Eflornithine (α-difluoromethylornithine or DFMO) is an orally bioavailable small molecule. Eflornithine is an irreversible inhibitor of ornithine decarboxylase (ODC) that presents a cytostatic effect in rapidly dividing cells.  By inhibiting this enzyme, eflornithine has been shown to slow or delay tumor growth, and has shown activity in certain cancers, including AA.   Eflornithine is approved by FDA in intravenous form to treat patients with African trypanosomiasis (sleeping sickness) and was subsequently approved by FDA in a topical form to treat patients with excessive facial hair, or hirsutism. 

Eflornithine Clinical Development:  A Late-Stage Asset  

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In controlled, randomized and single arm clinical trials, eflornithine has demonstrated an increase in overall survival (OS) of patients with newly diagnosed or recurrent anaplastic astrocytoma.

In these clinical trials, the primary and reversible side effects seen from eflornithine therapy in a small percentage of patients were diarrhea and hearing loss. None of the patients discontinued therapy due to side effects.

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 280 patients across 60 leading clinical trial centers in the United States and Europe.

In 2014, the Company received Breakthrough Therapy Designation (BTD) for eflornithine from the FDA. 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.  

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Eflornithine Mechanism of Action

Eflornithine is an irreversible inhibitor of ODC, an important enzyme that regulates cell division.  ODC is a key enzyme in 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 as well 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.