A Comprehensive Monograph on Camostat (DB13729): Pharmacology, Clinical Development, and Therapeutic Profile

Executive Summary

Camostat is a synthetic, orally bioavailable small-molecule drug classified as a broad-spectrum serine protease inhibitor. Developed by Ono Pharmaceutical, it was first approved in Japan in 1985 under the trade name Foipan® for the treatment of acute symptoms of chronic pancreatitis and later, in 1994, for postoperative reflux esophagitis.[1] For over three decades, it has been a standard therapy for these conditions in Japan and South Korea, where it is valued for its ability to modulate enzymatic activity and inflammation in the gastrointestinal tract.[4]

The drug garnered significant global attention during the COVID-19 pandemic due to its potent in vitro inhibition of Transmembrane Protease, Serine 2 (TMPRSS2), a host cell enzyme essential for the entry of SARS-CoV-2 and other respiratory viruses into human cells.[4] This strong preclinical rationale spurred an extensive global program of clinical trials aimed at repurposing Camostat as an antiviral agent. However, despite this promise, numerous Phase II and Phase III randomized controlled trials consistently failed to demonstrate a significant clinical or virologic benefit in patients with COVID-19.[9] This disconnect between potent

in vitro activity and clinical failure is largely attributable to the drug's challenging pharmacokinetic profile. Camostat is a prodrug that is rapidly and extensively metabolized to its active form, GBPA (FOY-251), which itself has a very short biological half-life of approximately one hour. This results in low oral bioavailability and an inability to maintain plasma concentrations above the required therapeutic threshold for a sustained period, a critical limitation for treating an acute, high-burden viral infection.[12]

Despite the discontinuation of its development for COVID-19, Camostat remains a molecule of significant interest. Its well-established safety profile, coupled with its anti-inflammatory and antifibrotic properties, has led to a strategic pivot in its clinical investigation towards chronic diseases. Notably, it is currently being evaluated in a Phase 2 trial for its potential kidney-protective effects in Chronic Kidney Disease (CKD).[15] Furthermore, its long-standing use for chronic pancreatitis has been recognized with recent orphan drug designations from the U.S. Food and Drug Administration (FDA) in 2011 and the European Medicines Agency (EMA) in 2025, signaling renewed interest in its development for this indication in Western markets.[17] Camostat thus represents a multifaceted therapeutic agent whose journey from a niche gastrointestinal drug to a global antiviral candidate, and now to a potential therapy for chronic inflammatory and fibrotic conditions, provides a compelling case study in drug development and repurposing.

Drug Identity and Physicochemical Characteristics

A precise understanding of the chemical and physical properties of Camostat is fundamental to interpreting its pharmacological activity, formulating it for clinical use, and ensuring the reproducibility of research. The compound is most commonly utilized and studied in its mesylate salt form, which enhances its stability and solubility.

Nomenclature and Identifiers

Camostat is known by a variety of names and unique identifiers across different chemical, regulatory, and drug databases. Establishing this comprehensive list is essential for accurate cross-referencing of literature and data. The primary distinction is between the active compound, Camostat (free base), and its clinically administered form, Camostat mesylate.

• Primary Name: Camostat [1]
• DrugBank ID: DB13729 [User Query]
• Type: Small Molecule [User Query]
• Synonyms: FOY-305, FOY 305, FOY305 [1]
• Trade Names: The original and most common trade name is Foipan® (Ono Pharmaceutical).[1] Other brand names used in Japan and South Korea include Foypan, Archiment, Camoent, Camostat Mesilate, Camostate, Camoston, Camotat, Carmozacine, Foipan Ilsung, Kamostaal, Leanac, Leseplon, Libilister, Mecilpan, Mospan, Pancrel, and Raintat.[7]
• CAS Numbers: A critical distinction exists between the two primary forms of the compound:
• 59721-28-7 for Camostat (free base) [20]
• 59721-29-8 for Camostat mesylate [20]
• Other Database Identifiers:
• PubChem CID: 2536 [1]
• ChemSpider ID: 2440 [1]
• KEGG ID: D07606 [1]
• ChEBI ID: CHEBI:135632 (for Camostat), CHEBI:31347 (for Camostat mesylate) [1]
• UNII: 0FD207WKDU [1]
• IUPHAR/BPS: 6432 [1]

Chemical and Physical Properties

Camostat is a benzoate ester, formally described as the product of the condensation of the carboxyl group of 4-guanidinobenzoic acid with the hydroxyl group of 2-(dimethylamino)-2-oxoethyl (4-hydroxyphenyl)acetate.[4] Its structure contains a guanidinium head group, a central aromatic ester core, and a C-terminal amide tail, features that are critical for its interaction with the active sites of serine proteases. The mesylate salt is prepared from equimolar amounts of Camostat and methanesulfonic acid.[25]

• Chemical Formula: C20​H22​N4​O5​ (free base) [1]; C20​H22​N4​O5​⋅CH4​O3​S (mesylate salt).[25]
• Molecular Weight:
• Free Base: 398.42 g/mol (Average mass: 398.419).[20]
• Mesylate Salt: 494.52 g/mol.[23]
• IUPAC Nomenclature: Multiple systematic names are used, reflecting the complexity of the molecule. The most common include:
• N,N-Dimethylcarbamoylmethyl 4-(4-guanidinobenzoyloxy)phenylacetate.[1]
• 4-(2-(2-(dimethylamino)-2-oxoethoxy)-2-oxoethyl)phenyl 4-guanidinobenzoate.[20]
• For the mesylate salt: 4-{2-[2-(dimethylamino)-2-oxoethoxy]-2-oxoethyl}phenyl 4-carbamimidamidobenzoate methanesulfonate.[25]
• Structural Identifiers:
• InChI Key: XASIMHXSUQUHLV-UHFFFAOYSA-N (free base).[20]
• SMILES Code: O=C(OC1=CC=C(CC(OCC(N(C)C)=O)=O)C=C1)C2=CC=C(NC(N)=N)C=C2 (free base).[20]
• Solubility and Storage:
• The mesylate salt is soluble in water (up to 100 mM) and DMSO (up to 100 mM).[26]
• For long-term stability, the compound should be stored in a dry, dark environment at -20°C (for months to years). For short-term storage, 0-4°C is sufficient.[20]
• It is stable enough to be shipped as a non-hazardous chemical at ambient temperature for several weeks.[20]

The following table provides a consolidated summary of the key physicochemical properties of Camostat and its mesylate salt. This distinction is vital, as the molecular weight difference impacts molar calculations in experimental settings, and the mesylate salt is the form predominantly used in clinical and research applications due to its superior pharmaceutical properties.

Property	Value (Free Base)	Value (Mesylate Salt)	Source(s)
DrugBank ID	DB13729	DB13729	[User Query]
CAS Number	59721-28-7	59721-29-8	20
Chemical Formula	C20​H22​N4​O5​	C20​H22​N4​O5​⋅CH3​SO3​H	20
Molecular Weight (g/mol)	398.42	494.52	20
IUPAC Name	N,N-Dimethylcarbamoylmethyl 4-(4-guanidinobenzoyloxy)phenylacetate	4-{2-[2-(dimethylamino)-2-oxoethoxy]-2-oxoethyl}phenyl 4-carbamimidamidobenzoate methanesulfonate	1
InChI Key	XASIMHXSUQUHLV-UHFFFAOYSA-N	FSEKIHNIDBATFG-UHFFFAOYSA-N	20
SMILES	O=C(OC1=CC=C(CC(OCC(N(C)C)=O)=O)C=C1)C2=CC=C(NC(N)=N)C=C2	CS(O)(=O)=O.CN(C)C(=O)COC(=O)CC1=CC=C(OC(=O)C2=CC=C(NC(N)=N)C=C2)C=C1	20
Solubility	Not specified	Soluble in Water (100 mM), DMSO (100 mM)	26

Pharmacology and Mechanism of Action

Camostat exerts its therapeutic effects through the broad-spectrum inhibition of serine proteases, a diverse family of enzymes involved in numerous physiological and pathological processes, including digestion, blood coagulation, inflammation, and viral pathogenesis. Its mechanism of action, while rooted in this common principle, is tailored to the specific enzymatic targets relevant to each clinical indication.

Pharmacological Classification

Camostat is classified as a synthetic, orally active, small-molecule serine protease inhibitor.[4] Its official classifications provide further insight into its recognized therapeutic roles:

• MeSH (Medical Subject Headings) Classification: It falls under the categories of "Protease Inhibitors" and, more specifically, "Trypsin Inhibitors," highlighting its potent effect on this key digestive and inflammatory enzyme.[4]
• ATC (Anatomical Therapeutic Chemical) Code: Camostat is assigned the code B02AB04. This places it within the class of "Proteinase inhibitors" (B02AB) under the broader therapeutic groups of "Antifibrinolytics" (B02A) and "Antihemorrhagics" (B02).[4] This classification underscores its activity on enzymes of the coagulation and fibrinolysis systems, such as plasmin and thrombin, and is relevant to its potential for drug interactions with other hemostatic agents.

Molecular Targets and Pharmacodynamics

Camostat functions as an irreversible or "suicide" inhibitor. Its guanidinium-based structure allows it to dock non-covalently within the active site of target proteases, positioning its central ester group for nucleophilic attack by the catalytic serine residue (e.g., Ser441 in TMPRSS2).[27] This results in the formation of a stable, long-lived covalent acyl-enzyme complex, which effectively deactivates the enzyme.[27]

The drug exhibits potent, often nanomolar-range, inhibitory activity against a wide array of trypsin-like serine proteases. Its key molecular targets include:

• Trypsin: A primary target, with a reported inhibitor constant (Ki​) of 1.0 nM.[29] This potent inhibition is central to its therapeutic effect in pancreatitis.
• Transmembrane Protease, Serine 2 (TMPRSS2): A critical host cell factor for viral entry. Camostat inhibits TMPRSS2 with a half-maximal inhibitory concentration (IC50​) of 6.2 nM.[31]
• Matriptase (ST14): A membrane-anchored serine protease involved in epithelial barrier function and tumorigenesis, inhibited with a Ki​ of 4.0 nM.[29]
• Plasma Kallikrein: An enzyme involved in inflammation and blood pressure regulation, which is effectively inhibited by Camostat.[23]
• Thrombin and Plasmin: Key enzymes in the coagulation and fibrinolytic cascades, respectively, are also inhibited.[4]
• Prostasin: A protease involved in regulating epithelial sodium transport, inhibited with a Ki​ of 0.576 µM.[29]
• Epithelial Sodium Channel (ENaC): Indirectly inhibited through the inhibition of channel-activating proteases like prostasin, with a reported IC50​ of 50.0 nM.[29]
• Cholecystokinin (CCK): Animal studies suggest Camostat administration leads to increased CCK release, which in turn may mediate some of its effects on pancreatic secretion.[4]

Therapeutic Mechanisms by Indication

Chronic Pancreatitis

The therapeutic benefit of Camostat in chronic pancreatitis stems from a multi-pronged mechanism that addresses both the enzymatic dysregulation and the downstream inflammatory and fibrotic consequences of the disease.

1. Inhibition of Trypsin Autodigestion: The pathogenesis of pancreatitis is often initiated by the premature activation of trypsinogen to trypsin within pancreatic acinar cells. This active trypsin then triggers a cascade of digestive enzyme activation, leading to pancreatic autodigestion, cell death, and inflammation.[4] By potently inhibiting trypsin, Camostat directly interrupts this primary trigger, reducing enzymatic damage and alleviating acute symptoms.[35]
2. Anti-inflammatory Action: The initial enzymatic injury in pancreatitis leads to a robust inflammatory response. Camostat has been shown to suppress the production and release of key pro-inflammatory cytokines, including Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and Tumor Necrosis Factor-α (TNF-α).[4] This dampens the inflammatory cascade, reducing pain and further tissue damage.
3. Antifibrotic Effects: Chronic inflammation leads to pancreatic fibrosis, a process driven by the activation and proliferation of pancreatic stellate cells (PSCs). Preclinical studies have demonstrated that Camostat attenuates pancreatic fibrosis by directly inhibiting the activity of monocytes and PSCs. It reduces the production of Monocyte Chemoattractant Protein-1 (MCP-1), a key signaling molecule that recruits inflammatory cells, and inhibits the proliferation of PSCs, thereby slowing the progression of fibrotic tissue deposition.[36]

Postoperative Reflux Esophagitis

Following certain types of gastric surgery, such as distal gastrectomy, patients can experience reflux of duodenal contents into the esophagus. Unlike typical acid reflux, this "alkaline reflux" contains bile and pancreatic juice, which are highly damaging to the esophageal mucosa.[38] The mechanism of Camostat in this context is direct and localized. By inhibiting the enzymatic activity of trypsin within the refluxed pancreatic fluid, Camostat prevents the proteolytic degradation of the esophageal lining. This reduces mucosal injury and inflammation, leading to significant relief of symptoms such as heartburn, regurgitation, and epigastric pain.[39] Clinical studies have validated this mechanism by showing that oral Camostat administration leads to a significant decrease in trypsin activity measured in esophageal washings, which correlates directly with symptomatic and endoscopic improvement.[39]

Antiviral Activity (Influenza and Coronaviruses)

The antiviral mechanism of Camostat is host-directed, targeting a cellular enzyme that viruses hijack for their own replication cycle. This approach offers the advantage of being less susceptible to viral mutations that can confer resistance to drugs targeting viral proteins.

1. Inhibition of TMPRSS2-Mediated Viral Entry: A diverse range of respiratory viruses, including influenza viruses and multiple coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2), depend on the host cell serine protease TMPRSS2 for entry.[8] These viruses express a surface glycoprotein (hemagglutinin for influenza, spike protein for coronaviruses) that must be proteolytically cleaved or "primed" to expose a fusion peptide. This priming step, mediated by TMPRSS2 on the surface of airway epithelial cells, is essential for the fusion of the viral and host cell membranes.[34]
2. Blocking Membrane Fusion: Camostat potently inhibits TMPRSS2, thereby preventing the cleavage of the viral spike protein. This blockade effectively traps the virus at the cell surface, preventing its entry and the subsequent release of its genetic material into the host cell to initiate replication.[4]
3. Broad-Spectrum Potential and Resistance Mitigation: Research has shown that SARS-CoV-2 can utilize other TMPRSS2-related proteases, such as TMPRSS11D and TMPRSS13, for cellular entry.[8] Importantly, Camostat also inhibits these related proteases. This suggests that the virus may not be able to easily develop resistance by simply switching to an alternative protease for activation, giving Camostat a potentially durable and broad-spectrum antiviral mechanism.[8]

The failure of Camostat in numerous large-scale COVID-19 clinical trials does not invalidate this well-established in vitro mechanism. Instead, it highlights a critical principle in pharmacology: a potent mechanism of action is necessary but not sufficient for clinical efficacy. The evidence strongly suggests that the clinical failure was a consequence of a pharmacodynamic mismatch. The drug's pharmacokinetic properties—specifically its low bioavailability and very short half-life—prevented it from achieving and, more importantly, sustaining concentrations in the respiratory tract that were high enough to effectively inhibit TMPRSS2 and halt the rapid replication of SARS-CoV-2 in infected individuals.[11] This demonstrates that even with a sound, host-directed antiviral mechanism, successful drug repurposing for acute infections is critically dependent on a favorable pharmacokinetic profile or the development of novel formulations to ensure adequate target engagement at the site of infection.

Pharmacokinetics and Metabolism

The clinical utility and limitations of Camostat are profoundly influenced by its pharmacokinetic (PK) profile. As a prodrug with rapid and extensive metabolism, its systemic exposure is dictated by the kinetics of its active metabolite. Understanding this profile is essential for optimizing dosing regimens and for explaining the observed outcomes in clinical trials for various indications.

Overview: A Prodrug with Rapid Metabolism

Camostat mesylate functions as a prodrug. Following oral administration, it is not the parent molecule that exerts the primary systemic therapeutic effect. Instead, it undergoes rapid hydrolysis by ubiquitous carboxylesterases, a process that likely begins during and immediately after absorption from the gastrointestinal tract.[4] This enzymatic cleavage converts Camostat into its principal active metabolite,

4-(4-guanidinobenzoyloxy)phenylacetic acid, which is commonly referred to as GBPA or FOY-251.[13]

This conversion is so efficient that the parent Camostat molecule is often undetectable in plasma samples, making GBPA the primary analyte of interest for pharmacokinetic and pharmacodynamic (PK/PD) modeling.[13] GBPA retains the serine protease inhibitory activity of the parent compound. Subsequently, GBPA is further metabolized via hydrolysis by arylesterases into

4-guanidinobenzoic acid (GBA), which is considered pharmacologically inactive.[4]

Absorption and Bioavailability

• Absorption Rate: Camostat is absorbed rapidly from the gastrointestinal tract. Following a single 200 mg oral dose, its active metabolite GBPA reaches peak plasma concentrations (Tmax​) in approximately 40 minutes, indicating a swift onset of systemic availability.[33] The absorption rate constant ( ka​) has been estimated at 0.67 h−1.[13]
• Bioavailability: A significant challenge for Camostat is its very low oral bioavailability (Fbio​), which has been estimated to be only about 5%.[13] This means that only a small fraction of the orally administered dose reaches systemic circulation as the active metabolite, a key factor limiting its overall exposure and potential efficacy for systemic conditions.
• Food Effect: The absorption of Camostat is markedly influenced by food intake. Clinical studies in healthy adults have demonstrated that administering the drug with a meal or 30 minutes prior to a meal significantly reduces the plasma exposure (both Cmax​ and AUC) of the active metabolite GBPA compared to administration in a fasted state. However, if the drug is administered 1 hour before a meal, the resulting plasma exposure is not significantly different from that achieved under fasted conditions.[12] This finding has direct clinical implications, leading to recommendations for dosing in a fasted state or at least one hour before meals to maximize therapeutic effect, particularly for indications like COVID-19 where high systemic concentrations were sought.

Distribution

• Volume of Distribution (Vd​): Pharmacokinetic modeling indicates that the volume of distribution for the active metabolite GBPA is approximately 22.4 liters.[13] This relatively low value suggests that GBPA distribution is largely confined to the plasma and extracellular fluid compartments, with limited penetration into deep tissues. Another source reports a volume of distribution at steady state for the parent compound as 0.34-1.31 L/kg, consistent with limited distribution.[33]
• Protein Binding: In vitro studies with human serum proteins show that the parent Camostat molecule is modestly bound, with a protein binding percentage of 25.8-28.2%.[33]

Metabolism and Elimination

• Metabolism: The metabolic pathway of Camostat is dominated by esterase-mediated hydrolysis, first to the active GBPA and then to the inactive GBA.[43] Crucially, this metabolism does not involve the cytochrome P450 (CYP) enzyme system.[25] This characteristic is a significant advantage, as it confers a very low potential for pharmacokinetic drug-drug interactions with other medications that are substrates, inhibitors, or inducers of CYP enzymes. This clean interaction profile is a double-edged sword; while it enhances safety, the high efficiency of esterase hydrolysis is also the direct cause of the drug's short half-life and limited exposure.
• Biological Half-Life (T1/2​): The elimination half-life of the active metabolite GBPA is exceptionally short, consistently reported to be between 1.0 and 1.58 hours.[29] The inactive metabolite GBA has a slightly longer half-life of approximately 2 hours.[43] This rapid elimination means that plasma concentrations of the active drug decline quickly, making it difficult to maintain levels above a therapeutic threshold with conventional dosing schedules (e.g., three times daily).
• Route of Elimination: Camostat and its metabolites are primarily eliminated from the body via the kidneys. Studies show that 89.8-95.6% of an administered dose is excreted in the urine, with only a minor fraction (1.0-1.7%) eliminated through feces.[33]
• Clearance: The total clearance of Camostat mesylate is estimated to be 4.5-7.3 mL/min/kg.[33] For the metabolites, the apparent clearance (CL/F) of GBPA and GBA after single oral doses of 100-300 mg ranged from 141.7 to 179.6 L/h and 675.1 to 718.6 L/h, respectively, reflecting rapid elimination.[43]

The following table consolidates key pharmacokinetic parameters for Camostat and its primary metabolites, GBPA and GBA, from various studies.

Parameter	Analyte	Value	Dosing Condition	Source(s)
Bioavailability (Fbio​)	Camostat	~5%	Oral	13
Tmax​ (Peak Time)	GBPA	40 min	200 mg single oral dose	33
Cmax​ (Peak Conc.)	GBPA	72.68 ng/mL	100 mg single oral dose	43
	GBPA	156.8 ng/mL	200 mg single oral dose	43
	GBPA	273.9 ng/mL	300 mg single oral dose	43
AUC (Total Exposure)	GBPA	152.3 h·ng/mL	100 mg single oral dose	43
	GBPA	307.4 h·ng/mL	200 mg single oral dose	43
	GBPA	464.8 h·ng/mL	300 mg single oral dose	43
Half-life (T1/2​)	GBPA	1.01 h	100 mg single oral dose	43
	GBA	1.94 h	100 mg single oral dose	43
	Camostat	3.8-4.7 h	Not specified	4
Volume of Distribution (Vd​)	GBPA	22.4 L	Oral	13
Protein Binding	Camostat	25.8-28.2%	In vitro	33
Clearance (CL/F)	GBPA	141.7 L/h	100 mg single oral dose	43
Route of Elimination	Camostat	89.8-95.6% Urine	Oral	33

Clinical Development and Efficacy

The clinical development of Camostat has followed a unique trajectory, beginning with its establishment as a standard-of-care therapy for specific gastrointestinal disorders in Asia, followed by a period of intense global investigation for antiviral repurposing, and now a pivot towards chronic inflammatory and fibrotic diseases.

Approved Indications in Asia

Camostat has been a licensed medication in Japan and South Korea for several decades, where it is used to manage conditions driven by excessive protease activity.

Chronic Pancreatitis

Camostat mesylate was first approved in Japan in 1985 for the "alleviation of acute symptoms of chronic pancreatitis".[1] It is also used for this indication in South Korea.[7]

• Standard Dosing Regimen: The conventional dosage for this indication is 600 mg per day, typically administered as two 100 mg tablets (200 mg) three times daily.[1]
• Clinical Evidence: Its long-standing use is supported by numerous earlier studies demonstrating efficacy in improving symptoms and pancreatic function.[35] However, more recent, rigorous clinical evidence from Western trials has been less conclusive. The TACTIC study (NCT02693093), a large Phase 2, randomized, placebo-controlled trial conducted in the United States, evaluated the efficacy of Camostat (100, 200, and 300 mg three times daily) for treating pain in 264 patients with chronic pancreatitis. The trial failed to meet its primary endpoint, showing no statistically significant difference in pain reduction between any of the Camostat dose groups and the placebo group.[45] This discrepancy between historical use and recent trial data highlights the need for further research to identify specific patient populations or disease phenotypes that may respond to this therapy.

Postoperative Reflux Esophagitis

In 1994, Camostat gained a second approved indication in Japan for the treatment of postoperative reflux esophagitis.[1]

• Standard Dosing Regimen: The recommended dosage for this condition is 300 mg per day, administered as one 100 mg tablet three times a day, typically after each meal to coincide with potential reflux events.[1]
• Clinical Evidence: The efficacy for this indication is supported by prospective, randomized controlled studies. One trial involving 80 patients who had undergone gastrectomy demonstrated that an 8-week course of Camostat (300 mg/day) was significantly more effective (p<0.05) than control medications in alleviating key symptoms such as heartburn, regurgitation, and epigastric soreness.[38] Another study confirmed this clinical benefit and linked it directly to the drug's mechanism of action, showing that treatment with Camostat led to a significant reduction in trypsin activity in esophageal aspirates, which correlated with both symptomatic improvement and better endoscopic findings.[39]

Investigational Repurposing for COVID-19: A Case of Unfulfilled Promise

The discovery that SARS-CoV-2 requires the host protease TMPRSS2 for cellular entry positioned Camostat as a prime candidate for drug repurposing. This led to a massive global research effort, including numerous clinical trials.

• Phase 1 Foundational Studies: To support the use of higher doses needed for a potent antiviral effect, Phase 1 studies were conducted in healthy adults. These trials evaluated high-dose regimens, such as 600 mg four times daily (2400 mg/day), and confirmed that even at these elevated doses, Camostat was safe and well-tolerated. These studies provided the critical safety and pharmacokinetic data necessary to proceed to larger efficacy trials.[12]
• Phase 2 and 3 Efficacy Trials: Despite the strong preclinical rationale and favorable safety profile, the clinical efficacy trials for COVID-19 were overwhelmingly negative.
• Failure to Meet Primary Endpoints: A consistent finding across multiple large, randomized, placebo-controlled trials was that Camostat did not provide a significant benefit over placebo for key primary endpoints. These included time to viral clearance (negative PCR test), time to clinical improvement or symptom resolution, and rates of hospitalization or death.[2] This lack of efficacy was observed in both outpatient and hospitalized settings and across different trial platforms, such as the ACTIV-2 trial in the U.S. and the ACOVACT trial in Austria.[1] Ono Pharmaceutical's own Phase 3 trial in Japan also failed to meet its primary endpoint, leading the company to formally discontinue its development for COVID-19.[2]
• Inconsistent Secondary Endpoint Signals: While the primary outcomes were negative, one Phase 2 outpatient trial (NCT04353284) did report a statistically significant benefit on a secondary endpoint: patients receiving Camostat experienced a more rapid resolution of specific symptoms, notably the loss of taste and smell, and fatigue.[51] However, this isolated finding was not sufficient to demonstrate overall clinical utility and was not consistently replicated in other studies.
• Confirmatory Meta-Analyses: The collective evidence was synthesized in several systematic reviews and meta-analyses. One analysis of nine RCTs involving 1,623 patients concluded that Camostat did not improve clinical outcomes compared to placebo.[11] A subsequent individual participant data meta-analysis, which included unpublished data from stalled trials, reinforced this conclusion, finding no virologic or clinical advantage for Camostat in treating COVID-19.[55]

Emerging and Ongoing Investigations: A Pivot to Chronic Disease

With the conclusion of the COVID-19 research program, the focus of Camostat's clinical development has shifted to chronic conditions where its anti-inflammatory and antifibrotic properties, rather than its acute antiviral effects, may be therapeutically relevant.

• Chronic Kidney Disease (CKD): A Phase 2 clinical trial (NCT06794593) is currently recruiting patients to evaluate the "Effect of Camostat for Kidney Protection in Chronic Kidney Disease".[15] The rationale for this investigation is supported by preclinical evidence showing that Camostat can reduce blood pressure and renal injury in animal models of hypertension, potentially through its inhibition of the protease prostasin, which is involved in regulating sodium channels in the kidney.[26]
• Protein-Losing Enteropathies (PLE): A Phase 2 trial (NCT05474664) investigating the use of Camostat mesylate for protein-losing enteropathy in patients who have undergone the Fontan operation has been completed.[58] PLE is a severe complication characterized by the loss of protein from the gut, and this study explored whether Camostat's anti-inflammatory effects could mitigate this condition.[59]
• Influenza: While no major clinical trials are currently active, a strong preclinical foundation exists for its potential use against influenza viruses. In vitro studies using primary human tracheal epithelial cells have shown that Camostat effectively inhibits the replication of both H1N1 and H3N2 influenza strains and reduces the associated production of inflammatory cytokines. The mechanism is identical to its action against coronaviruses: the inhibition of TMPRSS2-dependent cleavage of the viral hemagglutinin protein, which is required for viral entry.[31]

The following table summarizes the key clinical trials that have defined the development trajectory of Camostat across its various indications.

Indication	Trial ID (NCT)	Phase	Status	N (Patients)	Dosing Regimen	Primary Endpoint(s)	Key Outcome Summary	Source(s)
COVID-19 (Outpatient)	NCT04353284	2	Completed	70	200 mg QID	Reduction in nasopharyngeal viral load	Failed primary endpoint; showed faster resolution of some symptoms (loss of taste/smell)	51
COVID-19 (Outpatient)	NCT04518410 (ACTIV-2)	2	Terminated	216	Not Specified	Time to symptom improvement; viral clearance	No difference in symptom improvement, viral clearance, or hospitalization vs. placebo	1
COVID-19 (Hospitalized)	NCT04521296	2	Completed	342	Not Specified	Time to clinical improvement	No significant difference in time to clinical improvement vs. placebo (7 vs. 8 days)	9
COVID-19 (Hospitalized)	NCT04657497	3	Completed	155	600 mg QID	Time to viral clearance	No significant difference in time to viral clearance vs. placebo (median 11 days for both)	2
Chronic Pancreatitis (Pain)	NCT02693093 (TACTIC)	2	Completed	264	100, 200, or 300 mg TID	Change in daily worst pain score	No significant difference in pain improvement vs. placebo at any dose	46
Postoperative Reflux Esophagitis	N/A	Post-marketing	Approved	80	300 mg/day	Symptom relief (heartburn, regurgitation)	Significantly greater symptom relief compared to control group (p<0.05)	38
Chronic Kidney Disease	NCT06794593	2	Recruiting	Est. 60	Not Specified	Change in urine albumin-to-creatinine ratio (UACR)	Ongoing	15
Protein-Losing Enteropathy	NCT05474664	2	Completed	15	100 mg BID/TID	Change in serum albumin and stool alpha-1 antitrypsin	Showed reductions in gastrointestinal protein losses, particularly in patients with baseline diarrhea	58

Safety, Tolerability, and Risk Profile

The safety profile of Camostat mesylate is well-characterized, drawing from over three decades of post-marketing surveillance in Japan and South Korea, as well as a substantial body of data from recent clinical trials conducted globally. Overall, it is considered a well-tolerated drug with a favorable safety profile.

General Safety Profile

Camostat has been in clinical use since 1985 and is generally regarded as safe.[62] This long history of use provides a robust foundation for its safety assessment. This was further confirmed during the intensive investigation for COVID-19, where numerous Phase 1, 2, and 3 studies evaluated the drug, often at doses significantly higher than those approved for its gastrointestinal indications. For instance, a dose of 600 mg four times daily (2400 mg/day) was found to be safe and well-tolerated in healthy volunteers.[12] Across multiple randomized controlled trials in patients with COVID-19, the incidence of adverse events was consistently similar between the Camostat and placebo groups, with no new or unexpected safety signals emerging.[9]

Adverse Events

The adverse reactions associated with Camostat can be categorized into common, generally mild events and rare but more serious events that warrant clinical vigilance.

• Common Adverse Events: The most frequently reported side effects are primarily related to the gastrointestinal system and skin. These include:
• Nausea [6]
• Diarrhea [7]
• Abdominal discomfort or bloating [5]
• Rash and pruritus (itching) [6]

These events are typically mild to moderate in severity and often do not require discontinuation of the drug.66

• Rare but Serious Adverse Events: The Japanese product information leaflet warns of several rare but potentially severe adverse reactions. Patients should be counseled on the signs of these events and instructed to seek immediate medical attention if they occur [4]:
• Shock and Anaphylactoid Symptoms: These severe allergic reactions can manifest as a sudden drop in blood pressure (hypotension), respiratory distress, cold sweats, and widespread itching.[5]
• Thrombocytopenia: A significant decrease in blood platelet count, which can lead to bleeding complications such as epistaxis (nose bleeding), gum bleeding, or subcutaneous bleeding (bruising) in the limbs.[6]
• Hepatic Dysfunction and Jaundice: Liver injury indicated by symptoms like general malaise, loss of appetite, and yellowing of the skin and sclera (whites of the eyes).[6]
• Hyperkalemia: Abnormally high levels of potassium in the blood, which can cause serious cardiac issues. Initial symptoms may include numbness of the lips or limbs, muscle weakness, or paralysis.[6]

Contraindications and Precautions

While Camostat is widely applicable, there are specific situations where its use is either contraindicated or requires careful consideration.

• Contraindications: The only absolute contraindication is a known history of hypersensitivity or allergic reaction to Camostat mesylate or any of its excipients.[6]
• Precautions and Warnings: Caution should be exercised when prescribing Camostat to the following patient populations:
• Patients with Severe Hepatic or Renal Disease: As these conditions may exacerbate the drug's adverse effects, careful monitoring is advised.[7]
• Pregnant and Breastfeeding Women: The safety of Camostat in these populations has not been definitively established. Therefore, it should only be used if the potential therapeutic benefit to the mother is judged to outweigh the potential risks to the fetus or infant, and under strict medical supervision.[6]

Drug-Drug Interactions

The risk profile for drug-drug interactions with Camostat is primarily pharmacodynamic in nature, with a low risk of pharmacokinetic interactions.

• Pharmacokinetic (PK) Interactions: The potential for Camostat to alter the metabolism of other drugs is low. This is because it is metabolized by esterases rather than the cytochrome P450 (CYP) enzyme system. In vitro studies have confirmed that neither Camostat nor its active metabolite GBPA significantly inhibits major CYP enzymes (including CYP1A2, 2C9, 2C19, 2D6, and 3A4) or key drug efflux transporters like P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP).[25] This clean PK profile makes it an attractive option for patients on complex medication regimens.
• Pharmacodynamic (PD) Interactions: The interactions of clinical concern stem from Camostat's intrinsic activity as a protease inhibitor affecting the coagulation and fibrinolytic systems.
• Increased Thrombogenic Risk: Due to its antifibrinolytic properties, Camostat may have an additive effect with other drugs that promote clotting. Co-administration with anticoagulants (e.g., warfarin), other antifibrinolytic agents (e.g., aminocaproic acid, aprotinin), or various coagulation factor concentrates (e.g., Factor IX, Factor XIII, Anti-inhibitor coagulant complex) may increase the risk of thrombotic events.[7]
• Decreased Efficacy of Thrombolytics: Conversely, the therapeutic efficacy of thrombolytic (clot-busting) drugs, such as Alteplase, Reteplase, Streptokinase, and Urokinase, can be diminished when used concurrently with Camostat, as Camostat's antifibrinolytic action opposes their mechanism.[33]

The following table summarizes the most clinically relevant drug-drug interactions for Camostat.

Interacting Drug/Class	Potential Effect	Mechanism	Clinical Recommendation	Source(s)
Anticoagulants (e.g., Warfarin)	Enhanced anticoagulant effect; increased risk of bleeding	Pharmacodynamic (PD)	Monitor coagulation parameters closely. Caution is advised.	7
Antifibrinolytics (e.g., Aprotinin, Aminocaproic acid)	Increased thrombogenic activities; additive pro-thrombotic risk	Pharmacodynamic (PD)	Co-administration should be approached with caution due to the potential for an increased risk of thrombosis.	33
Coagulation Factors (e.g., Factor IX, Factor XIII)	Increased thrombogenic activities; additive pro-thrombotic risk	Pharmacodynamic (PD)	Use with caution and monitor for signs of thrombosis.	33
Thrombolytic Agents (e.g., Alteplase, Urokinase)	Decreased therapeutic efficacy of the thrombolytic agent	Pharmacodynamic (PD)	The antifibrinolytic action of Camostat may counteract the effect of thrombolytics. Concurrent use may not be advisable.	33

Regulatory Landscape and Development History

The journey of Camostat from its inception to its current status is a story of regional success, followed by a surge of global interest and, ultimately, a strategic re-evaluation of its therapeutic potential. Its regulatory and development history reflects these distinct phases.

Development History

• Originator and Initial Development: Camostat mesilate was created and developed by Ono Pharmaceutical Co., Ltd., a Japanese pharmaceutical company with a history spanning over 300 years.[1] The compound, initially known as FOY-305, was first described in the scientific literature in 1981 as part of research into synthetic serine protease inhibitors.[4]
• Timeline of Key Milestones:
• 1985: Camostat mesilate received its first manufacturing and marketing approval in Japan under the trade name Foipan®. The initial indication was for the "alleviation of acute symptoms associated with chronic pancreatitis".[1]
• 1994: The approved indications in Japan were expanded to include the "treatment of postoperative reflux esophagitis," solidifying its role as a specialized gastrointestinal medication.[2]
• 1996: The substance patent for Camostat expired, opening the door for generic manufacturing.[2]
• 2011: A first step towards Western markets was taken when Camostat received an Orphan Drug Designation from the U.S. FDA for the treatment of chronic pancreatitis.[17]
• 2020: With the onset of the COVID-19 pandemic, Camostat was identified as a high-priority candidate for drug repurposing due to its potent inhibition of TMPRSS2. This triggered a global wave of preclinical and clinical research, including numerous Phase 2 and 3 trials.[4]
• 2021: Following the failure of its pivotal Phase 3 clinical trial to meet its primary endpoint, Ono Pharmaceutical announced the discontinuation of its development program for Camostat in the treatment of COVID-19.[2]
• 2025: In a significant strategic revival, Camostat mesilate was granted an Orphan Drug Designation by the European Medicines Agency for the treatment of chronic pancreatitis, indicating renewed interest in its original indication for European markets.[18]

Global Regulatory Status

The regulatory approval of Camostat is geographically limited, reflecting its development history and the mixed results from recent clinical trials.

• Approved Markets:
• Japan: Approved since 1985 for chronic pancreatitis and since 1994 for postoperative reflux esophagitis.[1]
• South Korea: Also approved for use in treating chronic pancreatitis and reflux esophagitis.[7]
• United States (Food and Drug Administration - FDA):
• Approval Status: Camostat is not approved by the FDA for any indication and is not marketed in the United States.[1]
• Orphan Drug Designation: On May 18, 2011, the FDA granted Orphan Drug Designation to Camostat for the "Treatment of chronic pancreatitis." The sponsor was listed as NIXS Corporation / Nichi-Iko Pharmaceutical Co., Ltd..[17] This designation provides development incentives, such as tax credits and market exclusivity, but it is not a marketing approval. The status remains "Designated" but "Not FDA Approved for Orphan Indication".[17]
• Europe (European Medicines Agency - EMA):
• Approval Status: Camostat is not approved for marketing in the European Union.
• Orphan Designation: On January 16, 2025, the European Commission, following a favorable opinion from the EMA's Committee for Orphan Medicinal Products, granted an orphan designation to "Camostat mesilate" for the "Treatment of chronic pancreatitis".[18] The designation number is EU/3/24/3021, and the sponsor is Pangenix Pharma Limited.[19]

The timeline of these orphan designations reveals a compelling strategic narrative. The initial FDA designation in 2011 by Nichi-Iko suggests an early, though perhaps ultimately unsuccessful, effort to introduce the drug to the US market for its established indication. The intense global focus on Camostat during the COVID-19 pandemic did not lead to an antiviral approval but generated a significant amount of modern clinical data. The very recent EMA designation in 2025 by a new sponsor, Pangenix Pharma, signals a strategic revival for the drug in the West. This new effort suggests a belief that a viable regulatory and commercial pathway exists for Camostat in Europe for chronic pancreatitis, potentially leveraging a different clinical strategy or focusing on a specific patient sub-population not captured in previous trials like the TACTIC study. This marks a significant new chapter in the long life-cycle of this molecule.

Comparative Analysis: Camostat vs. Nafamostat

Camostat and Nafamostat are both synthetic, guanidinium-based serine protease inhibitors that were developed in Japan and are approved for similar indications, such as pancreatitis.[73] During the COVID-19 pandemic, both were identified as leading candidates for repurposing due to their shared mechanism of inhibiting the host cell protease TMPRSS2.[75] However, despite their structural similarities, they exhibit critical differences in potency, pharmacokinetics, and routes of administration that have profound implications for their clinical utility.

Potency and Efficacy

• In Vitro Potency: A consistent finding across multiple independent in vitro studies is that Nafamostat is significantly more potent than Camostat at inhibiting TMPRSS2-mediated viral entry. Reports indicate that Nafamostat is approximately 10- to 15-fold more potent, with a half-maximal effective concentration (EC50​) in the low-nanomolar range, compared to the mid-nanomolar range for Camostat.[73] For example, one study reported that 1-10 nM of Nafamostat could significantly inhibit SARS-CoV-2 infection, a concentration range far lower than that required for Camostat.[75]
• Molecular Binding Mechanism: This difference in potency is rooted in their molecular interactions with the TMPRSS2 active site. Molecular dynamics simulations and modeling studies have revealed that while both drugs bind to the catalytic center, Nafamostat demonstrates a higher population of the pre-covalent Michaelis complex and greater specificity for the target.[75] This suggests that Nafamostat binds more readily and efficiently, allowing it to form the stable covalent bond that inactivates the enzyme more effectively than Camostat.[78]
• Preclinical Efficacy: The superior potency of Nafamostat has translated to better outcomes in preclinical models. In a Syrian golden hamster model designed to test chemoprophylaxis against airborne SARS-CoV-2 transmission, intranasally administered Nafamostat successfully prevented infection in exposed animals. In stark contrast, intranasally administered Camostat at the same dose failed to prevent infection.[74]

Pharmacokinetics and Administration

• Route of Administration: This is the most significant practical difference between the two drugs. Camostat is orally bioavailable, which makes it suitable for outpatient treatment and long-term administration.[74] Nafamostat is limited to intravenous (IV) infusion, restricting its use to hospitalized or clinical settings where IV access is available.[73] This difference heavily influenced their respective investigation strategies during the COVID-19 pandemic, with Camostat being trialed primarily in outpatients and Nafamostat in hospitalized patients.
• Biological Half-Life: Both drugs suffer from the major clinical drawback of having extremely short plasma half-lives.[74] This necessitates frequent dosing (for Camostat) or continuous infusion (for Nafamostat) to maintain therapeutic concentrations, which complicates their clinical use, particularly for acute infections.

Clinical Trial Evidence

The clinical trial evidence for both drugs in the context of COVID-19 has been largely inconclusive. A systematic review and meta-analysis that included randomized controlled trials for both agents found that the available evidence was insufficient to determine whether either drug provided a mortality benefit or was definitively safe for the treatment of adults with COVID-19. The analysis was limited by small patient numbers, low event rates, and high heterogeneity between studies.[10] Ultimately, neither drug demonstrated the robust clinical benefit required to become a standard of care for COVID-19.

The comparison between Camostat and Nafamostat presents a classic dilemma in drug development: the trade-off between the convenience of an oral formulation and the superior potency of an intravenous drug. Camostat's oral availability made it a more attractive candidate for widespread outpatient use against COVID-19, but its lower potency and challenging pharmacokinetic profile likely contributed to its clinical failure. Nafamostat, while significantly more potent in vitro and effective in preclinical models, was constrained by its IV-only administration, limiting its potential application to a smaller, more severely ill patient population. This head-to-head analysis suggests that neither compound represented an optimal therapeutic solution. The ideal next-generation TMPRSS2 inhibitor would need to combine the oral bioavailability of Camostat with the enhanced potency and target specificity of Nafamostat, providing a clear strategic direction for future drug design in this class.

Synthesis and Future Outlook

Camostat mesylate is a molecule with a rich and complex history, embodying both the successes and failures of pharmaceutical development and repurposing. Its profile is one of stark contrasts: a long-standing, approved therapy in Asia for specific gastrointestinal conditions, yet a clinical disappointment in its highly anticipated role as a global antiviral. A comprehensive synthesis of the available evidence reveals a drug whose therapeutic potential is fundamentally governed by the interplay between its broad enzymatic inhibition and its challenging pharmacokinetic properties.

Synthesis of Findings: A Multifaceted Profile

The core identity of Camostat is that of a broad-spectrum serine protease inhibitor. This single pharmacological principle underpins its diverse therapeutic mechanisms. In chronic pancreatitis and postoperative reflux esophagitis, its efficacy is derived from the localized inhibition of digestive proteases like trypsin, which in turn mitigates tissue damage, inflammation, and pain. Its decades of safe and effective use for these indications in Japan and South Korea are a testament to the validity of this targeted, regional approach.

The scientific rationale for repurposing Camostat against SARS-CoV-2 was exceptionally strong. Its potent, nanomolar-level inhibition of the host protease TMPRSS2—an enzyme critical for viral entry—offered a compelling, host-directed antiviral strategy that would be resilient to viral mutations. However, the extensive global clinical trial program for COVID-19 failed to translate this in vitro promise into real-world clinical benefit. The primary reason for this failure lies not in a flawed mechanism but in a fundamental PK/PD mismatch. The drug's low oral bioavailability and extremely short half-life make it exceedingly difficult to maintain systemic concentrations high enough to effectively suppress a rapidly replicating respiratory virus at its primary site of infection. While the COVID-19 trials were ultimately negative, they were not without value; they generated a vast repository of modern, high-quality safety and pharmacokinetic data on Camostat, particularly at high doses, which will be invaluable for guiding its future development.

Future Directions and Unanswered Questions

The future of Camostat is unlikely to be in the treatment of acute viral infections. Instead, its development is pivoting towards chronic conditions where its well-documented anti-inflammatory and antifibrotic properties can be leveraged more effectively over time, and where its pharmacokinetic limitations are less of a barrier.

• A New Focus on Chronic Inflammatory and Fibrotic Diseases: The most promising new frontier for Camostat is in chronic diseases. The ongoing Phase 2 trial in Chronic Kidney Disease (CKD) represents the leading edge of this strategic shift.[15] The preclinical data suggesting it can reduce renal injury and fibrosis provide a solid foundation for this investigation.[26] Success in this area would open up a massive new market and address a significant unmet medical need. Similarly, its investigation in rare conditions like Protein-Losing Enteropathy demonstrates its potential as a targeted anti-inflammatory agent for complex gastrointestinal disorders.[58]
• Revisiting Chronic Pancreatitis in Western Markets: The conflicting evidence for its use in chronic pancreatitis—decades of successful use in Asia versus the negative outcome of the recent US-based TACTIC trial—presents a critical unanswered question.[46] It is possible that the drug is effective only for acute exacerbations rather than chronic pain, or that specific patient subgroups (defined by genetics, etiology, or disease stage) are more likely to respond. The recent orphan drug designation granted by the EMA in 2025 suggests that a new sponsor believes this question is worth answering and that a viable path to approval in Europe exists.[19] Future clinical trials will need to be designed with greater precision to identify a responsive population.
• A Scaffold for Next-Generation Inhibitors: Perhaps the most enduring legacy of Camostat will be its role as a chemical scaffold for the development of new and improved serine protease inhibitors. The lessons learned from its clinical journey are clear: a successful therapeutic in this class will need to retain its broad anti-protease activity while incorporating chemical modifications that dramatically improve its pharmacokinetic profile, particularly its oral bioavailability and biological half-life. The structural and mechanistic insights gained from comparing Camostat to Nafamostat provide a clear roadmap for designing next-generation molecules that combine the oral convenience of the former with the superior potency of the latter.[27]

In conclusion, Camostat mesylate is a molecule that has transitioned from a regionally successful drug to a global object of scientific inquiry and back again. While its time as a prospective COVID-19 therapy has passed, its story is far from over. Its future lies in the careful and strategic application of its anti-inflammatory and antifibrotic effects to chronic diseases and in serving as a foundational blueprint for the creation of more effective medicines to come.

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