Phase 2 Data Support Use of RNX-051 in Cancerous and Precancerous CRC

Reponex Pharmaceuticals A/S has reported that treatment with the drug candidate RNX-051 demonstrated an impact on the bacterial biomass of patients with right-sided colorectal cancer (CRC) and right-sided colon polyps/adenomas (precursors of cancer), meeting the primary end point of the clinical proof-of concept, phase 2 MEFO trial (NCT04312360).

In the trial’s adenoma arm (n = 12), there was also a large reduction in the biofilm of the bowel lining–which was measured as more than 30-fold reduction–1 week after the treatment, from a mean of 0.003% to 0.0001% of bacterial biomass (P = .025). Furthermore, there was an impact on the presence of specific immune cells crucial in the anti-cancer immune response, such as macrophages and T-cells.

In non-treated adenomas, the macrophage density was 2.2%, whereas in treated adenomas, it increased to 3.4% (P = .030). Similarly, CD3 T-cell density was 524 cells/mm² in non-treated adenomas and increased to 727 cells/mm² in treated adenomas (P = .018). Metagenome sequencing revealed no decrease in bacterial diversity post-treatment, but there was a significant increase in the genus bacteroides (median, 6.9%-10.8%; P = .016), a commensal gut bacterium housing both anti- and pro-inflammatory species.

“Reponex management concludes that its patented medicinal product RNX-051 appears to be highly effective for its intended purpose. Just a single local application drastically reduces tumor-associated biofilm and can even totally eliminate the cancer-promoting fusobacterium nucleatum in the tumor at one week after the treatment,” the press release reported.

Patients with precursor lesions to CRC, also known as adenomas, possess a gut microbiota that differs from that of healthy individuals, with specific bacteria playing roles in chronic inflammation and molecular interactions within bowel cells which can potentially culminate in cancer. One pivotal mechanism involves the production of a biofilm coating the inner bowel wall.

Furthermore, in patients with cancer, bacteria like fusobacterium nucleatum and bacteroides fragilis alter the tumor microenvironment, raising the risk of metastasis by modulating immune cell function, particularly those engaged in anticancer activities, although the precise mechanisms are intricate. Treatment with RNX-051 was found to alter the environment within the colon and CRC itself, leading investigators to believe that this may lower the risk of adenoma formation.

There were 2 treatment arms on the MEFO trial: the adenoma arm and an arm consisting of patients with cancers in the right side of the bowel (n = 10). In the study, RNX-051 was given in the form of a muco-adhesive spray and the adenomas or tumor were subsequently removed approximately 1 week after the intervention.

Advanced microscopy techniques were utilized to target specific bacteria and tumor microenvironment cells, and comprehensive immune analyses, including genomic studies of bacteria as well as precursor and cancerous lesions, provided a detailed understanding of these conditions both pre– and post-treatment intervention.

Furthermore, the trial's primary end point was to induce change in the biofilm for patients on the adenoma arm and improve the tumor-related bacterial composition in the cancer arm. Another end point across both arms to focus on the modulation of the immune cells in a positive way to increase their ability to kill precursor or cancer cells.

When treating those in the cancer arm, patients with a high bacterial biofilm content experienced a significant reduction in biofilm within the tumor periphery, decreasing from a mean of 0.255% to 0.013% of bacterial biomass (P = .025). Concurrently, there was an observable shift in the immune cell balance within the tumor core, evidenced by an increase in the ratio of active T-cells promoting tumor cell death, rising from a mean CD8/CD3 ratio of 0.30 to 1.19 (P = .016).

Metagenome sequencing revealed a notable and statistically significant effect post-treatment in the cancer arm. Application of RNX-051 led to a considerable reduction or elimination of the cancer-promoting fusobacterium nucleatum (median, 15.2%-0%; P = .008), coupled with an increase in cancer-protective lactobacillales (median, 0.23%-2.72%; P = .023) within the tumor center, without diminishing the diversity of the mucosa-associated gut microbiota.

Findings from MEFO represent a new area for evaluating the efficacy of RNX-051 treatment, both as a single and repeated dose, in adenoma prevention. However, for patients with CRC, further investigation is warranted to explore the potential benefits of immune cell composition shifts in cancer-promoting bacteria in a broader patient cohort. Combination trials of RNX-051 with immune therapy may offer further advantages for these patients.

Reference

Pharma Equity Group’s subsidiary, Reponex Pharmaceuticals A/S, reports highly positive final results from the phase-2 clinical trial of the company’s patented drug candidate RNX-051. News release. April 5, 2024, Accessed April 5, 2024. https://www.globenewswire.com/news-release/2024/04/05/2858388/0/en/Pharma-Equity-Group-s-subsidiary-Reponex-Pharmaceuticals-A-S-reports-highly-positive-final-results-from-the-phase-2-clinical-trial-of-the-company-s-patented-drug-candidate-RNX-051.html