AZD-1656: A Comprehensive Monograph on a Glucokinase Activator's Journey from Metabolic Regulation to Immunomodulation

Executive Summary

AZD-1656 is an investigational, orally active, small molecule that functions as a potent and selective allosteric activator of the enzyme glucokinase (GCK). Originally developed by AstraZeneca as a novel therapy for Type 2 Diabetes Mellitus (T2DM), the compound demonstrated promising short-term efficacy in lowering blood glucose levels through a dual mechanism of enhancing glucose-stimulated insulin secretion from the pancreas and promoting hepatic glucose uptake. However, despite its initial success, the development program for T2DM was discontinued following Phase 2b trials, which revealed a lack of durable, long-term glycemic control and raised potential concerns regarding hepatic lipid accumulation in certain preclinical contexts.

The trajectory of AZD-1656 underwent a significant strategic pivot following the discovery of GCK's critical role in regulating the metabolism and function of immune cells, particularly regulatory T cells (Tregs). This immunomodulatory potential was substantiated in the Phase 2 ARCADIA trial, which, while failing its primary endpoint in hospitalized COVID-19 patients, provided the first human proof-of-concept for the drug's ability to rebalance the immune system. These findings catalyzed the asset's revival.

In 2024, Conduit Pharmaceuticals exclusively licensed AZD-1656 from AstraZeneca, repositioning it for high-unmet-need autoimmune diseases. The drug's most significant asset is its extensive safety database, established across more than 20 clinical trials involving over 1,000 subjects. A comprehensive meta-analysis confirms its favorable tolerability profile, with the primary adverse event of note being a manageable, non-statistically significant trend towards hypoglycemia. This established safety profile substantially de-risks its further development. Conduit is now advancing AZD-1656 into Phase 2a clinical trials for Systemic Lupus Erythematosus (SLE) and ANCA-associated Vasculitis (AAV), supported by a robust and expanding intellectual property portfolio of new composition-of-matter and method-of-use patents. The future of AZD-1656 now hinges on demonstrating clinical efficacy in these new indications, where its novel, non-steroidal immunomodulatory mechanism could represent a first-in-class therapeutic approach.

1.0 Drug Identification and Physicochemical Profile

This section establishes the definitive chemical, structural, and physical identity of AZD-1656, consolidating all known identifiers and properties into a comprehensive reference.

1.1 Nomenclature and Identifiers

To ensure unambiguous identification across scientific literature, clinical trial registries, and chemical databases, the compound is cataloged under several names and identifiers.

• Generic Name: AZD-1656 [1]
• Synonyms: AZD-1656, AZD 1656, AZD1656 [2]
• DrugBank ID: DB14810 [1]
• CAS Number: 919783-22-5 [4]
• Other Identifiers:
• PubChem Compound ID (CID): 16039797 [4]
• UNII (Unique Ingredient Identifier): 660M185X4D [4]
• ChEMBL ID: CHEMBL3219124 [7]
• Guide to Pharmacology (GtoPdb) Ligand ID: 7701 [7]

1.2 Molecular Structure and Chemical Classification

AZD-1656 is a synthetic organic compound with a complex structure designed for specific biological target engagement.

• Modality: Small Molecule [1]
• Molecular Formula: C24​H26​N6​O5​ [2]
• Molecular Weight: The average molecular weight is approximately 478.5 g/mol, with a monoisotopic mass of 478.1965 Da.[2]
• IUPAC Name: 3-((5-(azetidin-1-ylcarbonyl)pyrazin-2-yl)oxy)-5-((1S)-2-methoxy-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide [2]
• SMILES (Isomeric): COC[C@@H](Oc1cc(Oc2ncc(nc2)C(=O)N2CCC2)cc(c1)C(=O)Nc1ncc(nc1)C)C [2]
• InChIKey: FJEJHJINOKKDCW-INIZCTEOSA-N [2]
• Chemical Classification: Structurally, AZD-1656 is classified as a diarylether, containing two aryl groups linked by an ether functional group.[1] Its architecture incorporates several key functional motifs, including azetidine, pyrazine, and benzamide groups, which contribute to its binding affinity and pharmacological properties.[1]

1.3 Physicochemical Properties and Druglikeness Assessment

The physicochemical properties of AZD-1656 were optimized during its development to support oral administration and favorable pharmacokinetic behavior.

• Solubility: The compound exhibits very low intrinsic water solubility, measured at 0.0443 mg/mL.[1] This characteristic necessitates the use of enabling formulations for clinical administration. It is highly soluble in organic solvents like Dimethyl sulfoxide (DMSO) at concentrations up to 250 mg/mL.[5] Various formulation protocols have been developed to enhance its solubility for in vivo studies, utilizing co-solvents and excipients such as DMSO, PEG300, Tween-80, and sulfobutylether-beta-cyclodextrin (SBE-β-CD).[5]
• Lipophilicity: The partition coefficient (logP), a measure of lipophilicity, has been calculated by various models to be in the range of 0.8 to 2.88, indicating moderate lipophilicity that balances membrane permeability with aqueous solubility.[1]
• Hydrogen Bonding Capacity: The molecule has 1 hydrogen bond donor and between 9 and 11 hydrogen bond acceptors, depending on the computational model used.[1]
• Polar Surface Area (PSA): The topological polar surface area is consistently calculated as 128.66 A˚2, a key determinant of membrane permeability and oral absorption.[1]
• Druglikeness Assessment: AZD-1656 was designed to conform to established guidelines for oral drug candidates. It is compliant with Lipinski's Rule of Five, the Ghose Filter, and the MDDR-like Rule, predicting good oral bioavailability.[1] However, it is noted to violate Veber's Rule, likely due to its number of rotatable bonds.[1]

The physicochemical profile of AZD-1656 reflects a deliberate property-based design strategy, a common approach in modern medicinal chemistry to co-optimize potency and drug-like properties from an early stage.[10] While the core molecule possesses favorable characteristics for oral absorption and bioavailability, its low aqueous solubility presents a significant biopharmaceutical hurdle. The necessity for complex formulations to achieve therapeutic exposure in clinical trials underscores that the final drug product's performance is as critical as the active pharmaceutical ingredient's intrinsic properties. This reliance on formulation technology is a key consideration for manufacturing scalability, complexity, and the ultimate cost of goods, and is an area of active development by its current sponsor.[11]

Table 1: Key Identification and Physicochemical Properties of AZD-1656

Property	Value	Source(s)
Generic Name	AZD-1656	1
Key Identifiers	CAS: 919783-22-5; DrugBank ID: DB14810; PubChem CID: 16039797	1
Molecular Formula	C24​H26​N6​O5​	2
Molecular Weight	478.5 g/mol	2
IUPAC Name	3-((5-(azetidin-1-ylcarbonyl)pyrazin-2-yl)oxy)-5-((1S)-2-methoxy-1-methylethoxy)-N-(5-methylpyrazin-2-yl)benzamide	2
Isomeric SMILES	COC[C@@H](Oc1cc(Oc2ncc(nc2)C(=O)N2CCC2)cc(c1)C(=O)Nc1ncc(nc1)C)C	2
Water Solubility	0.0443 mg/mL	1
logP (Range)	0.8 – 2.88	1
Polar Surface Area	128.66 A˚2	1
Rule of Five Compliance	Yes	1

2.0 Preclinical and Clinical Pharmacology

This section details the biological mechanisms of AZD-1656, tracing the scientific understanding from its intended role as a metabolic regulator to its subsequently discovered and now primary role as an immunomodulatory agent.

2.1 Primary Mechanism of Action: Allosteric Activation of Glucokinase

The primary molecular target of AZD-1656 is the enzyme Glucokinase (GCK), also referred to as Hexokinase-4 (UniProt ID: P35557).[1]

• Mechanism of Activation: AZD-1656 is a potent, selective, and orally active allosteric activator of GCK.[5] It binds to a site on the enzyme that is distinct from the glucose-binding site, inducing a conformational change that stabilizes the enzyme in a more active state. This enhances the binding of glucose and accelerates its phosphorylation to glucose-6-phosphate.[12] The compound exhibits high potency, with a half-maximal effective concentration ( EC50​) of 60 nM.[5] Furthermore, it demonstrates high selectivity, with an over 100-fold preference for GCK compared to other hexokinase isozymes, minimizing off-target effects on glucose metabolism in other tissues.[13]
• Physiological Role of Glucokinase: GCK is a critical enzyme in mammalian glucose homeostasis, functioning as a "glucose sensor" in specialized cells.[14] Its expression is largely restricted to tissues central to systemic glucose regulation: the β-cells of the pancreas and the hepatocytes of the liver.[1] GCK catalyzes the first, rate-limiting step in glycolysis—the phosphorylation of glucose.[14] Unlike other hexokinases, GCK has a relatively low affinity for glucose, meaning its activity increases significantly only when blood glucose concentrations are elevated, such as following a meal. This property allows it to precisely regulate metabolic responses to changes in glycemia.[1]

2.2 Pharmacodynamic Effects on Glucose Homeostasis

The initial therapeutic hypothesis for AZD-1656 was based on its ability to lower blood glucose through a coordinated, dual action on the pancreas and liver.[12]

• Pancreatic Effect: In pancreatic β-cells, GCK activation amplifies the metabolic flux of glucose, leading to increased ATP production. This, in turn, triggers the closure of ATP-sensitive potassium channels, cell depolarization, and ultimately, enhanced glucose-stimulated insulin secretion (GSIS).[12]
• Hepatic Effect: In hepatocytes, GCK activation increases the rate of glucose phosphorylation. This traps glucose within the cell as glucose-6-phosphate, creating a steeper concentration gradient that facilitates further glucose uptake from the bloodstream. The resulting glucose-6-phosphate is then shunted towards glycogen synthesis for storage, effectively reducing hepatic glucose output.[13]

These dual pharmacodynamic effects were confirmed in early human clinical trials. In euglycemic clamp studies involving healthy volunteers, administration of AZD-1656 led to dose-dependent increases in serum insulin and necessitated a higher glucose infusion rate to prevent hypoglycemia, providing clear evidence of its potent glucose-lowering action.[17] In patients with T2DM, treatment with AZD-1656 resulted in clinically meaningful reductions in both fasting plasma glucose (by up to 21%) and mean 24-hour plasma glucose (by up to 24%).[18]

2.3 The Immunomodulatory Hypothesis: GCK Activation and T-Cell Regulation

The scientific narrative of AZD-1656 was fundamentally altered by the growing understanding of GCK's role beyond systemic metabolism, particularly within the immune system. This new context provided a compelling rationale for the drug's repurposing.

• Emerging Role of GCK in Immunity: Research has revealed that GCK is also expressed in specific immune cell populations, most notably regulatory T cells (Tregs).[13] Tregs are a specialized subset of T cells that are critical for maintaining immune homeostasis and preventing autoimmunity. Their function and, crucially, their ability to migrate from the bloodstream into inflamed tissues are highly dependent on cellular metabolism, with glycolysis being a key energy pathway.[16]
• Hypothesized Immunomodulatory Mechanism: The central hypothesis is that by selectively activating GCK within Tregs, AZD-1656 enhances their glycolytic capacity. This metabolic boost is thought to improve their "fitness" and migratory potential, enabling them to more effectively traffic to and accumulate at sites of inflammation. An increased presence of these potent immunosuppressive cells at such sites would help to resolve inflammation, dampen excessive immune responses, and restore immune tolerance.[19] This mechanism provides a direct and novel therapeutic rationale for investigating AZD-1656 in autoimmune and inflammatory diseases.[16]
• Clinical Proof-of-Concept (ARCADIA Trial): This hypothesis gained significant support from biomarker data generated during the ARCADIA trial in diabetic patients with COVID-19. Although the trial did not meet its primary clinical endpoint, immunophenotyping of patient blood samples revealed that those treated with AZD-1656 had a distinct immunological profile compared to the placebo group. Specifically, the AZD-1656 group showed evidence of a less pro-inflammatory immune state and a more robust adaptive immune response, consistent with a rebalancing of the immune system mediated by an agent like a Treg enhancer.[19] This was the first human clinical data to substantiate the drug's immunomodulatory effect.

2.4 Preclinical Efficacy and Toxicology Insights

Preclinical studies provided the foundational evidence for both the metabolic and immunomodulatory effects of AZD-1656.

• Glucose Lowering: In various animal models of T2DM, including insulin-resistant obese Zucker rats and hyperglycemic gkwt/del mice, AZD-1656 consistently demonstrated potent glucose-lowering efficacy, validating its primary mechanism of action.[5]
• Cardiomyopathy Model: The immunomodulatory effects were explored in a db/db mouse model of diabetic cardiomyopathy, a condition characterized by chronic cardiac inflammation. In this model, a six-week treatment with AZD-1656 led to significant improvements in cardiac function, including attenuated diastolic dysfunction and reduced infarct size following ischemia. These benefits were directly linked to a reduction in cardiac inflammation and fibrosis, providing strong preclinical support for the immunometabolic hypothesis.[13]
• Toxicology: Across its extensive clinical development program, no significant toxicology risks have been identified for AZD-1656, with the exception of the on-target effect of hypoglycemia.[13] Notably, an earlier GKA candidate from AstraZeneca was discontinued due to testicular toxicology associated with a specific pyridine-carboxylic acid chemical motif. This moiety was deliberately engineered out of the AZD-1656 structure, mitigating this specific risk.[10]

The scientific journey of AZD-1656 is a compelling example of how a drug's mechanism can be re-evaluated and re-contextualized. The discontinuation of the program for diabetes was not a result of a failure in target engagement—the drug clearly and potently activates GCK—but rather a failure of the therapeutic hypothesis within the complex, chronic setting of T2DM. The immunomodulatory effect, initially a secondary pharmacological observation, has now become the central pillar of its revival. This evolution demonstrates that a drug's ultimate value is intrinsically linked not just to its primary, intended mechanism but to the full spectrum of its biological activities across different physiological systems. The dual function of GCK in both metabolism and immunity represents a fundamental nexus of "immunometabolism." AZD-1656's story suggests that targeting such nodes can be a powerful therapeutic strategy. However, it also illuminates a key challenge: modulating a target with such pleiotropic effects can lead to desired outcomes in one system (immune suppression) while risking unintended consequences in another, such as the hepatic lipid accumulation observed in some preclinical models.[3] The success of its future development will depend on identifying a therapeutic window that maximizes the immunomodulatory benefit while minimizing any potential metabolic risks.

3.0 Pharmacokinetics and Metabolism

This section describes the absorption, distribution, metabolism, and excretion (ADME) profile of AZD-1656, including the role of its active metabolite, which together dictate its dosing regimen and interaction potential.

3.1 Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of AZD-1656 has been characterized in multiple Phase 1 clinical trials.

• Absorption: Following oral administration, AZD-1656 is rapidly absorbed, leading to a quick onset of action.[17]
• Metabolism/Biotransformation: The compound is metabolized in the body, primarily forming a single major active metabolite known as AZD5658.[17] While the specific enzymatic pathways, such as the involvement of individual cytochrome P450 (CYP) isozymes, are not explicitly detailed in the available documentation, a series of dedicated drug-drug interaction studies were conducted, suggesting that a thorough investigation of metabolic pathways was performed.[23]
• Elimination: The parent drug, AZD-1656, is characterized by rapid elimination from the body.[18] Renal excretion of both the parent compound and its metabolite is low, indicating that this is not a major route of clearance.[18] This suggests that hepatic metabolism followed by biliary excretion is likely the primary elimination pathway.
• Dose Proportionality: The pharmacokinetics of AZD-1656 are predictable and well-behaved. Studies have shown that its PK profile is largely dose- and time-independent, with a proportional increase in total drug exposure (as measured by the area under the plasma concentration-time curve, or AUC) for both AZD-1656 and its metabolite as the dose is increased.[17]

3.2 The Role of the Active Metabolite, AZD5658

The biotransformation of AZD-1656 results in a pharmacologically active metabolite that contributes to the overall therapeutic effect.

• Potency: The metabolite, AZD5658, is described as being equipotent to the parent drug, AZD-1656, meaning it has a similar ability to activate the GCK enzyme.[17]
• Pharmacokinetics: A key difference lies in its pharmacokinetic profile. AZD5658 has a longer elimination half-life than the parent compound. Despite this, its systemic exposure is substantially lower, with its AUC representing only approximately 15% of the parent drug's AUC over a 24-hour period.[18]
• Clinical Relevance: The presence of this longer-lasting but less abundant active metabolite contributes to the overall duration of the pharmacodynamic effect. Both AstraZeneca and now Conduit Pharmaceuticals have consistently monitored the plasma concentrations of both the parent drug and the metabolite in their clinical programs to fully understand the PK/PD relationship.[25] Reflecting its own pharmacological activity, AZD5658 is also being developed by Conduit as a distinct clinical candidate.[26]

3.3 Drug-Drug Interaction Profile

AstraZeneca conducted a comprehensive series of Phase 1 clinical trials specifically designed to evaluate the potential for drug-drug interactions (DDIs) with commonly co-administered medications in the T2DM patient population. These studies included:

• Simvastatin (NCT01096940): An evaluation of the pharmacokinetic interaction between AZD-1656 and the widely used statin, simvastatin.[28]
• Gemfibrozil (NCT01083212): A study to assess the effect of gemfibrozil, a potent inhibitor of certain CYP enzymes, on the pharmacokinetics and pharmacodynamics of AZD-1656.[30]
• Warfarin (D1020C00027): An investigation into the effect of AZD-1656 on the pharmacokinetics and anticoagulant effect of warfarin, a drug with a narrow therapeutic index metabolized by CYP enzymes.[31]
• Pioglitazone (D1020C00028): A study to determine if there were reciprocal pharmacokinetic effects between AZD-1656 and the T2DM drug pioglitazone.[24]

While the specific results of these DDI studies are not available in the provided documentation, their execution demonstrates a thorough and standard approach to characterizing the drug's metabolic profile and safety during early-phase development.

The combined pharmacokinetic profile of a potent, short-acting parent drug and a longer-acting, equipotent metabolite with lower exposure creates a complex and dynamic relationship between drug concentration and biological effect. This particular profile may have presented challenges in the original diabetes program, where maintaining stable, 24-hour glycemic control is paramount. The fluctuating levels of GCK activation could have contributed to glycemic variability and, potentially, to the eventual desensitization or tachyphylaxis observed in longer-term studies. However, for the new autoimmune indications, this same PK profile could prove to be advantageous. It could provide a "pulsed" or "hit-and-run" mechanism, delivering an initial high level of target engagement to effectively stimulate Treg migration, followed by a sustained, lower-level effect from the metabolite. This dynamic might be sufficient to achieve the desired immunomodulation without causing the sustained, high-level metabolic disruption that could lead to adverse effects like the hepatic steatosis seen in some chronic preclinical models.[3] Thus, a PK profile that may have been a liability for one chronic disease could be an asset for another.

Furthermore, Conduit's decision to co-develop both AZD-1656 and its metabolite AZD5658 as separate assets is a sophisticated and insightful strategy.[26] This approach indicates that the company is not merely repurposing a single molecule but is strategically exploring a "chemical family" to identify the optimal PK/PD profile for treating autoimmune diseases. It is plausible that the longer-acting, more stable profile of AZD5658 might provide a more desirable and consistent level of immunomodulation with a superior therapeutic index compared to the parent drug, or vice versa. This dual-asset strategy represents a form of internal pipeline diversification and lifecycle management built around a single, validated biological mechanism.

4.0 Clinical Development for Metabolic Disorders

This section provides a historical analysis of the original clinical development program for AZD-1656 as a treatment for Type 2 Diabetes Mellitus (T2DM), detailing its progression through clinical trials and the key findings that ultimately led to its discontinuation for this indication.

4.1 Early Phase Trials in Healthy Volunteers and T2DM Patients

AstraZeneca conducted an extensive Phase 1 program to thoroughly characterize the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AZD-1656.

• Studies in Healthy Volunteers (NCT00726427, NCT00741689): The initial human studies involved single ascending doses of AZD-1656, up to 180 mg, administered to both Western and Japanese healthy male subjects. To safely explore the drug's full pharmacodynamic range without inducing hypoglycemia, these studies were conducted under euglycemic clamp conditions. The results showed that AZD-1656 was well tolerated across the dose range. Pharmacodynamically, it produced a clear, dose-dependent glucose-lowering effect (demonstrated by the increased glucose infusion rate required to maintain normal blood sugar) and stimulated insulin secretion. Importantly, the pharmacokinetic and pharmacodynamic profiles were comparable between the Western and Japanese populations, suggesting no significant ethnic differences that would complicate global development.[17]
• Studies in T2DM Patients: Following the healthy volunteer studies, multiple trials were initiated in the target patient population. These studies assessed both single and multiple ascending doses of AZD-1656 in patients with T2DM, evaluating the drug both as a monotherapy and as an add-on to the standard-of-care medication, metformin.[1] These trials consistently confirmed the glucose-lowering effects seen in healthy volunteers and established a predictable and manageable safety and pharmacokinetic profile in patients.[18] One study (D1020C00017) specifically compared the 24-hour glucose profiles following once-daily versus twice-daily dosing to optimize the regimen for later-phase trials.[34]

4.2 Dose-Ranging and Efficacy Studies (Phase 2)

The culmination of the early development program was a large, multicenter Phase 2b study designed to establish the optimal dose and confirm the efficacy of AZD-1656 in a broader patient population.

• Phase 2b Study Design (NCT01020123): This pivotal dose-ranging study enrolled 458 T2DM patients who were inadequately controlled on metformin.[3] Patients were randomized to one of several arms: fixed doses of AZD-1656 (20 mg or 40 mg), individually titrated doses of AZD-1656 (in two different ranges), placebo, or an active comparator, the sulfonylurea glipizide. The primary endpoint was the change in hemoglobin A1c (HbA1c) from baseline after 4 months of treatment.[9]
• Initial Efficacy Results: The study successfully demonstrated the drug's efficacy. After 4 months, patients in the titrated AZD-1656 arms showed statistically significant reductions in HbA1c from baseline compared to placebo. The magnitude of the reduction (mean change of approximately -0.8%) was clinically meaningful and comparable to that achieved with the active comparator, glipizide.[9]
• Safety and Tolerability: In this larger study, AZD-1656 continued to be well tolerated. A key finding was its favorable safety profile relative to the active comparator, with a notably lower incidence of hypoglycemia than that observed with glipizide.[9]

4.3 Analysis of Waning Efficacy and Discontinuation for T2DM

Despite the positive 4-month efficacy and safety results, findings from the extension phase of the study revealed a critical limitation that ultimately led to the termination of the program.

• Loss of Durable Efficacy: When treatment was continued, the glycemic control achieved with AZD-1656 was not sustained. The effect on HbA1c began to diminish after 4 months and was substantially reduced by the 6-month time point.[9] This lack of durable efficacy was a major setback, as long-term, stable glucose control is a prerequisite for any new diabetes therapy. This finding was the primary driver behind AstraZeneca's decision to discontinue the development of AZD-1656 for T2DM.[10]
• Potential Biological Mechanisms for Failure: The waning efficacy observed in the clinical trial prompted further investigation into the underlying biology, revealing potential mechanisms that could explain the phenomenon.
• Disruption of GCK Regulation: Preclinical research in mouse models has shed light on the complex regulation of GCK by the Glucokinase Regulatory Protein (GKRP) in the liver. Genetic variants in the GCKR gene are common in humans (e.g., rs1260326) and can lead to a relative deficiency in GKRP function. Studies in mouse models mimicking these human variants showed that chronic treatment with AZD-1656 in a GKRP-deficient state led to a progressive decline in glucose-lowering efficacy over time.[3] This suggests that constant, pharmacological activation of GCK may bypass or disrupt the natural GKRP feedback loop, leading to a state of cellular adaptation or desensitization.
• Risk of Hepatic Steatosis: A second concern arose from the same preclinical models. Chronic administration of AZD-1656, particularly in the context of GKRP deficiency, was associated with an increase in liver triglycerides and the development of hepatocyte microvesicular steatosis (fatty liver).[3] This raised a significant safety flag, as inducing or exacerbating non-alcoholic fatty liver disease (NAFLD) would be an unacceptable risk for a medication intended for long-term use in a population already at high risk for this condition.[14]

The discontinuation of AZD-1656 for T2DM was not a consequence of an overt safety failure in human trials but a calculated strategic decision rooted in a lack of commercially viable, durable efficacy. The transient nature of the glucose-lowering effect suggested that the biological system was adapting to the chronic, high-level activation of GCK, highlighting the inherent challenges of targeting enzymes embedded within complex and tightly regulated metabolic networks. In the highly competitive T2DM market, which is populated by numerous therapies offering sustained, long-term benefits, a drug with only transient efficacy holds limited value. The preclinical findings related to GKRP variants and hepatic steatosis provided a plausible biological explanation for the clinical observations and added a layer of long-term risk that further justified AstraZeneca's portfolio management decision. This experience offers a crucial lesson for the field of metabolic drug development: simply "turning on" a key metabolic enzyme may not be a sustainable therapeutic strategy. The future of such targets may depend on more nuanced approaches, such as developing "chrono-therapeutics" that provide intermittent activation timed to physiological needs (as suggested by preclinical work [39]), or designing molecules that modulate the natural regulatory proteins like GKRP rather than completely bypassing them.

5.0 Repurposing and Clinical Development for Immunomodulatory Indications

This section chronicles the revival of AZD-1656, focusing on the pivotal clinical trial data and strategic decisions that shifted its development trajectory from metabolic disease to immunology.

5.1 The ARCADIA Trial (NCT04516759): Key Findings from COVID-19

The ARCADIA trial represents the turning point in the development history of AZD-1656, providing the first human evidence for its immunomodulatory potential.

• Trial Rationale: The study was conceived based on the emerging science of immunometabolism and the specific hypothesis that AZD-1656's ability to activate GCK in immune cells could be beneficial in mitigating the hyperinflammatory "cytokine storm" that drives severe outcomes in COVID-19, particularly in high-risk diabetic patients.[19]
• Study Design: ARCADIA was a robustly designed Phase 2, randomized, double-blind, placebo-controlled, multicenter clinical trial. It enrolled 153 diabetic patients who were hospitalized with COVID-19 across 28 hospitals in the United Kingdom, Romania, and the Czech Republic.[3]
• Primary Endpoint Result: The trial did not achieve its pre-specified primary endpoint, which was a statistically significant improvement in clinical status at Day 14 as measured by the WHO 8-point Ordinal Scale. The proportion of patients showing improvement was numerically higher in the AZD-1656 group (76.3%) compared to the placebo group (69.9%), but this difference did not reach statistical significance (p=0.19).[20]
• Pivotal Secondary and Biomarker Findings: Despite the primary endpoint miss, the trial yielded several critical findings that reshaped the drug's future:
• Mortality Signal: A clinically important trend towards lower mortality was observed in the AZD-1656 arm. Overall mortality was 5% in the AZD-1656 group versus 12.3% in the placebo group (p=0.090).[20] A post-hoc analysis revealed a more striking difference in early mortality: at Day 7, there were zero deaths among patients receiving AZD-1656, compared to six deaths in the placebo group ( p=0.011).[20]
• Proof-of-Concept for Immunomodulation: The most crucial outcome was the direct evidence from immunophenotyping of patient blood samples. This biomarker analysis showed that patients treated with AZD-1656 exhibited a less pro-inflammatory immune profile and a more effective adaptive immune response compared to those on placebo. This was the first human data to confirm that the drug exerts a tangible immunomodulatory effect, consistent with the hypothesis of enhancing Treg function.[19]

In conclusion, while ARCADIA was technically a "failed" trial based on its primary endpoint, it was a profound strategic success. It generated the critical human proof-of-concept data that validated the immunomodulatory mechanism of AZD-1656 and provided the scientific foundation for its repurposing into autoimmune diseases.[16]

5.2 The ADOPTION Trial (NCT05216172): Immune Tolerance in Transplantation

Building on the immunomodulatory hypothesis, the ADOPTION trial was initiated to explore the potential of AZD-1656 in a different clinical context involving immune dysregulation.

• Trial Rationale: This study was designed to test whether AZD-1656 could promote immune tolerance in the setting of organ transplantation. The primary hypothesis was that by enhancing the function and migration of Tregs, the drug could help prevent graft rejection while also providing the benefit of managing post-transplant diabetes, a common complication.[39]
• Study Design: ADOPTION was a Phase 2, single-center, placebo-controlled, double-blind randomized clinical trial sponsored by Queen Mary University of London. The study planned to enroll up to 50 patients who had recently undergone a renal transplant.[39]
• Current Status: The trial is now listed on clinicaltrials.gov as having been completed in June 2024, with a final enrollment of 26 patients.[39] The clinical and biomarker results from this study have not yet been publicly disclosed in the provided materials.

5.3 Current Pipeline: Phase 2 Strategy for Autoimmune Diseases

The compelling data from the ARCADIA trial prompted the full strategic pivot of AZD-1656 towards autoimmune diseases, led by its new developer.

• Developer: Conduit Pharmaceuticals has secured the exclusive global rights to develop, manufacture, and commercialize AZD-1656 for all human indications through a licensing agreement with AstraZeneca.[27]
• Target Indications: Conduit is strategically focusing on multisystem autoimmune diseases where there remains a significant unmet medical need for safer and more effective oral therapies. The company is actively planning and preparing to initiate Phase 2a clinical trials in two primary indications:
• Systemic Lupus Erythematosus (SLE), with a specific focus on patients with renal involvement (Lupus Nephritis, LN).[3]
• ANCA-associated Vasculitis (AAV).[3]
• Preclinical Validation: To optimize the design of these upcoming human trials, Conduit has partnered with the contract research organization Charles River Laboratories. This collaboration will involve conducting further preclinical studies in well-established animal models of lupus to refine dosing, identify relevant biomarkers, and generate additional mechanistic data to increase the probability of clinical success.[26]

The repurposing of AZD-1656 serves as a powerful case study in extracting significant value from a previously "failed" asset through rigorous scientific investigation. The ARCADIA trial investigators demonstrated exceptional scientific acumen by looking beyond the missed primary endpoint to the underlying biology. Their inclusion of robust biomarker analysis, specifically immunophenotyping, provided the critical mechanistic link that gave the drug a new lease on life. This highlights a crucial lesson in modern drug development: well-designed trials, even those that fail to meet their primary objective, can generate immensely valuable data that opens entirely new and unforeseen avenues for development. Conduit's strategy to target broad-spectrum autoimmune diseases like SLE and AAV is ambitious yet mechanistically sound. If the hypothesis that AZD-1656 enhances Treg function holds true in these chronic conditions, it could represent a paradigm shift: a novel, oral, non-steroidal immunomodulator that works by restoring the body's own regulatory checkpoints rather than through broad immunosuppression. Such a mechanism could potentially offer a superior long-term safety profile compared to traditional immunosuppressants and many biologics. The central challenge, however, will be to translate the systemic immunomodulatory effects observed in the acute inflammatory setting of COVID-19 into durable clinical efficacy in the complex, chronic pathophysiology of diseases like lupus and vasculitis.

6.0 Comprehensive Safety and Tolerability Profile

This section provides a holistic assessment of the safety and tolerability of AZD-1656, drawing upon the extensive data generated across its entire clinical development history, which represents one of the asset's most significant strengths.

6.1 Overview of Adverse Events from >20 Clinical Trials

The safety profile of AZD-1656 has been established through a comprehensive clinical program that is unusually large for a drug entering Phase 2 for a new indication.

• Extensive Human Exposure: AZD-1656 has been administered to more than 1,000 human subjects in over 20 distinct clinical trials. This includes exposure in over 960 patients with diabetes, with some individuals receiving treatment for up to 6 months.[19]
• General Tolerability: Across this wide range of Phase 1 and Phase 2 studies, AZD-1656 has been consistently reported as being generally well tolerated.[9] This favorable profile was re-confirmed in the ARCADIA trial for COVID-19, where there was no significant difference in the overall incidence of adverse events between the AZD-1656 group (35.7%) and the placebo group (33.3%).[20]

6.2 Meta-Analysis of Safety Data: A Statistical Perspective

A recent systematic review and meta-analysis of 23 randomized controlled trials provides the most robust and statistically powerful assessment of the drug's safety profile to date. This analysis pooled data from trials in both healthy volunteers and diabetic patients, allowing for a comprehensive comparison against placebo.[3]

• Non-Serious Adverse Events: The analysis found no statistically significant difference in the overall risk of non-serious adverse events for patients taking AZD-1656 compared to placebo. The cumulative Relative Risk (RR) was 1.09, with a 95% confidence interval (CI) of 0.96 to 1.24 (p=0.19), indicating that the observed small increase in risk was likely due to chance.[3]
• Serious Adverse Events (SAEs): There was no evidence of an increased risk of SAEs with AZD-1656. In fact, the pooled data showed a trend towards a lower risk of SAEs in the AZD-1656 group, with a cumulative RR of 0.85 (95% CI 0.21–3.48).[3]
• Hypoglycemia: As expected for a potent glucokinase activator, hypoglycemia is the most notable adverse event of special interest. The meta-analysis revealed a two-fold increase in the risk of hypoglycemic events with AZD-1656 compared to placebo. However, this increased risk did not reach the threshold for statistical significance (Cumulative RR = 2.03, 95% CI 0.94–4.39, p=0.07). This trend towards increased risk was observed across low, medium, and high dose ranges, confirming it as an on-target, dose-related effect.[3]

Table 2: Summary of Safety Profile from Meta-Analysis vs. Placebo

Adverse Event Category	Relative Risk (95% CI)	p-value	Source(s)
Total Non-Serious AEs	1.09 (0.96–1.24)	0.19	16
Serious AEs	0.85 (0.21–3.48)	Not Significant	16
Hypoglycemic Events	2.03 (0.94–4.39)	0.07	16

The extensive safety database compiled by AstraZeneca is arguably the single greatest asset of the AZD-1656 program. Having been tested in over 1,000 individuals, its general safety and tolerability profile is exceptionally well-characterized for a molecule at its current stage of development for autoimmune disease. This established safety record significantly de-risks its continued clinical investigation. It allows the current developer, Conduit Pharmaceuticals, to bypass much of the costly and time-consuming early-phase safety and toxicology studies that are required for a typical new chemical entity. This capital-efficient approach enables them to move directly into Phase 2 proof-of-concept trials to answer the most critical remaining question: efficacy. For a potential investor or pharmaceutical partner, this means that development capital can be deployed more efficiently, focusing resources on determining if the drug works in lupus and vasculitis rather than on re-establishing its fundamental safety.

The borderline statistical significance of the hypoglycemia risk (p=0.07) is a critical nuance that warrants careful consideration. While it does not constitute a major safety warning, it is a clear on-target pharmacological effect that must be proactively monitored and managed in all future clinical trials. The risk-benefit calculation for this adverse event will be fundamentally different in the new target populations. Patients with chronic autoimmune diseases are typically euglycemic (have normal blood sugar), unlike the hyperglycemic patients in the original diabetes trials. This heightened sensitivity to glucose-lowering effects suggests that the optimal therapeutic dose for immunomodulation may be lower than the doses that were required to achieve robust glycemic control in T2DM. This creates the possibility of a therapeutic window where the desired immune effects can be achieved with a minimal and clinically manageable risk of hypoglycemia. A key objective of the upcoming Phase 2a trials will be to carefully explore this dose-response relationship to identify an optimal dose that maximizes immunomodulatory benefit while ensuring patient safety.

7.0 Current Status, Intellectual Property, and Future Outlook

This section analyzes the current commercial and strategic landscape for AZD-1656, detailing its transition to Conduit Pharmaceuticals and the multifaceted strategy being employed to create future value and secure market exclusivity.

7.1 The AstraZeneca-Conduit Pharmaceuticals Licensing Agreement

The revival of AZD-1656 was formalized through a strategic licensing agreement that transferred development rights to a company focused on repurposing promising assets.

• The Agreement: In August 2024, Conduit Pharmaceuticals announced it had entered into an exclusive license agreement with AstraZeneca. The agreement granted Conduit the global rights to develop, manufacture, and commercialize AZD-1656 and its active metabolite, AZD5658, for all human indications.[27]
• Deal Terms: In exchange for these rights, AstraZeneca received an upfront consideration in the form of common stock in Conduit Pharmaceuticals. The deal also includes significant downstream value for AstraZeneca, which is entitled to a share of future sublicense revenues, including any upfront payments, development milestones, and sales royalties that Conduit receives from future partners. As part of the agreement, AstraZeneca provides its extensive preclinical and clinical data package and a supply of the drug substance to facilitate the rapid initiation of new trials. Notably, AstraZeneca retains a right of first negotiation to re-acquire or partner on the compounds if Conduit decides to out-license the assets in the future.[27]

7.2 Global Patent Strategy and Market Exclusivity

A cornerstone of Conduit's strategy is the creation of a new and robust intellectual property (IP) estate around AZD-1656 to ensure long-term market exclusivity for its new therapeutic applications, a critical step for a repurposed asset.

• New Composition-of-Matter Patents: Conduit has successfully prosecuted and been granted new composition-of-matter patents for AZD-1656 in several major global pharmaceutical markets. These patents, which likely cover novel crystalline forms (cocrystals) of the drug, have been issued by the United States Patent and Trademark Office (USPTO), the Japan Patent Office (JPO), IP Australia, and the Korean Intellectual Property Office (KIPO).[11] The granted US patent provides market protection for up to 20 years, effectively resetting the patent clock for the asset.[48]
• Method-of-Use Patents: The new IP portfolio is further strengthened by patents covering the specific methods of use. These patents are directed at the treatment of autoimmune diseases, explicitly naming conditions such as lupus and ANCA vasculitis.[39] A separate patent granted in Japan also covers the use of AZD-1656 for treating pneumonia and/or myocarditis associated with coronavirus infection, stemming from the ARCADIA trial findings.[50]
• Future IP Expansion: Conduit is continuing to expand its IP position. The company has recently filed four new patent applications based on AI-driven analysis that cover combinations of AZD-1656 and AZD5658 with existing therapies.[39] This forward-looking strategy aims to create future combination products with enhanced efficacy or safety profiles.

7.3 Competitive Landscape and Future Outlook

AZD-1656 is being repositioned from a challenging metabolic market into a competitive but opportunity-rich immunology space.

• GKAs in Diabetes: The GKA drug class has faced significant challenges in the T2DM field, with most development programs, including AZD-1656, being discontinued due to issues with durable efficacy or side effects. Dorzagliatin is one of the few GKAs that has progressed to late-stage clinical trials for diabetes, but the class is not considered a major player in the current T2DM treatment paradigm.[39]
• Therapies for Autoimmune Disease: The therapeutic landscape for SLE and AAV is dynamic and competitive, featuring established immunosuppressants and a growing number of targeted biologics. However, there remains a significant unmet need for safe, effective, and convenient oral therapies that can provide long-term disease control with fewer side effects than traditional agents. AZD-1656's novel mechanism of enhancing Treg function, if proven effective, could differentiate it significantly from existing therapies that primarily rely on broad immune suppression.
• Future Development Path: The immediate future and ultimate value of AZD-1656 are critically dependent on the outcomes of the planned Phase 2a proof-of-concept trials in SLE and AAV. Positive data from these studies would provide the first clinical validation of the immunomodulatory hypothesis in a chronic autoimmune disease setting. Such a result would dramatically increase the asset's value and make it highly attractive for a partnership or out-licensing deal with a larger pharmaceutical company to fund the expensive Phase 3 trials and subsequent commercialization, a path that aligns perfectly with Conduit's stated business model.[26]

Conduit's business model is a prime example of strategic arbitrage within the pharmaceutical industry. The company acquired a clinically de-risked asset, which was viewed as stalled or non-core by its originator, for a relatively low upfront cost structured heavily towards future success. They are now systematically creating substantial new value by applying a novel scientific hypothesis and, critically, by building a formidable new intellectual property wall around the asset. Instead of simply licensing an old compound with a limited patent life, Conduit's investment in developing and patenting new crystalline forms has allowed them to secure fresh composition-of-matter protection, fundamentally resetting the commercial clock and transforming the asset's long-term valuation.[11]

The company's forward-thinking approach is further exemplified by its use of artificial intelligence to identify and patent potential combination therapies.[39] This strategy effectively builds a "pipeline-in-a-product," pre-emptively defining future lifecycle management opportunities and potential next-generation treatments. This makes AZD-1656 a more attractive asset for a potential larger partner, as it comes with not only a de-risked safety profile and a novel mechanism but also a built-in, IP-protected plan for future development and market positioning.

8.0 Expert Analysis and Strategic Recommendations

This final section synthesizes the comprehensive data presented in this report into a strategic analysis of AZD-1656's potential, culminating in actionable recommendations for its future development and risk mitigation.

8.1 Synthesis of Key Strengths, Weaknesses, Opportunities, and Threats (SWOT)

A SWOT analysis provides a clear framework for understanding the strategic position of the AZD-1656 program.

• Strengths:
• Extensive Human Safety Database: The drug's safety and general tolerability are well-established in over 1,000 subjects, significantly de-risking further clinical development.
• Novel Immunomodulatory Mechanism: The GCK-Treg axis represents a potentially first-in-class mechanism for treating autoimmune diseases, offering differentiation from existing therapies.
• Human Proof-of-Concept: The ARCADIA trial provided direct human evidence of the drug's immunomodulatory effects, lending strong support to the repurposing hypothesis.
• Oral Administration: As an orally available small molecule, AZD-1656 offers a significant convenience advantage over many injectable biologic therapies for autoimmune disease.
• Robust Intellectual Property: A new and growing global portfolio of composition-of-matter and method-of-use patents provides a strong foundation for long-term market exclusivity.
• Weaknesses:
• History of Clinical Failure: The discontinuation for T2DM due to waning efficacy, while for a different indication, remains a part of the asset's history and may raise questions about long-term target engagement.
• Potential for Metabolic Side Effects: The on-target risk of hypoglycemia, although manageable and not statistically significant in meta-analysis, will require careful monitoring in euglycemic patients. Preclinical signals of hepatic lipid accumulation in specific genetic contexts also warrant long-term vigilance.
• Unproven Efficacy in Chronic Autoimmunity: The immunomodulatory effects observed in an acute viral illness (COVID-19) have not yet been shown to translate into clinical benefit in a chronic autoimmune disease setting.
• Opportunities:
• High Unmet Medical Need: SLE and AAV are serious conditions where many patients fail to achieve adequate disease control with current therapies, creating a significant opportunity for a novel oral agent.
• First-in-Class Potential: If successful, AZD-1656 could establish GCK activation as a new therapeutic paradigm for a range of autoimmune and inflammatory disorders.
• Capital-Efficient Development: The existing safety package allows for a streamlined and cost-effective path directly to Phase 2 proof-of-concept studies.
• Biomarker-Driven Strategy: The mechanism lends itself to a biomarker-driven approach, potentially allowing for the selection of patients most likely to respond to therapy.
• Threats:
• Phase 2 Efficacy Failure: The primary threat is that the drug will fail to demonstrate a clinically meaningful effect in the upcoming SLE and AAV trials.
• Competitive Landscape: The field of immunology is highly competitive, with numerous companies developing novel oral and biologic therapies for lupus and vasculitis.
• Long-Term Safety: The possibility remains that unforeseen safety issues could emerge with longer-term dosing than was studied in the diabetes program.

8.2 Critical Assessment of the Repurposing Strategy

The scientific rationale for repurposing AZD-1656 is sound and evidence-based. It is not a speculative endeavor but is grounded in a convergence of basic science elucidating the role of GCK in T-cell metabolism and the compelling biomarker data from the ARCADIA clinical trial. The strategy to target multisystem autoimmune diseases like SLE and AAV is appropriate, as these conditions are characterized by the type of systemic immune dysregulation that a Treg-enhancing mechanism is well-suited to address.

The commercial strategy employed by Conduit Pharmaceuticals is astute, leveraging the de-risked nature of the asset to enable a capital-efficient path to key value inflection points. The successful rebuilding of the patent estate is a critical achievement that has transformed a late-lifecycle asset into a new entity with significant commercial potential. The primary risk has been effectively shifted from safety to efficacy, which is the ideal position for a clinical-stage biotechnology company.

8.3 Recommendations for Future Clinical Development and Risk Mitigation

To maximize the probability of success and mitigate the key remaining risks, the following strategic actions are recommended for the upcoming Phase 2a program:

• Implement a Biomarker-Driven Patient Selection Strategy: The clinical development plan should move beyond a purely clinical definition of disease. It is strongly recommended to incorporate baseline biomarker measurements, such as circulating Treg counts/function or levels of key inflammatory cytokines (e.g., IL-6), to stratify patients. This will not only provide deeper mechanistic insight but could also enrich the trial population for individuals most likely to respond, thereby increasing the statistical power to detect an efficacy signal.
• Prioritize Identification of the Optimal Therapeutic Window: The Phase 2a trials must be designed to carefully explore the dose-response relationship. The primary objective should be to identify the lowest effective dose for immunomodulation while minimizing the risk of hypoglycemia. This involves implementing frequent glucose monitoring, especially during the initial dosing period, and defining clear protocols for managing any hypoglycemic events.
• Incorporate Rigorous Safety Monitoring for Metabolic Parameters: Given the preclinical signals and the drug's mechanism, all future trials must include a robust plan for monitoring hepatic function and lipid profiles at baseline and regular intervals. While a risk has not been demonstrated in humans, proactive monitoring is essential for ensuring long-term safety.
• Initiate Early-Stage Partnering Discussions: Leveraging the strong existing safety package and the newly established IP portfolio, Conduit should begin engaging with potential pharmaceutical partners in parallel with the execution of the Phase 2a trials. Securing a partner contingent upon positive Phase 2a data will be critical for financing the larger, more expensive Phase 3 program and for accessing the global commercial infrastructure needed for a successful launch.

Works cited

1. AZD-1656: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 7, 2025, https://go.drugbank.com/drugs/DB14810
2. AZD-1656 - precisionFDA, accessed September 7, 2025, https://precision.fda.gov/ginas/app/ui/substances/660M185X4D
3. AZD-1656 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed September 7, 2025, https://synapse.patsnap.com/drug/0e1281dcc3624eb382e2dc739f0ff7aa
4. Details of the Drug | DrugMAP, accessed September 7, 2025, https://drugmap.idrblab.net/data/drug/details/DMUE90I
5. AZD1656 | Glucokinase Activator - MedchemExpress.com, accessed September 7, 2025, https://www.medchemexpress.com/azd1656.html
6. Azd-1656 | C24H26N6O5 | CID 16039797 - PubChem, accessed September 7, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/azd-1656
7. Compound: AZD-1656 (CHEMBL3219124) - ChEMBL - EMBL-EBI, accessed September 7, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL3219124
8. AZD1656 | Ligand page | IUPHAR/BPS Guide to PHARMACOLOGY, accessed September 7, 2025, https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7701
9. Dose-ranging study with the glucokinase activator AZD1656 in patients with type 2 diabetes mellitus on metformin - PubMed, accessed September 7, 2025, https://pubmed.ncbi.nlm.nih.gov/23464532/
10. Recent Disclosures of Clinical Candidates (SMR Award Lecture) – Highlights from the Society for Medicines Research Symposium,, accessed September 7, 2025, http://smr.org.uk/smr/Archive/PastMeetings/Downloads/20121205.pdf
11. Conduit Pharmaceuticals Provides Research and Development Update on Progress for Pipeline Assets AZD1656, AZD5658, and AZD5904 - BioSpace, accessed September 7, 2025, https://www.biospace.com/press-releases/conduit-pharmaceuticals-provides-research-and-development-update-on-progress-for-pipeline-assets-azd1656-azd5658-and-azd5904
12. Chronic glucokinase activator treatment at clinically translatable exposures gives durable glucose lowering in two animal models of type 2 diabetes, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC3966745/
13. Immunomodulation by AZD1656 reverses cardiac dysfunction, metabolic remodelling and reduces infarct size in type 2 diabetic cardiomyopathy | bioRxiv, accessed September 7, 2025, https://www.biorxiv.org/content/10.1101/2025.04.10.648128v1.full-text
14. Present status of clinical deployment of glucokinase activators - PMC, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4364845/
15. Glucokinase Activators AZD6370 and AZD1656 Do Not Affect the Central Counterregulatory Response to Hypoglycemia in Healthy Males - Oxford Academic, accessed September 7, 2025, https://academic.oup.com/jcem/article/97/9/3319/2537078
16. Safety profile of glucokinase activator AZD1656: systematic review and meta-analysis of 23 randomised trials in diabetic and healthy volunteers with relevance to immunomodulatory therapy - PMC - PubMed Central, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12396980/
17. Tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator AZD1656, after single ascending doses in healthy subjects during euglycemic clamp - PubMed, accessed September 7, 2025, https://pubmed.ncbi.nlm.nih.gov/22943931/
18. Safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus - PubMed, accessed September 7, 2025, https://pubmed.ncbi.nlm.nih.gov/22775976/
19. A randomised, double-blind, placebo-controlled, multicentre clinical trial of AZD1656 in diabetic patients hospitalised with COVID-19 - PubMed Central, accessed September 7, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9386394/
20. A randomised, double-blind, placebo-controlled, multicentre clinical ..., accessed September 7, 2025, https://pubmed.ncbi.nlm.nih.gov/35996565/
21. (PDF) A randomised, double-blind, placebo-controlled, multicentre clinical trial of AZD1656 in diabetic patients hospitalised with COVID-19: The ARCADIA Trial - implications for therapeutic immune modulation - ResearchGate, accessed September 7, 2025, https://www.researchgate.net/publication/362763359_A_randomised_double-blind_placebo-controlled_multicentre_clinical_trial_of_AZD1656_in_diabetic_patients_hospitalised_with_COVID-19_The_ARCADIA_Trial_-_implications_for_therapeutic_immune_modulation
22. Compromised chronic efficacy of a Glucokinase Activator AZD1656 in mouse models for common human GCKR variants | bioRxiv, accessed September 7, 2025, https://www.biorxiv.org/content/10.1101/2024.07.24.604910v1
23. Azetines | DrugBank Online, accessed September 7, 2025, https://go.drugbank.com/categories/DBCAT001212
24. Investigate the effect of AZD1656 on the pharmacokinetics of Pioglitazone and vice versa in Type 2 Diabetes Mellitus - AstraZeneca Clinical Trials, accessed September 7, 2025, https://www.astrazenecaclinicaltrials.com/study/D1020C00028/
25. To Assess the Pharmacokinetics of AZD1656 and its Metabolite in Type 2 Diabetes Mellitus Patients - AstraZeneca Clinical Trials, accessed September 7, 2025, https://www.astrazenecaclinicaltrials.com/study/D1020C00007/
26. Conduit Pharmaceuticals Pipeline Update: AZD1656, AZD5658, & AZD5904, accessed September 7, 2025, https://www.clinicaltrialvanguard.com/news/conduit-pharmaceuticals-pipeline-update-azd1656-azd5658-azd5904/
27. Press Release dated August 8, 2024 - SEC.gov, accessed September 7, 2025, https://www.sec.gov/Archives/edgar/data/1896212/000149315224030681/ex99-1.htm
28. Simvastatin Completed Phase 1 Trials for Type 2 Diabetes Mellitus | DrugBank Online, accessed September 7, 2025, https://go.drugbank.com/drugs/DB00641/clinical_trials?conditions=DBCOND0029752&phase=1&status=completed
29. study To Assess the Pharmacokinetics of AZD1656 during Coadministration with Simvastatin - AstraZeneca Clinical Trials, accessed September 7, 2025, https://www.astrazenecaclinicaltrials.com/study/D1020C00029/
30. Gemfibrozil Completed Phase 1 Trials for Type 2 Diabetes Mellitus Treatment - DrugBank, accessed September 7, 2025, https://go.drugbank.com/drugs/DB01241/clinical_trials?conditions=DBCOND0029752&phase=1&purpose=treatment&status=completed
31. Investigate the effect of AZD1656 on the pharmacokinetics and pharmacodynamics of Warfarin in type 2 diabetes mellitus (T2DM) patients - AstraZeneca Clinical Trials, accessed September 7, 2025, https://www.astrazenecaclinicaltrials.com/study/D1020C00027/
32. Healthy Lifestyle Behaviors Completed Phase 1 Trials for AZD-1656 (DB14810) | DrugBank Online, accessed September 7, 2025, https://go.drugbank.com/indications/DBCOND0059969/clinical_trials/DB14810?phase=1&status=completed
33. Glipizide Completed Phase 2 Trials for Type 2 Diabetes Mellitus Treatment - DrugBank, accessed September 7, 2025, https://go.drugbank.com/drugs/DB01067/clinical_trials?conditions=DBCOND0029752&phase=2&purpose=treatment&status=completed
34. To evaluate 24-hr glucose after OD vs BD AZD1656, accessed September 7, 2025, https://frfr-prd-astrazeneca-keystone-engage.app-trialscope.com/study/D1020C00017/
35. To evaluate safety and tolerability after multiple oral doses of AZD1656 in type 2 diabetes patients on top of metformin - AstraZeneca Clinical Trials, accessed September 7, 2025, https://www.astrazenecaclinicaltrials.com/study/D1020C00015/
36. Safety, pharmacokinetics and pharmacodynamics of multiple-ascending doses of the novel glucokinase activator AZD1656 in patients with type 2 diabetes mellitus - ProSciento, accessed September 7, 2025, https://prosciento.com/safety-pharmacokinetics-and-pharmacodynamics-of-multiple-ascending-doses-of-the-novel-glucokinase-activator-azd1656-in-patients-with-type-2-diabetes-mellitus/
37. AZD 1656 - AdisInsight - Springer, accessed September 7, 2025, https://adisinsight.springer.com/drugs/800029234
38. (PDF) Compromised chronic efficacy of a glucokinase activator AZD1656 in mouse models for common human GCKR variants - ResearchGate, accessed September 7, 2025, https://www.researchgate.net/publication/383323434_Compromised_chronic_efficacy_of_a_glucokinase_activator_AZD1656_in_mouse_models_for_common_human_GCKR_variants
39. AZD1656 / AstraZeneca, Conduit Pharmaceuticals - Larvol Delta, accessed September 7, 2025, https://delta.larvol.com/Products/?ProductId=66f2d2d1-ae70-4936-9e78-9ef7d7dc5f9c
40. 1.0 Title Page Full Title AZD1656 in Transplantation with Diabetes tO PromoTe Immune TOleraNce Short Title The ADOPTION Study S - Clinical Trials, accessed September 7, 2025, https://cdn.clinicaltrials.gov/large-docs/72/NCT05216172/Prot_SAP_000.pdf
41. Conduit Pharmaceuticals Announces Phase 2a Clinical Trial of AZD1656 for Treating Multiple Autoimmune Diseases, Including Lupus, accessed September 7, 2025, https://www.lupus.org/news/conduit-pharmaceuticals-announces-phase-2a-clinical-trial-of-azd1656-for-treating-multiple
42. Conduit Pharmaceuticals Selects Initial Indications for Lead Clinical Candidate Targeting Autoimmune Disorders - BioSpace, accessed September 7, 2025, https://www.biospace.com/conduit-pharmaceuticals-selects-initial-indications-for-lead-clinical-candidate-targeting-autoimmune-disorders
43. Conduit Pharmaceuticals Announces Advancements in Lupus Treatment Research, accessed September 7, 2025, https://lupusgreaterohio.org/conduit-pharmaceuticals-announces-advancements-in-lupus-treatment-research/
44. Conduit Pharmaceuticals Partners with Charles River Laboratories to Evaluate AZD1656 for Lupus Treatment, accessed September 7, 2025, https://www.lupus.org/news/conduit-pharmaceuticals-partners-with-charles-river-laboratories-to-evaluate-azd1656-for-lupus
45. Conduit taps Charles River to build preclinical autoimmune case for AstraZeneca diabetes asset - Fierce Biotech, accessed September 7, 2025, https://www.fiercebiotech.com/research/conduit-taps-charles-river-build-preclinical-autoimmune-case-astrazeneca-diabetes-asset
46. Safety profile of glucokinase activator AZD1656: systematic review and meta-analysis of 23 randomised trials in diabetic and healthy volunteers with relevance to immunomodulatory therapy - PubMed, accessed September 7, 2025, https://pubmed.ncbi.nlm.nih.gov/40627284/
47. (PDF) Safety profile of glucokinase activator AZD1656: systematic review and meta-analysis of 23 randomised trials in diabetic and healthy volunteers with relevance to immunomodulatory therapy - ResearchGate, accessed September 7, 2025, https://www.researchgate.net/publication/393511128_Safety_profile_of_glucokinase_activator_AZD1656_systematic_review_and_meta-analysis_of_23_randomised_trials_in_diabetic_and_healthy_volunteers_with_relevance_to_immunomodulatory_therapy
48. Conduit Pharmaceuticals Receives US Patent Approval for Its Lead Asset Targeting Autoimmune Diseases - Drug Development and Delivery, accessed September 7, 2025, https://drug-dev.com/conduit-pharmaceuticals-receives-us-patent-approval-for-its-lead-asset-targeting-autoimmune-diseases/
49. Conduit Pharmaceuticals Secures Korean Patent for AZD1656, Strengthening Global IP Portfolio for Autoimmune Drug - BioPharma BoardRoom, accessed September 7, 2025, https://www.biopharmaboardroom.com/news/46/3313/conduit-pharmaceuticals-secures-korean-patent-for-azd1656-strengthening-global-ip-portfolio-for-autoimmune-drug.html
50. JP2023517130A - AZD1656 for use in treating pneumonia and/or myocarditis caused by coronavirus - Google Patents, accessed September 7, 2025, https://patents.google.com/patent/JP2023517130A/en
51. Glucokinase as an emerging anti-diabetes target and recent progress in the development of its agonists - PubMed, accessed September 7, 2025, https://pubmed.ncbi.nlm.nih.gov/35067153/