Eniluracil (DB03516): A Comprehensive Monograph on a Dihydropyrimidine Dehydrogenase Inactivator—From Clinical Failure to Renewed Therapeutic Promise

Executive Summary

Eniluracil is a small molecule, uracil analogue developed as a potent, mechanism-based, and irreversible inhibitor of the enzyme dihydropyrimidine dehydrogenase (DPD).[1] Its sole therapeutic purpose is to be co-administered with fluoropyrimidine chemotherapies, most notably 5-fluorouracil (5-FU), to fundamentally alter their pharmacokinetics and enhance their therapeutic index.[3] DPD is the rate-limiting enzyme responsible for the rapid catabolism of over 80% of an administered 5-FU dose, which results in a short plasma half-life and erratic oral bioavailability.[3] Eniluracil's complete and prolonged inactivation of DPD promised to transform 5-FU into a reliable, orally administered agent with predictable, linear pharmacology, effectively mimicking the therapeutic exposure of a continuous intravenous infusion.[3]

The initial clinical development of Eniluracil showed considerable promise, with Phase I and II studies confirming its profound pharmacological effects and demonstrating antitumor activity in various solid malignancies.[7] However, this trajectory was abruptly halted by the failure of two large-scale, pivotal Phase III trials in metastatic colorectal cancer. In these studies, the oral Eniluracil/5-FU combination regimen proved to be statistically inferior to the standard-of-care intravenous 5-FU/leucovorin, failing to meet its primary endpoint of equivalent overall survival and showing a shorter progression-free survival.[9]

Subsequent investigation revealed a critical flaw not in the drug's primary mechanism but in the clinical trial's design. The leading hypothesis, supported by preclinical and mechanistic studies, posits that the high 10:1 dose ratio of Eniluracil to 5-FU used in the trials led to an off-target competitive inhibition of 5-FU's essential anabolic activation enzymes.[7] This effectively attenuated the anticancer drug's efficacy. This crucial understanding has fueled a strategic revival of Eniluracil, now under development by Processa Pharmaceuticals as PCS6422. The new clinical strategy employs a rationally designed dosing schedule that temporally separates the administration of Eniluracil and a fluoropyrimidine prodrug, capecitabine, to allow for complete DPD inactivation without metabolic interference.[12]

Currently, Eniluracil remains an unapproved, investigational drug in active clinical trials for advanced gastrointestinal and breast cancers.[12] It represents a compound of profound pharmacological potential whose ultimate clinical utility is being re-evaluated under a revised, mechanism-informed development strategy that seeks to finally harness its benefits while avoiding the pitfalls of its past.

Drug Profile and Physicochemical Properties

A comprehensive understanding of Eniluracil begins with its fundamental chemical and physical characteristics, which are essential for its identification, handling, and formulation in both research and clinical settings.

Comprehensive Identification

Eniluracil is a small molecule drug identified by a consistent set of names and registry numbers across chemical, pharmacological, and clinical databases.[4]

• Primary Name: Eniluracil [1]
• DrugBank ID: DB03516 [User Query]
• CAS Number: 59989-18-3 [2]
• Synonyms and Code Names: The compound is widely known by its chemical name, 5-Ethynyluracil, and its systematic name, 5-Ethynyl-2,4(1H,3H)-pyrimidinedione.[1] During its development, it has been assigned several code names, including 776C85 and GW776C85 by its original developers, Glaxo Wellcome.[1] It is also registered under the National Service Center number NSC 687296.[1] In its current phase of development by Processa Pharmaceuticals, it is referred to as PCS6422.[12]

Chemical and Physical Data

The molecular structure and properties of Eniluracil define its behavior as a uracil analogue and its interactions with biological systems. Key data are summarized in Table 1. The molecular formula is $C_6H_4N_2O_2$, with a molecular weight of approximately 136.11 g/mol.[1] Its structure is characterized by a pyrimidinedione (uracil) ring with an ethynyl group ($C \equiv CH$) at the 5-position. This modification is critical to its mechanism of action.

Table 1: Physicochemical Properties of Eniluracil

Property	Value	Source(s)
Identifiers
DrugBank ID	DB03516	[User Query]
CAS Number	59989-18-3	2
Chemical Formula & Weight
Molecular Formula	$C_6H_4N_2O_2$	1
Molecular Weight	136.11 g/mol	16
Structural Information
SMILES	O=C1NC=C(C(N1)=O)C#C	1
InChIKey	JOZGNYDSEBIJDH-UHFFFAOYSA-N	1
Physical Properties
Melting Point	320 °C (decomposition)	19
Topological Polar Surface Area	58.2 Ų	18
XLogP3	-0.7	18
Solubility
Dimethylformamide (DMF)	10 mg/ml	1
Dimethyl sulfoxide (DMSO)	25 mg/ml	1
DMSO:PBS (pH 7.2) (1:7)	0.12 mg/ml	1
Storage (Powder)
Recommended	-20°C (up to 3 years)	2
Alternate	<-15°C, protect from light	20

Formulation and Storage

Eniluracil is supplied as a solid powder for research and clinical use.[2] Its solubility profile dictates the use of organic solvents for preparing stock solutions. It is soluble in dimethyl sulfoxide (DMSO) at concentrations up to 25 mg/ml and in dimethylformamide (DMF) at 10 mg/ml, but exhibits poor aqueous solubility.[1] For in vivo administration, specific formulation protocols have been developed, often involving a co-solvent system such as DMSO, PEG300, Tween-80, and saline to achieve a clear solution suitable for administration.[2]

Proper storage is critical to maintain the compound's integrity. As a solid, Eniluracil is stable for at least four years when stored appropriately.[1] The recommended storage condition for the powder is at -20°C, which ensures stability for up to three years.[2] Some suppliers recommend storage at or below -15°C with protection from light.[20] Once dissolved in a solvent, stock solutions should be stored at -80°C for long-term stability (up to 6 months) or at -20°C for shorter periods (up to 1 month).[2] The product is typically shipped at room temperature for domestic transit.[1]

Mechanism of Action and Preclinical Pharmacology

The therapeutic rationale for Eniluracil is entirely dependent on its potent and specific pharmacological interaction with the enzyme dihydropyrimidine dehydrogenase (DPD). It functions not as a direct cytotoxic agent but as a profound modulator of fluoropyrimidine chemotherapy.

Primary Mechanism: Irreversible DPD Inactivation

Eniluracil is a mechanism-based, irreversible inhibitor of DPD, also referred to as a "suicide inhibitor" or inactivator.[1] As a structural analogue of uracil, it is recognized by and binds to the active site of the DPD enzyme. This binding event initiates a catalytic process that results in the formation of a covalent bond between the inhibitor and the enzyme, leading to its permanent inactivation.[21] The potency of this interaction is reflected by a low inhibition constant ($K_i$) of 1.6 µM.[1] Because the inhibition is irreversible, the restoration of DPD activity in the body is not achieved by dissociation of the inhibitor but requires the de novo synthesis of new DPD protein, a process that can take several days.[6] This ensures a prolonged and durable pharmacodynamic effect from a single dose.

The Central Role of DPD in Fluoropyrimidine Metabolism

DPD is the initial and rate-limiting enzyme in the catabolic pathway of both endogenous pyrimidines (uracil and thymine) and their widely used chemotherapeutic analogues, such as 5-FU.[1] This enzyme is responsible for the rapid degradation of over 80% of an administered 5-FU dose, primarily within the liver and the gastrointestinal mucosa.[5] This extensive first-pass and systemic metabolism results in several key pharmacological challenges for 5-FU therapy:

1. Short Half-Life: Rapid catabolism leads to a very short plasma half-life of 5-FU, typically only 10-20 minutes after intravenous administration.[5]
2. Erratic Oral Bioavailability: High DPD activity in the gut wall and liver makes oral administration of 5-FU unreliable, with incomplete and highly variable absorption.[3]
3. Pharmacokinetic Variability: DPD activity levels can vary significantly between individuals due to genetic polymorphisms in the DPYD gene. This interpatient variability is a major cause of unpredictable 5-FU exposure, leading to inconsistent efficacy and a risk of severe, life-threatening toxicity in patients with DPD deficiency.[3]
4. Formation of Toxic Metabolites: The catabolism of 5-FU produces metabolites such as α-fluoro-β-alanine (FBAL), which do not contribute to anticancer activity but have been implicated in host toxicities, including neurotoxicity and hand-foot syndrome.[7]

Pharmacodynamic Consequences of DPD Inactivation by Eniluracil

By irreversibly inactivating DPD, Eniluracil effectively shuts down this entire catabolic pathway, leading to a cascade of profound pharmacodynamic changes. This blockade fundamentally alters the biological behavior of co-administered 5-FU, acting as a "pharmacokinetic switch." It converts 5-FU from a drug governed by rapid and variable enzymatic metabolism into one governed by slower and more predictable renal clearance.

This shift has several critical consequences. First, it prevents the formation of the catabolite FBAL, which is expected to reduce the incidence of associated toxicities.[7] Second, the blockade causes the accumulation of DPD's natural substrate, uracil, in the plasma. This elevation serves as a convenient and reliable systemic biomarker to confirm that DPD has been successfully inactivated.[22] Third, by eliminating DPD activity, Eniluracil removes a key mechanism of 5-FU resistance observed in tumors that overexpress the enzyme, potentially re-sensitizing them to treatment.[3] This fundamental change in 5-FU's disposition from metabolic to renal clearance also implies that a patient's renal function, a minor factor in conventional 5-FU therapy, becomes a critical determinant of drug exposure and safety when DPD is inhibited.[6]

Preclinical Efficacy Studies

Preclinical studies provided the foundational proof-of-concept for Eniluracil's therapeutic strategy. In rat models, the drug demonstrated high potency, with an effective dose for 50% inhibition ($ED_{50}$) of liver DPD at just 1.8 µg/kg.[1] In these models, Eniluracil itself was shown to have no intrinsic antitumor activity or toxicity when administered as a single agent.[2] However, when co-administered with 5-FU, it significantly potentiated the latter's antitumor effects and improved its overall therapeutic index.[1] This synergistic effect was demonstrated in multiple murine cancer models, including the MC-38 colon carcinoma and MOPC 315 myeloma, where a 2 mg/kg dose of Eniluracil enhanced the efficacy of 5-FU.[1] These preclinical findings strongly supported the advancement of Eniluracil into clinical trials as a modulator of 5-FU chemotherapy.

Clinical Pharmacokinetics and Pharmacodynamics (PK/PD)

The administration of Eniluracil to human subjects induces dramatic and predictable changes in the pharmacokinetics of co-administered 5-FU, which in turn dictates the safety and efficacy profile of the combination therapy.

Profound Alterations to 5-FU Pharmacokinetics

Clinical studies have consistently demonstrated that Eniluracil's inactivation of DPD completely remodels the absorption, distribution, metabolism, and excretion (ADME) profile of 5-FU.

• Absorption and Bioavailability: Eniluracil enables the oral administration of 5-FU with essentially 100% bioavailability, overcoming the erratic and incomplete absorption that makes oral 5-FU unviable on its own.[2]
• Metabolism and Elimination: The primary metabolic pathway for 5-FU is shut down. Consequently, the drug's elimination route shifts from DPD-mediated catabolism to renal excretion, with 45% to 75% of the administered dose being cleared by the kidneys.[6] This leads to a massive reduction in systemic clearance, reported as a greater than 20-fold decrease, with clearance values becoming comparable to the glomerular filtration rate (46 to 58 mL/min/m²).[3]
• Half-Life and Linearity: As a direct result of reduced clearance, the plasma half-life of 5-FU is prolonged dramatically, from its usual 10-20 minutes to a range of 4 to 6.5 hours.[3] This extended exposure mimics that of a continuous intravenous infusion. Furthermore, by removing the saturable, enzyme-based DPD catabolism, Eniluracil converts the pharmacokinetics of 5-FU from non-linear and unpredictable to perfectly linear and predictable, where drug exposure is directly proportional to the dose administered.[7]

Eniluracil's Own Pharmacokinetic Profile

The pharmacokinetic behavior of oral Eniluracil itself has been described as being similar to that of the co-administered oral 5-FU, suggesting comparable absorption and distribution characteristics.[6]

Clinical Pharmacodynamics and PK/PD Relationship

The pharmacodynamic effects of Eniluracil are rapid, potent, and durable. Oral doses as low as 10 to 20 mg twice daily are sufficient to achieve complete inactivation of DPD activity within one hour of administration.[3] This effect has been confirmed directly in patient samples, showing undetectable DPD activity in both peripheral blood mononuclear cells (PBMCs) and colorectal tumor tissue.[6] The duration of this enzymatic inhibition is prolonged, lasting for many days after the last dose of Eniluracil, with the time to full recovery being dependent on the dosing schedule.[6]

This profound alteration of 5-FU pharmacokinetics creates a direct and sensitive relationship between drug exposure and toxicity. The massive increase in 5-FU exposure necessitates a correspondingly substantial reduction in the 5-FU dose to maintain safety.[3] Clinical studies have established clear correlations between 5-FU exposure metrics and dose-limiting toxicities (DLTs). On short-term, 5-day dosing schedules, higher 5-FU area under the curve (AUC) values are predictive of neutropenia. In contrast, on chronic, 28-day schedules, elevated 5-FU AUC and steady-state concentrations are associated with the development of diarrhea.[6]

The very potency of Eniluracil, while its greatest asset, ultimately became a double-edged sword that contributed to its initial clinical failure. The profound PK modulation required a drastic reduction in the 5-FU dose from hundreds of milligrams to single-digit milligrams.[17] In the pivotal Phase III trials, this led to a co-formulation with a 10:1 mass ratio of Eniluracil to 5-FU.[7] This created a scenario where massive concentrations of one uracil analogue (Eniluracil) were present simultaneously with therapeutic concentrations of another (5-FU). This set the stage for an unforeseen secondary pharmacological interaction: competitive inhibition at the level of the anabolic enzymes, such as uridine phosphorylase, which are required to convert 5-FU into its active, cytotoxic metabolites.[9] Thus, the drug's primary success in blocking catabolism inadvertently created the conditions to block anabolism, neutralizing the therapeutic effect of 5-FU and leading to the trial's negative outcome.

Clinical Development and Efficacy: A Historical Perspective

The clinical development of Eniluracil is a multi-decade narrative of initial promise, unexpected pivotal failure, and subsequent scientific re-evaluation leading to a revived investigational program.

Phase I Studies: Defining a New Paradigm

The initial Phase I trials were designed to establish the safety, pharmacokinetics, and pharmacodynamics of the Eniluracil/5-FU combination and to determine the maximum tolerated dose (MTD) of 5-FU in the presence of DPD inactivation.[3] These studies confirmed the profound PK modulation, showing that the MTD of 5-FU was substantially lower than conventional doses.[17] Different dosing schedules were explored, primarily a short-course (5-day) regimen and a chronic (28-day) regimen. These early trials successfully identified the schedule-dependent nature of the DLTs, with myelosuppression being dose-limiting on the 5-day schedule and diarrhea on the 28-day schedule.[3] A notable Phase I study in head and neck cancer patients receiving concurrent radiation therapy was terminated early due to excessive toxicity; cumulative myelosuppression proved to be the DLT at very low 5-FU doses, and two patient deaths occurred, one from neutropenic sepsis.[24]

Phase II Studies: Mixed Signals of Efficacy and Toxicity

Phase II studies evaluated the Eniluracil/5-FU combination across a range of solid tumors, yielding mixed results that highlighted the regimen's potential but also its challenges.

In metastatic colorectal cancer (mCRC), a multicenter trial of a 28-day oral regimen in previously untreated patients reported a partial response rate of 25% and stable disease in 36% of patients. The investigators concluded this efficacy was comparable to standard infusional 5-FU therapies and that the toxicity profile, primarily diarrhea, was acceptable.[30] In contrast, a Southwest Oncology Group (SWOG) trial in patients with 5-FU-resistant mCRC found an overall response rate of only 10%, suggesting a lack of significant activity in this heavily pretreated population.[32] Another Phase II trial in untreated mCRC that used a 5-day schedule with leucovorin was hampered by severe toxicity, which occurred in 85% of patients and included one toxic death, limiting the regimen's clinical utility despite observing a 13% response rate.[28]

Studies in other tumor types were also conducted. A trial in patients with inoperable hepatocellular carcinoma found the 28-day regimen to be well-tolerated but observed minimal antitumor activity, with no confirmed responses.[34] Phase II trials were also completed in breast and pancreatic cancers.[3]

The Pivotal Phase III Failure in Colorectal Cancer

The clinical development program culminated in two large, multicenter, randomized Phase III studies in patients with advanced/metastatic CRC.[7] These trials were designed to prove the non-inferiority or superiority of an all-oral Eniluracil/5-FU regimen compared to the standard-of-care intravenous 5-FU plus leucovorin (the Mayo Clinic regimen).[10] The oral regimen consisted of Eniluracil 11.5 mg/m² and 5-FU 1.15 mg/m² administered twice daily for 28 days, followed by a 7-day rest period, representing a 10:1 dose ratio.[11]

The results of these trials were definitive and disappointing. The Eniluracil/5-FU arm failed to meet the primary endpoint of equivalent overall survival (OS). The median OS was 13.3 months for the Eniluracil group versus 14.5 months for the 5-FU/LV group.[10] Furthermore, the median progression-free survival (PFS) was statistically inferior for the Eniluracil arm (20.0 weeks vs. 22.7 weeks; p=0.01).[10] This unexpected outcome, demonstrating less antitumor benefit than the established standard of care, led the developer, GlaxoSmithKline, to halt the entire development program for Eniluracil.[9]

Investigating the Failure: The Competitive Inhibition Hypothesis

The failure of the Phase III trials prompted a critical re-examination of the combination's pharmacology. The leading hypothesis to explain the paradoxical results focused on the high 10:1 dose ratio of Eniluracil to 5-FU.[7] Because both Eniluracil and 5-FU are structurally similar uracil analogues, it was proposed that the vast excess of Eniluracil might be interfering with the essential metabolic activation (anabolism) of 5-FU.[7] For 5-FU to exert its cytotoxic effects, it must be converted intracellularly into active metabolites like FdUMP and FUTP. Mechanistic studies subsequently demonstrated that Eniluracil can act as a competitive inhibitor of uridine phosphorylase (UP), a key enzyme in this anabolic pathway.[9] This hypothesis was further validated in preclinical rat models, which showed that a high, 5-fold excess of Eniluracil significantly blunted the antitumor efficacy of 5-FU (25% cure rate) when compared to an adequate, non-excess dose of Eniluracil (88% cure rate).[7] This body of evidence strongly suggests that the clinical failure was an iatrogenic consequence of an improperly designed regimen that inadvertently blocked 5-FU's mechanism of action.

Table 2: Summary of Key Historical Clinical Trials for Eniluracil/5-FU

Phase	Trial ID / Reference	Indication	N	Regimen (Eniluracil:5-FU Dose & Schedule)	Key Efficacy Outcome	Key Safety Finding (DLT)	Conclusion
I	Mani et al. (1998) 17	Advanced Solid Tumors	65	5-day schedule; dose escalation	MTD of 5-FU determined	Myelosuppression	MTDs are considerably lower than conventional 5-FU doses.
II	Mani et al. (2000) 30	Untreated mCRC	55	10:1 ratio; 28-day oral BID	ORR: 25%; Median PFS: 22.6 wks	Diarrhea	Efficacy comparable to infusional 5-FU with acceptable toxicity.
II	Leichman et al. (SWOG-S9635) 33	Resistant mCRC	25	10:1 ratio; 28-day oral BID	ORR: 10%	Not specified	Lacks significant activity in this resistant population.
II	Meropol et al. (2001) 28	Untreated mCRC	60	5-day schedule + Leucovorin	ORR: 13%; Median PFS: 4.4 mos	Neutropenia, Diarrhea	Severe toxicity in 85% of patients limited clinical utility.
III	Schilsky et al. (2002) 10	Untreated mCRC	981	10:1 ratio; 28-day oral BID	Inferior Median OS (13.3 vs 14.5 mos); Inferior Median PFS (20.0 vs 22.7 wks)	Diarrhea	Did not meet criteria for equivalence to standard 5-FU/LV.

Safety and Tolerability Profile

The safety profile of Eniluracil is intrinsically linked to that of the co-administered fluoropyrimidine, as Eniluracil itself has demonstrated minimal intrinsic toxicity.[2] The adverse events observed in clinical trials are characteristic of 5-FU toxicity, but their pattern and severity are heavily influenced by the dosing schedule.

Schedule-Dependent Dose-Limiting Toxicities

A consistent finding across the clinical development program is that the primary DLTs are dictated by the schedule of drug administration, which reflects the different patterns of 5-FU exposure.[3]

• 5-Day Schedules: Regimens involving short, daily administration for 5 days are primarily limited by myelosuppression (bone marrow suppression). This manifests as Grade 3/4 neutropenia and, to a lesser extent, thrombocytopenia.[3]
• 28-Day Chronic Schedules: Regimens involving continuous daily dosing for 28 days are primarily limited by diarrhea. While myelosuppression can occur, severe gastrointestinal toxicity is the more frequent and dose-limiting event on this schedule.[3]

Comprehensive Spectrum of Adverse Events

Beyond the primary DLTs, a range of other treatment-related adverse events have been commonly reported in patients receiving Eniluracil/5-FU therapy. These include gastrointestinal effects such as nausea, vomiting, mucositis (stomatitis), and anorexia; constitutional symptoms like fatigue and asthenia; and other hematologic effects such as anemia.[17] The severity of these events is generally dose- and schedule-dependent.

A Notable Absence: Hand-Foot Syndrome (HFS)

One of the most significant observations regarding the safety profile of the Eniluracil/5-FU combination is the minimal incidence of hand-foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia.[8] This is a stark contrast to other forms of prolonged fluoropyrimidine exposure, such as continuous 5-FU infusions or oral capecitabine, where HFS is a frequent and often dose-limiting toxicity.[25] This clinical finding provides strong support for the hypothesis that HFS is not caused by 5-FU itself but by its catabolites, particularly FBAL. By blocking DPD, Eniluracil prevents the formation of these catabolites, thereby mitigating this specific and often debilitating side effect.[7] This unique aspect of its safety profile represents a potential key therapeutic advantage over other oral fluoropyrimidines.

Table 3: Common Grade 3/4 Adverse Events Associated with Eniluracil/5-FU Regimens by Schedule

Adverse Event	5-Day Schedule (Grade 3/4 %)	28-Day Schedule (Grade 3/4 %)	Key References
Myelosuppression (Neutropenia)	42%	5%	11
Diarrhea	30%	19%	11
Mucositis/Stomatitis	Common	4%	17
Nausea/Vomiting	Common	2%	17
Hand-Foot Syndrome	Minimal	Minimal	8
Note: Percentages are representative values from key trials and may vary between studies. Bold values indicate the primary DLT for that schedule.

The Re-Emergence of Eniluracil: Current Investigational Status

Following the discontinuation of its development by GSK, the scientific rationale for Eniluracil was re-evaluated, leading to its acquisition by new sponsors and the initiation of a revised clinical program designed to unlock its therapeutic potential.

Corporate Development and Stewardship

Eniluracil was originally developed in the 1990s by Burroughs Wellcome, which later became part of GlaxoWellcome and subsequently GlaxoSmithKline (GSK).[39] After the Phase III trial failures around 2002, GSK halted development.[35] In 2005, Adherex Technologies acquired an exclusive license to the compound, operating under the well-founded hypothesis that the previous trials failed due to an improper dosing regimen, not a fundamental flaw in the drug's concept.[35] Adherex conducted additional studies to support this hypothesis before the drug's rights were eventually acquired by Processa Pharmaceuticals in August 2020.[35] Processa is now advancing Eniluracil under the code name PCS6422.[14]

The New Therapeutic Strategy: Learning from the Past

The current clinical development strategy for PCS6422 (Eniluracil) is explicitly designed to overcome the mechanism of failure observed in the original Phase III trials.[13] This new approach incorporates several key modifications:

1. New Partner Drug: The combination partner is capecitabine, a widely used oral prodrug of 5-FU, which is converted to 5-FU intracellularly.[12]
2. Optimized Dose and Ratio: A low, fixed dose of Eniluracil (e.g., 40 mg) is used in combination with a significantly reduced dose of capecitabine (approximately 15% of its standard therapeutic dose). This ensures that Eniluracil is not present in vast molar excess relative to the generated 5-FU, thereby avoiding competitive inhibition of anabolic enzymes.[13]
3. Temporal Separation of Dosing: This is the most critical strategic change. Eniluracil is administered several hours (e.g., 11-16 hours) before the capecitabine dose.[13] This schedule is designed to allow sufficient time for Eniluracil to irreversibly inactivate DPD throughout the body and for any excess, unbound Eniluracil to be cleared from the plasma. When capecitabine is later administered and converted to 5-FU, the DPD enzyme is already inhibited, but the high concentrations of the competing Eniluracil molecule are no longer present, allowing for efficient anabolic activation of 5-FU.[26]

Ongoing and Recent Clinical Trials

The new strategy is being tested in a series of modern clinical trials:

• NCT04861987: A Phase 1b dose-escalation study was conducted to evaluate the safety and pharmacokinetics of fixed-dose PCS6422 with escalating doses of capecitabine in patients with advanced, refractory gastrointestinal (GI) tumors.[12] This study, which completed in 2024, successfully established a maximum tolerated dose for capecitabine in this combination (225 mg BID) and a recommended Phase 2 dose range (75-225 mg BID), paving the way for further efficacy studies.[12]
• NCT06568692: Building on the Phase 1b results, an adaptive-design, randomized, open-label Phase 2 trial was initiated in patients with advanced or metastatic breast cancer.[13] This ongoing trial compares two different dose levels of the PCS6422/capecitabine combination against standard-dose capecitabine monotherapy. The study's design is aligned with the FDA's Project Optimus initiative, which emphasizes finding the optimal dose-response relationship for both safety and efficacy early in development.[13]
• Topical Formulation: An earlier pilot study (NCT00827580) had also explored a novel application of Eniluracil as a topical ointment for the prevention of capecitabine-induced HFS, aiming to leverage its DPD-inhibitory mechanism locally in the skin.[44]

Regulatory Status and Future Outlook

Despite decades of research and clinical investigation, Eniluracil remains an unapproved, investigational agent. Its regulatory history is minimal, but its future prospects have been renewed by a more sophisticated clinical development approach.

Global Regulatory Status

Eniluracil is not approved for marketing in any major jurisdiction. A review of public databases from the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Australian Therapeutic Goods Administration (TGA) confirms that it does not hold a marketing authorization.[45] There is no evidence of a formal marketing application ever having been reviewed by the EMA or TGA.[46] While the EMA has issued guidance on the importance of DPD testing prior to fluoropyrimidine treatment, underscoring the clinical relevance of the pathway Eniluracil targets, this does not pertain to the drug itself.[51]

FDA Regulatory History

Eniluracil's interaction with the FDA has been limited but informative.

• Orphan Drug Designation: On December 15, 2005, the FDA granted Eniluracil an Orphan Drug Designation for the "Treatment of hepatocellular carcinoma" when used in combination with fluoropyrimidines.[41] This designation provides certain incentives for development but does not represent an approval. The drug's status remains "Designated" but "Not FDA Approved for Orphan Indication".[45]
• End-of-Phase 2 Meeting: In May 2013, the then-sponsor Adherex held an End-of-Phase 2 meeting with the FDA to discuss a potential registration pathway in metastatic breast cancer. The FDA did not support the company's proposal for a small, single-arm pivotal study and instead recommended larger, more conventional trial designs, which presented a resource challenge for the company at that time.[53]

Expert Conclusion and Forward Look

Eniluracil represents a compelling case study in pharmaceutical development, illustrating how a drug with a powerful and well-understood primary mechanism can fail due to an incomplete appreciation of its secondary pharmacology. The initial Phase III trials did not fail because the concept of DPD inactivation was flawed; they failed because the execution—specifically the dosing ratio and schedule—inadvertently created a new problem of anabolic inhibition.

The revival of Eniluracil by Processa Pharmaceuticals is built upon a strong, scientifically sound rationale that directly addresses this historical failure. The new strategy of using a low, fixed dose of Eniluracil with temporal separation from a low dose of capecitabine is a logical and elegant attempt to isolate the beneficial PK-modulating effects while avoiding the detrimental off-target metabolic interference.

The future of Eniluracil now hinges on the outcomes of its ongoing clinical trials. Its success will depend on demonstrating a clear and meaningful improvement in the therapeutic index compared to standard fluoropyrimidine therapy. This could manifest as superior efficacy, a significantly better safety profile—particularly a reduction in HFS and other toxicities—or a combination of both. If the current trials can validate this new approach, Eniluracil may finally realize its decades-old promise to provide a safer, more effective, and more convenient oral fluoropyrimidine-based therapy for patients with a wide range of solid tumors.

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