AZD9550: An Investigational Dual GLP-1R/GCGR Agonist for Metabolic Diseases

1. Executive Summary

AZD9550 is an investigational therapeutic agent under development by AstraZeneca, characterized by its dual agonism at the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR).[1] This compound is strategically positioned within AstraZeneca's Cardiovascular, Renal and Metabolism (CVRM) pipeline and is being evaluated for the treatment of complex metabolic disorders, primarily obesity and non-alcoholic steatohepatitis (NASH), now increasingly referred to as metabolic dysfunction-associated steatohepatitis (MASH).[1] Potential utility in Type 2 Diabetes Mellitus (T2DM) is also implicitly under investigation, given the study populations.[1] AZD9550 is administered via subcutaneous (SC) or intravenous (IV) routes, with the SC route being the focus for therapeutic delivery in later-phase trials.[2] Currently, the drug is advancing through Phase I/II and Phase IIb clinical trials.[1] A key aspect of its development strategy involves evaluating its efficacy and safety both as a monotherapy and in combination with AZD6234, a long-acting amylin analogue also developed by AstraZeneca, particularly for obesity management.[9] The simultaneous targeting of obesity and NASH/MASH underscores a therapeutic approach aimed at addressing the interconnected pathophysiology common to these prevalent metabolic conditions, leveraging the compound's dual mechanism of action to potentially achieve broader metabolic benefits than single-pathway agents.

2. Introduction to AZD9550

2.1. Identification and Development

The investigational drug AZD9550, also referred to as AZD 9550, is a novel compound originated and developed by the global biopharmaceutical company AstraZeneca.[1] It represents a focused effort within AstraZeneca's extensive research and development pipeline, specifically targeting metabolic diseases.[4]

2.2. Drug Class and Type

AZD9550 is classified as an investigational drug, meaning it has not yet received marketing approval from regulatory agencies like the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA).[3] Its pharmacological classification is a dual agonist that simultaneously targets two distinct G protein-coupled receptors: the Glucagon-like peptide 1 receptor (GLP-1R) and the Glucagon receptor (GCGR).[1] This dual mechanism of action is central to its therapeutic hypothesis.

There appears to be some ambiguity in source materials regarding its precise molecular type. One source explicitly categorizes AZD9550 as a small molecule drug [1], while another lists its class broadly as "Hepatoprotectants; Obesity therapies; Peptides; Small molecules".[10] It is confirmed to be a New Molecular Entity (NME).[10] Typically, GLP-1R and GCGR are activated by endogenous peptide hormones (GLP-1 and glucagon, respectively). Developing small molecule agonists for these receptors is a known strategy, potentially offering advantages in stability, manufacturing, or oral bioavailability over traditional peptide therapeutics, although this remains challenging.[18] The designation as a small molecule [1], if accurate, would represent a significant chemical engineering achievement. However, the current clinical development program exclusively utilizes subcutaneous and intravenous administration routes [2], which is consistent with either a peptide-based drug or a small molecule lacking sufficient oral bioavailability. The potential classification discrepancy might arise from the drug mimicking peptide actions or from early reporting variations. Regardless of its exact structural classification, its function as a dual agonist defines its pharmacological profile.

3. Mechanism of Action and Pharmacological Profile

3.1. Dual GLP-1R and GCGR Agonism

The core therapeutic principle of AZD9550 lies in its ability to concurrently activate both the GLP-1 receptor and the glucagon receptor.[1] These two receptors mediate distinct but potentially complementary physiological effects relevant to metabolic regulation.

Activation of GLP-1R is well-established to promote glucose homeostasis and weight reduction through multiple mechanisms. These include augmenting glucose-dependent insulin secretion from pancreatic β-cells, suppressing glucagon secretion from pancreatic α-cells during periods of hyper- or euglycemia, decelerating gastric emptying which blunts postprandial glucose excursions, and promoting satiety and reducing appetite via actions in the central nervous system.[14] These combined effects contribute to improved glycemic control and significant weight loss, as demonstrated by numerous approved GLP-1 RA therapies.[22]

Activation of GCGR, primarily by the endogenous hormone glucagon, traditionally opposes insulin action by stimulating hepatic glucose production (gluconeogenesis and glycogenolysis). However, GCGR agonism is also implicated in increasing energy expenditure, potentially enhancing thermogenesis, and influencing lipid metabolism, including effects on hepatic fat accumulation.[25] While GCGR agonism alone carries a risk of hyperglycemia, co-activation with GLP-1R is hypothesized to mitigate this risk due to the potent glucose-lowering and glucagon-suppressing effects of GLP-1R activation.[27]

3.2. Synergistic Effects on Metabolic Pathways

The rationale for developing a dual GLP-1R/GCGR agonist like AZD9550 stems from the hypothesis that engaging both pathways simultaneously will yield synergistic or additive benefits exceeding those achievable with selective agonism of either receptor alone.[14] The anticipated synergies include:

• Enhanced Weight Loss: Combining the appetite suppression and reduced caloric intake driven by GLP-1R activation with the potential increase in energy expenditure mediated by GCGR activation could lead to greater and more sustained weight reduction compared to GLP-1 RAs alone.[25]
• Improved Glycemic Control: The incretin effect of GLP-1R activation (enhanced insulin secretion, suppressed glucagon) can effectively manage hyperglycemia. The potential hyperglycemic effect of GCGR activation might be counterbalanced by the dominant GLP-1R actions, potentially resulting in robust glucose lowering with a potentially reduced risk of hypoglycemia compared to insulin-based therapies.[27]
• Enhanced Liver Fat Reduction: Both direct effects of GCGR activation on hepatic lipid metabolism and indirect effects resulting from systemic weight loss and improved insulin sensitivity driven by both pathways may contribute to a more pronounced reduction in liver fat content, a key pathological feature of NASH/MASH.[3]

AstraZeneca's stated aim for combination strategies involving its metabolic assets, including potentially AZD9550, is to achieve "maximum weight loss while protecting organs and not compromising tolerability" [13], reflecting the goal of leveraging multiple mechanisms for optimal outcomes. The development of AZD9550 embodies a specific pharmacological strategy: harnessing the metabolic benefits of glucagon signaling while mitigating its potential drawbacks through simultaneous GLP-1 receptor activation, aiming for superior efficacy in complex conditions like MASH where single-pathway interventions may be insufficient, particularly for reversing fibrosis.[25]

3.3. Comparison with GLP-1 Receptor Agonists (GLP-1 RAs)

GLP-1 RAs, such as semaglutide and liraglutide, have become cornerstone therapies for T2DM and obesity, demonstrating significant efficacy in glycemic control and weight reduction.[22] They have also shown promise in treating MASH, primarily by improving metabolic parameters and resolving steatohepatitis, although their impact on improving liver fibrosis has been less consistent or robust in some studies.[25]

Dual GLP-1R/GCGR agonists like AZD9550 are being developed with the expectation of providing advantages over GLP-1 RA monotherapy.[27] Data from other investigational dual agonists, such as survodutide (BI 456906), support this potential. Phase II trials of survodutide demonstrated significant weight loss and also showed promising rates of MASH resolution and fibrosis improvement by at least one stage, suggesting the dual mechanism might offer enhanced efficacy, particularly on the fibrotic component of MASH.[25] AstraZeneca itself previously developed cotadutide, another GLP-1/GCGR dual agonist administered daily.[16] While development of cotadutide was discontinued due to "strategic pipeline considerations" rather than safety concerns, the company explicitly stated that learnings from its program would inform the development of AZD9550.[16] The transition to AZD9550, designed for once-weekly administration, suggests a strategic decision to pursue a product with greater dosing convenience, aligning with market-leading competitors, while maintaining confidence in the therapeutic potential of the GLP-1/GCGR dual agonist approach.[16]

4. Clinical Development Program

4.1. Overview of Clinical Trials

AZD9550 is progressing through a structured clinical development program, moving from initial human safety assessments to evaluating its therapeutic effects in target patient populations. The program encompasses Phase I studies in healthy volunteers, Phase I/II studies in overweight/obese individuals with or without T2DM (with a focus on NASH/MASH), and a Phase IIb study investigating AZD9550 in combination with AZD6234 for obesity.[1] These trials employ standard methodologies, including randomization and placebo controls, to rigorously assess the drug's safety and efficacy.[7]

4.2. Summary of Key AZD9550 Clinical Trials

The following table summarizes key information available for the principal clinical trials involving AZD9550, based on the provided data:

Identifier(s) (NCT / Other)	Phase	Status (as of latest info)	Condition(s) Investigated	Key Objectives / Primary Endpoints	Enrollment (Target / Actual)	Start Date	Est. Primary Completion	Drug(s) Administered	Administration Route
NCT06862791 / D8460C00004 / EUCT-2024-516176-15-00 (ASCEND)	IIb	Recruiting	Obesity or Overweight with Co-morbidity (Excludes T2DM)	Efficacy (Weight loss % change @ 36 wks; ≥5% weight loss responders @ 36 wks), Safety, Tolerability	360 / N/A	Feb 2025	Jun 2026	AZD9550, AZD6234, Placebo (Combination & Monotherapy arms)	SC (once weekly)
NCT06151964 / D8460C00002 / CTIS 2023-504215-32-00 (CONTEMPO)	I/II	Recruitment Complete	Non-alcoholic steatohepatitis (NASH) in Overweight/Obese Participants +/- T2DM	Safety, Tolerability, PK, PD	88 / 88	Sep 2023	Jul 2026 (or May 2025) *	AZD9550, Placebo (Multiple ascending doses)	SC (once weekly in Parts C/D)
NCT05848440 / D8460C00001 / EudraCT 2022-003308-34	I	Completed	Healthy Participants (incl. Japanese cohort)	Safety, Tolerability, PK (Single ascending doses)	64 planned / 40 analyzed	May 2023	Nov 2023	AZD9550, Placebo	SC, IV

Note: Discrepancy exists in reported estimated completion dates for NCT06151964 between sources.7 N/A = Not Available in provided sources.

Data compiled from:.1

This table provides a consolidated view of the clinical development landscape for AZD9550, illustrating its progression from initial safety testing in healthy individuals to evaluating its efficacy, often in combination, within specific patient populations suffering from obesity or NASH/MASH. It highlights the systematic approach to dose-finding, safety assessment, and efficacy evaluation across different phases and target indications.

4.3. Detailed Review of Trials by Indication

4.3.1. Obesity and Overweight

The primary investigation of AZD9550 for weight management is the ASCEND trial (NCT06862791 / D8460C00004).[11] This is a large-scale, global Phase IIb study currently recruiting participants.[1] It employs a robust design: randomized, parallel-group, double-blind, and placebo-controlled.[11] The target population consists of 360 adults, aged 18 to 75 years, who have obesity (defined as Body Mass Index ≥ 30 kg/m2) or are overweight (BMI ≥ 27 kg/m2) with at least one documented weight-related comorbidity, such as hypertension or dyslipidemia.[1] Notably, individuals with Type 1 or Type 2 Diabetes Mellitus are explicitly excluded from this trial.[11]

The core objective of ASCEND is to evaluate the efficacy, safety, and tolerability of AZD9550 when co-administered with AZD6234 (a long-acting amylin analogue) [6] compared to placebo, as well as against each drug administered as monotherapy.[1] Treatment involves once-weekly subcutaneous injections over a 36-week period, with a total study participation time of approximately 47 weeks including screening and follow-up.[1]

The trial utilizes a reduced factorial design, incorporating multiple arms to test various dose combinations (low, medium, high) of AZD9550 and AZD6234, alongside high-dose monotherapy arms for each drug and a placebo arm.[11] This complex structure allows for an efficient assessment of potential dose-dependent synergistic effects between the two distinct mechanisms (GLP-1/GCGR agonism and amylin agonism). It aims to identify an optimal combination regimen that maximizes weight loss efficacy while maintaining an acceptable safety profile, potentially validating the "triple mechanism" concept mentioned in company communications.[13]

The co-primary efficacy endpoints are the percentage change in body weight from baseline after 36 weeks of treatment and the proportion of participants achieving a weight loss of at least 5% from baseline at 36 weeks, comparing the combination therapies against placebo.[9] Secondary endpoints further probe efficacy by assessing absolute change in body weight, comparing combination versus monotherapies, and evaluating the proportions of participants achieving higher thresholds of weight loss ($\ge$10% and $\ge$15%).[9] Immunogenicity, specifically the prevalence and incidence of anti-drug antibodies (ADAs) to both AZD9550 and AZD6234, is also a key secondary assessment.[19] The trial commenced recruitment in February 2025 and has an estimated primary completion date of June 2026.[1]

4.3.2. Non-alcoholic Steatohepatitis (NASH)/Metabolic Dysfunction-Associated Steatohepatitis (MASH)

The CONTEMPO trial (NCT06151964 / D8460C00002) serves as a key study evaluating AZD9550 in populations relevant to NASH/MASH.[7] This is a Phase I/II, randomized, single-blind, placebo-controlled study investigating multiple ascending doses (MAD) of AZD9550.[1] Recruitment for this trial, involving 88 participants, is reported as complete.[7] The study enrolled overweight and obese individuals (BMI range generally $\ge$27 to $\le$39.9 kg/m2, with slight variation by study part) aged 18 to 65 years.[7] Crucially, the study included participants with or without a diagnosis of T2DM, allowing for evaluation across different metabolic backgrounds.[1] Specific criteria regarding glycemic control (HbA1c levels) and prior/concurrent diabetes medications (e.g., metformin allowed, washout required for others in certain parts) were applied.[7]

Although the primary focus of CONTEMPO is on assessing the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of multiple subcutaneous doses of AZD9550 [1], the officially listed medical condition for the trial is NASH.[3] This designation, despite the trial not necessarily requiring biopsy-proven NASH for entry, signals the intended therapeutic path. The study likely incorporates PD endpoints relevant to NASH pathogenesis, such as changes in liver fat content (potentially measured by imaging), liver enzymes, glucose metabolism markers, and lipid profiles.[3] This approach allows AstraZeneca to gather essential safety, dosing, and PK information while obtaining early signals of biological activity in a population highly relevant to NASH/MASH, thereby informing the design of subsequent, larger efficacy trials specifically targeting histological endpoints in confirmed MASH patients. The study started in September 2023, with estimated primary completion dates reported variously as May 2025 [8] or July 2026 [7], possibly reflecting updates or different definitions of completion.

4.3.3. Early Phase and Healthy Volunteer Studies

The clinical journey of AZD9550 began with the First-In-Human (FIH) Phase I trial (NCT05848440 / D8460C00001 / EudraCT 2022-003308-34).[1] This single-center, randomized, single-blind, placebo-controlled study assessed single ascending doses (SAD) of AZD9550.[1] It enrolled healthy male and female participants (of non-childbearing potential) aged 18 to 55 years.[21] The trial successfully completed in November 2023.[10]

Key objectives were to establish the initial safety and tolerability profile of AZD9550 and to characterize its pharmacokinetics (PK), including absorption, distribution, metabolism, and excretion (ADME).[1] The study design included administration via both subcutaneous (SC) and intravenous (IV) routes across different dose cohorts.[2] Comparing PK parameters after IV (100% bioavailability assumed) and SC administration allows for the determination of absolute subcutaneous bioavailability. The trial also incorporated an assessment of immunogenicity by measuring anti-drug antibodies (ADAs).[21]

A notable feature of this FIH study was the inclusion of a specific cohort (Part B) consisting of healthy participants of Japanese descent.[21] Incorporating this population early in development reflects a proactive global strategy, aiming to gather data relevant for Japanese regulatory authorities and potentially streamline future development and registration in this key market by addressing potential pharmacokinetic or pharmacodynamic differences related to ethnicity from the outset.

4.4. Analysis of Key Inclusion/Exclusion Criteria

Across the AZD9550 clinical trials, participant selection is guided by specific inclusion and exclusion criteria designed to ensure patient safety and the integrity of the study data. Common inclusion criteria involve age ranges (typically 18-65 or 18-75 years) and BMI thresholds appropriate for the indication being studied (e.g., $\ge$30 kg/m2 or $\ge$27 kg/m2 with comorbidities for obesity; $\ge$27 or $\ge$25 up to 39.9 kg/m2 for the NASH-focused trial).[7] Participants are often required to have had stable body weight for a period (e.g., 3 months) prior to screening.[9] Standard requirements include the capacity to provide informed consent and comply with study procedures.[7]

Exclusion criteria are extensive and aim to remove individuals whose participation might be unsafe or whose underlying conditions could confound the interpretation of AZD9550's effects. Common exclusions include:

• Diabetes Status: History of Type 1 Diabetes Mellitus (T1DM) is typically exclusionary. For T2DM, criteria vary: the ASCEND obesity trial excludes T2DM entirely [11], while the CONTEMPO trial includes participants with and without T2DM but specifies acceptable baseline glycemic control (e.g., HbA1c range 6%-9% or <6.5%) and limits allowed background diabetes therapies.[7] Poorly controlled diabetes or symptoms of insulinopenia are generally exclusionary.[7]
• Prior Medications: Use of GLP-1 receptor agonists within a defined period (e.g., 3 months or 5 half-lives) prior to screening is a critical exclusion to avoid carry-over effects.[7] Use of other weight loss medications or certain interacting drugs (e.g., systemic corticosteroids, QTc-prolonging agents) is also restricted.[7]
• Comorbid Conditions: Significant gastrointestinal, renal (e.g., eGFR ≤ 60 mL/min/1.73m2), or hepatic disease (other than the target condition, NASH, where applicable) are common exclusions.[7] History of acute or chronic pancreatitis is also a frequent exclusion, given the association of incretin therapies with this condition.[11]
• Thyroid Cancer Risk: Elevated serum calcitonin levels suggestive of thyroid C-cell hyperplasia, or a personal/family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), are typically exclusionary, reflecting a known class warning for GLP-1 RAs related to rodent C-cell tumors.[7]
• Psychiatric Conditions: History of certain severe psychiatric disorders like psychosis, bipolar disorder, or recent major depressive disorder may be exclusionary.[7]
• Other: Previous bariatric surgery, obesity secondary to specific endocrine disorders (e.g., Cushing's syndrome), active cancer, significant cardiovascular conditions (e.g., recent MI, unstable angina, certain arrhythmias), pregnancy/breastfeeding, substance abuse, and inability to comply are also standard exclusions.[7]

The careful definition of T2DM status and exclusion of recent GLP-1 RA users are particularly important. They ensure that the study population is well-characterized metabolically and that the observed effects can be more reliably attributed to AZD9550 (or the combination with AZD6234), minimizing confounding factors from baseline disease severity or prior treatments with similar mechanisms.

5. Therapeutic Potential and Efficacy

5.1. Endpoints in Obesity Trials

The primary measure of success for AZD9550 in the obesity indication, as defined in the ongoing Phase IIb ASCEND trial (NCT06862791), centers on demonstrating statistically significant and clinically meaningful weight loss compared to placebo.[9] The co-primary endpoints are:

1. The mean percentage change in body weight from baseline to week 36.
2. The proportion of participants achieving at least 5% weight loss from baseline at week 36.

These endpoints align with regulatory guidance for the approval of anti-obesity medications, where a placebo-adjusted weight loss of at least 5% is often considered a benchmark for clinical relevance.[50] Furthermore, ASCEND includes key secondary endpoints that assess higher tiers of efficacy, such as the absolute change in body weight and the proportion of participants achieving $\ge$10% and $\ge$15% weight loss.[9] Comparisons between the combination arms and the monotherapy arms are also critical secondary objectives to establish the potential superiority of the co-administration strategy.[19]

5.2. Endpoints in NASH/MASH Trials

While the Phase I/II CONTEMPO trial (NCT06151964) prioritizes safety, PK, and PD, its focus on NASH implies that future, dedicated MASH efficacy trials (Phase IIb/III) for AZD9550 would target established regulatory endpoints for this indication.[2] Based on recent drug approvals and ongoing trials for competitors, these typically involve histological assessments from liver biopsies, aiming to demonstrate improvement in one or both of the following, without worsening of the other:

1. MASH Resolution: Reduction in steatosis, inflammation, and ballooning scores to a level where MASH is no longer diagnosed.
2. Fibrosis Improvement: A decrease of at least one stage in the liver fibrosis score.

The FDA approval of Resmetirom, for instance, was based on achieving either NASH resolution with no worsening of fibrosis or fibrosis improvement by at least one stage with no worsening of NASH activity score at 52 weeks.[41] Trials for semaglutide in MASH also target similar histological endpoints.[25] Early trials like CONTEMPO likely utilize non-invasive surrogate markers to gauge potential efficacy, such as quantification of liver fat reduction (e.g., via MRI-PDFF), changes in liver enzymes (ALT, AST), and improvements in non-invasive tests (NITs) for fibrosis (e.g., liver stiffness measurement, serum biomarkers).[3]

5.3. Metabolic Effects

Consistent with its dual mechanism targeting GLP-1R and GCGR, AZD9550 is expected to exert multiple effects on metabolic parameters, which are being evaluated as pharmacodynamic endpoints in clinical trials.[3] These include:

• Glucose Metabolism: Effects on fasting glucose, postprandial glucose, insulin sensitivity, and HbA1c levels are anticipated and particularly relevant in study cohorts including participants with T2DM.[3]
• Lipid Profile: Changes in circulating lipids, such as LDL cholesterol, HDL cholesterol, triglycerides, and other blood fats, are being examined.[3] Improvements in dyslipidemia are a potential benefit, particularly relevant for cardiovascular risk reduction in metabolic disease patients.
• Body Weight and Composition: Reduction in overall body weight and potentially body fat percentage are key expected outcomes, driven by effects on appetite, energy expenditure, and overall energy balance.[3]

5.4. Discussion based on Mechanism of Action and Preliminary Insights

Crucially, the provided research materials do not contain specific, quantitative efficacy results for AZD9550 from its clinical trials.[7] Links to trial result summaries exist on registry sites but do not provide the data itself within the snippets. Reports on trial status (e.g., completion of NCT05848440, recruitment completion of NCT06151964) are available, but without efficacy outcomes.[1]

However, the therapeutic potential can be inferred from its mechanism and data from related compounds. The dual GLP-1R/GCGR agonism holds promise for potent effects on both weight loss and liver health. As noted previously, the GLP-1R/GCGR dual agonist survodutide demonstrated significant MASH resolution and fibrosis improvement rates in a Phase II study [33], along with substantial weight loss in obesity trials.[44] This provides a positive precedent for the drug class. AstraZeneca has qualitatively mentioned "encouraging weight loss after single doses" observed in early AZD9550 testing (likely the Phase I SAD trial NCT05848440).[13] While promising, this lacks detail and confirmation from later-stage, multiple-dose studies.

The absence of published efficacy data for AZD9550 at this stage is not unusual for a drug in Phase I/II and IIb development. Data analysis from completed or ongoing trials like CONTEMPO and ASCEND is likely pending, with results typically first presented at major scientific conferences (such as those hosted by EASL, AASLD, ADA, or The Obesity Society [17]) or published in peer-reviewed journals. The current status reflects a program progressing through mid-stage development, where the therapeutic hypothesis is being rigorously tested, but definitive proof-of-concept data for AZD9550 specifically has yet to be publicly disclosed.

6. Safety, Tolerability, and Pharmacokinetics

6.1. Safety as a Primary Objective

Ensuring patient safety is paramount in drug development. Accordingly, the assessment of safety and tolerability constitutes a primary objective in the early- and mid-phase clinical trials for AZD9550, including the completed FIH trial (NCT05848440) and the ongoing/completed Phase I/II CONTEMPO trial (NCT06151964).[1] Safety is also a key component of the Phase IIb ASCEND trial.[11] Safety monitoring involves comprehensive tracking and evaluation of all adverse events (AEs), including serious adverse events (SAEs), as well as regular monitoring of vital signs (heart rate, blood pressure), electrocardiograms (ECGs, including QTc interval assessment), and clinical laboratory tests (hematology, chemistry, urinalysis).[7]

6.2. Expected Safety Profile

While specific adverse event data for AZD9550 are not available in the provided sources, expectations regarding its safety profile can be derived from its mechanism of action and data from related compounds. GLP-1 receptor activation is frequently associated with gastrointestinal side effects, primarily nausea, vomiting, and diarrhea, particularly upon treatment initiation or dose escalation.[22] Similar GI symptoms were reported as the most common AEs with the related GLP-1/GCGR dual agonist cotadutide.[34] AstraZeneca's oral GLP-1 RA candidate, AZD5004 (ECC5004), also showed good overall tolerability in Phase I but with dose-dependent increases in GI AEs.[12] Therefore, GI tolerability is likely a key aspect being monitored for AZD9550.

Other potential effects associated with the drug class include increases in heart rate, observed with some GLP-1 RAs and cotadutide.[34] Concerns regarding thyroid C-cell tumors, based on preclinical findings with GLP-1 RAs, lead to routine monitoring of serum calcitonin levels and exclusion of patients with relevant personal or family history (MTC/MEN 2) in clinical trials.[7] Importantly, AstraZeneca reported "no adverse effects in preclinical 9-month trial" for one of its metabolic assets (context suggests potentially AZD6234 or related program, but provides some reassurance on long-term preclinical safety for their pipeline).[6] Furthermore, the discontinuation of the previous dual agonist cotadutide was explicitly stated not to be due to any newly observed safety signals.[16]

6.3. Immunogenicity Assessment

The potential for the body to mount an immune response against therapeutic proteins or peptides, leading to the formation of anti-drug antibodies (ADAs), is an important consideration, particularly for injectable biologics or peptide-based drugs. ADAs can potentially neutralize the drug's effect, alter its pharmacokinetic profile, or, rarely, cause hypersensitivity reactions. Given that AZD9550 targets peptide hormone receptors and may itself be peptide-based or a modified peptide (despite the small molecule classification in one source), assessing its immunogenicity is crucial. The AZD9550 clinical program includes ADA measurement as an objective in the FIH trial and as a secondary endpoint in the Phase IIb ASCEND trial.[19] This proactive monitoring throughout development is essential to characterize and manage any potential risks associated with immunogenicity.

6.4. Pharmacokinetic (PK) and Pharmacodynamic (PD) Evaluations

Understanding how AZD9550 is absorbed, distributed, metabolized, and excreted (ADME) by the body (pharmacokinetics, PK) and how it affects physiological processes (pharmacodynamics, PD) are fundamental objectives of the early-phase clinical trials (NCT05848440, NCT06151964).[1] The Phase I FIH study utilized both subcutaneous (SC) and intravenous (IV) administration [2], allowing for characterization of fundamental PK parameters, including the absolute bioavailability of the SC injection.

A key development goal is to establish a profile suitable for once-weekly SC dosing, which is the regimen being used in the Phase I/II MAD cohorts (Parts C and D of CONTEMPO) and the Phase IIb ASCEND trial.[1] Achieving this requires an appropriate pharmacokinetic half-life that sustains therapeutic drug concentrations over the weekly dosing interval. Pharmacodynamic assessments in these trials focus on measuring the drug's biological effects, including changes in markers of glucose metabolism, lipid levels, liver fat, and body weight, to confirm target engagement and provide early indications of therapeutic activity.[3]

7. Administration and Dosing Regimen

7.1. Routes of Administration

The clinical development program for AZD9550 has explored two primary routes of administration:

• Subcutaneous (SC) Injection: This is the intended route for therapeutic use and is being employed in the multiple-dose Phase I/II CONTEMPO trial and the Phase IIb ASCEND obesity trial.[1] SC injection involves administering the drug solution just under the skin, typically enabling self-administration by patients for chronic therapies.
• Intravenous (IV) Injection: This route was utilized in a specific cohort (Part C) of the Phase I FIH trial (NCT05848440).[2] IV administration delivers the drug directly into the bloodstream, bypassing absorption barriers. Its use in early phase studies is typically for pharmacokinetic characterization, such as determining clearance, volume of distribution, and providing a reference for calculating the absolute bioavailability of other administration routes like SC injection.

7.2. Dosing Frequency

A key feature of AZD9550's intended therapeutic profile is its once-weekly dosing frequency for subcutaneous administration.[1] This regimen is being evaluated in the later parts of the CONTEMPO trial and throughout the ASCEND trial. This represents a significant potential advantage over the daily injection schedule of AstraZeneca's previous GLP-1/GCGR dual agonist candidate, cotadutide.[16]

The development focus on a once-weekly SC injection regimen is strategically important. It aligns AZD9550 with the dosing frequency of many highly successful incretin-based therapies currently on the market for T2DM and obesity, such as semaglutide (Ozempic, Wegovy), dulaglutide (Trulicity), and tirzepatide (Mounjaro, Zepbound) [22], as well as other investigational agents like survodutide and retatrutide.[26] For chronic conditions requiring long-term treatment, a weekly schedule offers substantially improved convenience and is likely to enhance patient adherence compared to daily injections, making it a critical factor for competitiveness and market acceptance.

8. Strategic Context and Competitive Landscape

8.1. AstraZeneca's Pipeline Strategy

AZD9550 is a key component of AstraZeneca's broader strategy within the Cardiovascular, Renal and Metabolism (CVRM) therapeutic area.[4] The company's commitment to the GLP-1/GCGR dual agonist mechanism is evident in the progression to AZD9550 following the discontinuation of the daily-dosed cotadutide, leveraging learnings from the earlier program while aiming for an improved, weekly-dosed profile.[16]

AstraZeneca is pursuing a multifaceted approach in the highly competitive metabolic disease space. Beyond AZD9550, their pipeline includes:

• AZD6234: A long-acting amylin analogue, also administered weekly via SC injection, being investigated in combination with AZD9550 in the ASCEND trial for obesity.[6] Amylin analogues work primarily by enhancing satiety and slowing gastric emptying. The combination aims for a "triple mechanism" (GLP-1, GCGR, Amylin) potentially leading to greater weight loss, improved weight quality (preserving lean mass), or better tolerability.[6]
• AZD5004 (ECC5004): An oral, small molecule GLP-1 receptor agonist acquired through an agreement with Eccogene.[6] This provides an alternative delivery route and mechanism (GLP-1 only) within their portfolio. AstraZeneca is exploring potential combinations involving AZD5004 with other agents like Farxiga (dapagliflozin, an SGLT2 inhibitor) or their oral PCSK9 inhibitor AZD0780.[13]

This diversified portfolio, encompassing different mechanisms (GLP-1, GCGR, Amylin) and delivery routes (injectable, oral), allows AstraZeneca to pursue multiple therapeutic strategies, including monotherapies and combinations, potentially addressing different patient needs and market segments. This approach mitigates risk and increases the likelihood of success in capturing value within the rapidly evolving landscape of obesity and metabolic disease treatments.

8.2. Comparison to Standard of Care (SoC)

AZD9550 aims to enter therapeutic areas with established and rapidly advancing standards of care.

• Obesity Standard of Care: The foundation of obesity management remains lifestyle intervention, encompassing dietary changes, increased physical activity, and behavioral therapy.[50] However, pharmacotherapy has become increasingly important for achieving and maintaining significant weight loss, particularly with the advent of highly effective incretin-based therapies. GLP-1 RAs like semaglutide (Wegovy) and liraglutide (Saxenda), and the dual GLP-1/GIP receptor agonist tirzepatide (Zepbound), have demonstrated unprecedented weight loss efficacy in clinical trials (often exceeding 15-20% mean weight loss with semaglutide and tirzepatide) and are setting high benchmarks for new entrants.[24] For AZD9550, especially in combination with AZD6234, demonstrating competitive efficacy (potentially approaching or exceeding that of existing agents) alongside a favorable safety and tolerability profile will be crucial for market positioning.
• NASH/MASH Standard of Care: The treatment landscape for NASH/MASH has historically been limited, relying primarily on lifestyle modifications (weight loss through diet and exercise) and managing associated comorbidities like T2DM, hypertension, and dyslipidemia.[41] A significant development occurred in March 2024 with the FDA's accelerated approval of Resmetirom (Rezdiffra), an oral thyroid hormone receptor-beta (THR-β) agonist. It is the first drug specifically approved for treating adults with noncirrhotic MASH with moderate to advanced liver fibrosis (stages F2-F3), used adjunctively to diet and exercise.[41] Off-label use of medications like pioglitazone and vitamin E has some guideline support in specific patient populations.[43] Furthermore, GLP-1 RAs, particularly semaglutide, are increasingly used off-label and are under investigation, showing promise for MASH resolution, with potential FDA approval anticipated.[25] AZD9550, with its dual mechanism targeting both metabolic dysfunction and potentially liver-specific pathways, aims to demonstrate efficacy on key histological endpoints (MASH resolution and/or fibrosis improvement) that could position it as a competitive option against Resmetirom and high-dose GLP-1 RAs in this evolving therapeutic area.

8.3. Potential Advantages and Differentiation

The primary potential advantage of AZD9550 lies in its dual GLP-1R/GCGR agonism. This mechanism is hypothesized to offer benefits beyond GLP-1 RA monotherapy by potentially:

• Achieving greater weight loss through combined effects on appetite suppression (GLP-1R) and energy expenditure (GCGR).[25]
• Providing more robust improvement in MASH, particularly regarding liver fibrosis, by leveraging potential direct hepatic effects of GCGR activation alongside the metabolic benefits of both pathways.[16]
• Addressing multiple facets of metabolic syndrome concurrently due to the broad physiological roles of GLP-1 and glucagon signaling.

Further differentiation may come from the combination strategy with the amylin analogue AZD6234. Amylin contributes to satiety and slows gastric emptying through mechanisms distinct from GLP-1, potentially leading to additive or synergistic weight loss and possibly improving the quality of weight loss (e.g., preferential fat mass reduction, preservation of lean body mass) or enhancing tolerability compared to high-dose single-agent therapies.[6]

8.4. Development Outlook

AZD9550 is currently in a critical mid-stage phase of development. The CONTEMPO Phase I/II trial (NCT06151964) in overweight/obese participants +/- T2DM, focused on NASH, has completed recruitment.[7] The ASCEND Phase IIb trial (NCT06862791) investigating the combination of AZD9550 and AZD6234 in obesity is actively recruiting.[1]

The path forward carries inherent risks, particularly in the challenging indication of MASH. Industry benchmarks suggest that Phase II drugs for MASH have approximately a 25% probability of successfully transitioning to Phase III development, reflecting the high bar for demonstrating efficacy on histological endpoints and the complexity of the disease.[2]

The progression of AZD9550 to Phase III trials will depend heavily on positive data readouts from the ongoing Phase II studies. These trials must demonstrate not only statistically significant but also clinically meaningful efficacy on primary endpoints (weight loss for ASCEND; safety/PK/PD and early efficacy signals for CONTEMPO, informing future MASH trials) along with an acceptable safety and tolerability profile. Positive results would validate the therapeutic hypothesis underpinning GLP-1/GCGR dual agonism and support further investment in late-stage development.

9. Conclusion and Future Directions

9.1. Synthesis of Profile and Status

AZD9550 represents a significant effort by AstraZeneca to develop a novel therapeutic for major metabolic diseases. As an investigational dual agonist of GLP-1R and GCGR, it employs a mechanism hypothesized to offer advantages over single-pathway incretin mimetics. Currently advancing through mid-stage clinical trials (Phase I/II for NASH-relevant populations, Phase IIb for obesity in combination with AZD6234), AZD9550 is being developed for once-weekly subcutaneous administration. Its clinical program includes rigorous assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy against placebo and, in the obesity trial, against its constituent monotherapies.

9.2. Summary of Potential Benefits and Outstanding Questions

The potential benefits of AZD9550 center on the promise of its dual mechanism: potentially superior efficacy in weight reduction and MASH improvement (including fibrosis reversal) compared to existing therapies, coupled with broad positive effects on related metabolic parameters. The once-weekly dosing regimen enhances its potential competitiveness and convenience for patients requiring chronic treatment. The combination strategy with the amylin analogue AZD6234 offers a further avenue for potentially optimizing weight loss outcomes.

However, several critical questions remain unanswered pending data from ongoing trials. Definitive evidence of AZD9550's efficacy magnitude in both obesity (as monotherapy and combination) and MASH (histological improvement) is needed. The long-term safety and tolerability profile, particularly concerning the frequency and severity of gastrointestinal adverse events and the potential for immunogenicity, requires thorough characterization. Furthermore, the precise contribution of each component (AZD9550 and AZD6234) and the optimal dosing strategy for the combination therapy need to be established through the ongoing ASCEND trial.

9.3. Importance of Ongoing and Future Trial Results

The future trajectory of AZD9550 is critically dependent on the outcomes of the currently active Phase II trials, CONTEMPO (NCT06151964) and ASCEND (NCT06862791). Data from CONTEMPO will provide essential safety, PK, and PD information, including early signals on metabolic markers relevant to NASH/MASH, guiding the design and feasibility of potential Phase III MASH studies. Results from ASCEND will be pivotal in determining the efficacy and safety of AZD9550, both alone and in combination with AZD6234, for obesity management, directly informing its competitiveness against market leaders.

Positive results from these studies are required to de-risk the program and justify progression to larger, longer, and more costly Phase III trials. These future trials would aim to confirm efficacy on registrational endpoints, further characterize long-term safety, and ultimately support regulatory submissions. The success of AZD9550, particularly in the complex MASH indication, may rely not only on achieving specific liver histological improvements but also on demonstrating meaningful benefits across the spectrum of associated cardiometabolic risk factors, aligning with an increasingly holistic approach to managing patients with metabolic diseases.[3] The forthcoming data readouts will be crucial in determining whether AZD9550 can fulfill the therapeutic potential suggested by its novel dual mechanism of action.

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