PARIS—Biopharmaceutical company Onxeo, best known for pharmaceuticals designed to treat orphan diseases, particularly in oncology, has uncovered what it says is dramatic potential for its drug Beleodaq in combination with checkpoint inhibitors in treatment against tumor growth. The study found that when combined with checkpoint inhibitors in mice, Beleodaq caused a 100-percent cessation of tumor growth.
Beleodaq, the trade name for belinostat, was FDA-approved in 2014 as a second-line treatment for patients with peripheral T cell lymphoma, a rare and fast-growing type of non-Hodgkin’s lymphoma, based on its tumor response rate and duration of response. The drug works by inhibiting histone deacetylases, preventing the T cells from becoming cancerous.
In conjunction with the University of Navarra’s University Clinic and the Center for Applied Medical Research in Spain, Onxeo has been exploring the combination of various compounds, including PD-1 and CTLA-4 checkpoint inhibitors, with Beleodaq in order to assess the synergistic effects on the activation of the immune response in several types of solid tumors.
Preclinical studies were performed in an immune-competent mouse syngeneic hepatocellular carcinoma model, in which responses to a combination of Beleodaq and checkpoint inhibitors were compared to responses from treatment with checkpoint inhibitors alone.
“What makes these findings particularly exciting is the fact that all mice responded to the combination therapy,” says Dr. Graham Dixon, chief scientific officer of Onxeo. “Our team is impressed by the 100-percent cessation of tumor growth during treatment, especially because only 20 to 25 percent of mice respond favorably to the application of just checkpoint inhibitors.”
The tumor cessation effect continued for approximately one week after the final dose of belinostat was administered. This suggests that the researchers can continue to seek optimal dosage and scheduling to prolong the benefits of the therapy. In addition, this allows the team to explore clues as to which checkpoint inhibitors are best to combine in future directions.
The research has produced another key finding of interest to oncology treatment. Studies performed on the spleens of the mice demonstrated the generation of an underlying immune response that correlated with the observed therapeutic effect of the combination treatment, showing an increase in production of interleukines (chemical messengers that control cell migration and activation) by activated T cells and a decrease in the number of regulatory T cells, when compared to mice treated only with checkpoint inhibitors.
“Our ability to measure the increase and decrease in T cells resulted in a deeper understanding at a mechanistic level of the inflammatory response, adding evidence to what we already know about the benefits of the combination therapy,” says Onxeo CEO Judith Greciet.
In the next step of the collaboration with University of Navarro experts Prof. Bruno Sangro and Dr. Pablo Sarobe, Onxeo will conduct follow-up studies to explore the product's potential with other cancer agents in specific cytotoxic cancers. “We [seek to] fully characterize these preclinical findings demonstrating the potential of Beleodaq in combination with checkpoint inhibitors in various tumor indications, and in particular, [we] are evaluating the immune response in the tumor microenvironment in order to improve the translation of the response into human patients,” says Dixon.
Onxeo specializes in the development of innovative drugs for the treatment of orphan diseases, driven by high therapeutic demand in one of the fastest growing segments of the pharmaceutical industry. Beleodaq joins its orphan oncology pipeline, which also includes Livatag, in Phase 3 trials for the treatment of hepatocellular carcinoma; AsiDNA, which has successfully undergone a proof-of-concept Phase 1 trial to treat metastatic melanoma; and Validive, currently in Phase 2 trials to treat head-and-neck cancer patients with severe oral mucositis.