Mepolizumab (Nucala): A Comprehensive Monograph on a Foundational Anti-Interleukin-5 Therapy

Executive Summary

Mepolizumab is a humanized IgG1 kappa monoclonal antibody that represents a cornerstone in the targeted treatment of diseases driven by eosinophilic inflammation. Marketed by GlaxoSmithKline under the brand name Nucala, it functions as a high-affinity antagonist of Interleukin-5 (IL-5), the principal cytokine governing the maturation, activation, and survival of eosinophils. By selectively neutralizing IL-5, mepolizumab induces a profound and sustained reduction in circulating and tissue eosinophil levels, thereby mitigating the inflammatory cascade central to a spectrum of pathologies.

Initially approved for severe eosinophilic asthma, mepolizumab's clinical utility has expanded significantly, securing indications for eosinophilic granulomatosis with polyangiitis (EGPA), hypereosinophilic syndrome (HES), chronic rhinosinusitis with nasal polyps (CRSwNP), and, most recently, chronic obstructive pulmonary disease (COPD) with an eosinophilic phenotype. This expansion reflects a paradigm shift in medicine, moving from organ-centric disease definitions toward a biomarker-driven, mechanism-based approach to therapy. Across these indications, pivotal Phase 3 clinical trials have consistently demonstrated its efficacy in reducing disease exacerbations, decreasing reliance on oral corticosteroids (OCS), and improving clinical outcomes and quality of life.

The drug possesses a favorable pharmacokinetic profile, characterized by a long half-life of 16 to 22 days, which permits a convenient once-every-four-weeks subcutaneous dosing schedule. This, combined with the availability of at-home administration formats, significantly reduces treatment burden. The safety profile of mepolizumab is well-characterized and generally manageable. The most common adverse events include headache and injection site reactions. Key warnings pertain to the potential for hypersensitivity reactions and an increased risk of herpes zoster infection, a direct consequence of its targeted immunosuppressive mechanism. Mepolizumab has established itself as a foundational biologic therapy, offering a transformative option for patients with severe, eosinophil-driven inflammatory diseases that were previously difficult to control.

Mepolizumab: Profile and Formulation

Identification and Chemical Properties

Mepolizumab is a biologic therapeutic agent with a specific set of identifiers that are crucial for its classification and tracking in clinical and research settings.

• Generic Name: Mepolizumab [1]
• Brand Name: Nucala [2]
• Manufacturer: GlaxoSmithKline (GSK) [2]
• DrugBank ID: DB06612 [4]
• CAS Number: 196078-29-2 [4]
• Synonyms: The drug is also known by its development code, SB-240563, and a previous investigational name, Bosatria.[4]
• Regulatory Identifiers: Key regulatory codes include the Anatomical Therapeutic Chemical (ATC) classification system code R03DX09 and the FDA Unique Ingredient Identifier (UNII) 90Z2UF0E52.[2]

Molecular Structure and Formulation

Mepolizumab is a sophisticated biotech product with a precisely defined molecular structure and is supplied in several clinical formulations.

• Type: It is classified as a biotech drug, specifically a humanized monoclonal antibody (mAb).[2] It belongs to the immunoglobulin G1 (IgG1) kappa isotype and was developed by humanizing an antibody originally sourced from a mouse to reduce immunogenicity in humans.[2] The antibody is produced as a soluble glycoprotein using a recombinant Chinese Hamster Ovary (CHO) cell line, a standard platform for manufacturing complex biologics.[7]
• Structure: The antibody is a dimer composed of two identical heavy chains, each containing 449 amino acids, and two identical light chains, each with 220 amino acids.[2] The total estimated molecular weight of the glycoprotein is approximately 149 kDa. This mass is constituted by the protein component, which accounts for about 146 kDa, and a carbohydrate (sugar) component of approximately 3 kDa.[2]
• Commercial Formulations: Nucala is available exclusively for subcutaneous (SC) injection and is supplied in several formats to accommodate different clinical needs and administration settings [1]:
• A sterile, lyophilized (freeze-dried) powder containing 100 mg of mepolizumab in a single-use vial, which requires reconstitution before administration.
• A single-dose prefilled autoinjector containing a 100 mg/mL solution.
• A single-dose prefilled syringe, available in two strengths: 100 mg/mL and 40 mg/0.4 mL.
• Excipients: The lyophilized powder formulation is preservative-free and contains several inactive ingredients necessary for stability and solubility: sucrose, disodium hydrogen phosphate heptahydrate, and polysorbate 80.[7]

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Table 1: Mepolizumab Drug Profile Summary

Property	Detail
Generic Name	Mepolizumab
Brand Name	Nucala
Manufacturer	GlaxoSmithKline (GSK)
DrugBank ID	DB06612
CAS Number	196078-29-2
Drug Class	Interleukin-5 (IL-5) Antagonist, Monoclonal Antibody, Immunosuppressive Agent
Molecular Target	Interleukin-5 (IL-5)
Structure	Humanized IgG1 kappa Monoclonal Antibody
Molecular Weight	Approx. 149 kDa
Available Formulations	Lyophilized powder (100 mg vial), Prefilled Autoinjector (100 mg/mL), Prefilled Syringe (100 mg/mL, 40 mg/0.4 mL)

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Clinical Pharmacology

Pharmacodynamics: The Interleukin-5 Pathway and Mechanism of Action

The therapeutic effect of mepolizumab is rooted in its precise interaction with a key signaling pathway in the human immune system.

• The Role of IL-5 and Eosinophils: Interleukin-5 is the primary cytokine that orchestrates the life cycle of eosinophils, a type of white blood cell.[4] IL-5 is critically responsible for stimulating the growth and differentiation of eosinophil progenitor cells in the bone marrow, as well as promoting the recruitment, activation, and prolonged survival of mature eosinophils in the bloodstream and tissues.[7] In certain disease states, overproduction of IL-5 leads to hypereosinophilia (abnormally high levels of eosinophils). These elevated eosinophil levels are a central driver of the chronic inflammation, tissue damage, and fibrosis that characterize a range of conditions, including severe eosinophilic asthma, EGPA, and HES.[4]
• Mechanism of Action: Mepolizumab is engineered to function as a high-affinity antagonist of human IL-5.[1] It binds with high specificity and nanomolar potency to circulating IL-5, thereby preventing the cytokine from docking with its target: the alpha chain of the IL-5 receptor complex expressed on the surface of eosinophils.[2] This blockade of the IL-5/IL-5Rα interaction effectively inhibits IL-5 signaling. Consequently, the downstream biological effects of IL-5—namely, the production and survival of eosinophils—are profoundly reduced.[7]
• Pharmacodynamic Effect: The direct pharmacodynamic consequence of mepolizumab's action is a rapid and significant reduction in blood eosinophil counts, typically ranging from 60% to 90% below baseline levels, depending on the dose.[4] This depletion of eosinophils is the primary measurable effect of the drug and serves as the foundation for its therapeutic benefit in eosinophil-driven diseases. While the precise downstream mechanisms are complex, it is understood that this reduction in eosinophilic inflammation alleviates the pathological processes driving the clinical symptoms of these conditions.[2]

Pharmacokinetics: Absorption, Distribution, Metabolism, and Elimination (ADME)

The pharmacokinetic profile of mepolizumab dictates its dosing regimen and contributes significantly to its clinical utility.

• Absorption: Following subcutaneous injection, mepolizumab is absorbed slowly into the systemic circulation, with the median time to reach maximum plasma concentration (Tmax) ranging from 4 to 8 days.[2] The absolute bioavailability of the subcutaneously administered dose is estimated to be approximately 80%.[2] When administered according to the recommended four-week dosing interval, the drug accumulates, with steady-state concentrations being approximately double those seen after the first dose.[4]
• Distribution: Mepolizumab distributes from the plasma into the extracellular fluid. The population central volume of distribution (Vd) is estimated to be around 3.6 liters for a 70 kg individual, indicating that its distribution is largely confined to the vascular and interstitial spaces, which is typical for a large protein like a monoclonal antibody.[4]
• Metabolism: As a protein-based therapeutic, mepolizumab does not undergo metabolism via the hepatic cytochrome P450 enzyme system, which is the primary pathway for most small-molecule drugs. Instead, it is cleared from the body through degradation by proteolytic enzymes that are widely distributed throughout the body and not restricted to any single organ like the liver.[4] This metabolic pathway means that variations in liver or kidney function are unlikely to have a significant impact on the drug's clearance, obviating the need for dose adjustments in patients with hepatic or renal impairment.[7]
• Elimination: The elimination of mepolizumab is slow, with a mean terminal half-life ranging from 16 to 22 days.[2] This long half-life is a key feature of the drug. The estimated apparent population systemic clearance is approximately 0.28 L/day for a 70 kg individual.[4]

The pharmacokinetic characteristics of mepolizumab are fundamental to its clinical success and patient acceptance. The drug's long elimination half-life is the primary determinant that allows for a convenient and effective dosing schedule of once every four weeks.[4] A shorter half-life would necessitate more frequent injections, increasing the burden on the patient. This extended duration of action ensures that therapeutic concentrations are maintained throughout the dosing interval, providing continuous suppression of the IL-5 pathway. Furthermore, the development of formulations for subcutaneous administration, including user-friendly prefilled autoinjectors and syringes, empowers patients or their caregivers to administer the treatment at home after appropriate training.[11] This contrasts sharply with other biologics, such as reslizumab, which require intravenous infusion in a clinical setting.[17] The combination of a favorable pharmacokinetic profile enabling infrequent dosing with a convenient route of administration represents a significant advantage, reducing the overall treatment burden, enhancing patient autonomy, and likely improving long-term adherence to therapy for these chronic conditions.

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Table 2: Summary of Pharmacokinetic Parameters

Parameter	Value	Reference(s)
Bioavailability (SC)	~80%	2
Time to Max. Concentration (Tmax)	4 to 8 days	2
Volume of Distribution (Vd)	~3.6 L (for 70 kg individual)	4
Metabolism	Proteolytic degradation (body-wide)	4
Systemic Clearance	~0.28 L/day (for 70 kg individual)	4
Elimination Half-Life	16 to 22 days	2

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Clinical Efficacy: Evidence from Pivotal Trials

The approval of mepolizumab across its multiple indications is supported by a robust portfolio of Phase 3 clinical trials that have established its efficacy and safety.

Severe Eosinophilic Asthma (SEA)

Mepolizumab is indicated as an add-on maintenance treatment for patients with severe asthma characterized by an eosinophilic phenotype.[18] Clinical evidence consistently demonstrates its ability to reduce exacerbation frequency, enable the reduction of oral corticosteroid (OCS) dosage, and improve overall asthma control.[2]

• Pivotal Trials:
• DREAM (NCT01000506): This foundational dose-ranging study was instrumental in establishing the drug's efficacy. Patients receiving one of three intravenous (IV) doses of mepolizumab (75 mg, 250 mg, or 750 mg) experienced a statistically significant reduction in the rate of clinically significant exacerbations compared to placebo. The reductions were 48%, 39%, and 52%, respectively, with the 75 mg and 750 mg doses achieving high statistical significance (p<0.0001).[21]
• MENSA (NCT01691521): This pivotal Phase 3 trial confirmed the efficacy of both IV and subcutaneous (SC) formulations. The 100 mg SC dose, which became the standard for asthma, reduced the rate of clinically significant exacerbations by 53% compared to placebo (p<0.001). Importantly, it also reduced exacerbations requiring hospitalization or an emergency department visit by 61%.[20] The trial also documented significant improvements in lung function (forced expiratory volume in 1 second, or FEV1​) and health-related quality of life as measured by the St. George's Respiratory Questionnaire (SGRQ).[24]
• SIRIUS (NCT01691508): This critical Phase 3 study focused on the OCS-sparing effect of mepolizumab. It demonstrated that patients treated with mepolizumab were able to achieve a significantly greater reduction in their daily OCS dose compared to those on placebo. More than half (54%) of patients in the mepolizumab group achieved a reduction of 50% or more in their prednisone dose, highlighting its role in mitigating the substantial side effects of long-term steroid use.[25]
• MUSCA (NCT02281318): This Phase 3 trial further solidified the evidence base, showing a 58% reduction in the rate of exacerbations with mepolizumab treatment versus placebo.[20]
• Long-Term and Real-World Evidence: The benefits of mepolizumab are not limited to controlled trials. Open-label extension studies, such as COSMOS (NCT02135692), and real-world retrospective cohort studies have demonstrated that the efficacy and safety profile are sustained over several years of continuous treatment. These studies report continued low exacerbation rates and durable improvements in lung function and patient-reported outcomes like the Asthma Control Test (ACT) score.[14]

Eosinophilic Granulomatosis with Polyangiitis (EGPA)

Mepolizumab is approved for the treatment of adult patients with EGPA, a rare systemic necrotizing vasculitis also known as Churg-Strauss syndrome.[4]

• Pivotal Trial - MIRRA (NCT02020889): This was a landmark Phase 3 study that transformed the treatment landscape for EGPA.
• Co-Primary Endpoints: The trial met both of its primary endpoints. Mepolizumab-treated patients achieved a significantly greater number of accrued weeks in remission compared to the placebo group (28% vs. 3% had ≥24 weeks of remission; p<0.001). Furthermore, a significantly higher proportion of patients in the mepolizumab arm were in remission at both week 36 and week 48 (32% vs. 3%; p<0.001).[28]
• Key Secondary Endpoints: The annualized relapse rate was cut in half in the mepolizumab group compared to placebo (1.14 vs. 2.27; p<0.001). The trial also demonstrated a powerful steroid-sparing effect, with 44% of patients on mepolizumab able to taper their daily OCS dose to 4.0 mg or less, compared to only 7% of patients on placebo (p<0.001).[28]
• Long-Term Evidence: The open-label extension (OLE) of the MIRRA trial (NCT03298061) provided crucial long-term data. Over a mean exposure of 38.5 months, mepolizumab remained well-tolerated and produced sustained reductions in OCS use. Remarkably, 28% of patients were able to discontinue OCS therapy completely, a significant achievement in this steroid-dependent disease.[30]

Hypereosinophilic Syndrome (HES)

Mepolizumab is indicated for the treatment of patients aged 12 years and older with HES that has persisted for at least six months and for which there is no identifiable non-hematologic secondary cause.[2]

• Pivotal Trial (NCT02836496): The FDA approval was based on this robust Phase 3 study.
• Primary Endpoint: The trial successfully met its primary endpoint, demonstrating that mepolizumab treatment led to a 50% reduction in the proportion of patients who experienced a disease flare or withdrew from the study compared to placebo (28% vs. 56%; p=0.002).[32]
• Safety: The safety profile observed in the HES trial was consistent with that seen in the asthma and EGPA programs, with no new safety signals identified.[33]
• Long-Term Evidence: An open-label extension study (NCT03306043) followed patients from the pivotal trial and confirmed a positive long-term benefit-risk profile. Extended treatment with mepolizumab was associated with continued control of disease flares, sustained reductions in blood eosinophil counts, and further reductions in OCS use.[34]

Chronic Rhinosinusitis with Nasal Polyps (CRSwNP)

Mepolizumab is approved as an add-on maintenance treatment for adult patients with severe CRSwNP who have had an inadequate response to intranasal corticosteroids.[4]

• Pivotal Trial - SYNAPSE (NCT03085797):
• Efficacy: This trial demonstrated statistically significant and clinically meaningful improvements in the two co-primary endpoints at week 52 compared to placebo. Patients treated with mepolizumab had a greater reduction in the total endoscopic nasal polyp score (adjusted median difference of -0.73; p<0.001) and a greater improvement in their nasal obstruction score as measured by a visual analog scale (VAS) (adjusted median difference of -3.14; p<0.001).[35]

Chronic Obstructive Pulmonary Disease (COPD) with Eosinophilic Phenotype

In a significant expansion of its use, mepolizumab was recently approved as an add-on maintenance treatment for adult patients with inadequately controlled COPD who exhibit an eosinophilic phenotype.[19]

• Pivotal Trials:
• METREX (NCT02105948) and MATINEE (NCT04191339): The approval was based on data from these two large Phase 3 trials. Across both studies, mepolizumab demonstrated a clinically meaningful and statistically significant reduction in the annual rate of moderate-to-severe exacerbations compared to placebo. This benefit was observed in a broad population of COPD patients with a blood eosinophil count (BEC) of ≥150 cells/μL at baseline.[37] Mepolizumab is the first biologic to be studied and approved for this specific, biomarker-defined population within COPD.[37]

The trajectory of mepolizumab's clinical development and approvals reveals a fundamental evolution in how inflammatory diseases are understood and treated. Historically, conditions like asthma and COPD were defined and managed based on the affected organ system (the lungs) and their clinical presentation (e.g., reversible vs. irreversible airflow obstruction). Mepolizumab's initial approval for "severe eosinophilic asthma" marked a pivotal moment, as it was one of the first therapies to have a biomarker—the eosinophil—formally integrated into its indication.[13] This established the concept of treating a specific disease endotype. The subsequent approvals for EGPA, HES, and CRSwNP reinforced this principle, as all are diseases where eosinophilia is a known and central pathological feature.[4]

The most transformative step in this evolution is the recent approval for "COPD with an eosinophilic phenotype".[37] This indication formally recognizes that a substantial subset of patients with COPD, a disease traditionally considered to be dominated by neutrophilic inflammation, in fact has an underlying eosinophilic inflammatory driver that is amenable to anti-IL-5 therapy. This moves beyond organ-based classification to a "trans-organ," mechanism-based paradigm. The underlying pathology—eosinophilic inflammation driven by the IL-5 pathway—becomes the therapeutic target, irrespective of its clinical manifestation as asthma, vasculitis, or COPD. This has profound implications for the future of medicine, mandating a shift in diagnostic practices (e.g., routine BEC testing in COPD management) and paving the way for more personalized therapeutic strategies across a range of diseases.

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Table 3: Key Efficacy Outcomes from Pivotal Phase 3 Trials by Indication

Indication	Trial	Key Endpoint	Result vs. Placebo	Reference(s)
Severe Eosinophilic Asthma	MENSA (NCT01691521)	Reduction in Annualized Exacerbation Rate	53% reduction (p<0.001)	24
EGPA	MIRRA (NCT02020889)	Proportion in Remission (Wk 36 & 48)	32% vs. 3% (p<0.001)	29
HES	NCT02836496	Proportion with ≥1 Flare	28% vs. 56% (p=0.002)	33
CRSwNP	SYNAPSE (NCT03085797)	Change in Nasal Polyp Score (adjusted median)	-0.73 difference (p<0.001)	36
Eosinophilic COPD	MATINEE/METREX	Reduction in Moderate/Severe Exacerbations	Statistically significant reduction	37

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Comprehensive Safety, Tolerability, and Risk Management

The safety profile of mepolizumab has been extensively characterized through a large clinical development program and post-marketing surveillance.

Adverse Event Profile from Clinical Trials

• Common Adverse Events: Across its approved indications, the most frequently reported adverse events (AEs) with an incidence of 5% or greater are generally mild to moderate in severity. These include headache (reported in up to 19% of patients), injection site reactions (such as pain, redness, swelling, itching, or a burning sensation; ~8%), back pain (~5%), and fatigue (~5%).[2]
• Indication-Specific Adverse Events: While the core safety profile is consistent, some AEs have been noted more frequently in specific trial populations. For patients with CRSwNP, oropharyngeal pain and arthralgia (joint pain) were common.[19] In the COPD trials, back pain, diarrhea, and cough were reported.[15]
• Hepatotoxicity: Mepolizumab has demonstrated a favorable liver safety profile. It has not been associated with elevations in serum aminotransferase levels or instances of clinically apparent drug-induced liver injury. The LiverTox database, a resource from the National Institutes of Health, assigns mepolizumab a likelihood score of 'E', indicating it is an "unlikely cause of clinically apparent liver injury".[5]

Warnings, Precautions, and Contraindications

The prescribing information for mepolizumab includes several important warnings and precautions to guide its safe use.

• Black Box Warning: Mepolizumab does not carry an FDA-issued black box warning, the most serious type of warning assigned to prescription drugs.[39]
• Contraindications: The sole contraindication for mepolizumab is a known history of a hypersensitivity reaction to the active substance or to any of its excipients.[18]
• Hypersensitivity Reactions: Serious systemic hypersensitivity reactions, including anaphylaxis, have been reported following mepolizumab administration. These reactions can manifest as angioedema (swelling), bronchospasm, hypotension, urticaria (hives), and rash. While they generally occur within hours of the injection, some cases have a delayed onset of several days. If a hypersensitivity reaction is suspected, mepolizumab must be discontinued immediately and appropriate medical care provided.[13]
• Acute Symptoms: Mepolizumab is a long-term maintenance therapy designed to prevent symptoms and exacerbations. It is not a rescue medication and should not be used for the treatment of acute bronchospasm or status asthmaticus.[4]
• Opportunistic Infections (Herpes Zoster): Mepolizumab's mechanism of action involves suppression of a component of the immune system, which may increase the risk for certain infections. Specifically, cases of herpes zoster (shingles) have occurred in patients receiving mepolizumab in clinical trials.[18] Prescribing information recommends considering vaccination against the varicella-zoster virus, if medically appropriate, prior to initiating therapy.[13]
• Parasitic (Helminth) Infections: Eosinophils are known to play a role in the immunological response to some parasitic helminth (worm) infections. Therefore, it is recommended that patients with pre-existing helminth infections be treated for the infection before starting mepolizumab. If a patient becomes infected while on therapy and does not respond to standard anti-helminth treatment, discontinuation of mepolizumab should be considered until the infection resolves.[4]
• Corticosteroid Reduction: Patients on maintenance systemic or inhaled corticosteroids should not stop these medications abruptly when starting mepolizumab. Any reduction in corticosteroid dosage should be gradual and conducted under the direct supervision of a physician. A rapid reduction can lead to systemic withdrawal symptoms or unmask underlying conditions that were previously suppressed by the steroid therapy.[4]

Drug and Disease Interactions

• Formal Interaction Studies: No formal drug-drug interaction studies have been conducted with mepolizumab. Because it is a monoclonal antibody that is degraded via proteolysis rather than metabolized by cytochrome P450 enzymes, clinically significant pharmacokinetic interactions with small-molecule drugs are not expected.[7]
• Immunosuppressive Agents: As an immunosuppressive agent, mepolizumab has a theoretical potential for additive effects when used concurrently with other immunosuppressive or immunomodulatory drugs (e.g., abatacept, adalimumab), which could increase the risk of adverse effects, particularly infections.[4] Similarly, co-administration with live vaccines may result in a diminished vaccine response.[4] One drug interaction database identifies 7 major and 19 moderate potential interactions, primarily involving other biologics, immunosuppressants, and live vaccines.[43]
• Disease Interactions: The primary disease interaction of concern is with active infections, due to the drug's immunosuppressive effects. While no dose adjustment is required for patients with renal impairment, this is noted as a condition for which caution should be exercised.[43]

The safety profile of mepolizumab is a direct and logical consequence of its highly specific mechanism of action. The drug is designed to suppress the IL-5 pathway to deplete eosinophils, which is the basis of its therapeutic efficacy.[2] However, this targeted action also has predictable effects on the immune system. Eosinophils are a component of the host's innate defense against certain pathogens, most notably parasitic helminths and potentially some latent viruses.[18] Therefore, the specific warnings in the prescribing information regarding the need to treat pre-existing helminth infections and the observed increased risk of herpes zoster (shingles) are not unexpected "off-target" side effects. Rather, they are "on-target" consequences of the drug's intended pharmacological action. This illustrates a fundamental principle of targeted immunotherapy: high specificity provides potent efficacy against a pathological pathway but can also create specific vulnerabilities by disabling a component of the host's natural defense system. Understanding this connection is critical for proactive risk management, such as pre-screening for infections and considering vaccination.

Dosage, Administration, and Clinical Practice Guidelines

The dosing and administration of mepolizumab are tailored to the specific indication and patient population, with standardized protocols for preparation and delivery.

Indication-Specific Dosing Regimens (FDA & EMA)

All approved doses of mepolizumab are administered via subcutaneous (SC) injection once every 4 weeks.[10] The specific dose varies significantly by indication and patient age.

• Severe Eosinophilic Asthma:
• Adults and adolescents (12 years of age and older): 100 mg SC every 4 weeks.[10]
• Children (6 to 11 years of age): 40 mg SC every 4 weeks.[10]
• Eosinophilic Granulomatosis with Polyangiitis (EGPA):
• Adults (18 years of age and older): 300 mg SC every 4 weeks. This dose is administered as three separate 100 mg injections.[10]
• Hypereosinophilic Syndrome (HES):
• Adults and adolescents (12 years of age and older): 300 mg SC every 4 weeks. This dose is administered as three separate 100 mg injections.[10]
• Chronic Rhinosinusitis with Nasal Polyps (CRSwNP):
• Adults (18 years of age and older): 100 mg SC every 4 weeks.[10]
• Chronic Obstructive Pulmonary Disease (COPD) with Eosinophilic Phenotype:
• Adults: 100 mg SC every 4 weeks.[10]
• Special Populations: Based on population pharmacokinetic analyses, no dose adjustments are recommended for elderly patients or for patients with renal or hepatic impairment.[7]

Preparation, Storage, and Administration Protocols

Proper handling is essential to ensure the stability and sterility of the product.

• Storage: Unopened vials, autoinjectors, and prefilled syringes must be stored in a refrigerator at a temperature between 2°C and 8°C (36°F to 46°F). They should be kept in the original carton to protect them from light. The products must not be frozen.[7]
• Reconstitution (Lyophilized Powder Vial): This process should be performed by a healthcare professional.
• The 100 mg vial of lyophilized powder is reconstituted with exactly 1.2 mL of Sterile Water for Injection, USP, to yield a final concentration of 100 mg/mL.[10]
• The sterile water should be directed onto the center of the lyophilized cake. The vial should then be gently swirled with a circular motion for 10 seconds at 15-second intervals until the powder is fully dissolved. Shaking the vial is prohibited as it can cause foaming or precipitation of the protein.[10]
• The final reconstituted solution should be visually inspected. It should be clear to opalescent, and colorless to pale yellow or pale brown. The presence of small air bubbles is expected and acceptable, but if particulate matter is visible or the solution appears cloudy or milky, it must be discarded.[7]
• If not used immediately, the reconstituted solution is stable for up to 8 hours when stored below 30°C (86°F) according to the FDA label, or for up to 6 hours according to the Australian label. It should not be frozen.[7]
• Administration (All Formulations):
• Mepolizumab is for subcutaneous injection only. Recommended injection sites are the upper arm, thigh, or abdomen.[10]
• For the 300 mg dose required for EGPA and HES, three separate 100 mg injections must be administered. To minimize local reactions, it is recommended that the injection sites be at least 5 cm (approximately 2 inches) apart.[18]
• Prefilled autoinjectors and syringes should be removed from the refrigerator and allowed to sit at room temperature for at least 30 minutes before injection. They should not be warmed by any other means.[45]
• After appropriate training from a healthcare provider, patients or their caregivers may administer the injection at home, which is a key feature for long-term management.[15]

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Table 4: Summary of Approved Indications and Dosing Regimens (FDA & EMA)

Indication	Patient Population	Dose	Reference(s)
Severe Eosinophilic Asthma	Adults & Adolescents (≥12 yrs)	100 mg SC every 4 weeks	10
Severe Eosinophilic Asthma	Children (6-11 yrs)	40 mg SC every 4 weeks	10
EGPA	Adults (≥18 yrs)	300 mg SC every 4 weeks	10
HES	Adults & Adolescents (≥12 yrs)	300 mg SC every 4 weeks	10
CRSwNP	Adults (≥18 yrs)	100 mg SC every 4 weeks	10
Eosinophilic COPD	Adults (≥18 yrs)	100 mg SC every 4 weeks	10

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Comparative Therapeutic Landscape and Place in Therapy

Mepolizumab exists within a competitive and evolving landscape of biologic therapies for Type 2 inflammatory diseases. Its positioning is defined by its specific mechanism, its breadth of indications, and comparisons with other agents.

Comparison with Anti-IL-5/IL-5R Biologics (Benralizumab, Reslizumab)

Mepolizumab is one of three approved biologics that target the IL-5 pathway.

• Mechanism Differences: While all three drugs target the same pathway, there is a key mechanistic distinction. Mepolizumab and reslizumab are anti-IL-5 ligand inhibitors; they bind directly to the IL-5 cytokine, preventing it from activating its receptor.[50] In contrast, benralizumab is an anti-IL-5 receptor alpha (IL-5Rα) antibody. It binds to the receptor on the surface of eosinophils, not only blocking IL-5 signaling but also flagging the eosinophil for destruction by natural killer cells through a process called antibody-dependent cell-mediated cytotoxicity (ADCC).[17]
• Efficacy in Asthma:
• Indirect Comparisons: Due to a lack of direct head-to-head trials in asthma, the relative efficacy has been assessed through numerous indirect comparisons and network meta-analyses.[53] The broad consensus from these analyses is that mepolizumab, benralizumab, and reslizumab demonstrate broadly comparable efficacy in reducing asthma exacerbation rates and improving lung function. No single agent has been shown to be consistently superior across all patient populations and clinical outcomes.[55]
• Eosinophil Depletion: One notable biological difference is the depth of eosinophil depletion. Studies have shown that benralizumab's ADCC mechanism leads to a more profound and complete depletion of peripheral blood eosinophils (often to 0 cells/μL) in a higher percentage of patients compared to the substantial but less complete reduction achieved by mepolizumab.[52] The long-term clinical significance of this deeper depletion is still a subject of investigation.
• Efficacy in EGPA (Head-to-Head Trial):
• MANDARA Trial: This landmark Phase 3 study was the first head-to-head trial comparing two biologics in EGPA. The trial demonstrated that benralizumab was non-inferior to mepolizumab in meeting the primary endpoint of the proportion of patients in remission at weeks 36 and 48 (59% for benralizumab vs. 57% for mepolizumab).[58] A notable secondary finding was that a numerically higher proportion of patients treated with benralizumab were able to completely taper off OCS by the end of the study (41% vs. 26%), suggesting a potential advantage for benralizumab in this specific outcome within this disease.[58]
• Administration and Dosing: This is a key area of differentiation. Both mepolizumab and benralizumab are available for subcutaneous self-administration, a major convenience for patients. Reslizumab requires intravenous infusion in a healthcare facility, which significantly increases the treatment burden and limits its clinical use.[17] Benralizumab also offers a less frequent maintenance dosing schedule (every 8 weeks after loading doses) compared to mepolizumab's every 4 weeks.[50]

Positioning Against Other Biologic Classes (e.g., Anti-IL-4Rα)

• Broader Mechanism: Dupilumab, an anti-IL-4 receptor alpha (IL-4Rα) antibody, represents a different therapeutic approach. By blocking the shared receptor for both IL-4 and IL-13, it inhibits two key upstream cytokines in the Type 2 inflammatory cascade. This pathway not only influences eosinophilic inflammation but also drives other pathological features like IgE production, mucus hypersecretion, and airway hyperresponsiveness.[54]
• Comparative Efficacy: The choice between an anti-IL-5 agent like mepolizumab and an anti-IL-4/13 agent like dupilumab is highly nuanced. Some indirect comparisons suggest that dupilumab may lead to greater reductions in annualized exacerbation rates and more significant improvements in lung function and markers like fractional exhaled nitric oxide (FeNO), which is IL-13 dependent.[54] This suggests that patients with a mixed inflammatory profile (e.g., high eosinophils and high FeNO) might derive more benefit from the broader mechanism of dupilumab. Conversely, patients with a purely eosinophil-driven phenotype may respond equally well to the more targeted anti-IL-5 approach.

The therapeutic market for severe inflammatory diseases has matured beyond simple class-based choices. Initially, the availability of multiple anti-IL-5/IL-5R agents prompted the question of which was superior. Indirect comparisons in asthma revealed what appeared to be a general "class effect," with all agents showing similar efficacy in reducing exacerbations.[55] However, the landscape is now far more nuanced. The head-to-head MANDARA trial in EGPA provided the first direct evidence that while two biologics can be non-inferior on a primary endpoint, there may be important differences in key secondary outcomes, such as OCS-sparing.[58] This moves the decision-making process beyond a simple efficacy comparison.

Furthermore, practical considerations have become critical differentiators. The convenience of at-home subcutaneous administration offered by mepolizumab and benralizumab provides a distinct advantage over the intravenous route required for reslizumab.[17] The choice between an anti-IL-5 agent and an anti-IL-4/13 agent adds another layer of complexity, requiring clinicians to consider the patient's full biomarker profile (e.g., blood eosinophils, FeNO, IgE levels) to select the most appropriate mechanistic target. Therefore, the selection of a biologic is no longer a one-size-fits-all decision. It has evolved into a complex, multidimensional assessment that balances the specific disease indication, the primary therapeutic goal (e.g., exacerbation reduction vs. OCS-sparing), the patient's unique biomarker signature, and practical factors like administration preference and dosing frequency. This signifies a mature market where highly personalized medicine is becoming the standard of care.

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Table 5: Comparative Analysis of Anti-IL-5/IL-5R Biologics for Severe Eosinophilic Asthma

Feature	Mepolizumab (Nucala)	Benralizumab (Fasenra)	Reslizumab (Cinqair)
Target	IL-5 Ligand	IL-5 Receptor α (IL-5R$\alpha$)	IL-5 Ligand
Administration	Subcutaneous (SC)	Subcutaneous (SC)	Intravenous (IV)
Frequency	Every 4 weeks	Every 8 weeks (maintenance)	Every 4 weeks
Key Efficacy	~50% exacerbation reduction; OCS-sparing	~50% exacerbation reduction; OCS-sparing	~50−60% exacerbation reduction
Key Differentiator	Broadest range of approved eosinophilic indications; extensive long-term data.	Induces direct eosinophil apoptosis (ADCC); less frequent maintenance dosing.	IV administration in a clinical setting required.

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Regulatory Status and Future Directions

Mepolizumab has a well-established regulatory history and continues to be the subject of ongoing research to expand its clinical applications.

• FDA and EMA Approvals: Mepolizumab was first approved by the U.S. Food and Drug Administration (FDA) on November 4, 2015, for the add-on maintenance treatment of severe eosinophilic asthma in patients aged 12 and older.[3] Since then, its label has been progressively expanded by both the FDA and the European Medicines Agency (EMA) to include additional indications and patient populations:
• Eosinophilic Granulomatosis with Polyangiitis (EGPA) [2]
• Hypereosinophilic Syndrome (HES) [2]
• Chronic Rhinosinusitis with Nasal Polyps (CRSwNP) [19]
• Chronic Obstructive Pulmonary Disease (COPD) with an eosinophilic phenotype (FDA approval in 2025, EMA application accepted in March 2025).[37]
• Ongoing Research and Future Indications:
• The clinical development program for mepolizumab remains active. It has been investigated for other eosinophil-mediated conditions, such as atopic dermatitis and eosinophilic esophagitis (EoE), although these are not yet approved indications.[2]
• The global expansion of the COPD indication is a clear strategic priority for GSK, with regulatory submissions under review in Europe and China.[37]
• Long-term, real-world observational studies, such as the MARS study in Japan for patients with EGPA (NCT04551989), are ongoing. These studies are crucial for gathering data on the long-term safety and effectiveness of mepolizumab in routine clinical practice outside the controlled environment of a clinical trial.[62]
• Biosimilars: The patent protection for originator biologics is finite, and the development of biosimilar versions of mepolizumab is underway. For example, Bio-Thera Solutions is developing BAT2606, a mepolizumab biosimilar that has completed Phase 1 trials.[60] The eventual market entry of biosimilars is expected to increase competition and potentially lower treatment costs, which could broaden patient access in the future.

Conclusion and Expert Recommendations

Mepolizumab (Nucala) has firmly established itself as a highly effective and generally well-tolerated targeted biologic therapy. By specifically neutralizing Interleukin-5, it addresses the core driver of a range of severe inflammatory diseases characterized by eosinophilia. The robust body of evidence from pivotal clinical trials across severe eosinophilic asthma, EGPA, HES, CRSwNP, and eosinophilic COPD demonstrates its consistent ability to reduce disease exacerbations, decrease the burden of oral corticosteroids, and improve patient quality of life. Its favorable pharmacokinetic profile, allowing for infrequent subcutaneous administration, and its expanding list of approved indications have solidified its position as a foundational therapy in the management of eosinophil-driven conditions.

Based on the comprehensive analysis of the available data, the following expert recommendations are provided:

1. Place in Therapy: Mepolizumab should be considered a first-line biologic therapy for patients who meet the specific criteria for its approved indications, particularly for those with severe eosinophilic asthma, EGPA, and HES where its benefits are most profoundly established.
2. Personalized Treatment Selection: The choice between mepolizumab and other available biologics (e.g., benralizumab, dupilumab) should be a personalized one. This decision should be guided by a multifactorial assessment that includes the specific indication, the patient's biomarker profile (e.g., blood eosinophil count, FeNO), the primary therapeutic goal (e.g., maximum exacerbation reduction vs. optimal OCS-sparing), and patient-centered factors such as preference for dosing frequency and administration setting.
3. Risk Management and Patient Counseling: Clinicians must maintain a high index of suspicion for potential hypersensitivity reactions and should educate patients on their signs and symptoms. Patients should also be counseled on the increased risk of herpes zoster, and varicella vaccination should be considered where medically appropriate before initiating treatment. The importance of gradual, physician-supervised tapering of corticosteroids must be emphasized.
4. Impact on COPD Management: The recent approval of mepolizumab for COPD with an eosinophilic phenotype necessitates a paradigm shift in the diagnostic and therapeutic approach to this disease. Routine measurement of blood eosinophil counts should become standard practice in the management of patients with inadequately controlled COPD to identify the significant subset of individuals who may benefit from targeted anti-inflammatory therapy.
5. Future Research Priorities: To further refine clinical practice, future research should prioritize direct head-to-head comparative effectiveness trials of biologics across all relevant indications. Additionally, research aimed at identifying and validating predictive biomarkers is essential to optimize patient selection, predict treatment response, and advance the field of personalized medicine for eosinophilic diseases.

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