Verinurad (RDEA3170): A Comprehensive Monograph on a Selective URAT1 Inhibitor from Gout to Cardiorenal Indications

Introduction to Verinurad and URAT1 Inhibition

The Pathophysiology of Hyperuricemia and Gout

Hyperuricemia is a prevalent metabolic disorder defined by elevated serum uric acid (sUA) concentrations, typically at or above 6.8 mg/dL, which represents the saturation point of monosodium urate at physiological temperature and pH.[1] This condition is the central prerequisite for the development of gout, a debilitating form of inflammatory arthritis characterized by the deposition of monosodium urate crystals within joints, soft tissues, and organs.[1] The clinical manifestations of gout range from acute, intensely painful inflammatory flares to chronic, progressive disease leading to joint destruction, disfiguring tophi, and persistent pain.[2] The fundamental cause of hyperuricemia in the vast majority of patients—approximately 90%—is not the overproduction of uric acid but rather its inadequate renal excretion.[2] This critical physiological detail has established the renal urate transport system as a primary and highly logical target for therapeutic intervention.

The Role of Renal Urate Transporter 1 (URAT1) in Urate Homeostasis

The homeostasis of serum urate is predominantly regulated by the kidneys, where a complex interplay of transporters governs its filtration, reabsorption, and secretion. Central to this process is the urate transporter 1 (URAT1), an electroneutral antiporter encoded by the SLC22A12 gene.[3] URAT1 is strategically located on the apical membrane of proximal tubular cells in the kidney and is responsible for mediating the reabsorption of the majority of filtered urate from the tubular lumen back into the systemic circulation.[1] This reabsorption process occurs in exchange for various monovalent organic or inorganic anions, such as lactate and nicotinate.[3] Given its principal role in reclaiming filtered urate, URAT1 is the single most important determinant of sUA levels and, consequently, the primary molecular target for uricosuric pharmacotherapy.[5]

Therapeutic Rationale for Selective Uric Acid Reabsorption Inhibitors (SURIs)

The therapeutic strategy of inhibiting URAT1 is mechanistically straightforward: by blocking the transporter's function, drugs can prevent urate reabsorption, thereby increasing the fractional excretion of uric acid (FEUA) and promoting its elimination from the body.[7] This action directly addresses the underlying cause of hyperuricemia in most patients, leading to a reduction in sUA levels.[1] Historically, uricosuric agents such as probenecid and benzbromarone have been used for this purpose. However, their clinical utility has been constrained by limitations, including off-target effects and, in the case of benzbromarone, the risk of severe hepatotoxicity, which led to its withdrawal from many markets.[9] These shortcomings underscored the clinical need for a new generation of uricosuric agents with enhanced selectivity and an improved safety profile.

Positioning Verinurad as a Second-Generation SURI

Verinurad, also identified by its developmental code RDEA3170, emerged as a novel, highly potent, and selective URAT1 inhibitor (SURI) designed to meet this need.[1] Positioned as a second-generation agent and a successor to lesinurad, Verinurad was developed with the goal of achieving superior activity and target selectivity, thereby potentially offering a more favorable benefit-risk profile.[12] Its development journey has been complex, beginning with promising investigations for the treatment of gout and hyperuricemia before encountering significant challenges that prompted a strategic pivot to explore its potential in cardiorenal diseases, including chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF).[14]

Physicochemical Profile and Molecular Structure

Nomenclature and Chemical Identifiers

Verinurad is a small molecule drug identified by a comprehensive set of chemical and regulatory identifiers. Its officially recognized generic name is Verinurad, and it is widely known in scientific literature and clinical trials by its developmental code, RDEA3170 or RDEA-3170.[11] Key database identifiers include DrugBank Accession Number DB11873 and Chemical Abstracts Service (CAS) Registry Number 1352792-74-5.[11] The systematic International Union of Pure and Applied Chemistry (IUPAC) name for the compound is 2-[3-(4-cyanonaphthalen-1-yl)pyridin-4-yl]sulfanyl-2-methylpropanoic acid.[11] Its molecular formula has been established as

C20​H16​N2​O2​S.[11]

Structural Elucidation and Key Features

Chemically, Verinurad is classified as a naphthalene derivative, characterized by a core structure containing a naphthalene moiety, which consists of two fused benzene rings.[3] The molecule's architecture is composed of three key functional components: a 4-cyanonaphthalene group, a central pyridine ring, and a 2-methylpropanoic acid moiety.[11] These components are linked sequentially, with the 4-cyanonaphthalene group attached to the 3-position of the pyridine ring, which is then connected at its 4-position via a sulfanyl (thioether) linkage to the 2-methylpropanoic acid group. This distinct arrangement is captured by its SMILES (Simplified Molecular Input Line Entry System) string:

CC(C)(C(=O)O)SC1=C(C=NC=C1)C2=CC=C(C3=CC=CC=C32)C#N.[11]

Physicochemical Properties and Formulation Characteristics

Verinurad's physicochemical properties significantly influence its behavior as a pharmaceutical agent. It presents as a white to off-white or pale brown crystalline solid.[19] One of its most defining characteristics is its poor aqueous solubility, measured at 0.00471 mg/mL, which, combined with its high permeability, classifies it as a Biopharmaceutics Classification System (BCS) Class II compound.[3] This low water solubility necessitates formulation strategies to ensure adequate bioavailability and presents challenges in manufacturing. In contrast, it is soluble in organic solvents such as dimethyl sulfoxide (DMSO) and dimethylformamide (DMF).[19]

The molecule is highly lipophilic, with reported calculated logP values of 4.4 and 3.12.[3] It is also an amphoteric compound, possessing both an acidic and a basic functional group.[21] The carboxylic acid group confers its acidic nature, with a strongest acidic pKa of approximately 3.59, while the nitrogen atom in the pyridine ring provides a basic character, with a strongest basic pKa of around 4.8.[3]

From a structural chemistry perspective, Verinurad is an atropisomer, exhibiting axial chirality due to hindered rotation around a single bond. However, kinetic studies have confirmed that racemization occurs rapidly under physiological conditions, which mitigates potential safety concerns associated with the administration of a fixed enantiomer.[21] The molecule's propensity to form solvates has also been noted as a complex factor in its chemical process development.[21] Despite its complexity, Verinurad adheres to Lipinski's Rule of Five, with zero violations reported, indicating favorable "drug-like" properties for oral administration.[3]

Property	Value	Source(s)
Generic Name	Verinurad	3
Synonyms	RDEA3170, RDEA-3170	11
DrugBank ID	DB11873	3
CAS Number	1352792-74-5	11
IUPAC Name	2-[3-(4-cyanonaphthalen-1-yl)pyridin-4-yl]sulfanyl-2-methylpropanoic acid	11
Molecular Formula	C20​H16​N2​O2​S	11
Molecular Weight	348.42 g/mol (average)	3
Appearance	White to off-white crystalline solid	19
Water Solubility	0.00471 mg/mL	3
logP	4.4 (ALOGPS), 3.12 (Chemaxon)	3
pKa	Acidic: ~3.59; Basic: ~4.8	3
Lipinski's Rule of Five	Adheres (0 violations)	3

Nonclinical Pharmacology and Mechanism of Action

Primary Mechanism: Potent and Selective Inhibition of URAT1

The primary pharmacological action of Verinurad is the potent and highly specific inhibition of the URAT1 transporter.[6] By targeting URAT1 at its location on the apical membrane of renal proximal tubule cells, Verinurad effectively blocks the reabsorption of uric acid from the glomerular filtrate.[1] This inhibition leads to a direct and substantial increase in the urinary excretion of uric acid, which in turn lowers the concentration of uric acid in the serum.[8] This mechanism directly addresses the most common pathophysiological defect in patients with gout: renal under-excretion of urate.[2]

In Vitro Potency and Binding Affinity

In vitro studies have consistently demonstrated Verinurad's high potency. The half-maximal inhibitory concentration (IC50​) against human URAT1 is reported to be 25 nM (or 0.025 µM), classifying it as one of the most potent URAT1 inhibitors discovered.[6] Other reports have noted a half-maximal effective concentration (

EC50​) of 0.05 µM.[24] Radioligand binding assays have further elucidated its interaction with the transporter, confirming a competitive binding mechanism. The binding of radiolabeled Verinurad to URAT1 was shown to be inhibited by other known uricosuric agents, including benzbromarone, sulfinpyrazone, and probenecid, indicating that these compounds share or overlap in their binding sites within the transporter.[6]

Selectivity Profile: Comparative Activity Against Other Transporters

A key feature of Verinurad's pharmacological profile is its high degree of selectivity for URAT1 over other renal transporters. This selectivity is critical for minimizing off-target effects and potential drug-drug interactions.

1. Species Selectivity: Verinurad is markedly more potent against human URAT1 (IC50​ = 25 nM) than against its rat ortholog (IC50​ = 41 µM), representing a 1,640-fold difference in potency.[6] This species-specific activity is essential for the correct interpretation of data from preclinical animal models and for translating those findings to human pharmacology.
2. Transporter Selectivity: Crucially, Verinurad is highly selective for URAT1 over other organic anion transporters (OATs) that are also expressed in the kidney and play roles in drug disposition. Its inhibitory activity against human OAT1 (IC50​ = 4.6 µM) and OAT4 (IC50​ = 5.9 µM) is significantly weaker.[19] This translates to a selectivity ratio of approximately 184-fold for URAT1 over OAT1 and 236-fold for URAT1 over OAT4. This high level of target specificity was a primary design objective, intended to create a safer uricosuric agent by avoiding the inhibition of transporters like OAT1 and OAT3, which are associated with drug-drug interactions.[13]

Transporter	IC50​ (µM)	Selectivity Ratio (vs. hURAT1)	Source(s)
Human URAT1	0.025	1	6
Rat URAT1	41	1,640	6
Human OAT1	4.6	184	19
Human OAT4	5.9	236	19

Structural Basis for High-Affinity URAT1 Inhibition

Advanced structural biology techniques, including cryo-electron microscopy, have provided a detailed molecular framework for understanding Verinurad's interaction with URAT1.[26] These studies reveal that Verinurad binds within a central cavity of the transporter. This binding event stabilizes URAT1 in an inward-facing conformation, effectively locking the transporter and preventing the conformational cycling required to move urate across the cell membrane.[10]

Furthermore, mutagenesis studies have pinpointed specific amino acid residues within human URAT1 that are critical for Verinurad's high-affinity binding. These include Cys-32, Ser-35, Phe-365, and Ile-481.[6] The interaction with Cys-32 has been described as a unique feature of Verinurad compared to other uricosurics.[6] The substantial difference in potency between human and rat URAT1 is largely explained by variations at three of these key residues (positions 35, 365, and 481), which differ between the two species and are crucial for high-affinity drug binding.[6]

Pharmacodynamic Effect: Increased Fractional Excretion of Uric Acid (FEUA)

The direct and measurable consequence of Verinurad's potent URAT1 inhibition is a significant, dose-dependent increase in the renal excretion of uric acid. This is quantified by increases in the total amount of uric acid excreted in urine (AeUR) and, more specifically, the fractional excretion of uric acid (FEUA), which represents the percentage of filtered urate that is ultimately excreted.[8] This primary pharmacodynamic effect is the direct cause of the desired therapeutic outcome: the reduction of sUA levels.[8] In a study with healthy human volunteers, a single 40 mg dose of Verinurad was shown to increase FEUA and produce a profound reduction in sUA of up to 60% from baseline.[6]

Pharmacokinetics and Metabolism (ADME)

Absorption

Verinurad is characterized by rapid oral absorption.[27] In clinical studies conducted under fasted conditions, the time to reach maximum plasma concentration (

Tmax​) is typically observed between 0.5 and 2.0 hours post-dose.[1]

The presence of food significantly influences the absorption profile of Verinurad, though the effects have been variable across studies. Administration with a moderate-fat meal can delay absorption, extending the Tmax​ to a range of 3.0 to 5.0 hours.[1] The impact on overall exposure (Area Under the Curve, AUC) and peak concentration (

Cmax​) is complex. One study reported that food decreased Cmax​ by 37-53% and AUC by 23%.[27] Conversely, a study in healthy Japanese subjects noted a variable

increase in exposure with a meal, with AUC increasing by 0-97% and Cmax​ by 0-26% across different dose groups.[1] This variability underscores the importance of standardized administration relative to meals in clinical practice.

Distribution and Metabolism

While detailed information on Verinurad's volume of distribution and specific metabolic pathways is not extensively covered in the available materials, its plasma pharmacokinetic profile has been well-characterized. Following both single and multiple doses, Verinurad exhibits near dose-proportional pharmacokinetics, meaning that increases in Cmax​ and AUC are roughly proportional to the increase in dose, up to single doses of 40 mg and multiple daily doses of 15 mg.[1]

Upon once-daily administration, there is only modest accumulation of the drug in plasma. The accumulation ratio is approximately 1.2-fold for Cmax​ and 1.3-fold for AUC, indicating that the drug does not build up to unexpectedly high levels with repeated dosing.[15] The terminal elimination half-life (

t1/2​) of Verinurad has been reported to be approximately 15 hours following a single 10 mg oral dose.[28]

Excretion

The primary route of elimination for Verinurad involves the kidneys. Urinary pharmacokinetic parameters, such as the fraction of the administered dose excreted unchanged in the urine over 24 hours (fe0–24​), have been measured in clinical trials, confirming its renal clearance.[1]

Pharmacokinetic Profile Across Populations

Inter-ethnic differences in Verinurad exposure have been observed. An initial study found that after multiple 10 mg doses, Japanese subjects had a 38% higher Cmax​ and a 23% higher AUC compared to non-Asian subjects. This difference was largely attributed to lower average body weight in the Japanese cohort.[1] Subsequent analyses have supported this conclusion, suggesting that when pharmacokinetic parameters are corrected for body weight, the steady-state exposure to Verinurad is comparable among healthy Asian, Chinese, and non-Asian participants.[15] This indicates that body weight, rather than ethnicity-based metabolic differences, is the primary determinant of the observed pharmacokinetic variability.

Impact of Renal Impairment on Drug Exposure

Verinurad's pharmacokinetics are profoundly dependent on renal function, a critical consideration for a drug that targets the kidney and is intended for use in populations with potential renal comorbidities. A dedicated pharmacokinetic study in subjects with varying degrees of renal impairment revealed a progressive and substantial increase in drug exposure as kidney function declined.[15] Compared to individuals with normal renal function, the systemic exposure to Verinurad increased as follows:

• Mild renal impairment: Cmax​ increased by 53%, and AUC increased by 24%.
• Moderate renal impairment: Cmax​ increased by 73%, and AUC increased by 148%.
• Severe renal impairment: Cmax​ increased by 128%, and AUC increased by 130%.

This significant accumulation of the drug in patients with compromised renal function has major implications for its safety and dosing, particularly in the context of its later investigation in patients with CKD.

Parameter	Value / Observation	Condition / Population	Source(s)
Tmax​ (Fasted)	0.5–2.0 hours	Healthy Volunteers	1
Tmax​ (Fed)	3.0–5.0 hours	Healthy Volunteers	1
Effect of Food	Variable; AUC change from -23% to +97%	Healthy Volunteers	1
Terminal Half-life (t1/2​)	~15 hours	Healthy Volunteers (10 mg dose)	28
Accumulation Ratio (AUC)	~1.3	Healthy Volunteers (multiple doses)	15
Effect of Moderate Renal Impairment on AUC	↑148%	Single Dose Study	15

Clinical Development for Gout and Hyperuricemia

Phase I Studies

The initial clinical evaluation of Verinurad was conducted through Phase I studies in healthy male subjects, including both Japanese and non-Asian populations.[1] These foundational trials established the drug's preliminary safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles. The results were promising, confirming that Verinurad was rapidly absorbed, exhibited dose-proportional exposure, and produced a robust, dose-dependent reduction in sUA. A single 40 mg dose was capable of lowering sUA by up to 62%.[27] At this early stage of development, Verinurad was generally well-tolerated.[1]

Phase II Monotherapy Trials: Efficacy and the Emergence of a Critical Safety Signal

Following the successful Phase I studies, Verinurad advanced into two pivotal Phase II, randomized, double-blind, placebo-controlled trials designed to evaluate its efficacy and safety as a monotherapy. One study (NCT01927198) was conducted in Western patients with gout, while the other (NCT02078219) enrolled Japanese patients with either gout or asymptomatic hyperuricemia.[2]

Both trials successfully met their primary efficacy endpoints, demonstrating that Verinurad produced statistically significant and dose-dependent reductions in sUA levels over 12 to 16 weeks of treatment.[2]

• In the Western study, Verinurad at doses of 5, 10, and 12.5 mg reduced sUA by -17.5%, -29.1%, and -34.4%, respectively, compared to a +1.2% increase in the placebo group (p<0.0001 for all doses vs. placebo).[2]
• In the Japanese study, the sUA-lowering effect was even more pronounced, with reductions of -31.7%, -51.7%, and -55.8% for the same dose levels, compared to a -2.4% change for placebo (p<0.0001).[2] The greater efficacy observed in the Japanese cohort correlated with the higher systemic drug exposure seen in this population.[1]

Despite this clear evidence of efficacy, a critical safety signal emerged from these monotherapy trials. A pattern of renal-related treatment-emergent adverse events (TEAEs), most notably elevations in serum creatinine, was observed with a higher frequency in patients receiving Verinurad compared to placebo.[2] This finding was a pivotal moment in Verinurad's development. The on-target, potent uricosuric effect of the drug led to a rapid "dumping" of uric acid into the renal tubules, which was hypothesized to cause microcrystallization and subsequent acute kidney injury.[9] This safety concern was significant enough to lead to the definitive conclusion that

Verinurad monotherapy is not recommended for the treatment of hyperuricemia or gout.[2]

Study / Population	Treatment Arm	Mean % Change in sUA from Baseline	Key Safety Finding	Source(s)
Study 1 (Western)	Placebo	+1.2%	-	2
	Verinurad 5 mg	-17.5%	Increased incidence of renal-related TEAEs compared to placebo	2
	Verinurad 10 mg	-29.1%	"	2
	Verinurad 12.5 mg	-34.4%	"	2
Study 2 (Japanese)	Placebo	-2.4%	-	2
	Verinurad 5 mg	-31.7%	Increased incidence of renal-related TEAEs compared to placebo	2
	Verinurad 10 mg	-51.7%	"	2
	Verinurad 12.5 mg	-55.8%	"	2

Phase II Combination Therapy Trials with Xanthine Oxidase Inhibitors (XOIs)

The identification of the renal risk associated with monotherapy necessitated a shift in clinical strategy. The next phase of development focused on combining Verinurad with a xanthine oxidase inhibitor (XOI) such as allopurinol or febuxostat.[9] The scientific rationale for this approach was compelling: by simultaneously reducing the production of uric acid with an XOI and promoting its excretion with Verinurad, it would be possible to achieve profound sUA lowering while mitigating the risk of urate nephropathy by reducing the total urate load passing through the renal tubules.[7]

Clinical trials of this combination therapy demonstrated remarkable synergistic efficacy. The addition of Verinurad to an XOI produced dose-dependent sUA reductions that were significantly greater than those achievable with XOI monotherapy, even at high doses.[28] For instance, the combination of Verinurad (at doses ≥5 mg) with allopurinol 300 mg resulted in greater sUA lowering than allopurinol 600 mg alone.[28] When combined with febuxostat, Verinurad was shown to lower sUA by up to 80-82% from baseline.[32] Critically, this combination approach appeared to mitigate the renal safety concern. Urinary uric acid levels were maintained at levels comparable to baseline, suggesting that the dangerous "dumping" effect of monotherapy was effectively controlled.[9] The combination regimens were generally well-tolerated.

Discontinuation of Gout Indication: Rationale and Clinical Implications

Despite the strong efficacy and improved safety profile demonstrated in the Phase II combination therapy trials, the clinical development of Verinurad for the treatment of gout appears to have been terminated, as no Phase III trials for this indication were ever registered on ClinicalTrials.gov.[9] While an official statement from the developer, AstraZeneca, is not available in the provided materials, the decision can be understood within a broader strategic and commercial context.

This decision was likely heavily influenced by the commercial failure of Verinurad's predecessor, lesinurad (marketed as Zurampic and in a fixed-dose combination as Duzallo). Lesinurad, which shares the same mechanism of action and renal safety concerns, was approved by the FDA in 2015 but came with a black box warning regarding the risk of acute renal failure.[34] It was subsequently licensed to another company and ultimately withdrawn from the market in 2019 for "business reasons," not for lack of efficacy or new safety issues.[34] The market challenges for lesinurad included its high cost relative to cheap, effective generics like allopurinol, and a general reluctance among physicians to prescribe uricosuric agents due to the perceived risks of kidney stones and the complexity of managing combination therapy.[34] Verinurad, despite being a more potent agent, would have faced the exact same commercial headwinds. AstraZeneca likely concluded that the substantial investment required for a full Phase III program carried an unacceptably high commercial risk, with a low probability of achieving a sufficient return on investment, leading to the discontinuation of the gout indication.

Strategic Repositioning: Evaluation in Renal and Cardiovascular Disease

Scientific Rationale: The Link Between Hyperuricemia, CKD, and HFpEF

Following the cessation of its development for gout, Verinurad was strategically repositioned to investigate its potential in treating chronic kidney disease (CKD) and heart failure with preserved ejection fraction (HFpEF). This pivot was based on a substantial body of epidemiological evidence demonstrating strong, independent associations between elevated sUA and an increased risk for hypertension, CKD, metabolic syndrome, and HFpEF.[14] The underlying scientific hypothesis, often referred to as the "urate hypothesis," posited that uric acid is not merely a passive biomarker of these conditions but an active, causal contributor to their pathophysiology, potentially by promoting endothelial dysfunction, inflammation, and oxidative stress.[7] The profound sUA lowering achievable with the Verinurad-XOI combination—by over 80% in some studies—presented a unique and powerful tool to test this hypothesis in a rigorous clinical setting.[37]

The CITRINE Study (NCT03118739)

The initial exploration into this new therapeutic area was the CITRINE study, a Phase IIa trial that evaluated the combination of Verinurad and febuxostat in patients with type 2 diabetes, hyperuricemia, and albuminuria (a key sign of kidney damage).[37] Although the study was small (n=60), a post-hoc analysis suggested a potential clinical benefit. After 12 weeks of treatment, the combination therapy appeared to reduce albuminuria.[39] While preliminary, this finding was encouraging enough to provide the rationale for launching larger, more definitive Phase IIb trials to confirm the effect.

The SAPPHIRE Trial (NCT03990363): Assessing Albuminuria-Lowering Effects in CKD

The SAPPHIRE trial was a large-scale Phase IIb study designed to formally assess the nephroprotective potential of Verinurad. Its primary objective was to determine if adding Verinurad to allopurinol could reduce the urinary albumin-to-creatinine ratio (UACR) in patients with CKD and hyperuricemia over a period of 6 to 12 months.[14]

The results of the SAPPHIRE trial were unequivocal: the study failed to meet its primary endpoint.[39] The combination of Verinurad and allopurinol, administered at various doses, did not produce a statistically significant reduction in albuminuria at 34 weeks when compared with either allopurinol alone or placebo. Furthermore, no beneficial effect was observed on the rate of eGFR decline after 60 weeks of treatment.[39] Although the drug combination was highly effective at lowering sUA levels, this potent pharmacodynamic effect did not translate into a meaningful clinical benefit on the key markers of kidney disease progression.

The AMETHYST Trial (NCT04327024): Targeting Endothelial Dysfunction in HFpEF

Concurrently, the AMETHYST trial was conducted to evaluate Verinurad in a cardiovascular context. This Phase II randomized trial enrolled patients with HFpEF and elevated sUA levels. The primary goal was to investigate whether the Verinurad-allopurinol combination could improve exercise capacity, as measured by peak oxygen uptake (VO2​), and patient-reported symptoms, assessed by the Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS).[16]

Similar to the SAPPHIRE trial, the AMETHYST trial also failed to meet its primary endpoints.[38] Despite achieving a substantial mean reduction in sUA of -59.6%, the combination therapy did not lead to any significant improvement in peak

VO2​ or KCCQ-TSS compared to either allopurinol monotherapy or placebo.[38]

Analysis of Primary Endpoint Failures and Implications for the Urate Hypothesis

The negative outcomes from both the SAPPHIRE and AMETHYST trials represent a significant setback for the urate hypothesis, at least in the context of treating established disease. The failure to translate profound sUA lowering into clinical benefit in either CKD or HFpEF strongly suggests that, in these patient populations, elevated uric acid may be a consequence of the underlying disease (e.g., reduced renal clearance in CKD) or a co-existing comorbidity, rather than a primary, modifiable driver of disease progression. These results have provided crucial, albeit disappointing, evidence that challenges the therapeutic strategy of targeting uric acid to alter the course of established cardiorenal diseases.

Trial Name (ID)	Patient Population	Intervention	Primary Endpoint	Result	Source(s)
SAPPHIRE (NCT03990363)	Chronic Kidney Disease (CKD) with Albuminuria & Hyperuricemia	Verinurad + Allopurinol vs. Allopurinol vs. Placebo	Change in Urinary Albumin-to-Creatinine Ratio (UACR)	Failed. No significant reduction in UACR or eGFR decline.	14
AMETHYST (NCT04327024)	Heart Failure with Preserved Ejection Fraction (HFpEF) & Hyperuricemia	Verinurad + Allopurinol vs. Allopurinol vs. Placebo	Change in Peak Oxygen Uptake (VO2​) and KCCQ-TSS	Failed. No significant improvement in exercise capacity or symptoms.	38

Comprehensive Safety and Tolerability Profile

Consolidated Analysis of Adverse Events

Across its extensive clinical development program, Verinurad has been studied in various populations and therapeutic contexts. In general, particularly when administered in combination with an XOI, Verinurad has been shown to be well-tolerated.[1] In many of the controlled trials, the overall proportion of patients experiencing treatment-emergent adverse events (TEAEs) was similar between the Verinurad combination groups and the control groups (placebo or XOI alone).[2]

Focus on Renal Safety

Renal safety has been the most closely scrutinized aspect of Verinurad's profile, a direct consequence of its mechanism of action.

• Monotherapy: As established in the Phase II gout trials, Verinurad administered as a monotherapy is associated with an increased risk of renal-related adverse events, most notably transient elevations in serum creatinine.[9] This is considered an on-target effect resulting from the rapid and substantial increase in urinary urate concentration, which can lead to urate crystal precipitation in the tubules. This risk was deemed significant enough to preclude its development as a standalone therapy for gout.[30]
• Combination Therapy: The co-administration of Verinurad with an XOI was the primary strategy developed to mitigate this renal risk and prevent Verinurad-induced urate nephropathy.[38] This approach proved to be effective. In the large Phase IIb trials for CKD (SAPPHIRE) and HFpEF (AMETHYST), where all patients receiving Verinurad also received an XOI, the safety profile was favorable. The proportion of patients experiencing adverse events and serious adverse events was balanced across all treatment groups, and no new or unexpected safety signals emerged.[38]

Cardiovascular Safety Assessment

The cardiovascular safety of Verinurad was assessed in the AMETHYST trial, which enrolled patients with HFpEF, a population at high risk for cardiovascular events. While the study was not powered to definitively assess cardiovascular outcomes, the observed data were reassuring. The incidence of death or adjudicated cardiovascular events was numerically lower in the group receiving Verinurad plus allopurinol (3 events, 5.7%) compared to both the allopurinol monotherapy group (8 events, 15.1%) and the placebo group (6 events, 11.3%).[38] This finding, while not statistically significant, suggests that the drug does not carry an obvious cardiovascular risk and may even be favorable, though this would require confirmation in a much larger outcomes trial.

Drug-Drug Interaction Profile

The potential for drug-drug interactions has also been investigated. Pharmacodynamically, the therapeutic efficacy of Verinurad can be diminished when it is used in combination with thiazide diuretics (e.g., hydrochlorothiazide, chlorothiazide, bendroflumethiazide).[3] This is an expected interaction, as thiazide diuretics are known to inhibit uric acid secretion and raise sUA levels, thereby counteracting the effect of a uricosuric agent. Specific pharmacokinetic interaction studies have also been conducted, for example, to assess the effects of co-administration with cyclosporine and rifampicin.[16]

Developmental and Regulatory Context

Corporate History: From Ardea Biosciences to AstraZeneca

Verinurad's journey began in the pipeline of Ardea Biosciences, a biotechnology company based in San Diego, California.[42] In a significant strategic move to enter the gout market, AstraZeneca acquired Ardea Biosciences in 2012 for approximately $1 billion.[42] The primary driver for the acquisition was Ardea's lead candidate, lesinurad, which was already in Phase III development. However, the deal also included Ardea's earlier-stage assets, notably what was described as a "promising next-generation gout programme," which featured Verinurad (then known as RDEA3170 and in Phase I).[42] Following the acquisition, the development of AstraZeneca's entire gout portfolio, including both lesinurad and Verinurad, was led by the Ardea Biosciences subsidiary.[43]

Comparative Analysis: Verinurad vs. Lesinurad and Other Uricosurics

To understand Verinurad's place in the therapeutic landscape, it is essential to compare it with other uricosuric agents.

• vs. Lesinurad: Verinurad is structurally related to lesinurad and was developed as a more potent and selective successor.[12] Lesinurad (Zurampic) was approved by the FDA in 2015 but its label included a black box warning for acute renal failure, and it was mandated for use only in combination with an XOI.[35] Verinurad's development mirrored these safety concerns, but it did not ultimately advance to regulatory submission for gout.
• vs. Probenecid: Probenecid is a much older uricosuric agent that is still used clinically.[46] Compared to probenecid, Verinurad offers vastly superior target selectivity and potency. However, both drugs share the same fundamental class risk of precipitating uric acid kidney stones, which necessitates patient counseling on maintaining adequate hydration.[35]
• vs. Benzbromarone: Benzbromarone is another potent uricosuric that was removed from many European markets due to reports of severe, sometimes fatal, hepatotoxicity.[9] Verinurad has not been associated with this risk, highlighting the improved safety profile of modern, highly selective SURIs with respect to liver function.

Market Context and the Discontinuation of Lesinurad (Zurampic, Duzallo)

The commercial trajectory of lesinurad provides critical context for the decisions made regarding Verinurad's development. Despite being an effective, FDA-approved medication, lesinurad failed to achieve commercial success. AstraZeneca licensed the US rights to Ironwood Pharmaceuticals in 2016.[43] By 2019, Ironwood had discontinued both Zurampic and the fixed-dose combination Duzallo, citing "business reasons".[34] The market failure was attributed to a combination of factors: the high price of a branded drug in a therapeutic area dominated by inexpensive and effective generics like allopurinol; physician reluctance to adopt new uricosurics due to the well-known renal risks; and the added complexity of requiring combination therapy from the outset.[34] This precedent created a formidable commercial barrier for any new branded uricosuric. It demonstrated that even a clinically successful drug could fail in the marketplace, a cautionary tale that undoubtedly influenced AstraZeneca's decision to halt the costly Phase III development of Verinurad for gout, even in the face of positive Phase II combination data.

Conclusion and Future Outlook

Summary of Verinurad's Developmental Trajectory

The development history of Verinurad is a compelling narrative that encapsulates many of the complexities and challenges of modern pharmaceutical research and development. It began as a pharmacologically superior, "best-in-class" molecule—a highly potent and selective URAT1 inhibitor that demonstrated exceptional sUA-lowering efficacy. However, its very potency proved to be its primary liability in the context of gout, as the on-target effect of rapid uricosuria created an unacceptable risk of renal adverse events when used as a monotherapy.

While this risk was effectively mitigated through combination therapy with XOIs, the program was ultimately halted, likely due to a challenging commercial landscape heavily influenced by the market failure of its predecessor, lesinurad. The subsequent strategic pivot to test the urate hypothesis in CKD and HFpEF was a scientifically rational and ambitious attempt to salvage a valuable asset. However, this high-risk endeavor did not succeed, as the profound sUA lowering failed to translate into clinical benefits in these established disease states.

Critical Assessment of its Therapeutic Potential

Verinurad remains an exceptionally powerful pharmacological tool for reducing serum uric acid. For the treatment of gout, the clinical data strongly indicate that its potential could only be realized as part of a combination therapy with an XOI. In this role, it is highly effective, but its path to market is likely closed due to commercial considerations.

For the indications of CKD and HFpEF, the current evidence from the SAPPHIRE and AMETHYST trials does not support its use. The negative results from these well-designed trials are a significant contribution to the medical literature, casting considerable doubt on the hypothesis that lowering sUA is a viable strategy for modifying the course of these diseases once they are established. This suggests that in these conditions, hyperuricemia may be more of a consequence or a biomarker of disease severity and poor outcomes rather than a causal and modifiable risk factor.

Unanswered Questions and Future Directions for Research

The story of Verinurad leaves several important questions unanswered. While lowering sUA may not be effective in treating established CKD or HFpEF, could it play a role in the prevention of these conditions in high-risk individuals with hyperuricemia? This remains an open and important area for future research. The failure of the urate hypothesis in these trials underscores the critical importance of distinguishing between epidemiological association and biological causation when selecting therapeutic targets. The journey of Verinurad serves as a valuable lesson in drug development, illustrating how a molecule with exemplary pharmacology can ultimately fail to become a medicine due to a complex interplay of on-target safety liabilities, challenging commercial dynamics, and the failure of a plausible but ultimately unproven biological hypothesis.

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