Comprehensive Monograph on Albiglutide (DB09043)

Executive Summary

Albiglutide is a second-generation, long-acting glucagon-like peptide-1 (GLP-1) receptor agonist developed by GlaxoSmithKline (GSK) for the treatment of type 2 diabetes mellitus (T2DM).[1] Marketed under the brand names Tanzeum in the United States and Eperzan in Europe, it represented a significant molecular engineering effort to overcome the pharmacokinetic limitations of native GLP-1.[2] Its key structural attribute is a recombinant fusion protein composed of a dipeptidyl peptidase-4 (DPP-4)-resistant GLP-1 dimer genetically linked to human albumin.[1] This design successfully conferred an extended terminal half-life of approximately five days, allowing for the convenience of once-weekly subcutaneous administration, a notable improvement over earlier daily or twice-daily agents in its class.[5]

Clinically, Albiglutide demonstrated effective glycemic control as both monotherapy and add-on therapy, significantly reducing HbA1c and fasting plasma glucose levels compared to placebo.[7] The culmination of its clinical development was the Harmony Outcomes trial, a landmark cardiovascular outcomes study that demonstrated Albiglutide's statistical superiority to placebo in reducing the composite of major adverse cardiovascular events (MACE) in a high-risk T2DM population.[9] This finding placed Albiglutide in a select group of antidiabetic agents with proven cardiovascular benefits.

Despite this clinical success, Albiglutide's lifecycle presents a compelling paradox. The drug failed to gain significant market traction and was ultimately withdrawn globally by GSK for commercial reasons, citing low prescription volumes and declining sales.[10] This commercial failure occurred in the context of a highly competitive therapeutic landscape where Albiglutide's efficacy in lowering HbA1c and, particularly, in promoting weight loss, was demonstrably inferior to that of other available and emerging GLP-1 receptor agonists like liraglutide, dulaglutide, and semaglutide.[6] The story of Albiglutide serves as a critical case study in pharmaceutical development, illustrating that in a rapidly evolving market, best-in-class efficacy on key clinical endpoints and a competitive side-effect profile are paramount for commercial viability, at times outweighing even proven cardiovascular benefits and dosing convenience.

Molecular Profile and Physicochemical Properties

Identification and Nomenclature

Albiglutide is a biologic drug classified as a biotech therapeutic, specifically a recombinant fusion protein.[1] Its unique identifiers are essential for its precise characterization in scientific and regulatory databases.

• Proper Name: Albiglutide [1]
• DrugBank ID: DB09043 [1]
• CAS Number: 782500-75-8 [4]
• Synonyms and Trade Names: Throughout its development and commercialization, Albiglutide was known by several names. Its primary trade names were Tanzeum in the United States and Eperzan in Europe.[2] Other synonyms include Albugon, Naliglutide, and the development code GSK 716155.[4]

Chemical Structure and Composition

Albiglutide's structure is a testament to the advanced protein engineering techniques used to create long-acting therapeutic peptides. It is a complex polypeptide consisting of 645 proteinogenic amino acids, forming a structure with 17 disulfide bridges.[6]

The molecule is a sequential dimer of a modified human GLP-1 analogue that is genetically fused to recombinant human albumin.[1] This fusion protein design is central to its pharmacological properties. The structure can be deconstructed into two key components:

1. The GLP-1 Dimer: This component consists of two tandem copies of a modified human GLP-1(7-36) peptide.[6] A critical modification was engineered into this sequence to confer resistance to enzymatic degradation. The naturally occurring alanine residue at position 8 of the GLP-1 sequence (the second amino acid of the active peptide) was substituted with a glycine residue.[4] Endogenous GLP-1 is rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DPP-4), which cleaves the peptide at this specific position.[18] The alanine-to-glycine substitution makes the peptide a poor substrate for DPP-4, thereby preventing this rapid degradation and extending its biological activity.[6]
2. Human Albumin: The DPP-4-resistant GLP-1 dimer is genetically fused to human albumin.[1] Albumin is a large, long-lived plasma protein. Fusing the therapeutic peptide to albumin dramatically increases the overall molecular size of Albiglutide, which in turn significantly prolongs its elimination half-life by preventing rapid renal clearance through glomerular filtration.[5]

The complete amino acid sequence of Albiglutide is as follows [6]:

HGEGTFTSDV SSYLEGQAAK EFIAWLVKGR HGEGTFTSDV SSYLEGQAAK EFIAWLVKGR DAHKSEVAHR FKDLGEENFK ALVLIAFAQY LQQCPFEDHV KLVNEVTEFA KTCVADESAE NCDKSLHTLF GDKLCTVATL RETYGEMADC CAKQEPERNE CFLQHKDDNP

Physicochemical Properties

The molecular design of Albiglutide dictates its physical and chemical characteristics.

• Chemical Formula: C3232​H5032​N864​O979​S41​.[3]
• Average Molecular Weight: Approximately 72,970.0 Da, or 72.9 kDa.[3] This high molecular weight, primarily due to the albumin component, is fundamental to its pharmacokinetic profile.
• Physical Form: In its lyophilized state, Albiglutide is a white to yellow powder.[1] For administration, it was supplied in a pen injector where the powder was reconstituted with a clear, colorless solvent, resulting in a yellow solution for injection.[1]
• Stability and Storage: The material is reported to be stable under normal conditions.[1] For long-term preservation, storage of the powder at -20°C is recommended.[4] The commercial pen injectors were intended for refrigerated storage.[10] Upon decomposition, such as through heating, it may emit irritating or toxic fumes.[1]
• Solubility: Albiglutide is soluble in water, with a reported solubility of 100 mg/mL.[4]

The molecular design of Albiglutide is directly responsible for both its primary therapeutic advantage and its ultimate competitive disadvantage. The challenge in developing GLP-1-based therapies stems from the native hormone's extremely short half-life of less than two minutes, a result of rapid degradation by the DPP-4 enzyme.[18] Albiglutide's developers addressed this by employing a dual strategy: first, engineering DPP-4 resistance via the Ala8->Gly substitution, and second, dramatically increasing the molecule's size by fusing it to albumin to slow renal clearance.[1] This approach was highly successful from a pharmacokinetic standpoint, extending the half-life to approximately five days and enabling the convenience of once-weekly dosing.[5] However, this solution had an unintended pharmacodynamic consequence. The large size of the albumin fusion protein appears to limit its ability to cross the blood-brain barrier.[6] GLP-1 receptors located in the central nervous system are known to play a significant role in mediating appetite suppression and, consequently, weight loss.[18] By restricting access to these central receptors, the molecular design that solved the half-life problem simultaneously blunted a key therapeutic effect, leading to less effective weight loss compared to smaller, more centrally-acting GLP-1 receptor agonists like liraglutide and semaglutide.[6] This inherent link between Albiglutide's structure and its less competitive clinical profile on weight management was a critical factor in its market performance.

Preclinical and Clinical Pharmacology

Mechanism of Action

Albiglutide exerts its therapeutic effects as a potent and selective agonist of the glucagon-like peptide-1 (GLP-1) receptor.[1] By mimicking the actions of the endogenous incretin hormone GLP-1, it enhances the body's natural glucose-regulating mechanisms, which are often impaired in individuals with type 2 diabetes.[6] The activation of GLP-1 receptors, which are G-protein coupled receptors found on pancreatic islet cells and other tissues, triggers a cascade of downstream effects that collectively improve glycemic control.[3]

The key physiological actions resulting from Albiglutide's agonism at the GLP-1 receptor include:

1. Augmentation of Glucose-Dependent Insulin Secretion: Albiglutide stimulates the synthesis and secretion of insulin from pancreatic β-cells.[3] A crucial feature of this action is its glucose dependency; the insulinotropic effect is most pronounced when blood glucose levels are elevated and diminishes as glucose levels approach normal.[16] This glucose-sensing mechanism is a hallmark of the incretin class and significantly reduces the intrinsic risk of hypoglycemia, a major advantage over therapies like sulfonylureas or exogenous insulin.[18]
2. Inhibition of Glucagon Secretion: In a complementary, glucose-dependent manner, Albiglutide suppresses the secretion of glucagon from pancreatic α-cells.[18] Glucagon is a counter-regulatory hormone that raises blood glucose by promoting hepatic glucose production. By inhibiting inappropriately high glucagon levels, particularly after meals, Albiglutide helps to reduce overall hyperglycemia.[16]
3. Slowing of Gastric Emptying: Albiglutide delays the rate at which the stomach contents are emptied into the small intestine.[6] This action attenuates the rapid influx of dietary carbohydrates into the circulation after a meal, thereby blunting postprandial glucose excursions.[16] A clinical study using scintigraphy confirmed this effect on gastric emptying.[24]

Pharmacodynamic Profile

The pharmacodynamic effects of Albiglutide translate its mechanism of action into measurable clinical outcomes.

• Glycemic Control: Clinical trials consistently demonstrated that Albiglutide produces robust, dose-dependent improvements in glycemic control.[18] It significantly reduces 24-hour mean weighted glucose levels, fasting plasma glucose (FPG), and postprandial glucose (PPG).[16] These acute effects lead to sustained long-term reductions in glycated hemoglobin (HbA1c), the primary marker of long-term glycemic management.[5]
• Pancreatic Islet Cell Function: Albiglutide has been shown to modulate pancreatic hormone secretion favorably. It enhances β-cell insulin secretion in response to hyperglycemia while appropriately suppressing this secretion during hypoglycemia.[16] Importantly, it does not impair the counter-regulatory glucagon response from α-cells during hypoglycemic episodes, preserving a critical physiological defense against low blood sugar.[16]
• Weight Management: The effect of Albiglutide on body weight was modest. While it did not cause weight gain, the weight loss observed in clinical trials was often comparable to that seen with placebo and was significantly less than that achieved with other GLP-1 receptor agonists, such as liraglutide.[6] This limited effect on weight is attributed to its large molecular structure, which restricts its penetration into the central nervous system where GLP-1 receptors mediate appetite suppression.[6]
• Cardiovascular Parameters: Albiglutide was found to have a modest effect on increasing heart rate, a known class effect of GLP-1 receptor agonists, but did not cause any clinically significant prolongation of the corrected QT interval.[16] Its overall impact on cardiovascular outcomes was later definitively established in the Harmony Outcomes trial, which showed a significant reduction in major adverse cardiovascular events.[9]

The slowing of gastric emptying is a fundamental aspect of Albiglutide's pharmacology that represents a therapeutic trade-off. This mechanism is a key contributor to its efficacy, particularly in controlling postprandial glucose levels by moderating nutrient absorption.[18] However, this same physiological action is the primary driver of the most common and dose-limiting adverse events associated with the GLP-1 receptor agonist class: nausea, vomiting, and diarrhea.[6] Patient intolerance to these gastrointestinal side effects is a leading cause of therapy discontinuation.[27] Furthermore, by altering the transit time of co-administered oral drugs, this mechanism creates a potential for pharmacokinetic drug-drug interactions, primarily affecting the rate (

Cmax​ and tmax​) rather than the extent (AUC) of absorption.[6] The relative intensity of this effect can differentiate agents within the class. Albiglutide was noted to have a more favorable gastrointestinal tolerability profile, with lower rates of nausea compared to liraglutide, which could have been a competitive advantage.[13] Ultimately, this improved tolerability was insufficient to overcome its deficits in glycemic and weight-loss efficacy in the marketplace.

Pharmacokinetic Characteristics

The pharmacokinetic profile of Albiglutide is defined by its large molecular size and fusion to human albumin, resulting in slow absorption and a prolonged elimination half-life that underpins its once-weekly dosing regimen.

Absorption, Distribution, Metabolism, and Excretion (ADME)

• Absorption: Following subcutaneous injection, Albiglutide is absorbed slowly into the systemic circulation. Due to its large size, it is thought to be absorbed primarily via the lymphatic system rather than directly into capillaries.[16] This slow absorption process results in a delayed time to reach maximum plasma concentration ( tmax​), which occurs between 3 and 5 days post-administration.[3] With once-weekly dosing, steady-state plasma concentrations are achieved after approximately 4 to 5 weeks of continuous therapy.[6] Following a single 30 mg dose, the mean peak concentration ( Cmax​) was 1.74 mcg/mL and the mean area under the concentration-time curve (AUC) was 465 mcg·h/mL.[3]
• Distribution: The apparent volume of distribution (Vd​) of Albiglutide is approximately 11 Liters.[3] This relatively small volume of distribution indicates that the drug is primarily confined to the vascular and interstitial fluid compartments, which is consistent with a large protein therapeutic that does not distribute extensively into tissues.
• Metabolism: As a large polypeptide fusion protein, Albiglutide does not undergo metabolism by the hepatic cytochrome P450 (CYP) enzyme system.[3] Instead, its metabolic pathway is expected to be degradation into smaller peptides and constituent amino acids by ubiquitous proteolytic enzymes, primarily within the vascular endothelium, similar to the catabolism of endogenous human albumin.[3] This metabolic profile minimizes the risk of classic CYP-mediated drug-drug interactions.
• Elimination: The most notable pharmacokinetic feature of Albiglutide is its long terminal elimination half-life (t1/2​), which ranges from 4 to 8 days, with a mean of approximately 5 days.[4] This extended half-life is a direct result of its large molecular size preventing rapid renal filtration. The clearance of Albiglutide from the body is slow, at a rate of approximately 67 mL/h.[3] Minimal amounts of the drug are excreted unchanged in the urine.[4]

The pharmacokinetic profile was Albiglutide's central innovation. The initial GLP-1 receptor agonist therapies required frequent injections, such as twice daily for exenatide, which presented a significant burden for patients and a barrier to adherence.[18] The development of Albiglutide was part of a major industry-wide effort to create long-acting formulations that would allow for the convenience of once-weekly dosing.[4] At the time of its conception, this extended half-life was its key differentiating feature. However, the pharmaceutical landscape evolved rapidly. By the time Albiglutide was launched in 2014, it was not the only once-weekly option. Exenatide extended-release (Bydureon) was already on the market, and dulaglutide (Trulicity) was approved shortly thereafter.[28] These competitors achieved the same convenient dosing schedule through different molecular engineering strategies that ultimately yielded more favorable overall clinical profiles.[13] Consequently, Albiglutide's primary pharmacokinetic advantage was effectively neutralized by competitors who matched its convenience while surpassing its performance on the key efficacy metrics of glycemic control and weight loss.

Special Populations

• Renal Impairment: The effect of renal function on Albiglutide's pharmacokinetics was a key area of investigation. A dedicated clinical trial (NCT00938158) was conducted to evaluate its profile in subjects with varying degrees of renal impairment, including those with end-stage renal disease requiring hemodialysis.[24] While dose adjustments were not formally recommended, clinical experience in patients with severe renal impairment was limited. In this population, an increased frequency of gastrointestinal adverse events was observed, prompting a recommendation for cautious use.[16]
• Hepatic Impairment: Specific studies in patients with hepatic impairment were not conducted. However, because Albiglutide is metabolized by ubiquitous proteolysis rather than hepatic pathways, significant alterations in its pharmacokinetics were not anticipated in this population.[3]
• Injection Site: The site of subcutaneous injection (abdomen, thigh, or upper arm) did not have a clinically meaningful impact on the absorption, pharmacokinetics, or pharmacodynamics of Albiglutide.[18]

Table 1: Key Physicochemical and Pharmacokinetic Properties of Albiglutide

Parameter	Value	Source(s)
Drug Type	Recombinant Fusion Protein	1
Molecular Weight	~72.9 kDa	3
Chemical Formula	C3232​H5032​N864​O979​S41​	3
Route of Administration	Subcutaneous Injection	1
Dosing Frequency	Once-weekly	4
Time to Peak Concentration (tmax​)	3–5 days	3
Terminal Elimination Half-Life (t1/2​)	~5 days (range: 4–8 days)	4
Apparent Volume of Distribution (Vd​)	~11 L	3
Clearance (CL)	~67 mL/h	3

Clinical Efficacy in Type 2 Diabetes Mellitus

The HARMONY Clinical Development Program

The regulatory approvals of Albiglutide by both the U.S. FDA and the European Medicines Agency were supported by a comprehensive and robust Phase III clinical development program known as HARMONY.[28] This program was extensive, comprising eight individual trials that enrolled over 5,000 patients with T2DM, of whom more than 2,000 were treated with Albiglutide.[28]

The design of the HARMONY program was intended to evaluate the efficacy and safety of Albiglutide across the full spectrum of T2DM management. The trials assessed Albiglutide as a monotherapy for patients inadequately controlled with diet and exercise, as an add-on therapy to existing oral antidiabetic agents, and in direct comparison to a range of active comparators, including metformin, sulfonylureas (glimepiride), thiazolidinediones (pioglitazone), DPP-4 inhibitors (sitagliptin), and basal insulin (insulin glargine).[7] The program also included patients at different stages of the disease and those with renal impairment, providing a broad evidence base.[28] A notable strength of the program was its duration; five of the eight trials included long-term follow-up for up to three years, offering valuable data on the durability of Albiglutide's effects, a significant advantage over many registration programs that are limited to six months.[31]

Efficacy in Glycemic Control and Weight Management

Across the HARMONY program, Albiglutide consistently demonstrated clinically and statistically significant improvements in glycemic control.

• Monotherapy: In the HARMONY 2 trial, which evaluated Albiglutide as a monotherapy in patients uncontrolled by diet and exercise alone, both the 30 mg and 50 mg once-weekly doses were found to be superior to placebo in reducing HbA1c over 52 weeks. The least-squares mean treatment difference from placebo was -0.84% for the 30 mg dose and -1.04% for the 50 mg dose, both highly statistically significant (p<0.0001).[8]
• Add-on and Combination Therapy: When added to background therapies such as metformin, Albiglutide provided significant additional glycemic lowering compared to placebo.[7] For instance, in a trial of patients inadequately controlled on metformin, the addition of Albiglutide led to meaningful reductions in HbA1c.[7]
• Comparative Efficacy: While effective against placebo and some older agents, Albiglutide's performance in head-to-head trials against other GLP-1 receptor agonists revealed a competitive weakness. A 2015 meta-analysis concluded that Albiglutide was less effective than other agents in its class for both lowering HbA1c and promoting weight loss.[6] This was explicitly demonstrated in the HARMONY 7 trial, a head-to-head comparison where once-daily liraglutide resulted in significantly greater reductions in both HbA1c and body weight compared to once-weekly Albiglutide.[13]
• Effect on Body Weight: Albiglutide was generally weight-neutral or associated with modest weight loss and did not cause the weight gain often seen with insulin or sulfonylureas.[8] However, this effect was less pronounced than that observed with liraglutide and other competitors, a key disadvantage in a therapeutic area where weight management is a critical goal.[13]

The Harmony Outcomes Trial (NCT02465515)

The Harmony Outcomes trial was a large-scale, post-marketing cardiovascular outcomes trial (CVOT) mandated by the FDA as a condition of Albiglutide's approval.[9] Its primary objective was to establish the cardiovascular safety of Albiglutide in a high-risk population of 9,463 patients with T2DM and established atherosclerotic cardiovascular disease.[9] This randomized, double-blind, placebo-controlled study followed patients for a median of 1.6 years.[9]

The results of the Harmony Outcomes trial were highly significant and represented the pinnacle of Albiglutide's clinical achievements.

• Primary Endpoint (MACE): Albiglutide was not only non-inferior but demonstrated statistical superiority to placebo in reducing the primary composite endpoint of MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke). The event rate was 7.0% in the Albiglutide group versus 9.0% in the placebo group, corresponding to a 22% relative risk reduction (Hazard Ratio 0.78; 95% Confidence Interval [CI] 0.68-0.90; p=0.0006 for superiority).[9]
• Component Analysis: The benefit on the composite MACE endpoint was driven primarily by a significant reduction in the rate of myocardial infarction (4% in the Albiglutide group vs. 5% in the placebo group; p=0.003). There were no statistically significant differences between the groups for the individual endpoints of cardiovascular death or stroke.[9]
• Secondary Efficacy Endpoints: Consistent with the Phase III program, Albiglutide provided superior glycemic control and modest weight loss compared to placebo within the trial. At 16 months, the mean HbA1c was 0.52% lower and body weight was 0.83 kg lower in the Albiglutide group.[9]
• Safety in the CVOT: The trial confirmed the established safety profile of Albiglutide, with no new safety signals emerging. The incidence of severe hypoglycemia was low but slightly higher in the Albiglutide group (1% vs. 1%, p<0.05). Importantly, the rates of serious adverse events of interest, such as acute pancreatitis and pancreatic carcinoma, were very low (<1%) and did not differ between the Albiglutide and placebo groups.[9]

The positive cardiovascular outcome data from the Harmony Outcomes trial was a major clinical success, proving a tangible benefit beyond glucose control. However, this success was a case of "too little, too late." The FDA's mandate for CVOTs for all new diabetes drugs was a response to safety concerns raised by older medications like rosiglitazone, with the initial goal being simply to rule out cardiovascular harm (non-inferiority).[7] The Harmony Outcomes trial exceeded this requirement by demonstrating superiority, a significant achievement that placed Albiglutide alongside liraglutide and semaglutide as one of the few diabetes drugs with proven cardiovascular benefits at the time.[9] Yet, the commercial decision to withdraw the drug was announced by GSK in July 2017, while the trial was still in progress and its positive results were not yet public.[11] This timeline indicates that GSK's commercial analysis, based on persistently low prescription rates and declining market share, had already deemed the product's position in the market to be commercially unviable.[10] The company likely concluded that even a positive CVOT result would be insufficient to reverse its fortunes and overcome its efficacy disadvantages in a market being rapidly reshaped by more potent and effective agents. This highlights a critical lesson in pharmaceutical strategy: a single major positive outcome cannot always rescue a product that is perceived by prescribers as less effective on the core, day-to-day metrics of disease management, such as glucose lowering and weight loss.

Table 2: Summary of Efficacy and Safety Outcomes from the Harmony Outcomes Trial

Endpoint	Albiglutide Group (%)	Placebo Group (%)	Hazard Ratio (95% CI) / p-value
Primary Composite (CV Death, MI, Stroke)	7.0	9.0	HR 0.78 (0.68–0.90); p=0.0006
Cardiovascular Death	3	3	p=0.58
All Myocardial Infarction	4	5	p=0.003
All Stroke	2	2	p=0.30
All-Cause Mortality	4	4	p=0.64
Severe Hypoglycemia	1	1	p<0.05
Acute Pancreatitis	<1	<1	p>0.05

Data sourced from.[9]

Safety, Tolerability, and Risk Management

Adverse Event Profile

The safety and tolerability profile of Albiglutide is consistent with the GLP-1 receptor agonist class, characterized primarily by gastrointestinal side effects and reactions at the injection site.

• Common Adverse Events: In clinical trials, the most frequently reported adverse events (occurring in more than 10% of patients) were diarrhea, nausea, and injection site reactions. Hypoglycemia was also common, particularly when Albiglutide was used in combination with other antidiabetic agents known to cause it, such as sulfonylureas or insulin.[6] Upper respiratory tract infections were also reported more frequently than with placebo.[6]
• Gastrointestinal Tolerability: Nausea, vomiting, and diarrhea are well-established class effects of GLP-1 receptor agonists, linked to their mechanism of slowing gastric emptying. While these were common with Albiglutide, head-to-head data suggested that Albiglutide had a more favorable gastrointestinal profile than some competitors, with a notably lower incidence of nausea compared to liraglutide.[13]
• Injection Site Reactions: A distinguishing feature of Albiglutide's tolerability profile was a higher frequency of injection site reactions (e.g., redness, itching, or nodules) compared to other GLP-1 receptor agonists like liraglutide and dulaglutide.[6]
• Uncommon but Serious Adverse Events: Although infrequent, potentially severe adverse events were identified. Acute pancreatitis was observed in approximately 0.3% of patients in the clinical program.[6] Serious hypersensitivity reactions, including anaphylaxis, were also reported, albeit rarely (<0.1%).[6]

Contraindications, Warnings, and Precautions

The use of Albiglutide was governed by several important contraindications and warnings to mitigate potential risks.

• Boxed Warning: Risk of Thyroid C-Cell Tumors: In line with other drugs in its class, Albiglutide's labeling included a boxed warning regarding the risk of thyroid C-cell tumors, including medullary thyroid carcinoma (MTC).[3] This warning is based on dose-dependent and treatment-duration-dependent increases in these tumors observed in rodent studies.[6] The relevance of this finding to humans is unknown, but due to the potential risk, the drug was contraindicated in certain patient populations.[10]
• Contraindications: Albiglutide was contraindicated in:

1. Patients with a personal or family history of MTC.[3]
2. Patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), a genetic condition that predisposes individuals to MTC.[3]
3. Patients with a prior serious hypersensitivity reaction to Albiglutide or any of its components.[31]

• Warnings and Precautions:
• Pancreatitis: Postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, have been associated with GLP-1 receptor agonists. Albiglutide was not studied in patients with a history of pancreatitis, and its use was to be discontinued if pancreatitis was suspected.[10]
• Renal Impairment: Caution was advised when using Albiglutide in patients with severe renal impairment, as this population experienced a higher incidence of gastrointestinal side effects that could lead to volume depletion and worsening renal function.[16]
• Severe Gastrointestinal Disease: The use of Albiglutide was not recommended in patients with pre-existing severe gastrointestinal disease, such as severe gastroparesis, as its effects on gastric emptying could exacerbate these conditions.[11]

Clinically Significant Drug-Drug Interactions

• Pharmacokinetic Interactions: The primary mechanism for pharmacokinetic interactions with Albiglutide is its effect on slowing gastric emptying.[6] This can potentially alter the rate and extent of absorption of co-administered oral medications. However, dedicated interaction studies with representative drugs like simvastatin, warfarin, digoxin, and oral contraceptives did not find clinically meaningful changes in overall exposure (AUC), although delays in achieving peak concentration ( tmax​) were observed.[6]
• Pharmacodynamic Interactions: The most clinically significant interactions are pharmacodynamic in nature.
• Increased Risk of Hypoglycemia: The risk of hypoglycemia is substantially increased when Albiglutide is used concurrently with insulin or insulin secretagogues (e.g., sulfonylureas, meglitinides). Dose reductions of the concomitant insulin or secretagogue were often necessary to mitigate this risk.[3]
• Altered Glycemic Efficacy: A wide range of medications can affect glucose metabolism and potentially alter the therapeutic efficacy of Albiglutide. For example, corticosteroids, thiazide diuretics, and some antipsychotics can increase blood glucose and diminish Albiglutide's effectiveness. Conversely, agents like beta-blockers and ACE inhibitors can enhance its glucose-lowering effects.[3]

Regulatory and Commercial History

Global Regulatory Approvals

Albiglutide was invented by Human Genome Sciences and subsequently co-developed with GlaxoSmithKline.[6] It successfully navigated the regulatory pathways in both Europe and the United States, achieving marketing authorization in 2014.

• European Medicines Agency (EMA): The EMA granted marketing authorization for Albiglutide under the brand name Eperzan on March 26, 2014.[6] The approved indication was for the treatment of type 2 diabetes mellitus in adults to improve glycemic control, both as monotherapy and in combination with other glucose-lowering agents.[1]
• U.S. Food and Drug Administration (FDA): The FDA approved Albiglutide under the brand name Tanzeum on April 15, 2014.[10] The Biologics License Application (BLA 125431) had been submitted over a year earlier, on January 14, 2013.[7] The indication was as an adjunct to diet and exercise to improve glycemic control in adults with T2DM.[28] Due to the identified risks of medullary thyroid carcinoma and acute pancreatitis, the FDA required a Risk Evaluation and Mitigation Strategy (REMS) to ensure the benefits of the drug outweighed its potential risks.[28]

Market Performance and Rationale for Withdrawal

Despite securing regulatory approvals in key markets, Albiglutide's commercial performance was lackluster, leading to its eventual discontinuation.

• Withdrawal Announcement: On July 26, 2017, GSK formally announced its decision to discontinue the manufacturing and sale of Tanzeum/Eperzan worldwide.[10] The company planned a phased withdrawal, with the commercial supply expected to be fully depleted by July 2018.[11] Healthcare providers were advised not to initiate any new patients on the therapy and to transition existing patients to alternative treatments.[11]
• Official Rationale: GSK was explicit that the withdrawal was for "commercial reasons only" and was "not related to efficacy or safety of the medicine".[12] The primary drivers cited were "limited prescribing of the medicine and declining sales".[10] The European Commission formally withdrew the marketing authorization at GSK's request on October 29, 2018.[43]
• Market Context and Competitive Landscape: The commercial failure of Albiglutide can be understood through the lens of market dynamics. It entered a fiercely competitive and rapidly innovating therapeutic class. Prescription data from the period of 2016 to 2021 starkly illustrates this reality: prescriptions for Albiglutide declined by 100%, while its direct once-weekly competitor, dulaglutide (Trulicity), experienced a staggering 525% increase in prescriptions during the same timeframe.[39] This data vividly demonstrates Albiglutide's inability to capture and retain market share against a more compelling competitor.

The failure of Albiglutide was not a failure of the drug itself to meet regulatory standards for safety and efficacy, but rather a failure of competitive differentiation. In isolation, its clinical profile was solid, showing clear benefits over placebo and older oral agents.[7] However, therapeutic decisions are made based on relative benefits. Head-to-head clinical trial data clearly showed Albiglutide was inferior to the market leader at the time, liraglutide, on the critical endpoints of HbA1c reduction and weight loss.[13] Concurrently, dulaglutide launched with a similar convenience profile but a more user-friendly autoinjector and a strong efficacy profile, leading to its rapid market dominance.[39] Furthermore, the impending arrival of semaglutide, with its even greater efficacy in both glycemic control and weight loss, cemented Albiglutide's untenable competitive position. GSK's decision to withdraw was a pragmatic business calculation that the significant costs of marketing, manufacturing, and post-marketing commitments for a product with a small and shrinking market share were not justifiable. The official explanation of "commercial reasons" is a direct reflection of this failure to compete effectively.

Comparative Analysis within the GLP-1 Receptor Agonist Class

Positioning of Albiglutide

Albiglutide was positioned as a second-generation, long-acting GLP-1 receptor agonist. Its key innovation was the use of albumin-fusion technology to achieve a prolonged half-life, enabling the convenience of a once-weekly dosing schedule.[4] This was a significant advantage over first-generation agents like twice-daily exenatide and once-daily liraglutide.

Head-to-Head Comparisons

Direct and indirect comparisons with other major GLP-1 receptor agonists are essential to understand Albiglutide's clinical profile and market fate.

• vs. Liraglutide (Victoza®, once-daily): The HARMONY 7 trial provided a direct head-to-head comparison. The results showed that once-daily liraglutide was statistically superior to once-weekly Albiglutide in reducing both HbA1c and body weight. In terms of tolerability, Albiglutide was associated with lower rates of nausea but significantly higher rates of injection-site reactions.[13]
• vs. Dulaglutide (Trulicity®, once-weekly): While no direct head-to-head trial against Albiglutide is cited, network meta-analyses and indirect comparisons place dulaglutide in a more favorable position. Dulaglutide demonstrated non-inferiority to liraglutide in glycemic control, and liraglutide was superior to Albiglutide, implying dulaglutide's superior efficacy.[14] Dulaglutide also had very low rates of injection-site reactions, another advantage over Albiglutide.[13]
• vs. Semaglutide (Ozempic®, once-weekly): Semaglutide entered the market after Albiglutide's decline but quickly established itself as the most potent agent in the class. Head-to-head trials (e.g., SUSTAIN-7) showed semaglutide was superior to dulaglutide in improving glycemic control and reducing body weight.[14] By extension, it was significantly more effective than Albiglutide.

Efficacy Hierarchy and Key Differentiators

Based on the wealth of comparative clinical trial data, a clear efficacy hierarchy within the GLP-1 receptor agonist class has emerged for the key endpoints of HbA1c reduction and weight loss [14]:

Semaglutide > Liraglutide ≈ Dulaglutide > Exenatide Extended-Release > Albiglutide ≈ Lixisenatide

While Albiglutide's once-weekly dosing was a key convenience feature, this was matched by dulaglutide, semaglutide, and exenatide ER, neutralizing it as a competitive advantage over time.[44] In terms of cardiovascular outcomes, Albiglutide (Harmony Outcomes), liraglutide (LEADER), and subcutaneous semaglutide (SUSTAIN-6) all successfully demonstrated a statistically significant reduction in MACE, suggesting a potential beneficial class effect for atherosclerotic cardiovascular disease, although differences in trial populations and specific component outcomes exist.[9]

Table 3: Comparative Profile of Albiglutide and Other Major GLP-1 Receptor Agonists

Feature	Albiglutide	Liraglutide	Dulaglutide	Semaglutide (Subcutaneous)
Dosing Frequency	Once-Weekly	Once-Daily	Once-Weekly	Once-Weekly
HbA1c Reduction	Moderate	High	High	Very High
Weight Loss	Low/Neutral	Moderate	Moderate	Very High
GI Side Effects (Nausea)	Lower	Higher	Moderate	Higher
Injection Site Reactions	Higher	Lower	Very Low	Lower
Proven MACE Reduction	Yes	Yes	Yes	Yes

Relative rankings based on data from.[13]

Concluding Expert Assessment

Albiglutide was a scientifically sound and clinically beneficial therapeutic agent. Its molecular design, a fusion of a DPP-4-resistant GLP-1 dimer to human albumin, was an innovative and successful strategy to achieve a long pharmacokinetic half-life, enabling the convenience of once-weekly administration. The drug met all regulatory requirements for safety and efficacy, culminating in the demonstration of a statistically significant reduction in major adverse cardiovascular events in the Harmony Outcomes trial—a high bar for any antidiabetic therapy.

Despite these achievements, Albiglutide's story is ultimately one of commercial failure, and its legacy is that of a cautionary tale in pharmaceutical strategy. The critical failure point was its "good, but not great" efficacy profile in a therapeutic area defined by rapid, continuous innovation. Its market entry coincided with the availability of other once-weekly agents and was soon followed by the launch of therapies that were demonstrably superior on the key clinical metrics that drive prescriber and patient choice: glycemic control and, most critically, weight loss. Head-to-head and network meta-analysis data consistently placed Albiglutide at the lower end of the efficacy spectrum within its class.

The decision by GlaxoSmithKline to withdraw Albiglutide for commercial reasons, even before the positive cardiovascular outcome data became public, underscores a fundamental principle of the modern pharmaceutical market: a drug's success is determined not by its performance against placebo, but by its value proposition relative to all other available options. Albiglutide demonstrates that an incremental advance in convenience cannot compensate for a competitive disadvantage in core efficacy. It serves as a definitive case study of how a clinically successful and cardiovascularly beneficial drug can fail in the marketplace due to a lack of sufficient differentiation.

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