NOX Enzyme Inhibitors: A Novel Approach Across Indications
NOX enzymes, also known as nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, are the only known enzymes that are solely dedicated to producing reactive oxygen species (ROS). At appropriate concentrations, ROS help regulate cell proliferation, differentiation, and migration, as well as modulate the innate immune response, inflammation, and fibrosis.
The disruption of redox homeostasis has been implicated in multiple disease pathways, with oxidative stress caused by excess ROS being a likely underlying mechanism for many disorders, including cardiovascular diseases, neurodegenerative disorders, and cancer.1 As such, NOX enzyme inhibitors recently emerged as promising novel experimental drugs in a new therapeutic class.
SETANAXIB: A NEW APPROACH TO PRIMARY BILIARY CHOLANGITIS
Primary biliary cholangitis (PBC) is a progressive, chronic, autoimmune liver disease that impacts approximately 140,000 people in the United States. The autoimmune response of PBC is believed to originate from the production of autoantibodies directed toward the epithelial cells of the bile ducts in the liver, resulting in inflammation and the eventual destruction of the bile ducts.
This results in the accumulation of increased bile acid in the liver, a condition known as cholestasis, to levels that are toxic to the liver cells. If untreated, active liver tissue is destroyed and replaced by fibrous tissue, putting patients with PBC at risk for liver failure, as well as an increased risk of hepatocellular carcinoma.
Although there are several available treatments that address the inflammation, cholestasis, and bile acid clearance associated with PBC, there is still a significant unmet need among patients with PBC, especially when it comes to meaningfully improved quality of life.
PHASE 2 TRIAL
Setanaxib was investigated in a 24-week, phase 2 trial in 111 patients and has received orphan drug designation for the treatment of PBC in the United States and Europe. Although the study did not meet its primary endpoint, it met key secondary endpoints related to change in alkaline phosphatase (ALP) level, liver stiffness score, and important quality of life metrics.
Patients who took setanaxib 400 mg bid achieved a significant reduction in ALP level of 12.9% (P<0.002 vs placebo) over the 24-week treatment period.
Furthermore, in a predefined patient population with a liver stiffness score ≥9.6 kPa, setanaxib had a more pronounced effect on ALP-level and reduction of fibrosis. Patients with elevated liver stiffness are at greater risk of disease progression.3 In patients with a liver stiffness score ≥9.6 kPa, setanaxib 400 mg bid achieved a 24% reduction in ALP level over the 24-week treatment period and a 22% reduction in liver stiffness score as compared with a 4% increase in those who took placebo (P=0.038).
Treatment with setanaxib 400 mg bid resulted in a statistically significant impact on fatigue, a common and disabling symptom of PBC that is not currently addressed by existing therapies, and demonstrated positive effects on the psychosocial aspects of the disease.
|PBC-40 QoL Domains||Placebo||Setanaxib 400mg OD1||Setanaxib 400mg BID2||p value (400mg BID vs placebo at week 24)|
Mean percent changes from Baseline in Quality of Life domains included in the PBC-40 questionnaire
* = p values statistically significant
1 = Once daily, 2 = Twice daily
Setanaxib also demonstrated a favorable safety profile in a phase 1 clinical trial that evaluated the safety and pharmacokinetics of the medication at doses up to 800 mg bid in healthy patients.
PHASE 2b/3 TRANSFORM TRIAL
Calliditas is currently enrolling eligible participants in a pivotal 52-week, randomized, placebo-controlled, double-blind trial with an adaptive phase 2b/3 design. In this trial, setanaxib will be administered as an add-on therapy to approximately 318 patients with PBC and an elevated liver stiffness score and intolerance or inadequate response to UDCA. The primary endpoint will be ALP-level reduction. Key secondary endpoints will include change in liver stiffness score and the effect on pruritus (itching) and fatigue.
SETANAXIB: TARGETING NOX4 EXPRESSION TO TREAT HEAD AND NECK CANCER
A patient’s response to immunotherapy can be affected by the tumor microenvironment, especially by the number of tumor-infiltrating lymphocytes (TILs) and cancer-associated fibroblasts (CAFs). The relationship between CAFs and prognosis in squamous cell carcinoma of the head and neck (SCCHN) has been established, with NOX4 highly overexpressed in CAFs. This overexpression drives myofibroblastic activation within tumors and shields them from CD8+ TILs. By targeting CAFs with setanaxib, Calliditas aims to improve patient response to immunotherapy. Using a CAF-rich tumor model in mice, the administration of setanaxib + pembrolizumab (versus either treatment alone) resulted in:
- Improved penetration of TILs into the tumor
- Slowed tumor growth
- Improved survival
PHASE 2 SCCHN TRIAL
In May 2022, Calliditas launched a phase 2 proof-of-concept trial in patients with SCCHN to investigate setanaxib in conjunction with immunotherapy-targeting CAFs. Approximately 50 patients will be enrolled in the study.
1. Altenhöfer S, Radermacher KA, Kleikers PW, Wingler K, Schmidt HHHW. Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxid Redox Signal. 2015;23(5):406-427. doi:10.1089/ars.2013.5814
2. Elbatreek MH, Mucke H, Schmidt HHHW. NOX inhibitors: from bench to naxibs to bedside. Handb Exp Pharmacol. 2021;264:145-168. doi:10.1007/164_2020_387
3. Mueller S, Sandrin L. Liver stiffness: a novel parameter for the diagnosis of liver disease. Hepat Med. 2010;2:49-67. doi:10.2147/hmer.s7394