AZD-1305: A Comprehensive Monograph on a Multi-Ion Channel Blocker for Atrial Fibrillation

Executive Summary

AZD-1305 was an investigational small molecule antiarrhythmic agent developed by AstraZeneca for the management and pharmacological conversion of atrial fibrillation (AF). Its development was predicated on a sophisticated therapeutic hypothesis aimed at overcoming the principal limitation of existing Class III antiarrhythmic drugs: the risk of life-threatening ventricular proarrhythmia. The drug was rationally designed as a multi-ion channel blocker, combining potent inhibition of the rapid component of the delayed-rectifier potassium current ($I_{Kr}$) with targeted blockade of the late inward sodium current ($I_{NaLate}$) and the L-type calcium current ($I_{CaL}$). This combination was intended to preserve the atrial antiarrhythmic efficacy derived from prolonging the action potential duration while simultaneously suppressing the cellular mechanisms, such as early afterdepolarizations (EADs), that trigger Torsade de Pointes (TdP).

Preclinical studies robustly supported this hypothesis. In various animal models, AZD-1305 demonstrated a desirable atrial-predominant electrophysiological profile, prolonging the effective refractory period more in atrial than in ventricular tissue. Critically, in direct comparisons with selective $I_{Kr}$ blockers like dofetilide, AZD-1305 produced a similar degree of QT interval prolongation but with a markedly lower incidence of TdP and less repolarization instability. These compelling preclinical findings provided a strong rationale for advancing the compound into human trials.

The clinical development program confirmed the drug's efficacy. In a pivotal Phase 2, dose-escalating study (NCT00915356), intravenous AZD-1305 demonstrated a clear dose-dependent ability to convert patients with recent-onset AF to normal sinus rhythm, achieving a conversion rate of 50% at the highest dose. However, this efficacy was inextricably linked to significant safety concerns. The trial revealed dose-dependent prolongation of the QT interval and, decisively, the emergence of TdP in two patients, one of whom required defibrillation. This clinical outcome directly contradicted the safety profile predicted by the preclinical models.

Ultimately, the benefit-risk profile for AZD-1305 was judged to be unfavorable, leading to the discontinuation of its development program. The story of AZD-1305 serves as a significant and cautionary case study in cardiovascular pharmacology. It highlights the profound challenge of the "translation gap"—the failure of even well-validated animal models to accurately predict human cardiac safety—and underscores the inherent difficulty of separating the therapeutic and proarrhythmic effects of drugs that potently block the hERG channel. Its failure has contributed to a broader shift in AF drug development, moving away from pure ion channel modulation and toward novel "upstream" therapies that target the underlying structural and inflammatory substrate of the arrhythmia.

1.0 Introduction: The Quest for a Safer Antiarrhythmic Agent

1.1 The Clinical Challenge of Atrial Fibrillation

Atrial fibrillation (AF) is the most commonly encountered sustained cardiac arrhythmia in clinical practice. It is characterized by disorganized, rapid, and irregular electrical activation of the atria, leading to an ineffective atrial contraction and an irregular, often rapid, ventricular response.[1] The pathophysiology of AF is complex, involving triggers such as early afterdepolarizations (EADs) and a susceptible atrial substrate, often remodeled by underlying conditions like hypertension, heart failure, and cardiomyopathies.[1] The clinical consequences of AF are significant, contributing to an increased risk of ischemic stroke, systemic embolism, heart failure, and overall mortality.[2]

Therapeutic strategies for AF are broadly divided into rate control, which aims to manage the ventricular response, and rhythm control, which seeks to restore and maintain normal sinus rhythm. While both are valid approaches, rhythm control is often preferred to alleviate symptoms and potentially modify the progressive nature of the arrhythmia.[2] Pharmacological rhythm control has historically relied on antiarrhythmic drugs (AADs), but their use is frequently limited by a narrow therapeutic window, incomplete efficacy, and the potential for serious adverse effects, most notably proarrhythmia.[2] This persistent trade-off between efficacy and safety has driven a decades-long search for novel AADs with improved therapeutic profiles.

1.2 The Proarrhythmic Risk of IKr Blockade

A cornerstone of rhythm-control therapy has been the use of Class III AADs. The defining mechanism of this class is the blockade of the rapid component of the delayed-rectifier potassium current ($I_{Kr}$), which is conducted by protein channels encoded by the human ether-a-go-go-related gene (hERG).[1] By inhibiting this major repolarizing current, Class III agents prolong the duration of the cardiac action potential (APD) and, consequently, the effective refractory period (ERP) of cardiac myocytes.[1] This increase in refractoriness is the primary basis for their antiarrhythmic effect, as it makes the myocardial tissue less susceptible to the high-frequency re-entrant circuits that sustain AF.

However, this mechanism carries an intrinsic and dangerous liability. Excessive prolongation of the APD can destabilize cardiac repolarization, creating a vulnerable window during which EADs can occur.[1] EADs are abnormal depolarizations that arise during the plateau or repolarization phase of the action potential and can trigger life-threatening polymorphic ventricular tachycardia, a specific form known as Torsade de Pointes (TdP).[1] This risk is not a rare side effect but a direct, mechanism-based consequence of potent $I_{Kr}$ blockade. The challenge for drug developers has therefore been to find a way to harness the antiarrhythmic benefit of APD prolongation while mitigating the inherent risk of TdP.[5]

1.3 Rationale for Multi-Ion Channel Blockade: The Therapeutic Hypothesis for AZD-1305

The development of AZD-1305 by AstraZeneca represented a highly rational and sophisticated attempt to solve the proarrhythmia dilemma of $I_{Kr}$ blockade. Rather than pursuing greater selectivity for the hERG channel, the strategy was to design a molecule with a carefully curated profile of "off-target" effects—a concept of rationally designed polypharmacology. The central therapeutic hypothesis was that by combining potent $I_{Kr}$ blockade with simultaneous inhibition of other key cardiac ion currents, it would be possible to uncouple the desired antiarrhythmic efficacy from the undesired proarrhythmic risk.[1]

The key secondary targets for AZD-1305 were the late inward sodium current ($I_{NaLate}$) and the L-type calcium current ($I_{CaL}$).[1] Both of these inward currents are known to be critical contributors to the formation of EADs. During the prolonged action potential plateau caused by $I_{Kr}$ blockade, reactivation of these channels can provide the depolarizing charge necessary to trigger an EAD.[1] The hypothesis, therefore, was that by concurrently blocking $I_{NaLate}$ and $I_{CaL}$, AZD-1305 would suppress the triggers for TdP, effectively building a safety mechanism directly into its pharmacological profile. This approach aimed to stabilize repolarization and prevent the excessive APD prolongation and beat-to-beat variability that are hallmarks of proarrhythmia, while preserving the beneficial increase in atrial refractoriness.[1] AZD-1305, and its predecessor compound AZD7009, were the embodiment of this strategy, representing a deliberate move away from the "magic bullet" paradigm of single-target selectivity toward a more holistic, multi-target approach to creating a safer and more effective antiarrhythmic agent.[5]

2.0 Chemical Profile and Physicochemical Properties

2.1 Identification and Nomenclature

AZD-1305 is a small molecule drug candidate identified by a comprehensive set of chemical and regulatory codes. It is most commonly referred to by its experimental drug name, AZD-1305 (also written as AZD1305 or AZD 1305).[11] Its primary identifiers across major scientific databases include:

• DrugBank Accession Number: DB11766 [1]
• CAS Registry Number: 872045-91-5 [1]
• PubChem Compound ID (CID): 15605092 and 44182376 [1]
• ChEMBL ID: CHEMBL3545169 [1]
• UNII (Unique Ingredient Identifier): CZO834LXQM [11]

The formal chemical nomenclature for the compound is provided by its IUPAC names, which include 2-Methyl-2-propanyl (2-{7-[2-(4-cyano-2-fluorophenoxy)ethyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethyl)carbamate and the stereochemically specific tert-butyl N--9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl]ethyl]carbamate.[1]

2.2 Molecular Structure and Stereochemistry

AZD-1305 has the molecular formula $C_{22}H_{31}FN_{4}O_{4}$ and a molar mass of approximately 434.51 g·mol⁻¹.[1] The molecule's architecture is centered on a rigid bicyclic scaffold known as oxabispidine, or 9-oxa-3,7-diazabicyclo[3.3.1]nonane.[16] This core structure was a key feature in a series of antiarrhythmic compounds developed by AstraZeneca, valued for its conformational rigidity and ability to correctly orient functional side chains toward their molecular targets.[17]

The specific stereoisomer developed for clinical use is defined by the (1R,5S) configuration of the oxabispidine ring, as indicated in its formal IUPAC name and stereospecific chemical identifiers.[11]

• Stereospecific InChI: InChI=1S/C22H31FN4O4/c1-22(2,3)31-21(28)25-6-7-26-12-17-14-27(15-18(13-26)30-17)8-9-29-20-5-4-16(11-24)10-19(20)23/h4-5,10,17-18H,6-9,12-15H2,1-3H3,(H,25,28)/t17-,18+ [11]
• Stereospecific InChIKey: BLLNYXOLLAVTRF-HDICACEKSA-N [11]
• Stereospecific SMILES: CC(C)(C)OC(=O)NCCN1C[C@@H]2CN(C[C@H](C1)O2)CCOC3=C(C=C(C=C3)C#N)F [11]

These identifiers precisely describe the three-dimensional arrangement of the molecule that was subjected to pharmacological and clinical evaluation.

2.3 Physicochemical Characteristics and Formulation Considerations

The transition of AZD-1305 from a chemical entity to a viable drug product involved navigating several challenging physicochemical properties. These material science hurdles are distinct from the compound's pharmacological activity but are equally critical for successful drug development. The decision to advance the compound despite these non-ideal characteristics underscores the high level of confidence in its underlying therapeutic hypothesis at the time.

The free base of AZD-1305 is a crystalline solid with limited aqueous solubility, reported at 0.0833 mg/mL, while being readily soluble in organic solvents like DMSO.[13] Its lipophilicity is moderate, with a calculated logP value in the range of 1.83 to 2.28.[13] The compound is a base with a measured pKa of 9.9 and is subject to degradation at elevated temperatures and in acidic conditions.[16]

A significant challenge in its solid-state characterization was the discovery of polymorphism. AZD-1305 exists in at least two crystalline forms, designated Form A and Form B.[16] The presence of multiple polymorphs can pose a major risk during development, as an unintended conversion from a metastable to a more stable form can alter solubility, dissolution rate, and ultimately, bioavailability. Extensive analysis determined that Form B was the most thermodynamically stable polymorph in the relevant temperature range and was therefore selected for further development.[16] This finding was later supported by advanced computational crystal structure prediction workflows, demonstrating the utility of modern in silico tools in de-risking solid form selection.[21]

Further pre-formulation challenges included a relatively low melting point of approximately 90°C for both forms, which can complicate manufacturing processes, and a strong, undesirable odor associated with the substance. The development team addressed the latter issue by increasing the particle size of the drug substance, which successfully reduced the odor.[16] After a comprehensive salt screening campaign failed to identify a salt form with superior overall properties, the free base of Form B was chosen as the active pharmaceutical ingredient for product development.[16]

Table 1: Key Identifiers and Physicochemical Properties of AZD-1305

Property	Value	Source(s)
DrugBank ID	DB11766	1
CAS Number	872045-91-5	1
IUPAC Name	tert-butyl N--9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl]ethyl]carbamate	11
Molecular Formula	$C_{22}H_{31}FN_{4}O_{4}$	1
Molar Mass	434.512 g·mol⁻¹	1
Water Solubility	0.0833 mg/mL	13
logP	1.83 - 2.28	13
pKa (Strongest Basic)	6.5 (Predicted), 9.9 (Measured)	13
Polymorphic Forms	2 (Form A, Form B)	16
Melting Point	~90°C	16
Hydrogen Bond Donors	1	13
Hydrogen Bond Acceptors	6	13

3.0 Preclinical Pharmacology and Mechanism of Action

3.1 Multi-Ion Channel Blockade Profile

The pharmacological activity of AZD-1305 is defined by its concurrent blockade of three distinct cardiac ion currents, a profile designed to optimize its antiarrhythmic and safety properties.

3.1.1 Inhibition of the Rapid Delayed-Rectifier Potassium Current (IKr / hERG)

Consistent with its classification as a Class III antiarrhythmic agent, the primary action of AZD-1305 is the potent blockade of the hERG potassium channel, which mediates the $I_{Kr}$ current.[1] This inhibition of a key repolarizing outward current is the fundamental mechanism by which AZD-1305 prolongs the cardiac action potential duration, a key requirement for terminating and preventing re-entrant arrhythmias like AF.[1]

3.1.2 Attenuation of the Peak and Late Sodium Currents (INapeak / INalate)

A critical feature of AZD-1305's mechanism is its inhibitory effect on the voltage-gated sodium channel Nav1.5.[1] Importantly, this blockade is not uniform. The drug exhibits a marked preference for the small, non-inactivating late component of the sodium current ($I_{NaLate}$) over the large, transient peak current ($I_{NaPeak}$) that is responsible for the rapid upstroke of the action potential.[1] In vitro patch-clamp studies in canine cardiomyocytes quantified this selectivity, determining a half-maximal inhibitory concentration ($IC_{50}$) of 4.3 µM for $I_{NaLate}$ and 66 µM for $I_{NaPeak}$.[8] This approximately 15-fold selectivity for the late current is central to the drug's intended safety profile, as $I_{NaLate}$ is a major contributor to the generation of EADs, and its inhibition is expected to stabilize repolarization without significantly depressing cardiac conduction.[1]

3.1.3 Blockade of the L-type Calcium Current (ICaL)

The third component of AZD-1305's profile is the blockade of voltage-gated L-type calcium channels.[1] The inward calcium current ($I_{CaL}$) during the action potential plateau also contributes to the depolarizing forces that can trigger EADs, particularly under conditions of APD prolongation.[1] By inhibiting $I_{CaL}$, AZD-1305 was designed to provide an additional layer of protection against TdP, suppressing the calcium oscillations that can lead to triggered arrhythmias.[1]

3.2 Atrial-Predominant Electrophysiological Effects

A highly desirable feature for an AF therapeutic is atrial selectivity, which promises to maximize efficacy in the target chamber while minimizing potentially harmful effects on the ventricles. Preclinical studies in canine models consistently demonstrated that AZD-1305 possesses such a profile.[9]

3.2.1 Differential Effects on Atrial vs. Ventricular Action Potential

In vitro and in vivo canine studies revealed that AZD-1305 prolongs the APD and ERP to a significantly greater extent in atrial tissue compared to ventricular tissue.[1] This atrial-predominant effect on repolarization is a key aspect of its therapeutic potential, concentrating its antiarrhythmic action where it is needed most.

3.2.2 Impact on Refractoriness, Conduction, and Excitability

The drug's sodium channel-blocking properties also translated into atrial-selective effects on excitability and conduction. AZD-1305 produced a greater use-dependent reduction in the maximum upstroke velocity of the action potential ($V_{max}$) in atrial myocytes (-51%) compared to ventricular myocytes (-31%) at a cycle length of 500 ms.[9] This indicates a more profound effect on sodium channel availability in the atria. This preferential block also led to a greater increase in the diastolic threshold of excitation (DTE) and a more significant slowing of conduction time in atrial versus ventricular preparations.[9] Furthermore, AZD-1305 induced post-repolarization refractoriness (PRR) in atrial tissue, a state where the tissue remains unexcitable even after full repolarization, which provides an additional anti-fibrillatory mechanism.[1]

Table 2: Summary of Preclinical Electrophysiological Effects of AZD-1305 in Canine Models

Parameter	Effect	Key Finding	Source(s)
Atrial APD	Prolonged	Preferential prolongation in atria vs. ventricles	25
Ventricular APD	Prolonged	Less pronounced prolongation compared to atria	25
Atrial $V_{max}$	Reduced	Greater use-dependent reduction (-51%) in atria	9
Ventricular $V_{max}$	Reduced	Less pronounced reduction (-31%) in ventricles	9
Atrial ERP	Increased	Greater increase in atria, due to APD prolongation and PRR	25
Diastolic Threshold of Excitation (DTE)	Increased	Preferential increase in atria	25
Atrial Conduction Time	Increased	Preferential slowing of conduction in atria	9

3.3 Preclinical Safety Pharmacology and Proarrhythmic Assessment

The preclinical data for AZD-1305 were remarkable not just for demonstrating efficacy but for appearing to validate the core therapeutic hypothesis of improved safety. The evidence suggested that the rational design had succeeded in creating a compound that retained the benefits of $I_{Kr}$ blockade while mitigating its chief danger.

3.3.1 Comparative Studies with Dofetilide

Head-to-head comparisons with dofetilide, a selective and potent $I_{Kr}$ blocker known for its proarrhythmic risk, were conducted in highly sensitive animal models. In the methoxamine-sensitized rabbit model, both AZD-1305 and dofetilide significantly prolonged the QT interval. However, while dofetilide induced TdP in 12 of 17 animals, AZD-1305 caused no TdP.[23] Similarly, in a canine model of chronic atrioventricular block, a condition that creates a substrate highly susceptible to TdP, dofetilide induced TdP in all 14 animals tested. In contrast, AZD-1305, despite causing a similar magnitude of QT prolongation, induced TdP in only 4 of 11 dogs.[7] In some experiments, AZD-1305 was even shown to be anti-arrhythmic, capable of suppressing TdP that had been induced by dofetilide.[5]

3.3.2 Effects on Repolarization Instability and Beat-to-Beat Variability

The mechanistic basis for this improved safety profile was investigated by examining markers of repolarization stability. A key finding was that dofetilide markedly increased the beat-to-beat variability of repolarization (BVR), a quantitative surrogate for TdP risk. In stark contrast, AZD-1305 did not significantly alter BVR, even while prolonging the APD.[7] This stabilizing effect was directly attributed to the drug's concurrent blockade of $I_{NaLate}$. By attenuating this inward current, AZD-1305 counteracted the repolarization instability and vulnerability to EADs that are precipitated by isolated $I_{Kr}$ inhibition.[1]

The consistency and strength of this preclinical evidence were compelling. The data from multiple models and methodologies all pointed to the same conclusion: the hypothesis was correct, and rational design had produced a potentially safer antiarrhythmic drug. This apparent success created a profound paradox when the drug entered clinical trials, as the failure of AZD-1305 was not due to a flawed preclinical rationale but rather to a fundamental inability of these animal models to predict the drug's effects in humans. This disconnect represents a stark example of the "translation gap" that remains a central challenge in cardiovascular drug development.

4.0 Pharmacokinetics and Metabolism

4.1 Absorption, Distribution, Metabolism, and Excretion (ADME) Profile in Humans

Phase 1 studies in healthy volunteers, such as NCT00689247, were conducted to characterize the disposition of AZD-1305 in the human body.[29] The data indicated that the drug is rapidly and extensively distributed following administration. The terminal elimination half-life was determined to be in the range of 5 to 12 hours.[10] This relatively short half-life made a standard immediate-release oral formulation unsuitable for a chronic, twice-daily maintenance therapy for AF, as it would lead to large fluctuations in plasma concentrations. This pharmacokinetic profile directly necessitated the development of an extended-release (ER) formulation to provide smoother, more sustained drug exposure over a 12-hour dosing interval.[16]

4.2 Influence of Formulation and Food on Pharmacokinetics

A dedicated Phase 1 study was performed to evaluate the pharmacokinetic performance of a new ER tablet formulation (ER1) relative to a reference formulation (ER-R) and to assess the impact of food.[31]

Under fasting conditions, a single 125 mg dose of the ER1 formulation produced an exposure profile similar to the reference formulation. Key pharmacokinetic parameters included a median time to maximum plasma concentration ($t_{max}$) of approximately 8.0 hours and a geometric mean terminal half-life ($t_{1/2}$) of about 10.6 hours, confirming the extended-release characteristics.[31]

The effect of food was assessed by administering the 125 mg ER1 tablet with a high-fat, high-calorie breakfast. The results showed that food had a minimal impact on the overall extent of absorption, as measured by the area under the plasma concentration-time curve (AUC). However, food did slightly decrease the peak plasma concentration ($C_{max}$) and modestly delayed the time to reach it, with the median $t_{max}$ increasing from 8.0 to 10.9 hours.[31]

The study also evaluated the formulation's performance under steady-state conditions with repeated dosing (50 mg twice daily). Steady-state concentrations were achieved after 5 days, with the drug exhibiting moderate accumulation; the accumulation ratio (Rac) for AUC was 2.9. The formulation provided a low fluctuation index of 0.51, indicating that it was successful in maintaining relatively stable plasma concentrations over the dosing interval, as intended.[31]

4.3 Cytochrome P450-Mediated Metabolism and Potential for Drug-Drug Interactions

A critical aspect of any drug's safety profile is its metabolic pathway and potential for interactions with other medications. Clinical and in silico studies revealed that AZD-1305 is primarily metabolized by the cytochrome P450 3A4 (CYP3A4) enzyme system.[10] This reliance on a single, major metabolic pathway creates a significant vulnerability to drug-drug interactions (DDIs).

This vulnerability was quantified in a dedicated DDI study (NCT00707551) where healthy volunteers received AZD-1305 alone and in combination with potent or moderate inhibitors of CYP3A4.[26] The results were dramatic. Co-administration with ketoconazole, a strong CYP3A4 inhibitor, resulted in a 7.7-fold increase in the AUC and a 4.8-fold increase in the $C_{max}$ of AZD-1305. Even a moderate inhibitor, verapamil, caused a 2.2-fold increase in AUC and a 2.0-fold increase in $C_{max}$.[26]

This metabolic profile constitutes a major clinical liability. The target patient population for AF is typically older and often has multiple comorbidities, such as hypertension, heart failure, and infections, resulting in polypharmacy. Many drugs commonly prescribed to these patients—including certain antibiotics (e.g., macrolides), antifungals, calcium channel blockers (diltiazem, verapamil), and amiodarone—are inhibitors of CYP3A4. A nearly eight-fold increase in exposure to an agent with a narrow therapeutic index and intrinsic proarrhythmic potential would be clinically unmanageable and would convert a therapeutic dose into a toxic one. This pharmacokinetic "Achilles' heel" would necessitate contraindicating a long list of common medications, creating a high risk of inadvertent overdose and severe adverse events in real-world clinical practice. This significant DDI potential almost certainly contributed to the overall assessment of an unfavorable benefit-risk profile.

5.0 Clinical Development Program

5.1 Phase 1 Studies: Safety, Tolerability, and Pharmacokinetics in Healthy Volunteers

The clinical development of AZD-1305 began with a series of Phase 1 studies designed to establish its safety, tolerability, and pharmacokinetic profile in healthy human subjects. These trials investigated both the intravenous formulation intended for acute cardioversion and various oral extended-release formulations for maintenance therapy.[12] The program included single and multiple ascending dose studies (e.g., NCT00688831) to define the dose-exposure relationship and identify the maximum tolerated dose.[26] To assess potential ethnic differences in drug handling, dedicated studies were conducted in both Japanese and Caucasian subjects (NCT00935025, NCT00738322).[12] These foundational studies provided the necessary safety and pharmacokinetic data to support the design and dosing regimens for the subsequent Phase 2 trials in patients.

5.2 Phase 2 Efficacy and Safety Studies

Following the initial characterization in healthy volunteers, the AZD-1305 program advanced into Phase 2 to evaluate its therapeutic potential in patients with cardiac arrhythmias.

5.2.1 Intravenous Cardioversion of Atrial Fibrillation (NCT00915356)

The pivotal study for the intravenous formulation was NCT00915356, a multicentre trial that ultimately determined the fate of the drug.

5.2.1.1 Study Design and Dose Escalation

This was a robustly designed, double-blind, randomized, placebo-controlled, dose-escalating study involving 228 enrolled patients with symptomatic AF of 3 hours to 3 months duration who had a clinical indication for cardioversion.[10] Patients were randomized in a 3:1 ratio to receive either AZD-1305 or a matching placebo via intravenous infusion for a maximum of 30 minutes.[10] The study employed four sequential, ascending dose groups with infusion rates of 50, 100, 130, and 180 mg/h.[10] The primary efficacy endpoint was the proportion of patients who converted from AF to normal sinus rhythm within 90 minutes of starting the infusion.[10] Key exclusion criteria were designed to minimize baseline risk and included serum potassium below 3.8 mmol/L and a baseline corrected QT interval (Fridericia's correction, QTcF) greater than 440 ms.[10]

5.2.1.2 Efficacy: Dose-Dependent Conversion Rates

The trial successfully demonstrated that AZD-1305 was effective in converting AF to sinus rhythm. The efficacy showed a clear dose-response relationship. While none of the 43 patients in the placebo group converted pharmacologically, the conversion rates in the AZD-1305 groups increased with dose: 8% (2 of 26) at 50 mg/h, 18% (8 of 45) at 100 mg/h, 38% (17 of 45) at 130 mg/h, and 50% (6 of 12) at 180 mg/h.[10] The differences versus placebo were statistically significant for the three highest doses ($p=0.006$ for the 100 mg/h group, and $p<0.001$ for the 130 mg/h and 180 mg/h groups), unequivocally establishing the drug's antiarrhythmic activity in humans.[10]

5.2.1.3 Safety: QT Prolongation and Torsade de Pointes

The demonstration of efficacy was overshadowed by critical safety findings that emerged at the therapeutic doses. As expected from its $I_{Kr}$-blocking mechanism, AZD-1305 caused a dose-dependent increase in the maximum QTcF interval, although there was considerable variability among individual patients.[10] The most serious adverse event was the occurrence of Torsade de Pointes. Two patients experienced this life-threatening arrhythmia: one patient in the 130 mg/h dose group experienced an asymptomatic episode, and a second patient in the highest dose group (180 mg/h) required emergency DC defibrillation.[10] Both patients recovered without lasting sequelae, but the occurrence of TdP in a controlled clinical trial setting was a decisive safety signal.

5.2.2 Studies in Atrial Flutter and Left Ventricular Dysfunction

The clinical development plan for AZD-1305 extended beyond AF. A completed Phase 2 invasive electrophysiology study (NCT00616629) evaluated the drug's effects in patients with atrial flutter, confirming that it prolonged effective refractory periods in both atria and the right ventricle in a clinical setting.[10] Another completed Phase 2 trial (NCT00748982) was conducted to investigate its effects in patients with left ventricular dysfunction, an important patient subgroup with a high prevalence of arrhythmias.[12] These studies indicate that AstraZeneca initially envisioned a broad clinical application for the compound.

Table 3: Overview of Key Clinical Trials for AZD-1305

NCT Identifier	Phase	Condition(s)	Purpose	Status	Source(s)
NCT00915356	2	Atrial Fibrillation	Efficacy and safety of IV cardioversion	Completed	12
NCT00616629	2	Atrial Flutter	Cardiac electrophysiology study	Completed	26
NCT00748982	2	Left Ventricular Dysfunction	Investigate effects on patients with LVD	Completed	12
D3190C00019	2	Atrial Fibrillation	Explore QTcF relationship with oral ER tablets	Completed	41
NCT00935025	1	Healthy Volunteers	Safety and PK of oral ER capsules (Japanese & Caucasian)	Terminated	12
NCT00957437	1	Healthy Volunteers	PK of different oral ER formulations	Completed	12
NCT00689247	1	Healthy Volunteers	ADME of oral and IV formulations	Completed	29

Table 4: Efficacy and Safety Results from the Phase 2 Cardioversion Trial (NCT00915356)

Dose Group (Infusion Rate)	Number of Patients (n)	Conversion Rate (%)	p-value vs. Placebo	Incidence of Torsade de Pointes (TdP)	Source(s)
Placebo	43	0%	-	0	10
50 mg/h	26	8%	0.14	0	10
100 mg/h	45	18%	0.006	0	10
130 mg/h	45	38%	<0.001	1 (Asymptomatic)	10
180 mg/h	12	50%	<0.001	1 (Required Defibrillation)	10

This table powerfully illustrates the central dilemma of AZD-1305. As the dose increased, the drug became progressively more effective at converting AF, fulfilling its therapeutic promise. However, this increase in efficacy was mirrored by the emergence of the very proarrhythmic event it was designed to prevent. The data clearly encapsulate the unfavorable benefit-risk profile that sealed the drug's fate.

6.0 Discontinuation and Critical Analysis

6.1 Unfavorable Benefit-Risk Profile: The Decisive Factor

The development of AZD-1305 was formally discontinued following the analysis of the Phase 2 cardioversion study (NCT00915356). The conclusion reached by the investigators and AstraZeneca was unambiguous: despite demonstrating dose-dependent efficacy in converting atrial fibrillation to sinus rhythm, the drug was associated with an unacceptable risk of QT prolongation and Torsade de Pointes. The benefit of pharmacological cardioversion did not outweigh the risk of inducing a potentially fatal ventricular arrhythmia. This unfavorable benefit-risk profile made further clinical development untenable.[10]

6.2 Lessons Learned from the AZD-1305 Program

The failure of AZD-1305, a product of sophisticated rational drug design, offers critical lessons for the field of antiarrhythmic therapy and cardiovascular drug development as a whole.

6.2.1 The Challenge of Translating Preclinical Safety to Clinical Outcomes

The most salient lesson from the AZD-1305 program is the stark demonstration of the "translation gap" in cardiac safety pharmacology. The preclinical evidence was overwhelmingly positive, suggesting that the multi-ion channel blocking strategy had successfully mitigated the proarrhythmic risk associated with $I_{Kr}$ inhibition.[7] The drug performed exactly as hypothesized in sensitive animal models, showing a clear safety advantage over a pure $I_{Kr}$ blocker. However, this meticulously constructed preclinical safety case collapsed in human trials. The emergence of TdP in patients, despite the protective secondary channel blocks, serves as a powerful cautionary tale. It underscores that while animal models are essential for understanding mechanisms and generating hypotheses, they cannot fully replicate the complex and subtle electrophysiological milieu of the human heart, particularly in a diverse patient population with underlying disease. The quantitative balance of currents required to prevent proarrhythmia in humans may be fundamentally different from that in preclinical species, a nuance that proved fatal to the AZD-1305 hypothesis.

6.2.2 The Enduring Dilemma of QT Prolongation in Antiarrhythmic Therapy

The AZD-1305 story also forces a critical re-evaluation of strategies centered on potent hERG channel blockade. The program was arguably one of the most advanced attempts to "engineer out" the proarrhythmic risk of this mechanism. Its failure suggests that for drugs whose primary antiarrhythmic effect relies on a significant prolongation of the QT interval via $I_{Kr}$ inhibition, the therapeutic window in a heterogeneous clinical population may be intrinsically and perhaps irreducibly narrow.[5] The wide inter-patient variability in QT response observed in the clinical trial highlights this challenge; a dose that is safe for one patient may be proarrhythmic for another.[10] This suggests that achieving a clinically meaningful level of $I_{Kr}$ blockade for effective AF conversion may be inseparable from an unacceptable level of TdP risk, regardless of concomitant blockade of other channels.

6.3 The Legacy of AZD-1305 and the Future of Atrial Fibrillation Drug Development

The discontinuation of AZD-1305, along with other promising multi-ion channel blockers, marked a significant turning point in the field. The repeated failures of drugs designed to modulate cardiac electrophysiology have tempered enthusiasm for strategies focused solely on ion channels and have catalyzed a shift toward novel therapeutic paradigms.[2] The current understanding of AF has evolved from viewing it as a purely electrical problem to recognizing it as an "atriomyopathy"—a progressive disease characterized by underlying structural, fibrotic, and inflammatory remodeling of the atria.[2]

Consequently, the focus of modern drug development has increasingly moved "upstream" to target these foundational disease processes. The legacy of AZD-1305 is that of a valuable failure. It represented the apex of a specific drug design philosophy, and its inability to translate to the clinic provided a clear signal that new approaches were needed. Future advancements in AF therapy are now more likely to come from agents that prevent or reverse atrial remodeling, target metabolic or inflammatory pathways, or modulate cell-cell coupling, rather than from yet another attempt to fine-tune the delicate balance of cardiac ion currents.[44] In this context, AZD-1305 stands as a critical data point that has helped guide the quest for a safe and effective AF therapy down more promising paths.

7.0 References

[1]

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