Reactive oxygen species (ROS) are unstable molecules that can damage DNA, RNA, and proteins, and are linked to inflammation and fibrotic conditions. NADPH oxidases (NOX) are enzymes responsible for producing ROS, making NOX inhibition a potential therapeutic strategy for various diseases, including cancer, inflammatory, and fibrotic conditions.
NOX Enzymes and Cancer-Associated Fibroblasts
Seven different NOX enzymes have been identified (NOX1-5, DUOX1, and DUOX2), each with similar functions but subtle structural differences that implicate them in different cellular processes. Recent research has linked NOX4 in tumor cells to the growth of cancer-associated fibroblasts (CAFs). These cells inhibit the body’s immune response to tumors by blocking CD8+ T-cells (tumor-infiltrating lymphocytes). Inhibiting NADPH oxidases in cancer could prevent the activation of CAFs, allowing CD8+ T-cells to penetrate the tumor and mount an immune response.
Current NOX Inhibitors in Development
Several companies are developing NOX inhibitor candidates. Glucox Biotech’s GLX7013114, a NOX4 inhibitor, is in development for diabetic retinopathy. GlaxoSmithKline’s GSK2795039 has been tested preclinically to limit dose-dependent cardiotoxicity from doxorubicin, a widely used cancer drug. Calliditas Therapeutics AB is also exploring several indications for its NOX inhibitor, setanaxib.
Setanaxib: Targeting Fibrosis and Cancer
Calliditas Therapeutics is testing setanaxib, a NOX1 and NOX4 inhibitor, in various fibrotic diseases, including cancers where cancer-associated fibroblasts play a crucial role, such as head and neck tumors. Research indicates that setanaxib can revert CAFs to their normal state, allowing CD8+ T-cells to penetrate the tumor and initiate an immune response. According to Professor Gareth Thomas, Professor of Experimental Pathology at the University of Southampton, "What we saw was an influx of CD8+ T-cells into the tumour in association with setanaxib treatment... If you can get rid of the exclusion [of CD8+ T-cells]… you can overcome the immunotherapy resistance driven by CAFs".
Clinical Data for Setanaxib in SCCHN
Calliditas announced Phase II data in squamous cell carcinoma of the head and neck (SCCHN) in May. The Phase II trial, involving 55 patients with SCCHN, showed a statistically significant improvement favoring setanaxib in progression-free survival (PFS) and overall survival (OS). At nine months, OS was 88 percent in a cohort of 27 patients treated with setanaxib and immunotherapy drug pembrolizumab, compared to 58 percent in the 28 patients who received only pembrolizumab. Furthermore, a higher number of patients on the setanaxib arm experienced disease stabilization, and responses were more durable compared to the placebo arm.
Potential Across Multiple Indications
Calliditas is also exploring setanaxib for conditions related to fibrotic diseases, such as primary biliary cholangitis (PBC) and Alport Syndrome. A Phase IIb trial in PBC, comparing two doses of setanaxib with placebo, is expected to have a data readout in Q3 2024. If successful, setanaxib could reach peak sales of over $2 billion. An investigator-led Phase II trial comparing setanaxib with placebo is ongoing, with results due in Q4 2024. Additionally, a Phase II trial in Alport Syndrome, comparing setanaxib plus standard RAS inhibitor therapy with placebo plus RAS inhibitor in approximately 18 patients, is expected to read out in Q1 2025. Alport Syndrome, a fibrotic disease of the kidneys, currently has no approved therapies.
With its potential in a wide range of indications, NOX inhibitors represent a significant opportunity in treating various diseases.
