Tranilast (DB07615): A Comprehensive Pharmacological and Clinical Monograph on a Pleiotropic Immunomodulator

Executive Summary

Tranilast, identified chemically as N-(3,4-Dimethoxycinnamoyl)anthranilic acid, is a small molecule drug with a complex and evolving pharmacological profile. Originally developed by Kissei Pharmaceuticals, it was first approved in Japan and South Korea in 1982 for the management of bronchial asthma, with its indications later expanded to include fibrotic skin conditions such as keloids and hypertrophic scars.[1] For decades, its identity was primarily defined by its anti-allergic properties, rooted in its ability to stabilize mast cell membranes and inhibit the release of inflammatory mediators.[1] This established its long-standing therapeutic role in several Asian countries, including China, where it remains in clinical use for these conditions.[2]

However, subsequent decades of research have unveiled a far more intricate and pleiotropic mechanism of action, fundamentally reshaping its scientific identity from a simple anti-allergic agent to a multifaceted immunomodulator. Beyond mast cell stabilization, Tranilast has been shown to exert potent anti-fibrotic effects through the direct inhibition of the transforming growth factor-beta (TGF-β) signaling pathway, a central mediator of tissue remodeling and fibrosis.[3] More recent discoveries have further expanded its known activities, identifying it as a direct and specific inhibitor of the NLRP3 inflammasome—a key platform in the innate immune system responsible for driving inflammation in a host of metabolic and autoimmune diseases.[5] Additionally, it has been characterized as an inhibitor of the TRPV2 ion channel, implicating it in processes of calcium homeostasis and neuronal function.[7]

This expanding understanding of its molecular targets has created a significant dichotomy in its global clinical and regulatory profile. While it maintains a legacy of use in Asia, Tranilast is not approved for any indication in Western markets, including by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[2] This divergence is largely attributable to the outcomes of the Prevention of Restenosis with Tranilast and its Outcomes (PRESTO) trial, a major clinical study conducted in a Western population. The trial not only failed to demonstrate efficacy for its investigated cardiovascular indication but also revealed a significant safety profile, including hepatotoxicity, hematological toxicity, and renal impairment, which had not been prominent in Asian post-marketing surveillance.[2]

The drug’s history thus presents a compelling case study in the geographical and temporal evolution of a pharmaceutical agent's identity. Its profile has shifted from a narrowly defined "anti-allergic" in 1980s Asia to a complex, multi-target "immunomodulator" in 21st-century global research. This evolution was not driven by its original development program but by independent academic inquiry that uncovered its deeper mechanisms long after its initial launch. These later discoveries have fueled significant interest in repositioning Tranilast for a new range of therapeutic areas, including oncology, autoimmune disorders like gout, and inflammasome-driven pathologies such as type 2 diabetes.[6] However, any future development is shadowed by the safety concerns raised in the PRESTO trial. Realizing its potential will require a nuanced approach that balances its unique mechanisms against a well-defined safety profile, likely involving targeted delivery systems, patient stratification based on pharmacogenetics, and a focus on indications with high unmet medical need where its benefits can demonstrably outweigh its risks.

Chemical Identity and Physicochemical Profile

2.1. Nomenclature and Structural Classification

Tranilast is a well-characterized small molecule with a precise chemical identity defined by multiple international standards. A comprehensive understanding of its structure and nomenclature is fundamental to interpreting its pharmacological activity and development history.

Systematic Identification

The molecule is systematically identified across various chemical and pharmaceutical databases to ensure unambiguous reference.

• International Union of Pure and Applied Chemistry (IUPAC) Name: The formal chemical name is 2-{amino}benzoic acid.[2] This name precisely describes the molecular architecture, including the stereochemistry of the double bond in the prop-2-enoyl linker.
• Common Names and Synonyms: In clinical and research contexts, it is most commonly known as Tranilast. Its primary brand name in approved markets is Rizaben.[2] A variety of synonyms and development codes are used in scientific literature, including N-(3,4-Dimethoxycinnamoyl)anthranilic acid, N-5', MK-341, and SB 252218.[1]
• Registry Numbers: It is uniquely indexed in major global registries:
• CAS Number: 53902-12-8 [1]
• DrugBank ID: DB07615 [1]
• PubChem CID: 5282230 [2]

Structural Analysis

Tranilast's chemical structure is the basis of its biological activity. It is classified as an anthranilic acid derivative, a class of compounds known for various biological activities.16 Critically, it is also described as an analog of a metabolite of the essential amino acid tryptophan.2 This connection to an endogenous metabolic pathway may provide insight into its biological origins and its potential to interact with native physiological systems.

The molecule consists of three key functional components:

1. An anthranilic acid (2-aminobenzoic acid) core, which serves as the structural backbone.
2. A 3,4-dimethoxycinnamoyl side chain, which is attached to the amino group of the anthranilic acid.
3. An amide linkage that covalently connects the two moieties.

From a stereochemical perspective, Tranilast is an achiral molecule, meaning it does not have a non-superimposable mirror image and is not optically active.[13] However, it possesses one E/Z stereocenter at the carbon-carbon double bond within the cinnamoyl linker. The biologically active form is the (E)-isomer, also known as the trans-isomer, which is explicitly denoted in its IUPAC name.[13]

2.2. Physicochemical Properties and Formulation Considerations

The physical and chemical properties of Tranilast dictate its behavior in biological systems and present specific challenges and opportunities for pharmaceutical formulation. These properties are a primary driver of its clinical development history and the strategies employed to optimize its delivery.

Core Properties

Tranilast has a molecular formula of C18​H17​NO5​ and a molecular weight of approximately 327.33 g/mol.1 In its solid state, it exists as a white to beige crystalline powder with a defined melting point range of 166.2–168.2 °C.15

Solubility Profile

Its solubility is a defining characteristic with significant biopharmaceutical implications. Tranilast is classified as being almost insoluble in water.2 In contrast, it exhibits good solubility in polar aprotic organic solvents such as dimethylsulfoxide (DMSO) and is also soluble in dioxane.2 This poor aqueous solubility is a major hurdle for oral and parenteral formulations.

Stability

The molecule exhibits photochemical instability when in solution, meaning it is susceptible to degradation upon exposure to light.2 This property necessitates careful handling, storage in light-protected containers, and consideration during the manufacturing and formulation processes to prevent loss of potency.

Biopharmaceutics Classification System (BCS) Implications

Based on its combination of low aqueous solubility and high membrane permeability, Tranilast is categorized as a Biopharmaceutics Classification System (BCS) Class II drug.3 This classification is critically important as it predicts that the rate and extent of oral absorption will be limited by the drug's dissolution rate in the gastrointestinal fluids rather than its ability to cross the intestinal wall.3

This BCS Class II characteristic is not merely a technical detail but a central factor in understanding its clinical challenges. The dissolution-rate-limited absorption inherently leads to a high potential for inter-patient pharmacokinetic variability. As the oral dose is increased, the gastrointestinal system's ability to dissolve the drug may become saturated, leading to disproportionate and unpredictable increases in plasma concentrations among different individuals.[3] This variability likely contributed to the safety issues observed in the PRESTO trial, where some patients may have experienced unexpectedly high peak concentrations, potentially driving the observed hepatotoxicity and other adverse events.[2] Consequently, the drug's fundamental physicochemical properties are directly linked to its clinical risk profile. Furthermore, these properties have necessitated the exploration of advanced drug delivery systems. The development of novel topical formulations, such as liposomal gels and microneedle arrays, represents a direct strategic response to overcome the limitations of poor solubility.[16] These technologies aim to deliver therapeutic concentrations directly to the target tissue (e.g., skin), thereby maximizing local efficacy while minimizing the systemic exposure and pharmacokinetic variability that are associated with its toxicity risks.

Pleiotropic Pharmacology and Mechanisms of Action

Tranilast exhibits a remarkable range of pharmacological activities that extend far beyond its original classification as an anti-allergic agent. Its efficacy in diverse pathological conditions stems from its ability to modulate multiple, distinct biological pathways. These mechanisms are not entirely independent but rather form an interconnected network of immunomodulation and tissue remodeling, which collectively explains its therapeutic effects across seemingly disparate diseases like asthma, keloid scarring, and gout.

3.1. Primary Anti-allergic Mechanism: Mast Cell Stabilization

The foundational mechanism of action, which led to its initial development and approval, is its function as a potent mast cell stabilizer.[21] Mast cells are key effector cells in Type I hypersensitivity reactions, and their stabilization is a cornerstone of therapy for allergic disorders.

Tranilast's action on mast cells is comprehensive. It inhibits the critical process of degranulation, the fusion of intracellular granules with the plasma membrane, which is triggered by allergens binding to IgE receptors.[23] This stabilization prevents the release of two major classes of inflammatory mediators:

• Preformed Mediators: It blocks the release of mediators stored within mast cell granules, most notably histamine, which is responsible for acute allergic symptoms like vasodilation, bronchoconstriction, and itching. It also inhibits the release of proteases such as tryptase and chymase.[2]
• Newly Synthesized Mediators: It suppresses the production and release of lipid-derived mediators that are synthesized upon mast cell activation, including prostaglandins and leukotrienes, which contribute to the later phases of the inflammatory response.[24]

Electrophysiological studies have provided direct evidence for this stabilizing effect. At pharmacologically relevant, albeit high, concentrations (500 µM to 1 mM), Tranilast has been shown to almost completely suppress the exocytotic process in mast cells. This was demonstrated by its ability to prevent the increase in whole-cell membrane capacitance, a direct measure of granule fusion with the cell membrane. Furthermore, it was observed to counteract the physical deformation of the plasma membrane that occurs during degranulation, providing a biophysical basis for its stabilizing properties.[23]

3.2. The Anti-Fibrotic Axis: Targeting the TGF-β Pathway

A second major mechanism of action, and one that is central to its efficacy in treating keloids, hypertrophic scars, and other fibrotic diseases, is its multifaceted inhibition of the transforming growth factor-beta (TGF-β) signaling pathway.[3] TGF-β1 is a master regulator of fibrosis, promoting the proliferation of fibroblasts and stimulating their synthesis of extracellular matrix (ECM) components, particularly collagen.

Tranilast interferes with this pro-fibrotic signaling cascade at multiple levels:

• Suppression of TGF-β1 Release: In a crucial feedback loop, fibroblasts in fibrotic tissues like keloids produce and release TGF-β1, which then acts in an autocrine and paracrine manner to perpetuate the fibrotic process. Tranilast has been shown to directly inhibit the release of TGF-β1 from keloid fibroblasts, thereby breaking this self-sustaining cycle of activation.[4]
• Pre-translational Inhibition of Collagen Synthesis: Tranilast specifically counteracts the stimulatory effect of TGF-β1 on collagen production. Mechanistic studies have demonstrated that it achieves this at a pre-translational level, significantly decreasing the cellular content of messenger RNA (mRNA) for procollagen chains, such as pro α1(I) collagen mRNA.[28] This indicates that its inhibitory action occurs at the level of gene transcription, preventing the synthesis of the building blocks of collagen fibers.
• Inhibition of Fibroblast Proliferation: Beyond ECM synthesis, Tranilast directly inhibits the excessive proliferation of fibroblasts, which is a hallmark of active fibrosis.[2]

Notably, this anti-fibrotic effect appears to be selective. Studies have shown that Tranilast inhibits collagen synthesis in pathologically activated fibroblasts from keloids and scleroderma to a greater extent than in normal, healthy skin fibroblasts. It also does not affect the synthesis of non-collagen proteins, highlighting a specific effect on the fibrotic process rather than general cellular toxicity.[27]

3.3. Broad Anti-inflammatory Effects: Direct Inhibition of the NLRP3 Inflammasome

A more recently elucidated mechanism, which dramatically broadens the potential therapeutic scope of Tranilast, is its role as a direct and specific inhibitor of the NLRP3 inflammasome.[6] The NLRP3 inflammasome is a multi-protein complex of the innate immune system that responds to a wide array of microbial and endogenous danger signals. Its aberrant activation is a key driver of pathology in numerous autoinflammatory and metabolic diseases, including gout, type 2 diabetes, and cryopyrin-associated periodic syndromes (CAPS).[2]

The molecular interaction between Tranilast and the inflammasome is highly specific:

• Direct Binding to NLRP3: Biochemical studies have shown that Tranilast physically binds directly to the NACHT (nucleotide-binding and oligomerization) domain of the NLRP3 sensor protein itself.[5]
• Blockade of Inflammasome Assembly: The NACHT domain is essential for the oligomerization of NLRP3 molecules, which is the critical first step in assembling a functional inflammasome complex. By binding to this domain, Tranilast physically obstructs this oligomerization process.[5]
• Inhibition of Downstream Signaling: This blockade of assembly prevents the recruitment of the adapter protein ASC and pro-caspase-1. As a result, caspase-1 is not activated, and the potent pro-inflammatory cytokine interleukin-1β (IL-1β) is not cleaved into its mature, secreted form.[6]

This inhibitory action is highly targeted. Experiments have confirmed that while Tranilast potently inhibits the NLRP3 inflammasome, it has no effect on other inflammasome pathways, such as those mediated by the AIM2 or NLRC4 sensors.[5] This specificity suggests a lower risk of broad immunosuppression compared to less targeted anti-inflammatory agents.

3.4. Emerging Mechanisms and Molecular Targets

Ongoing research continues to identify additional molecular targets for Tranilast, further contributing to its pleiotropic profile.

• TRPV2 Channel Blockade: Tranilast has been identified as an inhibitor of the Transient Receptor Potential Vanilloid 2 (TRPV2) channel, a non-selective cation channel involved in calcium signaling.[2] The functional consequences of TRPV2 inhibition are diverse, as the channel is implicated in cancer cell proliferation, immune cell function, and neuronal activity. This mechanism provides a compelling rationale for its investigation in neurological disorders. For instance, in animal models of Alzheimer's disease, Tranilast administration was shown to reverse cognitive deficits, an effect linked to its modulation of TRPV2-mediated calcium homeostasis and downstream signaling pathways related to synaptic plasticity.[32]
• Anti-angiogenic Properties: Tranilast demonstrates anti-angiogenic activity, the ability to inhibit the formation of new blood vessels.[7] This effect is thought to be mediated, at least in part, by the inhibition of vascular endothelial growth factor (VEGF).[15] This property underpins its investigational use in diseases characterized by pathological angiogenesis, such as cancer and diabetic retinopathy.[3]
• Cardiovascular Modulation: The drug exhibits direct effects on the cardiovascular system. It has been shown to antagonize the physiological effects of angiotensin II, a key hormone in blood pressure regulation and cardiovascular remodeling, possibly through an interaction at the angiotensin II type 1 (AT1) receptor.[7] This is consistent with findings that it inhibits angiotensin II-induced contractions in vascular smooth muscle and ameliorates angiotensin II-induced myocardial fibrosis in cardiac fibroblasts.[34]

The convergence of these mechanisms creates a powerful, synergistic network. For example, mast cells, the primary target of Tranilast's anti-allergic action, are also significant sources of pro-fibrotic mediators like TGF-β and pro-inflammatory cytokines.[22] Therefore, by stabilizing mast cells, Tranilast indirectly reduces a key trigger for fibrosis. Similarly, the NLRP3 inflammasome, which Tranilast directly inhibits, is responsible for producing IL-1β, a cytokine that can further stimulate fibroblasts and drive inflammation leading to fibrosis.[6] Thus, NLRP3 inhibition represents another upstream mechanism contributing to its anti-fibrotic effect. Finally, TGF-β itself is a crucial player in the tumor microenvironment, promoting angiogenesis and immune evasion.[12] Consequently, Tranilast's anti-TGF-β activity is mechanistically linked to its potential anti-cancer effects. This integrated view reveals that Tranilast is not simply a drug with four separate actions, but rather a single agent that modulates a central hub of interconnected pathways governing inflammation, immunity, and tissue repair.

Clinical Pharmacokinetics and Metabolism (ADME)

The disposition of Tranilast in the human body—its absorption, distribution, metabolism, and excretion (ADME)—is a critical determinant of its efficacy and safety. Its pharmacokinetic profile is characterized by gradual oral absorption, limited distribution, and significant metabolism primarily mediated by a genetically variable enzyme, which has profound implications for its clinical use and risk profile in different populations.

4.1. Absorption

Following oral administration, Tranilast is absorbed from the gastrointestinal tract. Studies in healthy Chinese subjects receiving a single 200 mg oral capsule demonstrate that this absorption process is gradual rather than rapid.[36] Peak plasma concentrations (

) of approximately 42.2 µg/mL are achieved at a median time to peak () of about 2.8 hours.[36] As a BCS Class II drug with low aqueous solubility, its absorption is rate-limited by its dissolution, which can lead to significant inter-individual variability, particularly at higher doses.[3]

4.2. Distribution

Data on the distribution of Tranilast are limited. The apparent volume of distribution () calculated from oral dosing studies is relatively small, at approximately 88.4 mL/kg.[36] This suggests that the drug does not distribute extensively into deep tissue compartments and is largely confined to the plasma and well-perfused organs. Despite this, Tranilast has been reported to be blood-brain barrier permeable, a crucial characteristic that enables its investigation for neurological conditions and supports the observation of central nervous system effects in preclinical models.[8]

4.3. Metabolism

Tranilast undergoes extensive biotransformation in the body, with two primary metabolic pathways identified:

• Phase II Glucuronidation: This is the major metabolic route for Tranilast. The carboxylic acid group on the anthranilic acid moiety is conjugated with glucuronic acid to form an inactive glucuronide metabolite. This reaction is catalyzed by the enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1), which is the predominant isoform responsible for its clearance in both the liver and intestines. Minor contributions from other UGT isoforms, including UGT1A3, UGT1A8, UGT1A9, and UGT1A10, have also been noted.[2]
• Phase I Demethylation: A secondary, less prominent pathway involves Phase I metabolism, specifically the O-demethylation of one of the methoxy groups on the cinnamoyl ring to form the active metabolite 4-demethyltranilast (also known as N-3).[37]

The central role of UGT1A1 in Tranilast's metabolism is a critical and perhaps underappreciated liability that likely contributes significantly to the divergent safety profiles observed between Asian and Western populations. UGT1A1 is known to be a highly polymorphic gene, with common genetic variants that lead to reduced enzyme activity. The most well-known of these is the UGT1A1*28 polymorphism, the primary cause of Gilbert's syndrome, which is characterized by mild, unconjugated hyperbilirubinemia. This polymorphism is notably more prevalent in Caucasian populations, where approximately 10% of individuals are homozygous for the variant, compared to its lower prevalence in East Asian populations.

Individuals with reduced UGT1A1 activity (i.e., poor metabolizers) would be expected to clear Tranilast more slowly, leading to significantly higher systemic drug exposure (AUC) and peak concentrations () for a given dose. This pharmacogenetic difference provides a compelling explanation for the safety signals observed in the PRESTO trial, which was conducted primarily in a Western population. The reports of hyperbilirubinemia in that trial are a classic clinical sign of UGT1A1 inhibition or functional overload.[37] Furthermore, the alarmingly high rate of hepatotoxicity (elevated transaminases in 11% of patients) could be a direct consequence of this genetically driven overexposure in a substantial subset of the study population.[2] Conversely, the drug's long-standing reputation for having a favorable safety profile in Japan and South Korea may be, in part, a reflection of the lower frequency of poor metabolizer genotypes in those populations.[11] This strongly suggests that any future clinical development of Tranilast in genetically diverse populations would necessitate prospective UGT1A1 genotyping to allow for personalized dosing strategies aimed at mitigating the risk of severe toxicity.

4.4. Excretion

Tranilast and its metabolites are eliminated from the body with a mean terminal elimination half-life () of approximately 7.6 hours.[36] The total body plasma clearance, adjusted for bioavailability (

), is approximately 8.1 mL/h/kg.[36] The specific routes of excretion (renal vs. fecal) for the parent drug and its metabolites have not been fully detailed in the available literature.

Therapeutic Applications and Clinical Efficacy

Tranilast possesses a dual clinical identity: it is an established therapy for a defined set of allergic and dermatological conditions in several Asian countries, while also being a subject of intense investigation for a wide array of novel applications globally. Its therapeutic potential is being explored in oncology, systemic fibrosis, and autoimmune disorders, driven by the expanding understanding of its pleiotropic mechanisms of action.

5.1. Approved Indications in Allergic and Dermatological Disorders

In Japan, South Korea, and China, Tranilast has been a part of the therapeutic armamentarium for several decades.[1]

• Allergic Disorders: Its primary approved use is in the management of allergic conditions, including bronchial asthma, allergic rhinitis, and atopic dermatitis.[1] It is important to note that for bronchial asthma, Tranilast functions as a prophylactic or maintenance therapy to prevent attacks and is not indicated for the rapid relief of acute bronchospasm.[38] Its efficacy in these conditions is attributed to its foundational mechanism as a mast cell stabilizer, preventing the release of histamine and other key mediators of allergic inflammation.
• Fibrotic Skin Conditions: Tranilast is also approved for the treatment of keloids and hypertrophic scars, benign but often symptomatic and disfiguring fibroproliferative disorders of the skin.[1] Its utility here is directly linked to its anti-fibrotic properties, particularly its inhibition of the TGF-β pathway. Clinical evidence supports its efficacy in this indication. A prospective study involving 35 patients with keloids and hypertrophic scars demonstrated significant clinical improvement with oral Tranilast. After 12 weeks of treatment, 71.4% of patients achieved a clinical rating of "good" or better. Symptomatically, there was a 51% reduction in itching and a 56% reduction in pain. Objectively, there was a 43% mean improvement in erythema (redness) as measured by colorimetry.[39] Furthermore, topical formulations have shown promise. An 8% liposomal gel of Tranilast was found to be effective in improving scar cosmesis after surgery and in preventing the formation of atrophic scars in patients with acne vulgaris undergoing treatment with oral isotretinoin.[16]

5.2. Investigational Frontiers in Oncology

A significant body of preclinical research has highlighted the potential of Tranilast as an anti-cancer agent, acting not as a traditional cytotoxic drug but as a modulator of the tumor and its microenvironment.[12]

• Mechanisms in Cancer: In vitro and in vivo studies have shown that Tranilast can inhibit proliferation, induce cell cycle arrest through the upregulation of inhibitors like p21, and promote apoptosis in a wide range of cancer cell lines, including those from glioma, breast, prostate, pancreatic, and non-small cell lung cancer (NSCLC).[40]
• Modulating the Tumor Microenvironment (TME): Perhaps its most compelling application in oncology is its ability to target and reprogram the TME. The TME, particularly a population of activated fibroblasts known as cancer-associated fibroblasts (CAFs), is a major driver of tumor progression, metastasis, and resistance to therapy. Tranilast has been shown to directly target CAFs, inhibiting their secretion of pro-tumorigenic cytokines like interleukin-6 (IL-6). In preclinical models of NSCLC, this action was sufficient to block CAF-mediated resistance to molecularly targeted therapies (e.g., EGFR inhibitors), re-sensitizing the cancer cells to treatment.[27]
• Targeting Cancer Stem Cells (CSCs): Tranilast has also demonstrated activity against cancer stem cells, a subpopulation of tumor cells responsible for therapy resistance and relapse. In models of breast cancer, it was shown to inhibit the formation of mammospheres (an in vitro surrogate for CSC activity) from drug-resistant CSCs. This effect was found to be mediated through its activity as an agonist of the Aryl Hydrocarbon Receptor (AHR).[44]

5.3. Potential in Systemic Fibrotic Diseases

Building on its proven efficacy in skin fibrosis, researchers are investigating Tranilast's potential to treat fibrosis in other organ systems, where TGF-β is also a central pathogenic driver.

• Pulmonary Fibrosis: In animal models of idiopathic pulmonary fibrosis (IPF), Tranilast administration significantly attenuated the development of lung fibrosis. Mechanistically, it was shown to suppress the TGF-β/SMAD2 signaling pathway within the lung tissue, leading to reduced production of ECM proteins like collagen and fibronectin.[45]
• Myocardial Fibrosis: In models of cardiac fibrosis, Tranilast inhibits the pathological processes induced by stimuli like angiotensin II. It was found to suppress the proliferation, migration, and fibrotic activity of human cardiac fibroblasts by modulating the S100A11/TGF-β1/Smad signaling axis.[34]
• Renal Fibrosis: Preclinical studies have also demonstrated a protective effect in the kidney. In a rat model of obstructive nephropathy, Tranilast treatment ameliorated renal tubular damage and significantly reduced fibrosis by decreasing tissue levels of TGF-β.[29]

5.4. Novel Applications in Autoimmune and Metabolic Disorders (NLRP3-driven)

The discovery of Tranilast as a direct NLRP3 inflammasome inhibitor has opened up an entirely new field of investigation for its use in diseases driven by inflammasome dysregulation.

• Gout and Rheumatoid Arthritis: Gouty arthritis is a classic NLRP3-driven disease, triggered by the formation of uric acid crystals in the joints. In mouse models of gout, Tranilast showed remarkable therapeutic effects.[6] It also demonstrated efficacy in models of rheumatoid arthritis, attenuating joint inflammation and bone destruction.[22] This has translated to clinical investigation, with Phase II trials exploring its use in combination with the urate-lowering drug allopurinol for patients with gout.[16]
• Urate-Lowering Effect: Compounding its anti-inflammatory benefit in gout, Tranilast has also been found to have a direct hypouricemic (urate-lowering) effect. It acts as a non-specific inhibitor of several key renal transporters involved in urate reabsorption, including URAT1 and GLUT9. This provides a unique dual mechanism of action for the treatment of gout.[16]
• Type 2 Diabetes (T2D): Chronic, low-grade inflammation mediated by the NLRP3 inflammasome is now recognized as a key contributor to insulin resistance and the pathogenesis of T2D. In diabetic mouse models, Tranilast treatment was shown to improve both hyperglycemia and insulin resistance and to reduce hepatic steatosis (fatty liver). These beneficial metabolic effects were entirely dependent on its ability to inhibit NLRP3, as the drug had no effect in NLRP3-deficient mice.[5]

These investigational applications suggest that Tranilast's most promising future may not be as a standalone monotherapy for complex diseases like cancer, but rather as a "stromal-normalizing agent" used in combination with other primary therapies. In cancer, resistance to treatment is often driven by the TME and CAFs.[43] By targeting CAFs and inhibiting their pro-tumorigenic signaling, Tranilast can disrupt the tumor's support system and re-sensitize it to cytotoxic or targeted drugs.[27] Similarly, in fibrotic diseases, its primary role is to "reprogram" dysregulated fibroblasts by blocking the master TGF-β signal.[4] This positions Tranilast as a powerful adjuvant agent that can normalize the fibrotic, pro-inflammatory stroma, thereby creating a more favorable environment for primary drugs to exert their effects more effectively.

Safety, Tolerability, and Risk Management

The safety profile of Tranilast is complex and marked by a significant disparity between data derived from decades of post-marketing experience in Asia and the findings from a large, prospective clinical trial conducted in a Western population. This dichotomy necessitates a careful and integrated assessment of its risks to guide any potential clinical use or future development.

6.1. Comprehensive Adverse Event Profile - A Tale of Two Profiles

The available data present two starkly different pictures of Tranilast's tolerability.

The "Well-Tolerated" Profile

In the context of its approved indications in Japan and South Korea, Tranilast is often described as being generally well-tolerated, with a low incidence of severe adverse effects.11 Animal studies have also shown it to be well-tolerated with no significant effects on body weight or major indicators of organ function in blood chemistry panels.40 The most commonly reported adverse reactions in clinical practice are typically mild to moderate and include 38:

• Gastrointestinal Disturbances: Nausea, loss of appetite, vomiting, abdominal pain, and diarrhea.
• Dermatological Reactions: Skin rash, itching (pruritus), hives (urticaria), and eczema.
• Genitourinary Symptoms: Cystitis-like symptoms, including frequent or painful urination and, rarely, hematuria (blood in the urine).
• Neurological Symptoms: Dizziness and headache have also been reported.

The "Significant Toxicity" Profile (PRESTO Trial)

In stark contrast to the post-marketing data from Asia, the PRESTO trial, a large, well-conducted study for the prevention of coronary restenosis, uncovered a pattern of more severe, organ-specific toxicities.2 These findings have largely defined its risk profile in the view of Western regulatory agencies. The key safety signals were:

• Hepatotoxicity: This was the most prominent concern, with reports of elevated liver transaminases to levels three times the upper limit of normal (3x ULN) in a notable 11% of patients receiving the drug. Clinical signs of hepatic dysfunction, including jaundice, were also observed.[2]
• Hematological Toxicity: Systemic administration was associated with the inhibition of hematopoiesis (blood formation), leading to cytopenias. Specific events included leukopenia (low white blood cell count), thrombocytopenia (low platelet count), and anemia.[2]
• Renal Toxicity: The trial also raised concerns about kidney function, with reports of renal dysfunction, decreased urine output, and, in some cases, kidney failure.[2]

6.2. Contraindications, Warnings, and Precautions

Based on its known risks, several contraindications and precautions are advised for the use of Tranilast.

• Absolute Contraindications: The drug is contraindicated in individuals with a known hypersensitivity to Tranilast or any of its components.[49]
• Use in Specific Populations:
• Pregnancy and Lactation: Tranilast should not be used by women who are pregnant or may become pregnant. It is also known to be secreted into breast milk, and therefore its use is not recommended in breastfeeding women.[2]
• Pre-existing Organ Dysfunction: Given the observed risks of hepato- and nephrotoxicity, caution should be exercised when administering Tranilast to patients with pre-existing liver or kidney disorders. Regular monitoring of organ function is recommended in such cases.[38]

6.3. Drug-Drug Interaction Profile

Tranilast has an extensive profile of potential drug-drug interactions, stemming from both pharmacokinetic (metabolic) and pharmacodynamic (effect-related) mechanisms.[1]

• Warfarin: A specific warning exists against the co-administration of Tranilast and the anticoagulant warfarin, as they are known to interact, likely leading to an enhanced anticoagulant effect and an increased risk of bleeding.[2]
• Metabolic Interactions: As its metabolism is heavily dependent on UGT1A1 and, to a lesser extent, cytochrome P450 enzymes like CYP2C9, Tranilast is susceptible to interactions with inhibitors and inducers of these pathways.
• UGT1A1: Tranilast itself appears to inhibit UGT1A1, which can increase the exposure and toxicity of other drugs that are substrates for this enzyme.[2]
• CYP2C9: Co-administration with strong CYP2C9 inhibitors (e.g., fluconazole) can increase plasma levels of Tranilast, potentially heightening the risk of side effects. Conversely, co-administration with CYP2C9 inducers (e.g., rifampin) can decrease Tranilast levels, potentially reducing its therapeutic efficacy.[49]
• Pharmacodynamic Interactions: Tranilast can have additive effects with other medications, increasing the risk of certain adverse events. Key examples include:
• Increased Bleeding Risk: When combined with other anticoagulants (e.g., apixaban), antiplatelet agents (e.g., clopidogrel, aspirin), or NSAIDs (e.g., ibuprofen).
• Hypoglycemia: When used with anti-diabetic medications such as sulfonylureas (e.g., glimepiride) or incretin mimetics (e.g., albiglutide).
• Hypotension: When combined with antihypertensive agents or other drugs that lower blood pressure (e.g., amlodipine, antipsychotics).
• Hyperkalemia: When co-administered with potassium-sparing diuretics (e.g., amiloride, spironolactone) or ACE inhibitors.

The following table summarizes the most clinically significant potential drug-drug interactions, providing guidance for risk management.

Table 6.1: Clinically Significant Drug-Drug Interactions with Tranilast

Interacting Drug/Class	Potential Clinical Effect	Putative Mechanism	Clinical Recommendation
Anticoagulants (e.g., Warfarin, Apixaban)	Increased risk of severe bleeding	Pharmacodynamic synergy; potential for metabolic inhibition	Co-administration with warfarin is specifically warned against.2 Use with any anticoagulant requires extreme caution and close monitoring for signs of bleeding.
Antiplatelet Agents (e.g., Aspirin, Clopidogrel)	Increased risk of bleeding	Pharmacodynamic synergy (additive antiplatelet effects)	Monitor for signs of bleeding, such as bruising or gastrointestinal hemorrhage.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs) (e.g., Ibuprofen, Diclofenac)	Increased risk of bleeding, particularly gastrointestinal	Pharmacodynamic synergy (inhibition of platelet function and potential for gastric mucosal injury)	Use combination with caution. Advise patients on the signs of GI bleeding.
Anti-diabetic Agents (e.g., Sulfonylureas, GLP-1 Agonists)	Increased risk of hypoglycemia	Pharmacodynamic synergy	Monitor blood glucose levels closely, especially upon initiation of Tranilast. Dose adjustment of the anti-diabetic agent may be necessary.
UGT1A1 Substrates (e.g., Irinotecan, Bilirubin)	Increased exposure and toxicity of the co-administered drug	Pharmacokinetic: Competitive inhibition of UGT1A1-mediated metabolism by Tranilast	Avoid combination if possible, particularly with narrow therapeutic index drugs. Consider dose reduction and therapeutic drug monitoring of the UGT1A1 substrate.
Potassium-Sparing Diuretics / ACE Inhibitors (e.g., Amiloride, Lisinopril)	Increased risk of hyperkalemia	Pharmacodynamic synergy (additive effects on potassium retention)	Monitor serum potassium levels regularly, especially in patients with renal impairment.
Strong CYP2C9 Inhibitors (e.g., Fluconazole)	Increased plasma concentration of Tranilast; increased risk of toxicity	Pharmacokinetic: Inhibition of Tranilast metabolism	Avoid combination if possible. If co-administration is necessary, consider a lower starting dose of Tranilast and monitor for adverse effects.
Strong CYP2C9 Inducers (e.g., Rifampin, Carbamazepine)	Decreased plasma concentration of Tranilast; potential loss of efficacy	Pharmacokinetic: Induction of Tranilast metabolism	Monitor for reduced therapeutic effect of Tranilast. Dose increase may be required.

Regulatory Landscape and Developmental History

The regulatory journey of Tranilast is a story of regional success followed by international setbacks, creating a starkly divided global landscape. Its history is defined by its initial development and long-standing approval in Asia, contrasted with its failure to gain marketing authorization in Western markets, a trajectory heavily influenced by the results of a single pivotal clinical trial.

7.1. Development and Approval in Asia

Tranilast was originally developed by the Japanese pharmaceutical company Kissei Pharmaceuticals.[1] Following successful clinical development, it received its first marketing approval in Japan and South Korea in 1982 for the indication of bronchial asthma. Its utility was later recognized for fibroproliferative skin disorders, and its approved indications were expanded in the 1980s to include the treatment of keloids and hypertrophic scars.[1] It has been marketed for decades in these regions under brand names such as Rizaben and continues to be used in clinical practice in Japan, South Korea, and China.[2]

7.2. Regulatory Review in Western Markets (FDA & EMA)

Despite its long history of use in Asia, Tranilast has never been approved for any indication in the United States or Europe.

• U.S. Food and Drug Administration (FDA): Tranilast is not an FDA-approved drug.[2] Its regulatory history with the agency is minimal but telling. On December 2, 2003, it was granted an Orphan Drug Designation for the treatment of malignant glioma, a status intended to encourage the development of drugs for rare diseases.[9] However, this designation did not culminate in a marketing application or approval. More recently, in 2016, the FDA took the step of proposing that Tranilast be excluded from the list of bulk drug substances that could be used by compounding pharmacies, signaling a cautious stance on its uncontrolled use in the U.S..[2]
• European Medicines Agency (EMA): Similar to the U.S., Tranilast does not have a general marketing authorization in the European Union.[50] It did, however, receive an Orphan Designation from the EMA on July 27, 2010. This designation was granted for a highly specific and niche indication: the "prevention of scarring post glaucoma filtration surgery".[3] As with the FDA designation, this has not yet led to a full marketing approval.

7.3. Analysis of Key Clinical Trials and Future Outlook

The divergent regulatory paths of Tranilast can be largely traced back to the outcome of one major clinical trial: the Prevention of Restenosis with Tranilast and its Outcomes (PRESTO) trial. This large-scale study was a collaboration between Kissei Pharmaceuticals and SmithKline Beecham (now part of GSK) and represented an ambitious attempt to expand Tranilast's indications into the lucrative Western cardiovascular market.[2]

The PRESTO trial was designed to evaluate whether Tranilast could prevent restenosis—the re-narrowing of a coronary artery—following percutaneous transluminal coronary revascularization procedures like angioplasty. The trial failed to meet its primary efficacy endpoint; Tranilast was not found to be effective for this application.[2] More damagingly, the rigorous monitoring within this well-controlled study uncovered the significant safety profile of hepatotoxicity, hematological toxicity, and renal impairment that had not been a prominent feature of its post-marketing safety data from Asia.[2]

This single trial had a profound and lasting impact on the drug's global trajectory. The combination of failed efficacy in a high-profile indication and the emergence of a severe adverse event profile effectively halted its development for major indications in the West. This created a legacy of "toxic data" that is difficult for developers to overcome. In the eyes of Western regulators, the robust, prospective data from this single large trial likely carries more weight than decades of regional, real-world evidence from Asia, which may lack the same level of systematic data collection. This history serves as a powerful lesson in drug development: a drug's reputation and regulatory viability can be permanently defined by the most rigorous and challenging trial it undergoes.

Future Outlook

Today, Tranilast stands as a molecule of significant scientific interest but high developmental risk. Its future in markets outside of Asia likely depends on a strategic approach to drug repositioning that directly addresses the challenges posed by its history. A successful path forward would require:

1. Focus on Niche Indications: Targeting diseases with high unmet medical need, such as the orphan-designated indications of malignant glioma or post-surgical scarring, where the risk-benefit calculation may be more favorable.
2. Novel Delivery Systems: Prioritizing the development of topical or localized delivery systems (e.g., gels, microneedles, intra-tumoral injections) to maximize efficacy at the target site while minimizing the systemic exposure that drives its toxicity.
3. Pharmacogenetic Stratification: Implementing mandatory prospective screening for UGT1A1 polymorphisms in any future clinical trials. This would allow for the exclusion of high-risk poor metabolizers or the implementation of genotype-guided dosing to mitigate the risk of toxicity.
4. Leveraging Unique Mechanisms: Focusing on therapeutic areas where its unique mechanisms of action, such as NLRP3 inflammasome inhibition or TME modulation, offer a distinct advantage over existing therapies.

By adopting such a carefully managed strategy, it may be possible to "rehabilitate" Tranilast and unlock its therapeutic potential for new patient populations, despite the formidable obstacles created by its complex developmental past.

Conclusions

Tranilast (DB07615) is a multifaceted pharmacological agent whose scientific and clinical identity has evolved significantly since its initial development as an anti-allergic drug. This comprehensive analysis reveals a molecule with a pleiotropic mechanism of action, a complex safety profile tied to its pharmacokinetics, and a divided regulatory status that reflects its challenging developmental history.

First, the pharmacological profile of Tranilast is exceptionally broad. Its foundational activity as a mast cell stabilizer is complemented by at least three other distinct and potent mechanisms: potent anti-fibrotic activity via inhibition of the TGF-β pathway, broad anti-inflammatory effects through direct and specific blockade of the NLRP3 inflammasome, and neuromodulatory potential via inhibition of the TRPV2 ion channel. These mechanisms are not isolated but form an interconnected network, explaining its efficacy across a wide spectrum of pathologies, from allergic rhinitis and keloids to its investigational potential in cancer, systemic fibrosis, and autoinflammatory diseases like gout. This positions Tranilast as a powerful immunomodulatory and tissue-normalizing agent.

Second, the clinical pharmacokinetics and metabolism of Tranilast are central to understanding its safety and tolerability. As a BCS Class II drug, its oral absorption is limited by its poor aqueous solubility, leading to high pharmacokinetic variability. More critically, its primary reliance on the polymorphic enzyme UGT1A1 for metabolic clearance is a key liability. The higher prevalence of poor metabolizer genotypes (e.g., UGT1A1*28) in Western populations provides a compelling pharmacogenetic explanation for the severe hepatotoxicity and other adverse events observed in the PRESTO trial, a safety profile that was not apparent from decades of use in Asia. This highlights that Tranilast's safety is not uniform across populations and that risk is strongly linked to genetic factors governing its metabolism.

Third, the regulatory and developmental history of Tranilast serves as a crucial case study in global drug development. Its established use in several Asian countries stands in stark contrast to its unapproved status in the United States and Europe. The failure of the PRESTO trial on both efficacy and safety grounds created a significant "toxic data" legacy that has largely precluded its development for major indications in the West. While orphan drug designations have been granted, overcoming this regulatory barrier remains a formidable challenge.

In synthesis, Tranilast is a drug of considerable therapeutic promise but significant developmental risk. Its future does not lie in broad, systemic applications but rather in a highly strategic and nuanced approach. The most viable path forward involves drug repositioning for niche indications with high unmet need, where its unique mechanisms offer a clear advantage. Success is contingent upon the development of innovative, localized drug delivery systems to minimize systemic exposure and the mandatory implementation of pharmacogenetic screening to personalize therapy and mitigate the clear, genetically-driven risk of toxicity. By embracing these risk management strategies, the unique therapeutic potential of this complex molecule may yet be realized for new patient populations.

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