Setanaxib, a first-in-class selective NADPH oxidase 1/4 inhibitor for primary biliary cholangitis: A randomized, placebo-controlled, phase 2 trial.

BACKGROUND: Primary biliary cholangitis (PBC) is a rare liver disease with significant unmet need for second-line/add-on treatments. Setanaxib, a NOX1/4 inhibitor, has shown anti-fibrotic effects in in vitro and animal studies. This phase 2, randomized, multicentre study investigated the efficacy and safety of setanaxib in patients with PBC. METHODS: Patients with ≥6 months of ursodeoxycholic acid (UDCA) treatment were randomized 1:1:1 to oral setanaxib 400 mg once daily (OD), twice daily (BID), or placebo, in addition to UDCA for 24 weeks. Other inclusion criteria included alkaline phosphatase (ALP) ≥1.5 × ULN and gamma-glutamyl transferase (GGT) ≥1.5 × ULN. The primary endpoint was percentage change from baseline in GGT at Week 24; secondary endpoints included change from baseline in ALP, liver stiffness (LS; via transient elastography), fatigue at Week 24, and safety outcomes. p values compare setanaxib 400 mg BID and placebo groups. RESULTS: Of patients randomized (setanaxib 400 mg OD and BID: 38, and 36; placebo: 37), 104/111 completed Week 24. Mean (standard deviation [SD]) change in GGT to Week 24 was -4.9% (59.6%) for setanaxib 400 mg OD, -19.0% (28.9%) for setanaxib 400 mg BID, and -8.4% (21.5%) for placebo; p = .31. Patients treated with setanaxib 400 mg OD and BID showed decreased serum ALP levels from baseline to Week 24 (p = .002: setanaxib BID versus placebo). Patients treated with setanaxib 400 mg OD and BID showed mean (SD) percentage increases in LS to Week 24 of 3.3% (35.0%) and 7.9% (43.7%), versus 10.1% (33.1%) for placebo (p = .65). Changes in mean (SD) PBC-40 fatigue domain scores to Week 24 were +0.3% (24.9%) for setanaxib 400 mg OD, -9.9% (19.8%) for setanaxib 400 mg BID and +2.4% (23.1%) for placebo, p = .027. Two patients (one placebo, one setanaxib 400 mg BID) experienced serious treatment-emergent adverse events, deemed unrelated to study drug. CONCLUSIONS: The primary endpoint was not met. However, the secondary endpoints provide preliminary evidence for potential anti-cholestatic and anti-fibrotic effects in PBC, supporting the further evaluation of setanaxib in a future phase 2b/3 trial.

Impact of setanaxib on quality of life outcomes in primary biliary cholangitis in a phase 2 randomized controlled trial.

BACKGROUND: There is a real unmet need for primary biliary cholangitis (PBC) treatments that can improve quality of life impacting symptoms. In this post hoc analysis, we evaluated potential effects of the NADP oxidase 1/4 inhibitor, setanaxib, on patient-reported quality of life from a phase 2 trial in PBC. PATIENTS AND METHODS: The underpinning double-blind, randomized, placebo-controlled trial (NCT03226067) recruited 111 patients with PBC and inadequate response/intolerance to ursodeoxycholic acid. Patients self-administered oral placebo (n=37), setanaxib 400 mg once daily (OD; n=38), or setanaxib 400 mg twice daily (BID; n=36), in addition to ursodeoxycholic acid for 24 weeks. Quality of life outcomes were assessed using the validated PBC-40 questionnaire. Patients were stratified post hoc by baseline fatigue severity. RESULTS: At week 24, patients treated with setanaxib 400 mg BID reported greater mean (SE) absolute reductions from baseline in PBC-40 fatigue domain score [-3.6 (1.3)] versus those receiving setanaxib 400 mg OD [-0.8 (1.0)]) or placebo [0.6 (0.9)]. Similar observations were made across all PBC-40 domains except itch. In the setanaxib 400 mg BID arm, patients with moderate-to-severe fatigue at baseline had a greater reduction in mean fatigue score at week 24 [-5.8 (2.1)] versus those with mild fatigue [-0.6 (0.9)]; results were similar across all domains. Reduced fatigue was correlated with emotional, social, symptom, and cognitive improvements. CONCLUSIONS: These results support further investigation of setanaxib as a treatment for patients with PBC, particularly for those with clinically significant fatigue.

Targeting the NADPH Oxidase-4 and Liver X Receptor Pathway Preserves Schwann Cell Integrity in Diabetic Mice.

Diabetes triggers peripheral nerve alterations at a structural and functional level, collectively referred to as diabetic peripheral neuropathy (DPN). This work highlights the role of the liver X receptor (LXR) signaling pathway and the cross talk with the reactive oxygen species (ROS)-producing enzyme NADPH oxidase-4 (Nox4) in the pathogenesis of DPN. Using type 1 diabetic (T1DM) mouse models together with cultured Schwann cells (SCs) and skin biopsies from patients with type 2 diabetes (T2DM), we revealed the implication of LXR and Nox4 in the pathophysiology of DPN. T1DM animals exhibit neurophysiological defects and sensorimotor abnormalities paralleled by defective peripheral myelin gene expression. These alterations were concomitant with a significant reduction in LXR expression and increase in Nox4 expression and activity in SCs and peripheral nerves, which were further verified in skin biopsies of patients with T2DM. Moreover, targeted activation of LXR or specific inhibition of Nox4 in vivo and in vitro to attenuate diabetes-induced ROS production in SCs and peripheral nerves reverses functional alteration of the peripheral nerves and restores the homeostatic profiles of MPZ and PMP22. Taken together, our findings are the first to identify novel, key mediators in the pathogenesis of DPN and suggest that targeting LXR/Nox4 axis is a promising therapeutic approach.

NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors.

Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFß1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 "normalized" CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFß1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. SIGNIFICANCE: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/9/1846/F1.large.jpg.See related commentary by Hayward, p. 1799.

Spliceosomal peptide P140 for immunotherapy of systemic lupus erythematosus: results of an early phase II clinical trial.

OBJECTIVE: To assess the safety, tolerability, and efficacy of spliceosomal peptide P140 (IPP-201101; sequence 131-151 of the U1-70K protein phosphorylated at Ser140), which is recognized by lupus CD4+ T cells, in the treatment of patients with systemic lupus erythematosus (SLE). METHODS: An open-label, dose-escalation phase II study was conducted in two centers in Bulgaria. Twenty patients (2 male and 18 female) with moderately active SLE received 3 subcutaneous (SC) administrations of a clinical batch of P140 peptide at 2-week intervals. Clinical evaluation was performed using approved scales. A panel of autoantibodies, including antinuclear antibodies, antibodies to extractable nuclear antigens (U1 RNP, SmD1, Ro/SSA, La/SSB), and antibodies to double-stranded DNA (anti-dsDNA), chromatin, cardiolipin, and peptides of the U1-70K protein, was tested by enzyme-linked immunosorbent assay (ELISA). The plasma levels of C-reactive protein, total Ig, IgG, IgG subclasses, IgM, IgA, and IgE, and of the cytokines interleukin-2 and tumor necrosis factor alpha were measured by ELISA and nephelometry. RESULTS: IgG anti-dsDNA antibody levels decreased by at least 20% in 7 of 10 patients who received 3 x 200 microg IPP-201101 (group 1), but only in 1 patient in the group receiving 3 x 1,000 microg IPP-201101 (group 2). Physician's global assessment of disease activity scores and scores on the SLE Disease Activity Index were significantly decreased in group 1. The changes occurred progressively in the population of responders, increased in magnitude during the treatment period, and were sustained. No clinical or biologic adverse effects were observed in the individuals, except for some local irritation at the highest concentration. CONCLUSION: IPP-201101 was found to be safe and well tolerated by subjects. Three SC doses of IPP-201101 at 200 microg significantly improved the clinical and biologic status of lupus patients.