AZD-3427: A Comprehensive Analysis of a Novel Long-Acting Relaxin Mimetic for Heart Failure and Pulmonary Hypertension

Executive Summary

AZD-3427 is a first-in-class, investigational, long-acting relaxin mimetic being developed by AstraZeneca as a potential therapy for heart failure (HF) and associated pulmonary hypertension (PH). Engineered as a human recombinant Fc fusion protein, AZD-3427 is designed to overcome the critical limitation of its short-acting predecessors—a short plasma half-life—thereby enabling chronic subcutaneous administration for sustained therapeutic effect. The drug selectively targets the relaxin family peptide receptor 1 (RXFP1), a G-protein coupled receptor whose activation mediates a cascade of beneficial pleiotropic effects, including vasodilation, and anti-inflammatory and anti-fibrotic actions. These mechanisms are highly relevant to the complex pathophysiology of cardiorenal disease.

The development of AZD-3427 represents a significant strategic pivot, shifting the therapeutic paradigm for relaxin-based therapies from acute, in-hospital treatment to chronic, outpatient disease modification. This strategy is informed by the mixed results of earlier trials with short-acting relaxin analogues, which suggested that sustained receptor engagement may be necessary to alter the long-term trajectory of heart failure. Preclinical studies in non-human primates have demonstrated that prolonged administration of AZD-3427 leads to significant improvements in cardiac function. A first-in-human Phase 1a/b study confirmed a favorable safety, tolerability, and pharmacokinetic profile, with a terminal half-life of 13-14 days in heart failure patients and early signals of positive hemodynamic and renal effects.

AstraZeneca has initiated a sophisticated, multi-pronged Phase 2 clinical program to rigorously evaluate AZD-3427. The cornerstone of this program is the Re-PHIRE study (NCT05737940), a dose-ranging trial in patients with pulmonary hypertension due to left heart disease (PH-LHD), a population with high unmet medical need and no approved therapies. This core efficacy study is supported by dedicated mechanistic trials, including the Re-PERFUSE study (NCT06611423), which uses advanced PET imaging to quantify the drug's effect on renal perfusion. This comprehensive approach aims to provide robust evidence of both clinical benefit and the underlying biological mechanisms.

Within a competitive landscape of emerging relaxin agonists, AZD-3427 is positioned as a leading candidate due to its advanced stage of development and its well-defined clinical strategy targeting the high-need PH-LHD population. The upcoming data from its Phase 2 program will be pivotal, not only for the future of AZD-3427 but also for validating the therapeutic hypothesis that sustained RXFP1 agonism can be a transformative approach for patients with complex cardiovascular and renal diseases.

I. Introduction to AZD-3427: A Next-Generation Therapeutic Candidate

A. Molecular Profile and Rationale for a Long-Acting Agent

AZD-3427, also known by the synonyms AZD 3427 and AZD3427, is an investigational, first-in-class therapeutic agent developed by AstraZeneca.[1] It is classified as a peptide/protein therapeutic, specifically a long-acting mimetic of the human hormone relaxin.[1] Structurally, AZD-3427 is a human recombinant Fc fusion protein, an advanced biologic engineered to possess a significantly extended plasma half-life compared to its natural counterpart.[2]

The molecular design of AZD-3427 is a direct and strategic response to the primary pharmacological limitation of previous relaxin-based therapies: a short duration of action. Endogenous relaxin and its recombinant analogue, serelaxin, have very short half-lives, necessitating continuous intravenous infusion to maintain therapeutic concentrations.[6] This characteristic confines their use to the acute, in-hospital setting and precludes the possibility of chronic, long-term treatment required to modify the course of diseases like heart failure. To overcome this, AZD-3427 was engineered by covalently linking a peptide sequence derived from human relaxin-2 to the Fc (fragment, crystallizable) region of human immunoglobulin G1 (IgG1).[5]

This Fc-fusion technology is a well-established strategy for half-life extension.[10] The Fc domain of the fusion protein engages with the neonatal Fc receptor (FcRn), a cellular receptor present on endothelial and epithelial cells. Following pinocytosis, the Fc-fusion protein is taken into the acidic environment of the endosome, where the Fc domain binds to FcRn. This binding event rescues the protein from the default pathway of lysosomal degradation and instead recycles it back to the cell surface, where it is released into circulation at physiological pH.[13] This recycling mechanism effectively shields the drug from rapid clearance, dramatically prolonging its presence in the body. The successful application of this technology to AZD-3427 enables less frequent, subcutaneous (SC) administration, making it a viable candidate for the long-term management of chronic diseases.[1] Clinical development is exploring both subcutaneous and intravenous (IV) routes of administration.[4]

B. Developer and Strategic Context

AZD-3427 is an in-house asset developed by the global biopharmaceutical company AstraZeneca.[3] The drug is a key component of AstraZeneca's robust Cardiovascular, Renal, and Metabolism (CVRM) pipeline, which represents a core strategic focus for the company.[20] The development of AZD-3427 aligns perfectly with the company's stated ambition to move beyond symptomatic treatment and toward disease modification and potential cures by targeting the underlying biological drivers of complex, interconnected conditions.[23]

AstraZeneca's CVRM strategy emphasizes the critical interplay between cardiac, renal, and metabolic systems, recognizing that dysfunction in one organ often precipitates disease in another.[20] AZD-3427, with its potential to exert beneficial effects on both cardiac hemodynamics and renal perfusion, embodies this integrated approach. The investment in a sophisticated biologic like an Fc-fusion protein also reflects the company's commitment to leveraging next-generation therapeutic platforms, including advanced biologics and cell therapies, to tackle areas of high unmet medical need.[23]

The creation of a long-acting relaxin mimetic is a clear strategic pivot based on lessons learned from the broader pharmaceutical industry's experience with earlier, short-acting agents. The failure of the large confirmatory trial for the acute HF therapy serelaxin (RELAX-AHF-2) was a significant setback that cast doubt on the therapeutic viability of the relaxin pathway.[29] A prevailing hypothesis for this failure is that a brief, 48-hour infusion, while potentially offering transient hemodynamic relief, was insufficient to induce the profound anti-fibrotic and vascular remodeling effects that are believed to be central to relaxin's long-term benefits and are necessary to alter the chronic disease course.

AstraZeneca's development of AZD-3427 is predicated on a new therapeutic hypothesis: that sustained, chronic activation of the RXFP1 receptor is required for meaningful disease modification. This shifts the entire therapeutic paradigm for relaxin agonists from an acute, hospital-based intervention to a chronic, outpatient therapy. This change has profound implications for every aspect of the drug's development, from the design of clinical trials (which must be longer and use chronic endpoints) to the target patient populations (stable chronic HF rather than acutely decompensated HF) and the ultimate commercialization strategy (a patient- or clinic-administered SC injection instead of a hospital-based IV infusion). The success of AZD-3427 would therefore not only validate the drug itself but also this new, chronic-treatment hypothesis for the entire drug class.

Attribute	Description	Source(s)
Generic Name	AZD-3427	2
Synonyms	AZD 3427, AZD3427	2
Drug Type/Modality	Fc Fusion Protein, Peptide/Protein Therapeutic	2
Originator	AstraZeneca	3
Target	Relaxin Family Peptide Receptor 1 (RXFP1)	2
Mechanism of Action	Selective RXFP1 Agonist, Relaxin Mimetic	1
Route of Administration	Subcutaneous (SC), Intravenous (IV)	4
Therapeutic Areas	Cardiovascular Diseases, Respiratory Diseases	2
Highest Development Phase	Phase 2	2
Key Indications	Heart Failure (HFrEF & HFpEF), Pulmonary Hypertension (PH-LHD), Renal Impairment	1

II. Mechanism of Action and Pharmacological Rationale

A. The RXFP1 Receptor: A Multifunctional Target

The therapeutic activity of AZD-3427 is mediated through its function as a selective agonist for the Relaxin Family Peptide Receptor 1 (RXFP1).[1] RXFP1 is a class A G-protein coupled receptor (GPCR) and serves as the primary cognate receptor for the endogenous peptide hormone relaxin-2.[5] This receptor is expressed in a wide array of tissues relevant to cardiovascular and renal health, including the heart, kidneys, liver, lungs, and the vasculature, making it an ideal target for a systemic therapy aimed at a multi-organ disease like heart failure.[38]

The scientific rationale for targeting RXFP1 in heart failure stems from the receptor's pleiotropic effects. Activation of RXFP1 is known to trigger a cascade of beneficial physiological responses that directly counteract the key pathological processes of heart failure. These effects include potent vasodilation (both systemic and renal), robust anti-inflammatory actions, and significant anti-fibrotic properties.[1] By engaging a single target that can modulate these multiple, interconnected pathways, AZD-3427 has the potential to offer a more holistic treatment for the complex cardiorenal syndrome than therapies targeting a single pathological mechanism.

B. Downstream Signaling Pathways and Therapeutic Effects

Upon binding of an agonist like AZD-3427, the RXFP1 receptor initiates a complex and diverse array of intracellular signaling cascades. The most well-characterized of these is the canonical Gs-protein pathway. Agonist binding promotes coupling of RXFP1 to the stimulatory G-protein alpha subunit (Gs​α), which in turn activates the enzyme adenylyl cyclase. This leads to an increase in the intracellular concentration of the second messenger cyclic adenosine monophosphate (cAMP).[36] Elevated cAMP levels are known to mediate many of relaxin's effects, including vasodilation and the suppression of renal fibrosis.[43]

However, the signaling network downstream of RXFP1 is more intricate and extends beyond cAMP. Evidence from numerous preclinical studies has elucidated several other critical pathways that contribute to the receptor's therapeutic potential:

• Nitric Oxide (NO) Pathway: A key mechanism for the vasodilatory effect of relaxin involves the stimulation of nitric oxide (NO) production. RXFP1 activation leads to the phosphorylation and activation of endothelial nitric oxide synthase (eNOS), which generates NO, a potent vasodilator that relaxes smooth muscle cells in blood vessel walls, thereby improving blood flow and reducing vascular resistance.[40]
• Anti-Fibrotic Signaling: Fibrosis, the excessive deposition of extracellular matrix proteins, is a central driver of both cardiac and renal dysfunction in heart failure. RXFP1 activation has been shown to exert powerful anti-fibrotic effects by directly counteracting the pro-fibrotic signaling of transforming growth factor-β (TGF-β). Specifically, relaxin signaling inhibits the phosphorylation of Smad2, a key intracellular transducer in the TGF-β pathway, thereby blocking the downstream cascade that leads to collagen synthesis and fibroblast activation.[40]
• MAPK/ERK and PI3K Pathways: RXFP1 also engages other major signaling pathways, including the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)1/2 pathway and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway.[37] These pathways are fundamental regulators of cell survival, proliferation, and apoptosis. Their activation by RXFP1 likely contributes to the tissue-protective and anti-apoptotic effects of relaxin observed in models of cardiac and renal injury.

C. Functional Selectivity and the Potential of Biased Agonism

A sophisticated concept in modern pharmacology is "biased agonism" or "functional selectivity," which posits that a GPCR like RXFP1 can adopt multiple active conformations upon ligand binding.[42] Each conformation can preferentially couple to a different set of intracellular signaling partners (e.g., Gs vs. Gi vs. β-arrestin), leading to the selective activation of one downstream pathway over another. This opens the door to designing drugs that are "biased" toward producing a desired therapeutic effect (e.g., anti-fibrosis) while minimizing unwanted side effects that may be mediated by a different pathway.[42]

The explicit description of AZD-3427 as a "functionally selective" mimetic is therefore highly significant.[1] It suggests that AstraZeneca has deliberately engineered the molecule to be a biased agonist, a clear departure from the full agonism of endogenous relaxin or its recombinant form, serelaxin. The field has increasingly recognized that different signaling outputs from RXFP1 can lead to distinct physiological outcomes. For instance, the small molecule agonist ML290 has been shown to be biased toward activating cGMP and anti-fibrotic pathways, while having less effect on cAMP accumulation.[48] Another synthetic variant, B7-33, preferentially activates the ERK1/2 pathway over the cAMP pathway.[47]

This engineered selectivity may be a key differentiator for AZD-3427 and a strategy to overcome the limitations of its predecessors. The failure of serelaxin could be attributed not only to its short half-life but also to its non-selective activation of all RXFP1 downstream pathways, some of which might be less beneficial or even counterproductive in a chronic disease setting. By creating a functionally selective molecule, AstraZeneca is likely attempting to fine-tune the signaling cascade, aiming to maximize the desired anti-fibrotic and vasodilatory effects (e.g., via NO, cGMP, and TGF-β inhibition) while potentially minimizing other effects that are less desirable in the long-term treatment of heart failure. This represents a sophisticated drug design strategy where success depends not just on if the drug activates RXFP1, but how it activates it. This makes the mechanistic clinical studies in the development program critically important for understanding whether this engineered selectivity translates into a superior and safer clinical profile.

III. The Therapeutic Landscape in Heart Failure and Associated Pulmonary Hypertension

A. The Unmet Need in Complex Heart Failure

Heart failure (HF) represents a major global health crisis, affecting hundreds of millions of individuals and standing as a leading cause of morbidity and mortality.[9] Despite significant advances in pharmacological and device-based therapies over the past several decades, the prognosis for many patients with HF remains poor, with high rates of hospitalization and death.[3]

The syndrome is broadly classified based on the heart's pumping capacity, measured as the left ventricular ejection fraction (LVEF). HF with reduced ejection fraction (HFrEF), where the LVEF is 40% or less, is characterized by a weakened heart muscle that cannot pump effectively.[52] In contrast, HF with preserved ejection fraction (HFpEF), where the LVEF is 50% or greater, involves a stiff heart muscle that cannot relax and fill properly.[56] HFpEF is becoming increasingly prevalent, is often associated with a high burden of comorbidities like hypertension and diabetes, and has historically proven more challenging to treat effectively.

B. The Challenge of Pulmonary Hypertension due to Left Heart Disease (PH-LHD)

A frequent and ominous complication of both HFrEF and HFpEF is the development of pulmonary hypertension due to left heart disease (PH-LHD), which is classified as WHO Group 2 PH.[62] It is the most common form of PH, estimated to affect up to 80% of patients with LHD.[65] The hemodynamic definition of PH-LHD is a mean pulmonary arterial pressure (mPAP) greater than 20 mmHg in the setting of elevated left-sided filling pressures, indicated by a pulmonary artery wedge pressure (PAWP) greater than 15 mmHg.[65]

The presence of PH-LHD is a clear marker of advanced disease and is strongly associated with a worse prognosis, including more severe symptoms, significantly reduced exercise capacity, and higher rates of hospitalization and mortality.[1]

Pathophysiologically, PH-LHD exists on a spectrum. In its initial stages, it is often "passive" or "isolated post-capillary" (IpcPH), where the elevated pulmonary artery pressure is a direct consequence of the "back-pressure" from the failing left heart. However, over time, a subset of patients develops a "reactive" or "combined pre- and post-capillary" (CpcPH) phenotype. This more severe form is characterized by intrinsic remodeling and vasoconstriction of the pulmonary arteries themselves, leading to an increase in pulmonary vascular resistance (PVR) that is out of proportion to the elevation in left-sided pressures.[64] Patients with CpcPH have a particularly dismal prognosis.

C. Current Standard of Care and Its Limitations

The treatment for HFrEF is well-defined and based on a foundation of four pillars of guideline-directed medical therapy (GDMT): an angiotensin receptor-neprilysin inhibitor (ARNI) or an angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB); an evidence-based beta-blocker; a mineralocorticoid receptor antagonist (MRA); and a sodium-glucose cotransporter-2 (SGLT2) inhibitor.[52] These therapies have been proven to reduce mortality and hospitalizations. Diuretics are also used as needed to manage fluid retention and relieve symptoms of congestion.[52]

The treatment of HFpEF has been more challenging. Management has traditionally focused on controlling congestion with diuretics and treating underlying comorbidities such as hypertension and atrial fibrillation.[56] The recent demonstrated benefit of SGLT2 inhibitors in reducing HF hospitalizations in this population represents a major therapeutic advance and they are now recommended as a foundational therapy.[56]

A critical gap in the current therapeutic armamentarium is the lack of any approved therapies that specifically target the pulmonary vascular component of PH-LHD.[1] Clinical trials of drugs approved for pulmonary arterial hypertension (PAH, WHO Group 1), such as endothelin receptor antagonists and prostacyclin analogues, have not only failed to show benefit in PH-LHD but have in some cases been found to be harmful, likely due to their potential to increase pulmonary congestion by dilating the pulmonary vasculature without addressing the underlying high left-sided filling pressures.[64] This leaves a significant unmet medical need for a safe and effective treatment for the millions of HF patients complicated by PH, a need that AZD-3427 is specifically designed to address.

D. Historical Context: Lessons from the Serelaxin Trials

The development of AZD-3427 cannot be fully understood without considering the history of its predecessor, serelaxin. Serelaxin, a recombinant form of human relaxin-2 administered as a short-term intravenous infusion, was studied for the treatment of acute heart failure.

The initial Phase 3 RELAX-AHF trial yielded promising results. While it met only one of its two primary endpoints for dyspnea relief, it showed a striking and statistically significant 37% reduction in 180-day mortality compared to placebo.[74] This mortality signal was highly encouraging and led the U.S. FDA to grant serelaxin a "breakthrough therapy" designation.

However, the larger, confirmatory Phase 3 trial, RELAX-AHF-2, which was specifically powered to confirm this mortality benefit, failed to meet its primary endpoints. The trial enrolled over 6,500 patients and found no significant difference in 180-day cardiovascular mortality or in the rate of worsening heart failure at day 5 between the serelaxin and placebo groups.[29]

The failure of RELAX-AHF-2 prompted extensive analysis and commentary. Potential explanations included the possibility that the initial mortality finding was due to chance, or that there were subtle but important differences in the patient populations between the two trials.[30] Indeed, post-hoc analysis revealed that the patient population in the original RELAX-AHF trial represented a highly selected subgroup, comprising only about 20% of patients found in real-world AHF registries.[78] However, a more fundamental critique focused on the therapeutic strategy itself. The proposed mechanisms of relaxin—including anti-fibrotic and vascular remodeling effects—are biological processes that inherently occur over weeks to months. It is therefore plausible that a short, 48-hour infusion during an acute decompensation event is simply an insufficient duration of exposure to modify the underlying chronic disease processes that drive long-term mortality.

AstraZeneca's strategy with AZD-3427 directly confronts this critique. By investing in Fc-fusion technology to create a long-acting agent suitable for chronic administration, the company is testing a fundamentally different therapeutic hypothesis: that sustained, long-term activation of the RXFP1 receptor is necessary to unlock the full disease-modifying potential of the relaxin pathway. This historical context is not merely background information; it is the core justification for AZD-3427's existence and the design of its clinical program. The failure of serelaxin created a high-risk but potentially high-reward opportunity. The risk is the "guilt by association" with a failed predecessor. The reward is that if the "sustained agonism" hypothesis proves correct, AZD-3427 could succeed where serelaxin failed, validating a therapeutic concept that has been pursued for decades and potentially delivering a transformative therapy for a large patient population with a major unmet need.

IV. Preclinical and Early Clinical Development of AZD-3427

A. Preclinical Efficacy in Non-Human Primates

Before advancing to human trials, the therapeutic potential of AZD-3427 was evaluated in a highly relevant large animal model. The effects of chronic RXFP1 agonism were investigated in a non-human primate (NHP) model characterized by systolic dysfunction and metabolic syndrome, conditions that closely mimic key aspects of human heart failure.[6]

In this pivotal preclinical study, prolonged administration of AZD-3427 over a 21-week period yielded remarkable and statistically significant improvements in cardiac function. Key findings included a marked increase in left ventricular ejection fraction (EF), cardiac output (CO), and stroke volume (SV). Concurrently, the treatment led to a significant reduction in systemic vascular resistance (SVR), demonstrating a potent vasodilatory effect. Critically, these beneficial hemodynamic changes were achieved without any concomitant adverse changes in heart rate or blood pressure, suggesting a favorable and safe mechanism of action. The therapeutic effects were also shown to be reversible, as they gradually disappeared during a subsequent 18-week washout period, linking the observed benefits directly to the presence of the drug.[6]

These NHP data provided essential translational evidence supporting the core therapeutic hypothesis. They demonstrated that sustained, chronic agonism of the RXFP1 receptor with a long-acting agent like AZD-3427 could safely and effectively improve cardiac performance, providing a robust scientific foundation for progressing the molecule into human clinical trials for chronic heart failure.

B. Analysis of the Phase 1a/b First-in-Human Study (NCT04630067)

The first-in-human (FTIH) evaluation of AZD-3427 was conducted in the NCT04630067 study, a Phase 1a/b, randomized, single-blind, placebo-controlled trial. The study was designed in two parts: Part A evaluated single ascending doses (SAD) in 56 healthy volunteers, while Part B evaluated multiple ascending doses (MAD) in 48 patients with stable heart failure (both HFrEF and HF with EF ≥41%).[3]

Safety and Tolerability:

Across all dose levels tested in both healthy volunteers and patients with heart failure, AZD-3427 was found to be well tolerated.1 The establishment of a favorable safety profile in this initial study is a critical milestone, providing confidence to proceed to larger and longer-term studies in more vulnerable patient populations.

Immunogenicity:

A key risk for any biologic or fusion protein therapy is the potential for the patient's immune system to generate anti-drug antibodies (ADAs), which can neutralize the drug's effect or cause hypersensitivity reactions. In this study, no treatment-emergent ADAs were detected in any participant receiving AZD-3427.3 This is a very positive finding that mitigates a significant potential risk for a drug intended for chronic, long-term administration.

Pharmacokinetics (PK):

The pharmacokinetic analysis confirmed the success of the Fc-fusion engineering strategy. Following subcutaneous administration, AZD-3427 was absorbed slowly, and its exposure (as measured by area under the curve and maximum concentration) increased in an approximately linear fashion across the tested dose range.3 Most importantly, in patients with heart failure, AZD-3427 demonstrated a long terminal half-life of 13 to 14 days.3 This extended half-life validates the core design principle of the molecule and confirms that a convenient weekly or bi-weekly subcutaneous dosing regimen is feasible for maintaining therapeutic drug levels in a chronic setting.5

Pharmacodynamics (PD):

While a Phase 1 study is not powered to demonstrate definitive efficacy, it can provide early signals of a drug's biological activity. The study of AZD-3427 revealed pharmacodynamic changes consistent with the anticipated effects of a relaxin analogue. In the heart failure patient cohorts, there were numerical increases observed in stroke volume, a direct measure of cardiac pump function.3

Furthermore, a particularly noteworthy finding was a numerical increase in the estimated glomerular filtration rate (eGFR).[3] This suggests a beneficial effect on renal function, which is a critical observation given the high prevalence of renal impairment in heart failure patients and the interconnected nature of the cardiorenal syndrome. This finding aligns with the known renal vasodilatory effects of relaxin and provides the first human evidence that AZD-3427 may positively impact the renal component of the disease, a key part of its therapeutic rationale.[36]

Finding	Details	Source(s)
Population	Healthy Volunteers (n=56), Heart Failure Patients (n=48)	3
Safety	Generally well tolerated at all doses tested.	1
Immunogenicity	No treatment-emergent anti-drug antibodies (ADAs) detected.	3
Pharmacokinetics	Terminal Half-Life: 13-14 days in HF patients.Dose Proportionality: Approximately linear exposure after SC administration.	3
Pharmacodynamics	Hemodynamic Effects: Numerical increase in stroke volume observed.Renal Effects: Numerical increase in estimated glomerular filtration rate (eGFR) observed.	3

V. Mid-Stage Clinical Program Analysis: A Multi-Pronged Strategy

AstraZeneca's approach to the mid-stage development of AZD-3427 is notably sophisticated and scientifically rigorous. Rather than conducting a single, conventional Phase 2 trial, the company has initiated a comprehensive portfolio of studies designed to simultaneously evaluate efficacy, safety, and the underlying mechanisms of action across different physiological systems. This multi-pronged strategy includes a large, dose-ranging pivotal efficacy trial in the target population (Re-PHIRE), a dedicated renal hemodynamics study using advanced PET imaging (Re-PERFUSE), and a mechanistic study to directly confirm the drug's primary vascular effect.

This resource-intensive approach indicates a high level of corporate commitment and a strategic decision to build a comprehensive value proposition for AZD-3427. It moves beyond simply asking "Does the drug work?" to definitively answer the critical questions of "How does it work?" and "In which organs does it work?". The Re-PERFUSE study, in particular, is a high-science endeavor designed to provide unambiguous, quantitative proof of a key mechanistic benefit—improved renal perfusion—which could be a major differentiator. This strategy aims to de-risk the asset on multiple fronts, generate a rich dataset for regulatory discussions, and potentially open avenues for development in other cardiorenal indications.

A. The Re-PHIRE Study (Phase 2b, NCT05737940): The Core Efficacy Trial

The centerpiece of the mid-stage program is the Re-PHIRE study, a Phase 2b, randomized, double-blind, placebo-controlled, multi-center, dose-ranging trial.[1] The study has enrolled approximately 220 patients diagnosed with heart failure and concomitant pulmonary hypertension due to left heart disease (PH-LHD). Participants were randomized to receive one of three different doses of AZD-3427 or a placebo, administered via subcutaneous injection every two weeks for a treatment period of 24 weeks. As of January 2025, the trial is active but no longer recruiting participants.[1]

A key feature of the Re-PHIRE study is its inclusive patient population. The trial was designed to enroll a broad spectrum of PH-LHD phenotypes, with no restrictions based on left ventricular ejection fraction or baseline pulmonary vascular resistance. This encompasses patients with both isolated post-capillary PH (IpcPH) and the more severe combined pre- and post-capillary PH (CpcPH), allowing for the evaluation of AZD-3427's effects across the full range of the disease.[1]

The primary endpoint of the study is the change from baseline in pulmonary vascular resistance (PVR) after 24 weeks of treatment, as measured by invasive right heart catheterization (RHC).[1] The selection of PVR as the primary endpoint is significant. It is a direct measure of the resistance within the pulmonary arteries and is a strong prognostic indicator in both HF and PH. A significant reduction in PVR would provide compelling evidence that AZD-3427 can favorably modify the pulmonary vasculature, addressing a core pathological component of PH-LHD for which no approved therapies exist.[1]

To capture the full clinical impact of the drug, the study incorporates a comprehensive slate of key secondary endpoints, including:

• Other Hemodynamic Parameters: Changes in mean pulmonary arterial pressure (mPAP), pulmonary artery wedge pressure (PAWP), and systemic vascular resistance (SVR) will provide a more complete picture of the drug's vascular effects.[1]
• Functional Capacity: Change in the 6-Minute Walk Distance (6MWD) will assess for improvements in exercise capacity, a key measure of how patients feel and function.[1]
• Biomarkers: Change in levels of N-terminal pro B-type natriuretic peptide (NT-proBNP), a standard biomarker of cardiac wall stress and HF severity, will be evaluated.[1]
• Patient-Reported Outcomes: The Kansas City Cardiomyopathy Questionnaire (KCCQ) will be used to measure the drug's impact on patients' symptoms, physical function, social limitations, and overall quality of life.[1] The KCCQ is a well-validated, FDA-qualified tool where changes of 5, 10, and 20 points are recognized as small, moderate, and large clinically important differences, respectively. A strong positive signal on the KCCQ would provide powerful evidence of a patient-centric benefit.[86]

B. The Re-PERFUSE Study (Phase 1b, NCT06611423 / D8330C00004): Probing the Cardiorenal Axis

To specifically investigate the drug's effects on the kidneys, AstraZeneca initiated the Re-PERFUSE study. This is a Phase 1b, randomized, double-blind, placebo-controlled trial designed to enroll approximately 12 patients with HFrEF and concomitant renal impairment (defined as an eGFR between 30 and 90 mL/min/1.73m²).[34]

The primary objective of this highly mechanistic study is to provide direct, quantitative evidence of AZD-3427's effect on renal hemodynamics. The study will use advanced [15O]H2O Positron Emission Tomography (PET) imaging to measure the change in the volumetric fraction of perfused renal cortex after a single dose of AZD-3427 or placebo. Dopamine, a known renal vasodilator, is included as a positive control to validate the imaging methodology.[34] Positive data from Re-PERFUSE would provide powerful support for the hypothesis that AZD-3427 can directly address the renal dysfunction that is a key driver of morbidity and mortality in the cardiorenal syndrome.

C. Mechanistic Insights from the Vasodilatory Effects Study (NCT04890548)

To confirm the drug's fundamental pharmacological action, a dedicated mechanistic study (NCT04890548) was conducted in patients with both HFpEF and HFrEF.[17] The study was designed to provide unambiguous proof-of-mechanism for vasodilation. This was achieved by using intra-arterial (IA) infusions of ascending doses of AZD-3427 directly into the brachial artery of the forearm. The local vascular response was then measured using venous occlusion plethysmography to assess changes in forearm blood flow.[17]

The strategic value of this study lies in its ability to isolate and confirm the drug's primary proposed action. By demonstrating a direct vasodilatory effect in a localized vascular bed, independent of systemic hemodynamic changes, the study provides a clean and direct link between AZD-3427 and its intended biological activity, strengthening the overall evidence base for the drug.

Trial Name / Identifier	Phase	Status	Population	N (Enrollment)	Primary Endpoint / Objective	Key Rationale
NCT04630067	1a/b	Completed	Healthy Volunteers & HF Patients	105	Safety, Tolerability, PK, PD	First-in-human safety and PK foundation.
NCT04890548	Mechanistic	Completed	HFpEF & HFrEF Patients	~20	Forearm Blood Flow	Direct proof-of-mechanism (vasodilation).
Re-PHIRE (NCT05737940)	2b	Active, Not Recruiting	HF & PH-LHD Patients	~220	Change in Pulmonary Vascular Resistance (PVR)	Core efficacy and safety in target indication.
Re-PERFUSE (NCT06611423)	1b	Recruiting	HFrEF & Renal Impairment Patients	~12	Change in Renal Perfusion (by PET)	Mechanistic proof of renal hemodynamic benefit.

VI. Competitive Landscape and Market Positioning

A. Other Relaxin Agonists in Development

AZD-3427 is advancing in a competitive but still nascent field of relaxin-based therapeutics. Several other companies are exploring this pathway, each with different molecular approaches and at various stages of development.

• Bristol-Myers Squibb (BMS): BMS has shown long-standing interest in this area. The company holds a patent application for small molecule RXFP1 agonists intended for heart failure and fibrotic diseases.[36] Furthermore, a 2011 collaboration with Ambrx, Inc. led to the development of a long-acting relaxin derivative that entered a Phase 1 clinical trial in 2019 for the potential treatment of heart failure.[95] While the current status of this specific program is not detailed in recent materials, it highlights sustained engagement from a major pharmaceutical competitor.
• Tectonic Therapeutics (Acquired by AVROBIO): This company was developing TX-000045, another RXFP1 agonist. The asset was in Phase 1 clinical trials, with plans to advance to Phase 2, before the company's acquisition was announced in early 2024.[96]
• Moderna/AstraZeneca: In a strategic move to broaden its portfolio, AstraZeneca acquired the rights to mRNA-0184 from Moderna Therapeutics. This asset, which was in Phase 1 development, is an mRNA-based RXFP1 agonist.[96] This gives AstraZeneca two distinct therapeutic modalities—a biologic fusion protein (AZD-3427) and an mRNA therapy—targeting the same pathway, allowing them to explore different technological approaches to the same biological problem.
• AstraZeneca's AZD5462: In addition to AZD-3427, AstraZeneca is also developing AZD5462, an orally bioavailable small molecule RXFP1 agonist. This compound is also in Phase 2 clinical trials, indicating a dual-pronged strategy by the company to lead in this therapeutic space.[96]

B. Potential for Differentiation

Within this emerging landscape, AZD-3427 possesses several key attributes that could serve as points of differentiation.

• Modality: As a biologic Fc fusion protein, AZD-3427 is distinct from the small molecule agonists being developed by BMS and AstraZeneca's own AZD5462. Biologics often provide advantages in terms of high target specificity and long half-lives, which has been demonstrated for AZD-3427. However, they can also be associated with higher manufacturing costs and the potential for immunogenicity. The lack of detected ADAs in the Phase 1 study for AZD-3427 is a significant early de-risking event in this regard.[3]
• Development Stage: With a comprehensive Phase 2 program actively underway, AZD-3427 appears to be one of the most advanced long-acting relaxin agonists currently in clinical development.[2]
• Target Indication: The focused development strategy targeting PH-LHD is a crucial differentiator. While other programs may target the broader heart failure population, AstraZeneca is initially focusing on a specific, high-unmet-need sub-population where no approved therapies exist. A direct, measurable effect on pulmonary vasculature (PVR) could provide a clearer and potentially faster path to an initial market approval. Success in this niche could then serve as a foothold for future label expansion into the wider HFrEF and HFpEF populations.

Drug Candidate	Developer	Modality	Target	Highest Phase	Key Differentiator
AZD-3427	AstraZeneca	Fc Fusion Protein	RXFP1	Phase 2	Long-acting SC biologic with a focused initial indication in PH-LHD.
AZD5462	AstraZeneca	Small Molecule	RXFP1	Phase 2	Orally bioavailable small molecule for chronic HF.
BMS/Ambrx Candidate	BMS/Ambrx	Biologic	Relaxin	Phase 1 (status unclear)	Long-acting relaxin derivative.
TX-000045	Tectonic / AVROBIO	N/A	RXFP1	Phase 1	Early-stage RXFP1 agonist.
mRNA-0184	Moderna / AstraZeneca	mRNA	RXFP1	Phase 1	In vivo expressed biologic via mRNA technology.

VII. Synthesis, Strategic Outlook, and Recommendations

A. Critical Assessment of the Clinical Development Program

AstraZeneca's clinical development program for AZD-3427 is characterized by its scientific rigor and strategic foresight. The program's core strength lies in its direct approach to addressing the key hypothesized failure of past relaxin therapies—the insufficient duration of action. The engineering of a long-acting agent and its development for chronic use is a logical and well-justified strategy.

The parallel execution of mechanistic studies, such as the Re-PERFUSE renal PET study and the forearm vasodilation study, is a significant asset. This approach provides multiple opportunities to demonstrate the drug's biological activity, thereby de-risking the larger and more expensive efficacy trial. The selection of pulmonary vascular resistance (PVR) as the primary endpoint for the Re-PHIRE trial is both clinically relevant and prognostically important, offering a robust measure of potential disease modification in a population with no approved treatments.

However, the program is not without its challenges. The ambitious nature of the parallel studies makes it a costly endeavor. The reliance on invasive right heart catheterization for the primary endpoint of Re-PHIRE, while scientifically sound, presents logistical complexities for trial execution and may limit enrollment speed. Furthermore, the program operates under the shadow of the RELAX-AHF-2 failure. This history may create a higher bar for demonstrating clinical and regulatory success; a modest or borderline result for AZD-3427 might be viewed with skepticism.

B. Key Risks and Future Milestones

The future of AZD-3427 hinges on several key risks and upcoming milestones.

• Clinical Risk: The most significant risk is that the central "sustained agonism" hypothesis proves to be incorrect. It is possible that even a long-acting agent will fail to demonstrate a clinically meaningful benefit on top of the current, highly optimized standard of care for heart failure. The therapeutic landscape has evolved significantly since the serelaxin trials, most notably with the widespread adoption of SGLT2 inhibitors, which have powerful cardiorenal benefits of their own. Demonstrating a significant incremental benefit over this new, more effective standard of care will be a substantial challenge.
• Regulatory Risk: Even if the Re-PHIRE trial achieves statistical significance for its PVR primary endpoint, regulatory agencies may question the direct translation of this hemodynamic measure to "harder" clinical outcomes such as mortality and hospitalization. This was a key lesson from the serelaxin program, where promising early signals did not translate into confirmatory trial success. To build a compelling case for approval, it will be crucial for AZD-3427 to demonstrate not only a change in PVR but also consistent, positive trends across key secondary endpoints, particularly patient-reported outcomes (KCCQ) and functional capacity (6MWD).
• Future Milestones: The trajectory of AZD-3427 will be largely determined by data readouts anticipated in 2025. The primary completion date for the pivotal Re-PHIRE study (NCT05737940) is listed as July 2025, and the primary completion for the Re-PERFUSE renal PET study (NCT06611423) is September 2025.[4] The results from these trials will be pivotal for the future of the AZD-3427 program and will likely have a significant impact on the entire field of relaxin-based therapeutics.

C. Concluding Remarks: A High-Risk, High-Reward Asset

AZD-3427 represents a well-designed and scientifically sophisticated attempt to resurrect and redefine the therapeutic potential of the relaxin pathway for cardiovascular disease. Its molecular engineering as a long-acting Fc fusion protein is a direct and intelligent response to the primary perceived limitation of its predecessors. AstraZeneca's comprehensive and mechanism-focused clinical development program is a model of modern drug development, designed to yield a deep understanding of the drug's biological effects that goes far beyond a simple top-line efficacy result.

The asset embodies a classic high-risk, high-reward profile. The ultimate success of AZD-3427 depends on whether sustained, chronic RXFP1 agonism can deliver a clinically meaningful and statistically robust benefit in a specific, high-need patient population—PH-LHD—that has thus far been refractory to all targeted therapies. A positive outcome from the current clinical program would not only establish a first-in-class, potentially blockbuster therapy but would also validate a therapeutic concept that has been pursued for decades. Conversely, a negative outcome would likely signal the end of the road for the development of relaxin-based therapies in heart failure for the foreseeable future, making the upcoming trial results a critical inflection point for the field.

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