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 emerged as promising novel experimental drugs in a new therapeutic class.
SETANAXIB: TARGETING NOX4 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. Calliditas is evaluating setanaxib in a clinical study in head and neck cancer, building on promising in vivo preclinical data that suggests that setanaxib could significantly enhance the effects of immune-oncology therapies. Using a CAF-rich tumor model in mice, the administration of setanaxib + pembrolizumab (versus either treatment alone) resulted in:
- Reduction in tumor volume
- Improvement in survival
- Improvement in immune cell penetration to the tumor centre
PHASE 2 SCCHN TRIAL
We are conducting a double-blind, randomized, placebo-controlled, Phase 2 proof-of-concept study, which is investigating the effect of setanaxib 800 mg PO twice daily in conjunction with pembrolizumab 200 mg IV, administered every 3 weeks. The patient population consists of at least 50 patients with relapsed or metastatic SCCHN and tumors with moderate or high levels of cancer-associated fibroblasts. A schematic of the study design is shown below.
A tumor biopsy will be taken prior to randomization and again after approximately 9 weeks of treatment. Treatment will continue until disease progression or unacceptable toxicity, in keeping with standard practice for oncology trials. Calliditas read out interim data from the study in July 2023, and expects to read out final trial data in 1H 2024.
Further details of this study (reference: NCT0532365) can be found at www.clinicaltrials.gov.
PHASE 2 SCCHN TRIAL: INTERIM DATA
In July 2023, Calliditas read out interim data from the trial, which reflected encouraging early clinical progression-free survival (PFS) results and supports the presumed anti-fibrotic mode of action of setanaxib. The basis for the analysis consisted of a data from 20 patients with recurrent or metastatic SCCHN, of which 16 patients had evaluable tumor size and PFS-related results.
Twelve patients had tumor biopsies before and after treatment that were evaluable. The biomarker analysis included transcriptomic analysis and evaluated pathology markers such as SMA, Foxp3 regulatory T cells and PDL-1 Combined Positive Score. In terms of PFS, 7 out of the 16 evaluable patients were progression-free with either stable disease or partial response, of which 6 were in the setanaxib arm and 1 was in the placebo arm. Six of the 7 patients were still on the study drug at the time of the data readout, with the longest period on drug being reported as 21 weeks, related to a patient in the setanaxib arm.
The transcriptomic analysis showed that the two top pathways impacted by the treatment were fibrosis‑related signalling pathways (the Idiopathic Pulmonary Fibrosis Signalling Pathway and Hepatic Fibrosis/Hepatic Stellate Cell Activation Pathway), providing support for the presumed mode of action on activated cancer associated fibroblasts in head and neck cancer, as well as a potential anti-fibrotic effect in Calliditas’ other ongoing clinical programs.
Pathology analysis showed preliminary evidence of an increase in immunological activity within tumors of patients treated with setanaxib, with favorable changes in Foxp3 and PDL-1 CPS. As SMA levels at baseline were not balanced between the groups, and tumor biopsy samples were generally small, it was not possible to draw any conclusions regarding setanaxib’s impact on SMA reduction.
SETANAXIB IN PRIMARY BILIARY CHOLANGITIS
PBC is a progressive and chronic autoimmune disease of the liver that causes immune injury to biliary epithelial cells, resulting in cholestasis and fibrosis. It is an orphan disease and, based on its known prevalence rates, we estimate that there are approximately 140,000 patients in the United States, where the annual incidence ranges from 0.3 to 5.8 cases per 100,000. Calliditas received FDA Fast Track Designation for setanaxib in PBC in August 2021.
Ursodeoxycholic acid, a generic drug also known as ursodiol or UDCA, and obeticholic acid, known as Ocaliva, are the only treatments for PBC approved by the FDA and the European Commission. However, despite these treatment options, there is still an unmet medical need among PBC patients, in particular when it comes to important quality of life outcomes.
Phase 2 data from a trial with setanaxib in 111 patients with PBC demonstrated that setanaxib had a more pronounced effect on fibrosis and ALP reduction (alkaline phosphatase, a established independent predictor of prognosis in PBC) in patients with an estimated liver fibrosis stage of F3 or higher. Patients with elevated liver stiffness are at greater risk of disease progression.
Calliditas is conducting a randomized, placebo-controlled, double-blind Phase 2b trial in PBC patients with elevated liver stiffness We are expecting to read out data in mid-2024.