. . Muscoplat, C. C. . Dexter, D. L. . Mangold, G. L. . Chen, S. F. . Kelner, M. J. . McMorris, T. C. . Von Hoff, D. D. . Preclinical Antitumor Activity of 6-hydroxymethylacylfulvene, a Semisynthetic Derivative of the Mushroom Toxin Illudin S . Cancer Research . 57 . 2 . 279–283 . 1997 . 9000568 .
6. Schilder RJ et al. (2010 Oct). "A phase II evaluation of Irofulven (IND#55804, NSC#683863) as second-line treatment of recurrent or persistent intermediately platinum-sensitive ovarian or primary peritoneal cancer: A Gynecologic Oncology Group trial". J Gynecol Cancer. 20(7):1137-41. .
7. Hilger W et al.(July 2006),A phase I and pharmacokinetic study of irofulven and cisplatin administered in a 30-min infusion every two weeks to patients with advanced solid tumors. Invest New Drugs. 24(4):311-9. .
8. http://www.pharmacychoice.com/news/article.cfm?Article_ID=1610062 Both Danish sites now open in the Screening Study of prostate cancer patients for OV's Irofulven
9. Web site: 2021-07-27 . Lantern Pharma Reacquires Rights to Phase 2 Clinical Trial in Metastatic Prostate Cancer and Global Development & Commercialization of Irofulven (LP-100) from Allarity Therapeutics A/S . 2024-07-26 . Lantern Pharma Inc. . en.
10. Web site: ClinicalTrials.gov . 2024-01-26 . clinicaltrials.gov.
11. Prosz . Aurel . Duan . Haohui . Tisza . Viktoria . Sahgal . Pranshu . Topka . Sabine . Klus . Gregory T. . Börcsök . Judit . Sztupinszki . Zsofia . Hanlon . Timothy . Diossy . Miklos . Vizkeleti . Laura . Stormoen . Dag Rune . Csabai . Istvan . Pappot . Helle . Vijai . Joseph . 2023-11-23 . Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma . Scientific Reports . en . 13 . 1 . 20567 . 10.1038/s41598-023-47946-4 . 37996508 . 2045-2322. 10667362 . 2023NatSR..1320567P .
12. Web site: 2021-01-11 . Repairing DNA Damage in Cancer Cells Memorial Sloan Kettering Cancer Center . 2024-01-26 . www.mskcc.org . en.
13. 10.1021/jo035084j . 14750783 . Synthesis and Biological Activity of Enantiomers of Antitumor Irofulven . 2004 . McMorris . T. C. . Staake . M. D. . Kelner . M. J. . The Journal of Organic Chemistry . 69 . 3 . 619–23 .