Setanaxib (GKT137831): A Comprehensive Analysis of a First-in-Class NOX1/4 Inhibitor in Fibrosis and Oncology

1.0 Executive Summary

Setanaxib (GKT137831) is an investigational, first-in-class, orally bioavailable small molecule that functions as a dual inhibitor of NADPH oxidase isoforms NOX1 and NOX4. It represents a novel therapeutic paradigm targeting the enzymatic production of reactive oxygen species (ROS), a fundamental pathological process implicated in a wide array of diseases characterized by inflammation and fibrosis.

The primary mechanism of action of setanaxib involves the selective and potent inhibition of NOX1 and NOX4. This action curtails the excessive production of ROS, thereby downregulating critical pro-fibrotic and pro-inflammatory signaling cascades, most notably the transforming growth factor-beta (TGF-$\beta$) pathway. In the context of oncology, setanaxib exhibits a distinct mechanism by targeting Cancer-Associated Fibroblasts (CAFs) within the tumor microenvironment. This targeting reverses the fibrotic, immune-exclusive barrier created by CAFs, facilitating the infiltration of cytotoxic CD8+ T-cells and enhancing the efficacy of immune checkpoint inhibitors.

The clinical development of setanaxib has been extensive and has demonstrated a notable strategic evolution. In fibrotic diseases, its most advanced indication is Primary Biliary Cholangitis (PBC). An initial Phase 2 trial (NCT03226067), while missing its primary endpoint, revealed highly encouraging signals on clinically relevant secondary markers, including alkaline phosphatase (ALP), liver stiffness, and fatigue. This informed the design of a subsequent, pivotal Phase 2b trial (TRANSFORM, NCT05014672), which successfully met its primary endpoint of statistically significant ALP reduction. This result validates setanaxib's potential as a valuable add-on therapy for PBC patients with an inadequate response to the current standard of care. The drug is also in ongoing Phase 2 trials for other fibrotic conditions, including Idiopathic Pulmonary Fibrosis (IPF) and Alport Syndrome, leveraging its robust anti-fibrotic preclinical profile.

In oncology, setanaxib is being evaluated for its ability to modulate the tumor microenvironment. A Phase 2 trial (NCT05323656) investigating setanaxib in combination with the PD-1 inhibitor pembrolizumab for Squamous Cell Carcinoma of the Head and Neck (SCCHN) did not meet its primary endpoint based on tumor shrinkage. However, the study demonstrated statistically significant and clinically meaningful improvements in key survival outcomes, including Progression-Free Survival (PFS) and Overall Survival (OS). Crucially, translational biomarker data from tumor biopsies confirmed an increase in CD8+ T-cell infiltration, providing direct clinical evidence for its proposed immunomodulatory mechanism of action.

Across multiple clinical trials, including a high-dose Phase 1 study in healthy volunteers evaluating doses up to 1600 mg/day, setanaxib has demonstrated a favorable safety and tolerability profile. Treatment-emergent adverse events have been generally manageable and comparable to placebo, although a higher rate of treatment discontinuation was observed in the active arms of the TRANSFORM trial, warranting continued monitoring.

Strategically, setanaxib has emerged as a platform asset with a clinically validated dual mechanism applicable to both fibrosis and immuno-oncology. The successful pivot in clinical trial design for PBC and the compelling survival data in SCCHN underscore a nuanced yet highly promising path forward. Future success will be contingent upon the execution of pivotal Phase 3 trials, navigating regulatory pathways that may involve non-traditional endpoints in oncology, and capitalizing on potential strategic partnerships.

2.0 Introduction to Setanaxib: A Novel Pyrazolopyridine Dione Derivative

2.1 Chemical Identity and Physicochemical Properties

Setanaxib is an investigational small molecule drug classified chemically as a pyrazolopyridine dione derivative.[1] It is most frequently identified in scientific literature and clinical development by its code names, GKT137831 and GKT-831.[2] The compound is achiral and represents a distinct chemical entity being explored for its unique pharmacological properties.[6]

The formal chemical name for setanaxib, according to the International Union of Pure and Applied Chemistry (IUPAC) nomenclature, is 2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione.[7] Its molecular structure is defined by the chemical formula $C_{21}H_{19}ClN_{4}O_{2}$, corresponding to a monoisotopic mass of 394.1196536 and an average molecular weight of approximately 394.85 g/mol.[2]

Physicochemically, setanaxib is a pale yellow solid.[11] It demonstrates good solubility in organic solvents such as dimethyl sulfoxide (DMSO), with concentrations up to 65 mg/ml being achievable, but has more limited solubility in aqueous solutions like DMF:PBS (pH 7.2) at a 1:1 ratio (0.5 mg/ml).[11] The compound is stable for at least two years from the date of purchase when supplied as a solid and stored at -20°C. Solutions prepared in DMSO may be stored at -20°C for up to one month.[11] The compound's predicted boiling point is $560.5 \pm 60.0$ °C, and its predicted density is $1.42 \pm 0.1$ g/cm³.[11] These properties are consistent with a small molecule drug candidate intended for oral administration.

A consolidated summary of its key identifiers and properties is provided in Table 1. This information is critical for its unambiguous identification in scientific databases, regulatory filings, and research publications.

Table 1: Key Chemical and Physicochemical Properties of Setanaxib

Category	Attribute	Value / Identifier	Source(s)
Identification	Drug Name (INN)	Setanaxib	[4, 9]
	DrugBank ID	DB16869	[9]
	CAS Number	1218942-37-0	[2, 3, 9]
	FDA UNII	45II35329V	[8, 9, 11]
Nomenclature	IUPAC Name	2-(2-chlorophenyl)-4-[3-(dimethylamino)phenyl]-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6-dione	[7, 9]
	Common Synonyms	GKT137831, GKT-831, GKT831, GKT 137831	[2, 3, 11]
Structural Formula	Chemical Formula	$C_{21}H_{19}ClN_{4}O_{2}$	[2, 3, 9]
	Molecular Weight	394.85 g/mol (Average: 394.86)	[2, 3, 9]
	SMILES	CN1C(=O)C=C2C(=C1C3=CC(=CC=C3)N(C)C)C(=O)N(N2)C4=CC=CC=C4Cl	[2, 9, 10]
	InChIKey	RGYQPQARIQKJKH-UHFFFAOYSA-N	[1, 6, 9]
Physicochemical	Appearance	Pale yellow solid	11
Properties	Solubility	Soluble in DMSO (up to 65 mg/ml)	11
	Storage Conditions	-20°C (solid)	[11, 13]
	Stability	Stable for 2 years as supplied (solid); 1 month in DMSO at -20°C	11

2.2 Development History and Corporate Landscape

Setanaxib was discovered in the early 2000s by scientists at Genkyotex, a French biotechnology company based in Archamps, and was subsequently patented in 2007.[1] Its discovery was the result of a rational drug design program that began with a high-throughput screening campaign on several NADPH oxidase (NOX) isoforms. This effort identified an initial lead compound, GKT136901, also a pyrazolopyridine dione derivative. GKT136901 was then subjected to further structural modifications aimed at enhancing its binding affinity for NOX1 and NOX4 and improving its overall pharmacokinetic properties, which ultimately led to the discovery of setanaxib.[1]

Genkyotex advanced setanaxib through preclinical development and into multiple clinical trials, establishing a significant safety database with over 320 subjects exposed to the drug in completed Phase 1 and Phase 2 studies.[15] However, the company faced significant clinical development challenges. A Phase 2 proof-of-concept study in diabetic nephropathy initiated in 2014 failed to meet its primary endpoint of reducing albuminuria.[1] Subsequently, a Phase 2 trial in patients with Primary Biliary Cholangitis (PBC) also failed to meet its primary endpoint, which was the percentage change in serum gamma-glutamyl transferase (GGT).[1] These clinical setbacks likely suppressed the company's valuation and created an opportunity for a strategic acquisition.

In August 2020, Calliditas Therapeutics AB, a Stockholm-based specialty pharmaceutical company, announced a definitive agreement to acquire a controlling 62.7% interest in Genkyotex.[1] The transaction was valued at approximately €20.3 million in an off-market block trade, with the total consideration for 100% of Genkyotex shares estimated at ~€32 million.[16] The deal structure was notable for its inclusion of up to €55 million in potential future milestone payments, contingent upon achieving regulatory approvals for setanaxib in various indications.[16] This structure minimized the upfront financial risk for Calliditas while allowing Genkyotex shareholders to benefit from the drug's future success.

The acquisition of the controlling interest closed in November 2020, and by October 2021, Genkyotex was delisted and became a fully owned subsidiary of Calliditas.[1] Calliditas now holds the global rights to setanaxib for all indications and is actively managing its ongoing clinical development.[15]

The acquisition by Calliditas appears to have been a calculated strategic maneuver to acquire a late-stage, de-risked platform asset at a favorable valuation, with the intent of applying its own development expertise to unlock the asset's full potential. Genkyotex had already established a robust safety profile for setanaxib and had generated promising, albeit secondary, efficacy signals in its clinical trials.[1] Calliditas explicitly stated its plan to leverage its "strong late stage clinical team, CMC and regulatory expertise as well as our learnings from our Phase 3 Nefecon program to navigate and execute an efficient path forward for setanaxib".[17] This suggests that Calliditas' leadership identified potential in the asset that Genkyotex had been unable to fully realize, possibly due to suboptimal clinical trial design or a lack of resources to conduct a large-scale pivotal program. The subsequent success of the redesigned TRANSFORM trial in PBC, which met its primary endpoint after Calliditas took over development, serves as a strong validation of this strategic hypothesis, effectively turning a program with a history of missed primary endpoints into a late-stage clinical success.[22]

3.0 Mechanism of Action and Pharmacological Profile

3.1 The Role of NADPH Oxidase (NOX) in Pathophysiology

The NADPH oxidase (NOX) family of enzymes represents a unique class of proteins whose primary and dedicated function is the regulated production of reactive oxygen species (ROS).[24] Comprising seven members in humans (NOX1–5 and dual oxidases DUOX1 and 2), these transmembrane enzymes catalyze the transfer of electrons from NADPH to molecular oxygen, generating either superoxide ($O_{2}^{\bullet-}$) or hydrogen peroxide ($H_{2}O_{2}$) as their main catalytic end-product.[24] This distinguishes them from other cellular sources of ROS, such as the mitochondrial electron transport chain, where ROS are generated primarily as by-products of other metabolic processes.[24] This dedicated function makes the NOX enzymes highly attractive therapeutic targets for diseases driven by pathological oxidative stress.

While ROS play essential roles in physiological processes, including cell signaling, host defense, and cellular homeostasis, their overproduction leads to a state of oxidative stress.[24] This imbalance is a key contributor to tissue damage and the progression of numerous diseases. In the context of fibrosis, excessive ROS production has been shown to activate and mediate the effects of potent pro-fibrotic cytokines, most notably transforming growth factor-beta (TGF-$\beta$).[24] This creates a vicious cycle, as TGF-$\beta$ can, in turn, trigger further ROS production while simultaneously suppressing cellular antioxidant defenses, thereby amplifying oxidative stress and driving the fibrotic process forward in organs such as the liver, kidneys, and lungs.[24]

Among the NOX isoforms, NOX1 and NOX4 have been specifically implicated as key drivers of fibrotic pathologies across multiple organ systems.[24] In the context of cancer, NOX4 is frequently overexpressed in Cancer-Associated Fibroblasts (CAFs), where it contributes to the formation of a dense, fibrotic, and immune-suppressive tumor microenvironment (TME). This NOX4-driven activity in CAFs promotes a malignant phenotype and hinders the infiltration and function of anti-tumor immune cells, representing a significant mechanism of resistance to immunotherapy.[5]

3.2 Dual Inhibition of NOX1 and NOX4

Setanaxib is a potent and selective, first-in-class, orally bioavailable dual inhibitor of the NOX1 and NOX4 isoforms.[1] Its inhibitory activity has been well-characterized in cell-free assays using membranes prepared from cells heterologously overexpressing specific NOX isoforms. These assays have established its strong binding affinity, with inhibitor constant ($K_{i}$) values of approximately 110 nM for human NOX1 and 140 nM for human NOX4.[2]

The compound's selectivity is a key feature of its pharmacological profile. It is significantly less potent against other NOX family members, exhibiting an approximately 15-fold lower potency for NOX2 ($K_{i} = 1750 \pm 700$ nM) and a 3-fold lower potency for NOX5 ($K_{i} = 410 \pm 100$ nM).[3] This selectivity is clinically relevant, as non-selective inhibition of isoforms like NOX2 could interfere with essential physiological functions, such as the oxidative burst in neutrophils required for host defense. Indeed, studies have confirmed that setanaxib does not significantly inhibit the NOX2-driven neutrophil oxidative burst up to concentrations of 100 µM.[3] Furthermore, setanaxib does not possess direct ROS scavenging or general antioxidant properties, nor does it inhibit other ROS-producing enzymes like xanthine oxidase.[12] The specificity of setanaxib for its targets was further demonstrated in an extensive in vitro off-target pharmacological screen against a panel of 170 different proteins, including other ROS-producing and redox-sensitive enzymes. When tested at a concentration of 10 µM, setanaxib showed no significant inhibition of any of the tested proteins, confirming its high degree of specificity for the NOX1 and NOX4 enzymes.[3]

3.3 Downstream Effects on Pro-Fibrotic and Pro-Inflammatory Pathways

By specifically inhibiting the enzymatic activity of NOX1 and NOX4, setanaxib directly reduces the pathological overproduction of ROS, thereby mitigating oxidative stress and interrupting the downstream signaling cascades that drive fibrosis and inflammation.[2]

The anti-fibrotic effects of setanaxib are well-documented in a multitude of preclinical models. In models of liver fibrosis, setanaxib treatment leads to a marked attenuation of the disease process by inhibiting the activation of hepatic stellate cells (HSCs), which are the primary collagen-producing cells in the liver. This results in reduced collagen deposition and a significant downregulation of key fibrogenic markers, including TGF-$\beta$ and tissue inhibitor of metalloprotease 1 (TIMP-1).[3] In models of pulmonary hypertension, setanaxib has been shown to blunt the hypoxia-induced reduction of the anti-fibrotic nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPAR$\gamma$), which further contributes to its anti-fibrotic activity.[2]

The anti-inflammatory effects of setanaxib are also a direct consequence of its ROS-reducing mechanism. In models of diabetic nephropathy, treatment with setanaxib significantly attenuated macrophage infiltration in both the glomeruli and the tubulointerstitium of the kidney.[37] In models of ischemic retinopathy, setanaxib dampened the pro-inflammatory phenotype of resident retinal immune cells, including microglia and macroglia, leading to reduced vascular leakage and inflammation.[40]

Beyond its anti-fibrotic and anti-inflammatory properties, setanaxib has demonstrated cardioprotective effects. In a model of doxorubicin-induced cardiotoxicity, a condition known to be driven by excessive ROS production, setanaxib treatment ameliorated cardiac dysfunction and reduced cardiomyocyte apoptosis. This protective effect was attributed to the inhibition of the NOX1/NOX4/ROS/MAPK signaling pathway.[41] The compound has also been shown to have direct anti-proliferative effects on vascular cells, attenuating the hypoxia-induced proliferation of human pulmonary artery endothelial and smooth muscle cells, a key process in the development of pulmonary hypertension.[2]

Interestingly, while the foundational mechanism of setanaxib in fibrotic and inflammatory conditions is the reduction of ROS, a different and seemingly paradoxical effect has been observed in the context of certain cancers. In preclinical models of acute myeloid leukemia (AML), the antiproliferative activity of setanaxib, particularly when combined with cytotoxic agents, was found to be independent of NOX4 inhibition.[43] Instead of quenching ROS, setanaxib treatment led to an elevation of intracellular ROS levels in AML cells. Furthermore, it significantly enhanced the ROS formation induced by anthracycline chemotherapy agents like daunorubicin, resulting in synergistic cytotoxicity and increased apoptosis.[43]

This context-dependent effect on cellular redox balance suggests a more complex mechanism of action than simple NOX inhibition alone. In the specific metabolic environment of AML cells, setanaxib may be inhibiting a compensatory or protective redox pathway, leading to a net increase in cytotoxic ROS. This discovery opens a distinct therapeutic hypothesis for setanaxib in oncology. In addition to its established role as an immunomodulator that targets CAFs in solid tumors, it may also function as a potent "chemosensitizer" in hematological malignancies by disrupting their redox homeostasis. This dual-pronged potential significantly broadens the scope of its future therapeutic applications and warrants further investigation into its use in combination with other ROS-inducing cancer therapies.

4.0 Preclinical and Phase 1 Evaluation

4.1 In Vitro and In Vivo Efficacy in Disease Models

Setanaxib has demonstrated robust biological activity and therapeutic potential in a wide range of in vitro and in vivo pharmacological models, providing a strong scientific rationale for its clinical development across multiple indications.[1]

• Liver Fibrosis: In well-established mouse models of liver fibrosis induced by either carbon tetrachloride (CCl4) or bile duct ligation (BDL), daily oral administration of setanaxib significantly attenuated the development of fibrosis. This was evidenced by a marked reduction in hepatic collagen deposition, as assessed by Sirius red staining, and a decrease in the expression of markers of hepatic stellate cell (HSC) activation, such as alpha-smooth muscle actin ($\alpha$-SMA).[2]
• Diabetic Nephropathy (DN): In the OVE26 mouse model of type 1 diabetes, which develops severe kidney disease mirroring human DN, therapeutic administration of setanaxib (at 10 or 40 mg/kg/day) provided comprehensive renoprotection, even when initiated after the establishment of disease. Treatment significantly reduced urinary albumin excretion, glomerular hypertrophy, mesangial matrix expansion, and podocyte loss. These structural and functional improvements were accompanied by a reduction in renal cortex NADPH oxidase activity and ROS production.[37]
• Pulmonary Hypertension (PH): In mice exposed to chronic hypoxia to induce PH, treatment with setanaxib (60 mg/kg/day) attenuated key features of the disease, including right ventricular hypertrophy (RVH) and pulmonary vascular remodeling. In vitro, setanaxib inhibited the hypoxia-induced proliferation of human pulmonary artery endothelial and smooth muscle cells, a critical cellular process in PH pathogenesis.[2]
• Cardiovascular Disease: Setanaxib has shown protective effects in models of cardiovascular disease. It attenuated Angiotensin-II-induced proliferation and migration of adult mouse cardiac fibroblasts, a key process in cardiac fibrosis, by blocking the physical association between the AT1 receptor and Nox4.[45] In a model of doxorubicin-induced cardiotoxicity, setanaxib ameliorated cardiac dysfunction and reduced cardiomyocyte apoptosis by inhibiting the NOX1/NOX4/ROS/MAPK pathway.[41] In diabetic apolipoprotein E-deficient mice, setanaxib attenuated the acceleration of atherosclerosis.[2]
• Ischemic Retinopathy: In a rat model of oxygen-induced ischemic retinopathy, subcutaneous administration of setanaxib (60 mg/kg) reduced retinal inflammation, leukocyte adherence to the retinal vasculature, the pro-inflammatory phenotype of microglia and macroglia, and vascular leakage, demonstrating potent anti-inflammatory effects in the eye.[40]

4.2 Pharmacokinetics and Metabolism

Preclinical pharmacokinetic (PK) studies conducted in C57BL/6 mice have characterized the absorption, distribution, metabolism, and exposure of setanaxib, confirming its suitability for oral administration.[12] These studies revealed that setanaxib is metabolized in vivo to a main active metabolite, GKT138184. This metabolite is an N-desmethylated phase 1 metabolite of the parent compound and, importantly, possesses a nearly identical potency and selectivity profile against the NOX isoforms.[39]

PK studies involving daily oral dosing for 8 days at 5, 20, and 60 mg/kg/day showed that both setanaxib and GKT138184 achieve good plasma exposure. At steady state (Day 7), the combined plasma concentrations of the parent drug and its active metabolite were maintained above 200 ng/ml, a level corresponding to approximately 5 times the in vitro IC50, for 1.5 hours at the 5 mg/kg/day dose and for a full 8 hours at the 20 and 60 mg/kg/day doses.[39] This sustained exposure above the pharmacologically active threshold indicates that a once-daily dosing regimen is sufficient to achieve continuous target engagement in preclinical models. These PK data, demonstrating good exposure, absorption, and distribution, were instrumental in guiding dose selection for subsequent human clinical trials.

4.3 Phase 1 Human Safety and Pharmacokinetics

The safety and pharmacokinetic profile of setanaxib in humans has been established through several Phase 1 clinical trials conducted in healthy volunteers.[15] An extensive safety dataset has been compiled from over 320 subjects exposed to the drug in these early-stage studies.[15]

A key study in the Phase 1 program was a trial designed to assess the safety and PK of high-dose setanaxib in 46 healthy adult male and female subjects.[1] This trial consisted of two parts: a single ascending dose (SAD) part and a multiple ascending dose (MAD) part, with dosing escalating up to 1600 mg/day.[1] The results from this study were highly favorable, demonstrating that setanaxib was well tolerated even at these high doses. No safety signals or dose-limiting toxicities were identified during the trial.[1]

The favorable safety and pharmacokinetic profile established in this high-dose Phase 1 study was a critical milestone in the drug's development. It provided the necessary safety data to support the exploration of higher doses (e.g., 1200 mg/day and 1600 mg/day) in later-stage clinical trials for indications such as Primary Biliary Cholangitis and Squamous Cell Carcinoma of the Head and Neck, where greater target engagement might be required to achieve optimal efficacy. Other Phase 1 trials have also been completed, including studies to compare the relative oral bioavailability of different formulations (capsules vs. tablets) and to evaluate potential drug-drug interactions (NCT03740217, NCT04327089).[46]

5.0 Clinical Development Program in Fibrotic and Rare Diseases

The clinical development of setanaxib has been strategically focused on fibrotic and rare diseases where the underlying pathology is strongly linked to NOX1/4-mediated oxidative stress. The program has spanned several indications, with the most significant progress made in Primary Biliary Cholangitis (PBC), and ongoing investigations in Idiopathic Pulmonary Fibrosis (IPF) and Alport Syndrome. An overview of the clinical pipeline is presented in Table 2.

Table 2: Overview of Setanaxib Clinical Development Pipeline

Indication	Trial Identifier	Phase	Status	Key Objective/Endpoint	Source(s)
Primary Biliary Cholangitis (PBC)	NCT03226067	2	Completed	GGT Reduction (Primary); ALP, Liver Stiffness, Fatigue (Secondary)	1
	NCT05014672 (TRANSFORM)	2b	Completed	ALP Reduction (Primary)	[22, 50, 51]
Squamous Cell Carcinoma of the Head and Neck (SCCHN)	NCT05323656	2	Completed	Tumor Size Change (Primary); PFS, OS (Secondary)	52
Idiopathic Pulmonary Fibrosis (IPF)	NCT03865927	2	Completed	Safety & Efficacy	15
Alport Syndrome	NCT06274489	2a	Active, not recruiting	Safety, Tolerability, PK/PD, Preliminary Efficacy	[15, 56]
Diabetic Nephropathy (DKD)	Multiple	2	Discontinued	Albuminuria Reduction	[1, 57]
Phase 1 / DDI Studies	NCT03740217, NCT04327089	1	Completed	Bioavailability, PK, Drug-Drug Interactions	46

5.1 Primary Biliary Cholangitis (PBC)

5.1.1 Disease Background and Standard of Care

Primary Biliary Cholangitis (PBC) is a rare, chronic, and progressive autoimmune liver disease characterized by the immune-mediated destruction of small intrahepatic bile ducts.[27] This destruction leads to cholestasis (impaired bile flow), which causes the accumulation of toxic bile acids in the liver, triggering inflammation, fibrosis, and eventually cirrhosis, liver failure, or the need for a liver transplant.[27] The standard of care for PBC begins with lifelong therapy with ursodeoxycholic acid (UDCA), a hydrophilic bile acid that helps improve bile flow and can slow disease progression.[58] However, a significant portion of patients, estimated at up to 40%, have an inadequate biochemical response to UDCA, leaving them at high risk for disease progression.[58] For these patients, second-line options include the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) and off-label use of fibrates.[58] These options have limitations; OCA can cause or worsen pruritus (itching), a common and debilitating symptom of PBC, and is contraindicated in patients with advanced cirrhosis, while fibrates also have contraindications and potential side effects.[58] Furthermore, none of the current therapies effectively treat the profound fatigue that affects up to 80% of PBC patients. This leaves a significant unmet medical need for new therapies that can improve biochemical markers, halt or reverse fibrosis, and alleviate key symptoms like fatigue.[1]

5.1.2 Analysis of Initial Phase 2 Trial (NCT03226067)

Genkyotex conducted an initial Phase 2, randomized, multicenter study to investigate the efficacy and safety of setanaxib in 111 PBC patients with an inadequate response to UDCA.[1] Patients were randomized to receive placebo, setanaxib 400 mg once daily (OD), or setanaxib 400 mg twice daily (BID) in addition to their stable UDCA therapy for 24 weeks.[1]

The trial officially did not meet its primary endpoint, which was the percentage change from baseline in serum gamma-glutamyl transferase (GGT) at Week 24.[1] In the setanaxib 400 mg BID group, the mean change in GGT was -19.0%, compared to -8.4% in the placebo group, a difference that was not statistically significant (p = 0.31).[48]

Despite this outcome, a deeper analysis of the secondary and exploratory endpoints revealed highly promising and statistically significant signals of clinical activity, particularly in the 400 mg BID group. This trial provides a clear example of how a study that technically "fails" can still provide crucial data to guide future development. The key positive findings were:

• Alkaline Phosphatase (ALP) Reduction: The 400 mg BID dose led to a mean reduction in serum ALP levels of 12.9% over the 24-week treatment period. This reduction was statistically significant compared to placebo (p = 0.002).[1] ALP is a well-established surrogate marker for long-term clinical outcomes in PBC, making this finding highly relevant.
• Liver Stiffness Improvement: A post-hoc analysis focused on a subgroup of patients with more advanced fibrosis, defined by a baseline liver stiffness of $\ge$9.6 kPa as measured by transient elastography (FibroScan®). In this high-risk group, patients treated with setanaxib experienced a mean 22% reduction in liver stiffness, indicating a potent anti-fibrotic effect. In stark contrast, patients in the placebo group saw their liver stiffness increase by 4% over the same period.[1]
• Fatigue Improvement: Treatment with setanaxib 400 mg BID resulted in a statistically significant improvement in fatigue, a key symptom with no approved treatments. The mean PBC-40 fatigue domain score decreased by 9.9% from baseline, compared to a 2.4% increase in the placebo group (p = 0.027).[1] A post-hoc analysis further showed that this effect was most pronounced in patients with moderate-to-severe fatigue at baseline, who experienced a mean score reduction of -5.8.[49]

This collection of findings suggested that while GGT may have been an inappropriate primary endpoint, the drug was exerting tangible and positive effects on more clinically meaningful measures of cholestasis (ALP), fibrosis (liver stiffness), and patient-reported symptoms (fatigue). This sophisticated interpretation of the data, moving beyond the binary success/failure of the primary endpoint, provided the strong rationale needed to continue the drug's development in PBC.

5.1.3 The TRANSFORM Study (Phase 2b, NCT05014672)

Informed by the promising secondary signals from the initial Phase 2 trial and supported by positive data from a high-dose Phase 1 study, Calliditas initiated the pivotal TRANSFORM study.[50] The study was initially designed as an adaptive Phase 2b/3 trial but was later amended to a 24-week, randomized, placebo-controlled Phase 2b study.[22] The trial enrolled 76 patients with PBC and elevated liver stiffness who had an inadequate response to or intolerance of UDCA.[22] It was designed to test higher doses of setanaxib: a 1200 mg/day arm (800 mg AM + 400 mg PM) and a 1600 mg/day arm (800 mg BID), against placebo.[23]

In July 2024, Calliditas announced that the TRANSFORM trial successfully met its primary endpoint.[22] The key results were:

• Primary Endpoint (ALP Reduction): Both doses of setanaxib demonstrated statistically significant reductions in ALP from baseline to Week 24 compared to placebo.
• 1600 mg arm: 19% reduction vs. placebo (p=0.0057).[23]
• 1200 mg arm: 14% reduction vs. placebo (p=0.021).23 The separation from placebo was observed as early as week 8.65
• Other Key Findings: The study also reported "positive trends on liver stiffness" as assessed by FibroScan® at 24 weeks, reinforcing the anti-fibrotic potential of the drug.[22] The top-line data release did not mention the fatigue endpoint.[22]
• Safety: Setanaxib was generally well tolerated. The overall rates of treatment-emergent adverse events (TEAEs) and serious TEAEs were similar between the active treatment and placebo groups. However, the frequency of TEAEs leading to study discontinuation was higher in the combined setanaxib arms (14.0%) compared to the placebo arm (7.7%).[22]

The successful outcome of the TRANSFORM trial represents a major validation of Calliditas' development strategy and firmly establishes setanaxib as a promising late-stage candidate for the treatment of PBC.

5.2 Idiopathic Pulmonary Fibrosis (IPF)

5.2.1 Rationale and Current Treatment Landscape

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, and ultimately fatal interstitial lung disease characterized by the relentless scarring of lung tissue, leading to respiratory failure.[27] The current standard of care is limited to two approved anti-fibrotic drugs, pirfenidone and nintedanib.[66] While these therapies can slow the rate of decline in lung function, they do not halt or reverse the disease process and are associated with significant side effects that can limit their use.[67] There remains a profound unmet medical need for more effective and better-tolerated treatments for IPF. The strong preclinical evidence demonstrating setanaxib's potent anti-fibrotic effects in various organ systems, including the lungs, provides a compelling scientific rationale for its investigation as a novel therapy for IPF.[1]

5.2.2 Status of the Investigator-Led Phase 2 Trial (NCT03865927)

Setanaxib is currently being evaluated in an investigator-led Phase 2 clinical trial for the treatment of IPF (NCT03865927).[15] This study is fully funded by a substantial $8.9 million grant from the U.S. National Institutes of Health (NIH) and is being led by a prominent researcher in the field, Professor Victor Thannickal at the University of Alabama at Birmingham.[1] The trial is designed to evaluate the safety and efficacy of setanaxib (400 mg BID) in approximately 60 IPF patients who are also receiving standard-of-care therapy with either pirfenidone or nintedanib.[1] The study completed in July 2024, and topline data are anticipated in Q4 2024 or early 2025.[15]

5.3 Alport Syndrome

5.3.1 Rationale and Unmet Need

Alport syndrome is a rare genetic disorder caused by mutations in the genes encoding type IV collagen, a crucial component of the glomerular basement membrane in the kidney.[70] The disease is characterized by progressive kidney fibrosis, which ultimately leads to end-stage kidney disease, often in adolescence or early adulthood. It is also associated with hearing loss and eye abnormalities.[70] Currently, there are no FDA-approved therapies specifically for Alport syndrome. The standard of care is supportive and focuses on slowing the progression of kidney disease using renin-angiotensin system (RAS) blockers, such as ACE inhibitors or ARBs.[70] Despite this treatment, most patients still progress to kidney failure, representing a major unmet medical need.[70] The well-established renoprotective and anti-fibrotic effects of setanaxib demonstrated in preclinical models of kidney disease make it a strong therapeutic candidate for this condition.[71]

5.3.2 Overview of the Phase 2 Proof-of-Concept Study (NCT06274489)

In November 2023, Calliditas announced the initiation of a Phase 2a clinical study to evaluate setanaxib in patients with Alport syndrome (NCT06274489).[56] This is a randomized, double-blind, placebo-controlled proof-of-concept study that will enroll approximately 20 patients with a confirmed genetic diagnosis of Alport syndrome and significant proteinuria despite stable treatment with a RAS blocker.[72] The study will have a treatment duration of 24 weeks. The primary objectives are to evaluate the safety and tolerability of setanaxib in this patient population. The study will also assess the pharmacokinetics and pharmacodynamics of setanaxib and evaluate its preliminary efficacy by measuring its effect on urine protein-to-creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) compared to placebo.[56] Topline data from this important study are expected in the first half of 2025.[15]

6.0 Clinical Development Program in Oncology

6.1 Scientific Rationale: Modulating the Tumor Microenvironment

The scientific rationale for using setanaxib in oncology is fundamentally different from its application in fibrotic diseases. Rather than aiming to directly kill cancer cells, the strategy is to remodel the tumor microenvironment (TME) to make it more permissive to an anti-tumor immune response.[5] Many solid tumors, particularly Squamous Cell Carcinoma of the Head and Neck (SCCHN), are characterized by a high density of Cancer-Associated Fibroblasts (CAFs).[32] These activated fibroblasts produce an extensive extracellular matrix, creating a dense, fibrotic shield around the tumor that physically impedes the infiltration of cytotoxic CD8+ T-cells.[5] This phenomenon, known as immune exclusion, is a major mechanism of both primary and acquired resistance to immune checkpoint inhibitors like pembrolizumab.[73]

Preclinical research has shown that the NOX4 enzyme is highly overexpressed in CAFs and is a key driver of their myofibroblastic activation.[5] The therapeutic hypothesis is that by inhibiting NOX4 with setanaxib, it is possible to revert CAFs to a more quiescent, "normalized" state. This would break down the fibrotic barrier, allowing CD8+ T-cells to penetrate the tumor core and execute their cancer-killing function.[5] In this paradigm, setanaxib acts as an immunomodulatory agent designed to synergize with and overcome resistance to immunotherapy.

6.2 Squamous Cell Carcinoma of the Head and Neck (SCCHN)

6.2.1 Disease Background and Immunotherapy Resistance

Recurrent or metastatic SCCHN is an aggressive cancer with a poor prognosis.[75] While immune checkpoint inhibitors such as pembrolizumab have become a standard of care for these patients, the objective response rates remain modest, often around 20%.[32] A significant contributor to this limited efficacy is the CAF-rich, immune-suppressive TME that is characteristic of many of these tumors.

6.2.2 Analysis of the Phase 2 Combination Trial (NCT05323656)

To test its TME-modulating hypothesis, Calliditas conducted a randomized, double-blind, placebo-controlled Phase 2 trial in 55 patients with recurrent or metastatic SCCHN whose tumors were confirmed to have moderate or high CAF density.[52] The trial evaluated the efficacy and safety of setanaxib 800 mg BID administered in combination with the standard-of-care PD-1 inhibitor, pembrolizumab, compared to placebo plus pembrolizumab.[52]

The trial's outcome presents a fascinating and instructive case in modern oncology drug development. The study did not meet its primary endpoint, which was the best percentage change from baseline in tumor size, a traditional measure of direct anti-tumor activity (RECIST-like endpoint).[53]

However, analysis of the key secondary endpoints revealed statistically significant and clinically meaningful improvements in time-dependent survival outcomes for the setanaxib combination arm:

• Progression-Free Survival (PFS): The median PFS was 5.0 months for patients receiving setanaxib plus pembrolizumab, compared to 2.9 months for those receiving placebo plus pembrolizumab. This represented a 42% reduction in the risk of progression or death (Hazard Ratio = 0.58).[53]
• Overall Survival (OS): The combination treatment also led to a significant improvement in overall survival. At the 9-month landmark analysis, 88% of patients in the setanaxib arm were alive, compared to 58% in the placebo arm.[53] The analysis yielded a hazard ratio of 0.45, indicating a 55% reduction in the risk of death.[53]

6.2.3 Insights from Biomarker and Translational Data

Crucially, the clinical survival data were supported by translational biomarker analyses from tumor biopsies taken before and during treatment. These analyses provided direct evidence that setanaxib was engaging its intended target and modulating the TME as hypothesized. Transcriptomic analysis of the biopsy samples revealed a statistically significant increase in CD8+ T-cells within the tumor tissue of patients treated with setanaxib.[53] This finding confirms that the drug was successfully increasing tumor immunological activity and overcoming the immune exclusion mediated by CAFs. The trial also showed an improvement in the disease control rate, with 70% of patients in the setanaxib arm achieving at least stable disease, compared to 52% in the placebo arm.[53]

The results of the SCCHN trial challenge the conventional reliance on tumor shrinkage as the primary measure of success for immunomodulatory agents. The drug's mechanism of action is not directly cytotoxic but rather aims to re-engineer the TME to enable a more effective anti-tumor immune response. Such a process may not lead to rapid tumor regression but could result in durable disease control and prolonged survival, as reflected in the significantly improved PFS and OS data. This disconnect between the RECIST-based primary endpoint and the survival outcomes highlights that for this emerging class of TME-modulating drugs, time-to-event endpoints like PFS and OS may be more clinically relevant and appropriate as primary endpoints for future pivotal trials. The ability of Calliditas to successfully frame these results, leading to the issuance of a U.S. patent in June 2024 covering the use of setanaxib in combination with a PD-1 inhibitor for treating resistant solid tumors until 2039, demonstrates a clear strategic path forward and may set a precedent for the development and regulatory evaluation of similar agents.[77]

7.0 Integrated Safety and Tolerability Assessment

The safety and tolerability of setanaxib have been extensively evaluated throughout its development, from early-phase studies in healthy volunteers to multiple Phase 2 trials in diverse patient populations. This has resulted in a robust safety dataset derived from over 320 subjects, which consistently supports a generally favorable and manageable safety profile.[15]

The foundation of the safety assessment was laid in Phase 1 studies. A notable high-dose trial in 46 healthy volunteers evaluated single and multiple ascending doses of setanaxib up to 1600 mg/day.[1] This study was critical in establishing the drug's safety at dose levels higher than those initially tested in patients. The results were highly encouraging, as setanaxib was found to be well tolerated across all dose levels, with no dose-limiting toxicities or significant safety signals identified.[1] This provided the confidence to explore higher, potentially more efficacious, doses in subsequent Phase 2 studies.

In the Phase 2 trials for Primary Biliary Cholangitis (PBC), setanaxib continued to demonstrate good tolerability. In the initial study (NCT03226067), all doses up to 800 mg/day were well tolerated, with no safety signals observed compared to placebo. Two serious adverse events were reported during the trial, one in the placebo group and one in the setanaxib 400 mg BID group, but both were deemed by investigators to be unrelated to the study drug.[48] The subsequent Phase 2b TRANSFORM trial (NCT05014672), which tested higher doses of 1200 mg/day and 1600 mg/day, also found that setanaxib was generally well tolerated.[22] The overall number of treatment-emergent adverse events (TEAEs) and serious TEAEs was similar between the combined setanaxib arms and the placebo group.[23] However, it was noted that the frequency of TEAEs that led to study drug discontinuation was higher in patients receiving setanaxib (14.0%) compared to those receiving placebo (7.7%).[22]

In the oncology setting, the combination of setanaxib with the immune checkpoint inhibitor pembrolizumab was also found to be generally well tolerated in the Phase 2 SCCHN trial. The addition of setanaxib to the standard immunotherapy regimen did not result in any new or unexpected safety signals, indicating a manageable profile for the combination therapy.[53]

Overall, the integrated safety assessment indicates that setanaxib, at doses up to 1600 mg/day, has a favorable safety profile suitable for chronic administration in fibrotic diseases and for use in combination with immunotherapy in oncology.

8.0 Synthesis, Strategic Analysis, and Future Outlook

8.1 Critical Assessment of the Setanaxib Platform

Setanaxib has emerged as a unique and compelling first-in-class therapeutic asset. Its development journey has been characterized by strategic resilience and a sophisticated, data-driven approach that has successfully navigated the inherent challenges of drug development. The core strength of setanaxib lies in its dual mechanism of action, targeting the fundamental pathological process of ROS production, which has now been clinically validated in two distinct and highly valuable therapeutic areas: organ fibrosis and immuno-oncology.

The program's history is a testament to the value of learning from initial clinical setbacks. The initial Phase 2 trials in diabetic nephropathy and PBC, which missed their primary endpoints, could have led to the termination of the program. Instead, a meticulous analysis of secondary and exploratory data by its developers revealed clear signals of biological activity on clinically relevant endpoints. This led to an intelligent and successful redesign of the clinical strategy, culminating in a positive, endpoint-meeting Phase 2b trial in PBC and a Phase 2 trial in SCCHN that demonstrated a significant survival benefit.

The primary challenge for the setanaxib platform now lies in translating these promising Phase 2 successes into unambiguous Phase 3 victories that can meet the rigorous standards of global regulatory authorities. This will require large, well-executed pivotal trials and a continued focus on endpoints that best reflect the drug's mechanism of action.

8.2 Competitive Landscape and Market Positioning

Setanaxib is well-positioned to address significant unmet medical needs in its lead indications.

• In Primary Biliary Cholangitis (PBC): Setanaxib is positioned as a potential add-on therapy for the substantial population of patients who have an inadequate response to the first-line standard of care, UDCA. Its clinical profile offers several points of potential differentiation from existing second-line therapies. Unlike obeticholic acid, which can exacerbate pruritus, setanaxib has shown a signal for improving fatigue, a highly prevalent and debilitating symptom with no approved treatments.[1] Its demonstrated anti-fibrotic effects, evidenced by improvements in liver stiffness, could also provide a key advantage over competitors.[1] If approved, setanaxib could be positioned as a third add-on agent for patients with advanced fibrosis or as a preferred second-line agent for patients with significant fatigue.[78]
• In Squamous Cell Carcinoma of the Head and Neck (SCCHN): In the oncology space, setanaxib is not positioned as a standalone therapy but as a crucial combination agent designed to overcome resistance to immune checkpoint inhibitors. This is a large and rapidly growing market segment. The statistically significant improvements in PFS and OS observed in a CAF-rich population suggest a clear path for a biomarker-driven strategy. The recent issuance of a U.S. patent protecting the use of setanaxib in combination with a PD-1 inhibitor in resistant solid tumors until 2039 provides a long runway of market exclusivity and significantly strengthens its commercial potential.[77]

8.3 Future Development Pathways and Recommendations

The path forward for setanaxib will require strategic execution on multiple fronts.

• Primary Biliary Cholangitis (PBC): The logical next step is to advance to a pivotal Phase 3 trial. This trial should be designed based on the successful TRANSFORM study, likely focusing on the 1600 mg/day dose and using ALP reduction as the primary regulatory endpoint. To build a compelling value proposition for payers and clinicians, the trial should also include key secondary endpoints such as change in liver stiffness and a formal assessment of its effect on fatigue using validated patient-reported outcome instruments.
• Squamous Cell Carcinoma of the Head and Neck (SCCHN): A larger, potentially registrational Phase 3 trial is required to definitively confirm the PFS and OS benefits observed in the Phase 2 study. Given the drug's immunomodulatory mechanism, Overall Survival should be strongly considered as a co-primary or primary endpoint, as this is the most clinically meaningful outcome. A biomarker enrichment strategy, enrolling only patients with moderate-to-high CAF density tumors, will be critical to maximize the probability of success.
• Idiopathic Pulmonary Fibrosis (IPF) & Alport Syndrome: The upcoming data readouts from the ongoing Phase 2 trials in late 2024 and 2025 will be crucial decision points. Positive results in these indications, both of which have a high unmet medical need, would significantly expand the value of the setanaxib platform and warrant rapid progression into pivotal studies.
• Platform Expansion: The preclinical finding that setanaxib can induce, rather than reduce, ROS in AML cells presents an intriguing and underexplored therapeutic avenue.[43] Further preclinical research is warranted to investigate setanaxib's potential as a chemosensitizing agent in combination with other ROS-inducing therapies in hematological malignancies and other solid tumors. Success in this area could unlock significant new value for the platform.

8.4 Concluding Remarks

Setanaxib has successfully navigated a complex and challenging development path to emerge as a highly promising, multi-faceted, and first-in-class therapeutic candidate. Its journey from a series of trials with missed primary endpoints to subsequent successes in both PBC and SCCHN underscores the sophistication of its underlying mechanism and the strategic acumen of its current developer, Calliditas Therapeutics. While significant pivotal trial risks remain, setanaxib represents one of the most compelling and differentiated assets in late-stage development, with the validated potential to establish new treatment paradigms in both fibrotic diseases and cancer.

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