Eflornithine oral solution
Our lead product candidate, eflornithine, also known as α-difluoromethylornithine (DFMO), is the only irreversible, metabolic inhibitor targeting ornithine decarboxylase (ODC).
This unique and precise mechanism of action inhibits production of a key enzyme that can cause tumor growth in certain types of cancer.
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, oncogenes that work together to regulate many cancer processes, 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 for recurrent grade 3 astrocytoma
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. Subsequently, it was approved in 2023 as a maintenance therapy in high-risk neuroblastoma.
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 Clinical Development: STELLAR Study Results
In 2024, Orbus Therapeutics completed the STELLAR Phase 3 study (NCT02796261), which was designed to evaluate the efficacy and safety 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 study enrolled a total of 343 patients and, importantly, it included a large subset (n=194) of grade 3 IDH mutant astrocytoma patients, as defined by World Health Organization (WHO) specified molecular markers. More than 105 leading clinical trial centers in eight countries in North America and Europe participated in the study.
Eflornithine and lomustine achieved a clinically meaningful improvement in overall survival (OS) and progression free survival (PFS) compared to lomustine as a single agent for those patients with grade 3 IDH mutant astrocytoma who have progressed after irradiation and adjuvant temozolomide treatment. The results were presented at the Society for Neuro-Oncology Annual Meeting held in Houston, Texas.
The primary efficacy endpoint, overall survival (OS) in the intention-to-treat population of 343 patients had a hazard ratio (HR) = 0.94 and was not statistically significant.
In the 194 patients with recurrent grade 3 IDH mutant astrocytoma, clinically meaningful improvements in both OS and PFS were observed.
Median OS in the eflornithine + lomustine arm was 34.9 months compared to 23.5 months in the lomustine alone arm with HR = 0.64 (log rank p = 0.016).
PFS showed a correlating benefit with median PFS of 15.8 months in the eflornithine + lomustine arm and 7.2 months in the lomustine alone arm with HR = 0.58 (log rank p = 0.015).
The known side effect profile of eflornithine combined with lomustine was consistent with data from earlier studies and showed no unexpected safety signals. The most common grade 3+ treatment emergent adverse events of relevance were related to myelosuppression and hearing impairment. Similarly, the proportion of patients with grade 3+ hematology parameters and those with grade 3+ clinical chemistry parameters were as expected.
The STELLAR study results support the further development of eflornithine for patients with grade 3 astrocytoma as well as other cancers with ODC overexpression or in tumors with IDH mutation that are CDKN2A/B intact.
Orbus’ eflornithine oral solution is an investigational product and not approved for the treatment of any disease in the United States or any other country.