Eflornithine
Eflornithine, also known as α-diflurormethylornithine (DFMO), selectively targets and irreversibly inhibits ornithine decarboxylase (ODC), an enzyme essential for polyamine synthesis, and DNA and RNA function. Unlike multi-targeted tyrosine kinase inhibitors on the market or in development, eflornithine targets only one specific enzyme, ODC.
ODC is an important enzyme that regulates cell division and is the first step of the synthesis of polyamines, converting ornithine to putrescine. Putrescine is a precursor for spermidine which, in turn, is a precursor for spermine. These chemicals are called polyamines. It is known that mammalian polyamine biosynthesis is tightly controlled during normal cell growth with its regulation at the levels of transcription, translation and protein degradation. In addition, it is known that ODC is up-regulated in certain types of cancer.
Cell studies have demonstrated that polyamines are important for stabilizing DNA structure, the DNA double strand-break repair pathway and as antioxidants. Further evidence points to putrescine being important to the function of RNA and transcription, and underpins its importance as an essential enzyme for cell growth. In addition, polyamines also upregulate gap junction genes and downregulate tight junction genes. Both of these functions are important as gap junction genes are involved in communication between carcinogenic cells and tight junction genes act as tumor suppressors.
It has been shown that proto-oncogenic pathways appear to control ODC transcription and translation with dysregulation of pathways downstream of ras and myc resulting in elevation of ODC activity in a wide variety of cancers. Inhibition of ODC activity appears to revert the transformation of cells in vitro, reduces tumor growth in animal models and cause cell apoptosis in some tumors.
Eflornithine injection was approved by the FDA in 1990 for the treatment of African trypanosomiasis (sleeping sickness), but it was never made commercially available in the U.S. In 2000, the FDA approved a topical eflornithine cream for the reduction of unwanted facial hair in women.
In 2014, Orbus Therapeutics received breakthrough therapy designation from the FDA for eflornithine for the treatment of patients with anaplastic glioma. A new drug may be designated as a breakthrough therapy by the FDA if it is intended to treat a serious or life-threatening disease and preliminary evidence suggests it provides substantial improvement over existing therapies.
Eflornithine oral solution is an investigational product that has not been proven to be safe and effective in treating patients with recurrent anaplastic astrocytoma (rAA). Currently, eflornithine oral solution may only be administered to patients who participate in a clinical trial. Eflornithine oral solution is not licensed for the treatment of rAA in the United States or any other country.
Eflornithine Clinical Development: A Late-Stage Asset
In animal studies, eflornithine has been shown to inhibit the growth of malignant tumors, including intra cerebral mid- and high-grade gliomas. Eflornithine administration has also been shown to potentiate the anti-tumor activity of other chemotherapy agents.
In single-arm and controlled, randomized clinical trials, eflornithine oral solution increased survival in patients with both newly diagnosed and recurrent anaplastic glioma [1, 2, 3, 4]. The primary and reversible side effects of eflornithine were diarrhea and hearing impairment.
STELLAR Study
In September 2016, Orbus commenced a pivotal Phase 3 randomized clinical trial, called STELLAR, of eflornithine in patients with anaplastic astrocytoma. Designed to evaluate the efficacy and safety profile of eflornithine in combination with lomustine compared to lomustine alone in patients with anaplastic astrocytoma that recurs after surgery, irradiation and adjuvant temozolomide chemotherapy, the STELLAR study will enroll approximately 340 patients across 80 leading clinical trial centers in the United States, Canada and Europe.
Lomustine is the generic drug name for CCNU (also called CeeNU® or Gleostine®), a chemotherapy drug that is used to treat certain types of cancers, including brain cancers. Lomustine belongs to the class of chemotherapy drugs called alkylating agents. Alkylating agents affect the DNA in cells and delay or stop cell growth. Lomustine capsules are taken by mouth once every 6 weeks. It is often used as a treatment for patients with rAA in clinical practice. Lomustine is not specifically licensed for the treatment of rAA in the United States or in any other country.
The STELLAR study is registered with the United States Government Clinical Trials Registry and with the European Union Clinical Trials Registry
Click here for clinical trial information
References:
1. Shantz LM and Levin VA. Regulation of ornithine decarboxylase during oncogenic transformation: mechanisms and therapeutic potential. Amino Acids. 2007;33(2):213-223.
2. Levin VA, Prados MD, Yung WK, Gleason MJ, Ictech S, Malec M. Treatment of recurrent gliomas with eflornithine. J Natl Cancer Inst. 1992;84(18):1432-1437.
3. Levin VA, Hess KR, Choucair A, Flynn PJ, Jaeckle KA, Kyritsis AP, Yung WK, PradosMD, Bruner JM, Ictech S, Gleason MJ, Kim HW. Phase III randomized study of post radiotherapy chemotherapy with combination alpha-difluromethylornithine-PCV versus PCV for anaplastic gliomas. Clin Cancer Res. 2003;9(3):981-990
4. Levin VA, Ictech SE, Hess KR. Clinical importance of eflornithine (α-difluoromethylornithine) for the treatment of malignant gliomas. CNS Oncology. Published Online: 30 Jan 2018. https://www.futuremedicine.com/doi/10.2217/cns-2017-0031
