Pozelimab (Veopoz): A Comprehensive Monograph on a First-in-Class C5 Inhibitor for Complement-Mediated Disease

Section 1: Profile of a Novel Complement C5 Inhibitor

Pozelimab represents a significant advancement in the targeted modulation of the human immune system. As a high-precision biologic therapeutic, it is designed to intervene at a critical juncture of the complement cascade, a powerful yet potentially destructive component of innate immunity. This section establishes the fundamental identity of pozelimab, detailing its nomenclature, molecular architecture, and pharmacological classification, which together form the basis for its clinical application.

1.1 Identification and Nomenclature

To ensure clarity and precision across clinical, regulatory, and research domains, pozelimab is identified by a comprehensive set of names and codes.

• Nonproprietary Names: The International Nonproprietary Name (INN) assigned to the molecule is Pozelimab.[1] In the United States, the approved nonproprietary name, which includes a four-letter suffix to distinguish it from other biological products, is pozelimab-bbfg.[2]
• Brand Name: The commercial product is marketed under the trade name Veopoz.[2]
• Development and Regulatory Codes: During its development by Regeneron Pharmaceuticals, the antibody was designated REGN3918.[4] Its United States Adopted Name (USAN) council code is FG-06.[1]
• Database and Chemical Identifiers: Pozelimab is cataloged in major scientific databases under the following unique identifiers:
• DrugBank Accession Number: DB15218 [2]
• CAS (Chemical Abstracts Service) Registry Number: 2096328-94-6 [2]
• UNII (Unique Ingredient Identifier): 0JJ21K6L2I [1]

The following table consolidates these key identifiers and properties, providing a definitive reference for the molecule.

Attribute	Value	Source(s)
International Nonproprietary Name (INN)	Pozelimab	1
US Adopted Name (USAN)	pozelimab-bbfg	2
Brand Name	Veopoz	2
DrugBank ID	DB15218	2
CAS Number	2096328-94-6	2
UNII	0JJ21K6L2I	1
Development Code	REGN3918	4
Molecular Formula	C6418​H9898​N1690​O2026​S42​	2
Molar Mass	~144.5 - 144.8 kDa	2
Antibody Isotype	Human Immunoglobulin G4-kappa (IgG4P)	1
Originator/Developer	Regeneron Pharmaceuticals, Inc.	3

1.2 Molecular Structure and Physicochemical Characteristics

Pozelimab is a biotech therapeutic, specifically classified as a fully human, recombinant monoclonal antibody.[2] Its structure and origin are the product of advanced bioengineering designed to optimize its therapeutic function and minimize potential liabilities.

The molecular architecture of pozelimab is that of an Immunoglobulin G4-kappa (IgG4κ) antibody, meaning it is composed of two identical gamma-4 heavy chains and two identical kappa light chains.[1] Each heavy chain consists of 446 amino acids.[1] A critical and deliberate engineering feature is a proline substitution within the hinge region of the heavy chains, classifying it more precisely as an

IgG4P antibody.[8] This modification is not trivial; it addresses a known instability of native IgG4 antibodies. In their natural state, IgG4 molecules can undergo a process called "fab-arm exchange" in vivo, where a heavy-light chain pair from one antibody can swap with a pair from another IgG4 molecule. This process results in bispecific antibodies that are functionally monovalent with respect to their original target. By introducing a stabilizing proline substitution, the pozelimab molecule is locked into a stable, conventional bivalent structure. This ensures that both antigen-binding domains consistently target complement C5, maximizing avidity and providing the predictable, sustained inhibitory activity essential for its therapeutic effect.

The antibody has a chemical formula of C6418​H9898​N1690​O2026​S42​ and a corresponding molar mass of approximately 144,496 g·mol⁻¹, or ~144.5 kDa.[2] It is manufactured using recombinant DNA technology in a mammalian cell expression system, specifically

Chinese hamster ovary (CHO) cells.[2]

Pozelimab was invented using Regeneron's proprietary VelocImmune® technology.[13] This platform utilizes genetically engineered mice with a humanized immune system, enabling the production of optimized, fully human antibodies directly. The selection of a

fully human antibody sequence is a key strategic advantage. Unlike chimeric (mouse-human) or humanized antibodies, which retain non-human protein sequences, a fully human antibody is less likely to be recognized as foreign by the patient's immune system. This minimizes the risk of immunogenicity—the development of anti-drug antibodies (ADAs). ADAs can neutralize the therapeutic, leading to a loss of efficacy over time, or form immune complexes that can cause adverse events. For a therapy like pozelimab, which is intended for chronic, potentially lifelong administration in the treatment of autoimmune diseases, this low immunogenicity profile is critical for ensuring durable efficacy and long-term safety. This reflects a "design-for-durability" approach from the earliest stages of drug discovery.

1.3 Pharmacological Classification

Based on its mechanism of action, pozelimab is categorized within several overlapping pharmacological classes:

• Primary Classification: It is a Complement C5 Inhibitor, as its direct molecular target is the complement C5 protein.[2]
• Broader Classifications: It is also described as a Complement Inactivating Agent [4] and an Immune Modulator.[16]
• ATC Code: The Anatomical Therapeutic Chemical (ATC) classification system assigns it the code L04AJ11.[2]

Section 2: Mechanism of Action and Pharmacodynamics

The therapeutic efficacy of pozelimab is rooted in its precise and potent interruption of the terminal complement pathway. This section dissects the molecular interactions and the resulting pharmacodynamic effects that translate this targeted inhibition into a clinically meaningful outcome.

2.1 The Terminal Complement Pathway as a Therapeutic Target

The complement system is a network of circulating and membrane-bound proteins that serves as a primary effector arm of the innate immune system.[2] It can be activated through three main pathways (classical, lectin, and alternative), all of which converge on the cleavage of complement component C3. This leads to the subsequent cleavage of

complement component C5, a pivotal event that initiates the terminal complement pathway.[17]

The cleavage of C5 by C5 convertase enzymes yields two biologically active fragments:

1. C5a: A potent pro-inflammatory anaphylatoxin that recruits and activates immune cells, such as neutrophils and macrophages, promoting inflammation at sites of injury or infection.[16]
2. C5b: This fragment initiates the assembly of the Membrane Attack Complex (MAC), also known as C5b-9. C5b sequentially binds components C6, C7, C8, and multiple copies of C9 to form a transmembrane pore that can insert into the lipid bilayer of target cells, leading to osmotic lysis and cell death.[9]

While this cascade is essential for host defense against pathogens, particularly encapsulated bacteria, its dysregulation or hyperactivation is the central pathological driver of a range of diseases. In conditions like CHAPLE disease and Paroxysmal Nocturnal Hemoglobinuria (PNH), uncontrolled complement activation leads to the destruction of the body's own cells, chronic inflammation, and tissue damage.[2] Therefore, C5 represents an ideal therapeutic target to halt these downstream destructive processes.

2.2 High-Affinity Binding and Inhibition of C5 Cleavage

Pozelimab functions as a direct, high-affinity antagonist of complement C5.[4] Its mechanism of action is one of steric hindrance: by binding to a specific epitope on the C5 protein, it physically blocks the access of C5 convertase enzymes, thereby preventing the cleavage of C5 into C5a and C5b.[16] This single inhibitory step effectively shuts down the entire terminal complement pathway, preventing the generation of both the pro-inflammatory C5a and the lytic MAC.[9]

Preclinical binding studies quantify the potency of this interaction. At a physiological temperature of 37°C, pozelimab binds to human C5 with an exceptionally high affinity, demonstrated by a dissociation constant (Kd​) of 262 pM.[5] This tight binding ensures a durable and effective blockade. The antibody also cross-reacts with cynomolgus monkey C5 (

Kd​ of 8.55 nM), which enabled relevant preclinical safety and toxicology assessments.[5]

A crucial feature of pozelimab's design is its ability to bind not only to wild-type C5 but also to common C5 genetic variants.[3] This is a significant improvement over some first-generation C5 inhibitors. For example, a specific polymorphism in the C5 gene, resulting in an R885C amino acid substitution, is known to confer resistance to eculizumab in a subset of patients, leading to treatment failure. Preclinical data confirm that pozelimab effectively binds to this C5 variant, ensuring that its therapeutic effect is maintained across a broader patient population and overcoming a known mechanism of clinical resistance.[5] This represents a key molecular advancement designed to provide more reliable and universal complement inhibition.

The functional consequence of this high-affinity binding is potent inhibition of complement-mediated cell lysis. In in vitro assays using normal human serum, pozelimab effectively blocked hemolysis mediated by both the classical pathway (IC50 of 2.8 nM) and the alternative pathway (IC50 of 26 nM), demonstrating comprehensive suppression of complement activity regardless of the initiating trigger.[5]

2.3 Pharmacokinetics and In Vivo Pharmacodynamics

Pozelimab is formulated for both intravenous (for initial loading) and subcutaneous (for maintenance) administration.[2] Preclinical pharmacokinetic studies in C5-humanized mice demonstrated a prolonged biological profile, with a single 15 mg/kg subcutaneous dose yielding a half-life of approximately

13 days.[5]

In the clinical setting, the pharmacodynamic effect of pozelimab is profound and sustained. A key measure of terminal complement pathway activity is the total classical complement activity (CH50) assay. In a clinical study of patients with PNH, treatment with pozelimab resulted in the complete and durable suppression of this activity. Throughout the study period, CH50 levels remained fully suppressed at 0 kIU/L, indicating a complete functional blockade of the terminal complement cascade.[20]

This state of complete complement inhibition, while being the cornerstone of pozelimab's efficacy, is also directly responsible for its most significant safety liability. The MAC is a primary component of the immune system's defense against encapsulated bacteria, most notably Neisseria meningitidis. By design, pozelimab eliminates the body's ability to form the MAC. Therefore, the very mechanism that provides therapeutic benefit simultaneously induces a specific state of immunodeficiency. This establishes an unavoidable link between the drug's efficacy and its primary toxicity. The resulting increased risk of serious meningococcal infections is not an off-target side effect but a predictable, on-target consequence of its pharmacology. This understanding fundamentally shapes the clinical use of pozelimab, mandating that a proactive and rigorous risk mitigation strategy, centered on vaccination, is not merely an adjunct to therapy but an inseparable component of the treatment paradigm itself.

Section 3: The First Approved Indication: CD55-Deficient Protein-Losing Enteropathy (CHAPLE Disease)

Pozelimab achieved a landmark regulatory approval as the first-ever treatment for CHAPLE disease, an ultra-rare and devastating genetic disorder. This section provides a detailed analysis of the disease's pathophysiology and the pivotal clinical trial data that demonstrated the transformative efficacy of pozelimab, leading to its authorization.

3.1 Pathophysiology of an Ultra-Rare Disorder of Complement Hyperactivation

CHAPLE disease is an acronym for its defining features: Complement Hyperactivation, Angiopathic Thrombosis, and Protein-Losing Enteropathy.[2] It is an exceedingly rare autosomal recessive disorder, with fewer than 100 patients diagnosed worldwide.[2]

The underlying genetic cause is biallelic loss-of-function mutations in the CD55 gene.[2] This gene encodes the CD55 protein, also known as Decay-Accelerating Factor (DAF), a crucial glycosylphosphatidylinositol-anchored protein expressed on the surface of host cells. The primary function of CD55 is to protect the body's own cells from complement-mediated damage by accelerating the decay of C3 and C5 convertases, thereby preventing runaway complement activation on host tissues.[4]

In individuals with CHAPLE disease, the absence of functional CD55 leaves the endothelial cells lining blood and lymph vessels in the gastrointestinal tract and elsewhere vulnerable to attack by the complement system. This uncontrolled complement hyperactivation causes chronic endothelial damage, leading to a cascade of severe clinical consequences [3]:

• Protein-Losing Enteropathy (PLE): Damaged intestinal lymphatic and blood vessels leak large amounts of protein, including albumin and immunoglobulins, into the gut, leading to severe hypoalbuminemia and hypogammaglobulinemia.
• Angiopathic Thrombosis: Endothelial damage promotes a pro-thrombotic state, leading to potentially life-threatening blood clots in various vessels.
• Clinical Manifestations: Patients suffer from debilitating symptoms including severe peripheral and facial edema (due to low albumin), chronic diarrhea, abdominal pain, nausea, vomiting, malabsorption, and impaired growth.[15]

Prior to the availability of pozelimab, there were no approved treatments for CHAPLE disease, and management was limited to supportive care, such as frequent albumin infusions and nutritional support, which did not address the underlying mechanism of the disease.[23]

3.2 Analysis of the Pivotal Phase 2/3 Clinical Trial (NCT04209634)

The regulatory approval of pozelimab for CHAPLE disease was based on the strength of data from a single-arm, open-label, multicenter Phase 2/3 clinical trial.[2]

• Study Design: Given the ultra-rare nature of the disease, a traditional placebo-controlled trial was not feasible. Instead, the study used a design where each patient's outcomes on treatment were compared to their own pre-treatment data.[22]
• Patient Population: The trial enrolled 10 patients with a confirmed diagnosis of active CD55-deficient PLE, confirmed by both clinical history and biallelic CD55 loss-of-function mutation genotype.[21] The patient population was pediatric and adolescent, with ages ranging from 3 to 19 years (median age of 8.5 years).[13]
• Dosing Regimen: Treatment was initiated with a single 30 mg/kg intravenous loading dose of pozelimab on Day 1. This was followed by weekly subcutaneous maintenance doses based on body weight, starting on Day 8.[11]
• Primary Endpoint: The study's primary endpoint was a composite measure of efficacy assessed at Week 24: the proportion of patients achieving both normalization of serum albumin and an improvement or no worsening of clinical signs and symptoms.[11]

The following table summarizes the key characteristics and outcomes of this pivotal study.

Trial Attribute	Details	Source(s)
Trial Identifier	NCT04209634	2
Phase	Phase 2/3	11
Study Design	Open-label, single-arm, multicenter; outcomes compared to pre-treatment data	2
Patient Population	N=10; Ages 3-19 years (median 8.5); Confirmed active CD55-deficient PLE	11
Dosing Regimen	Day 1: 30 mg/kg IV loading dose. Day 8 onwards: Weekly weight-based SC maintenance dose.	11
Primary Endpoint	Proportion of patients with albumin normalization AND clinical improvement at Week 24	11
Key Efficacy Outcomes	Primary Endpoint Achievement: 100% (10 of 10 patients). Serum Albumin Normalization (≥3.5 g/dL): 100% by Week 12, maintained through ≥72 weeks. Clinical Benefit: 100% showed reduction in hospitalizations and albumin transfusions.	11

3.3 Efficacy Outcomes: Transformative Clinical and Biomarker Response

The results of the pivotal trial were not merely positive; they were definitive and transformative for the patients involved.

• Biomarker and Endpoint Achievement: All 10 patients (100%) met the composite primary endpoint of the study.[25] The effect on the key disease biomarker, serum albumin, was rapid and profound. All 10 patients achieved normalization of their serum albumin levels (defined as a concentration of at least 3.5 g/dL) by Week 12 of treatment. This normalization was durable, being maintained through at least 72 weeks of follow-up.[11] The median time for serum albumin to reach the normal range was just 15.5 days, highlighting the swift onset of action.[9]
• Clinical Improvement: The normalization of this key biomarker was mirrored by dramatic improvements in clinical outcomes. All 10 patients demonstrated a clinically meaningful reduction in both the number of hospitalizations and the number of albumin transfusions required during the first 48 weeks of treatment compared to the 48-week period prior to initiating pozelimab.[11]
• Patient-Reported Outcomes: To capture the impact on patients' daily lives, within-trial interviews were conducted. These qualitative data confirmed the clinical findings. At the Week 24 interviews, all patients reported a complete resolution of the core signs and symptoms of CHAPLE disease, including abdominal pain, diarrhea, facial and peripheral edema, nausea, and vomiting.[25]

The approval of pozelimab based on a small, open-label trial of only 10 patients was made possible by the unprecedented magnitude and uniformity of the treatment effect. In the context of a devastating disease with no other therapeutic options, the fact that every single patient responded rapidly, robustly, and durably on both a key biomarker and critical clinical outcomes provided a level of evidentiary certainty that transcended the inherent limitations of the trial design. This illustrates a key regulatory principle: for diseases with high unmet need, an exceptionally strong and consistent efficacy signal can be sufficient to support approval, even with a smaller-than-typical data package.

Furthermore, the success of pozelimab in CHAPLE disease serves as a powerful validation of a genetics-first approach to drug development. The therapeutic strategy followed a clear and compelling line of logic: a specific genetic defect (loss-of-function mutations in CD55) leads to a well-understood pathophysiology (uncontrolled terminal complement activation), which is then directly and precisely counteracted by the drug's mechanism of action (inhibition of C5). The 100% response rate in the clinical trial provides a resounding confirmation of this entire causal pathway. This success provides an invaluable roadmap and strong encouragement for the development of targeted therapies for other rare, genetically-defined diseases where the molecular basis of the pathology is clearly understood.

3.4 Safety and Tolerability in the CHAPLE Patient Population

In the pivotal trial for CHAPLE disease, pozelimab was generally well-tolerated. The most common adverse reactions, defined as those reported in two or more of the 10 patients, were upper respiratory tract infection, fracture, urticaria (hives), and alopecia (hair loss).[2]

Section 4: The Expanding Therapeutic Horizon: Investigational Programs

While the approval for CHAPLE disease established pozelimab as a vital therapeutic, it represents only the initial application of its potent mechanism. Regeneron is pursuing a broad clinical development program to evaluate pozelimab in a range of other complement-mediated diseases, often employing a strategic combination therapy to establish a best-in-class profile in more competitive therapeutic areas.

4.1 Paroxysmal Nocturnal Hemoglobinuria (PNH)

PNH is a rare, acquired blood disorder characterized by the chronic, complement-mediated destruction of red blood cells (intravascular hemolysis), leading to anemia, thrombosis, and end-organ damage.[16] Pozelimab has received

Orphan Drug designation from the U.S. FDA for the treatment of PNH.[1] The clinical development program in PNH is extensive:

• Phase 2: Several Phase 2 trials have been completed to evaluate the efficacy and safety of pozelimab, both as a monotherapy and in combination with cemdisiran, in patients with PNH, including those switching from existing complement inhibitors (e.g., NCT03946748, NCT04811716, NCT04888507).[28]
• Phase 3: A long-term Phase 3 study (R3918-PNH-2050 / EUCT: 2023-510336-36-00) is currently ongoing and actively recruiting patients in several European countries, including Spain, Hungary, Italy, and Poland, to further establish its long-term safety and efficacy profile.[29]

4.2 Age-Related Macular Degeneration and Geographic Atrophy (GA)

The complement cascade is strongly implicated in the pathogenesis of dry age-related macular degeneration (AMD), particularly its advanced form, Geographic Atrophy (GA), a leading cause of irreversible blindness.[30] Pozelimab is in late-stage development for this indication. A pivotal

Phase 3 trial (NCT06541704) is currently recruiting adult participants with GA to investigate subcutaneously administered pozelimab in combination with cemdisiran, or cemdisiran alone.[30] This program represents a significant expansion into a large-market indication.

4.3 Other Investigational Indications

The therapeutic potential of pozelimab is also being explored in other autoimmune disorders where complement activation plays a key pathogenic role:

• Myasthenia Gravis (MG): Pozelimab is under investigation for the treatment of generalized MG, a chronic autoimmune neuromuscular disease.[13]
• Healthy Volunteer Studies: Foundational Phase 1 trials have been completed in healthy adult volunteers, including in Japanese populations, to thoroughly characterize the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of pozelimab, both as a monotherapy and in combination with cemdisiran (NCT04601844, NCT04940364).[32]

4.4 The Dual-Inhibition Strategy: Combination Therapy with Cemdisiran

A cornerstone of Regeneron's development strategy, particularly for larger and more competitive indications like PNH and GA, is the combination of pozelimab with cemdisiran (DB16121).[20] Cemdisiran is an investigational small interfering RNA (siRNA) therapeutic developed in collaboration with Alnylam Pharmaceuticals.[34]

This combination employs a sophisticated dual-mechanism approach to C5 inhibition:

1. Pozelimab: Acts as a traditional inhibitor, binding to and neutralizing C5 protein already present in circulation.
2. Cemdisiran: Acts upstream at the genetic level. It is an N-acetylgalactosamine-conjugated siRNA designed to be taken up by hepatocytes, where it silences the messenger RNA (mRNA) that encodes for C5, thereby suppressing the liver's production of new C5 protein.[20]

The development of this combination therapy is a direct strategic response to the known clinical and commercial limitations of first- and second-generation C5 inhibitor monotherapies, such as eculizumab and ravulizumab. While effective, these earlier agents are administered intravenously and can be associated with breakthrough hemolysis if drug levels fall below a therapeutic threshold. The dual-mechanism approach of the pozelimab-cemdisiran combination is designed to provide a more profound, stable, and durable level of C5 suppression. By both reducing the production of C5 at its source and neutralizing what remains in circulation, the combination aims to achieve superior efficacy (fewer breakthrough events) and greater convenience (less frequent, subcutaneous self-administration).[33] Early clinical data support this rationale. In PNH patients switching from eculizumab, the combination was well-tolerated and provided sustained control of intravascular hemolysis.[20] Furthermore, data from an exploratory head-to-head Phase 3 cohort demonstrated that the combination achieved greater control of hemolysis, as measured by lactate dehydrogenase (LDH) levels, compared to the current standard-of-care C5 inhibitor, ravulizumab.[36]

The overall clinical development pipeline for pozelimab reveals a sophisticated "platform-in-a-product" strategy. Regeneron first proved the principle of C5 inhibition in an ideal setting: an ultra-rare, monogenic disease (CHAPLE) with a clear pathophysiology and no existing treatments, where the drug demonstrated absolute efficacy. This initial approval de-risked the mechanism and established its therapeutic value. The company is now leveraging this validated mechanism to execute a tiered expansion into a portfolio of diseases with progressively larger patient populations and market sizes: from ultra-rare (CHAPLE) to rare (PNH, MG) and finally to large-market indications (Geographic Atrophy). The enhanced pozelimab-cemdisiran combination serves as the key tool to unlock these more competitive, larger indications by offering a potentially best-in-class clinical profile. This phased, evidence-building approach represents a robust strategy for maximizing the value of the asset and transforming a single drug into a potential therapeutic franchise.

Section 5: Comprehensive Safety Profile and Risk Mitigation

The potent immunomodulatory activity of pozelimab necessitates a thorough understanding of its safety profile and the implementation of rigorous risk management strategies. The primary safety concern is a direct, on-target consequence of its mechanism of action, requiring a comprehensive and mandatory risk mitigation program.

5.1 Boxed Warning: Risk of Serious Meningococcal Infections

The U.S. prescribing information for Veopoz carries a Boxed Warning, the FDA's most stringent warning, regarding the risk of serious, life-threatening, and potentially fatal meningococcal infections caused by the encapsulated bacterium Neisseria meningitidis.[2] This risk is a well-established class effect for all terminal complement inhibitors. As detailed in Section 2, by blocking the formation of the Membrane Attack Complex (MAC), these drugs impair a critical component of the body's innate defense against encapsulated bacteria.[16] This increased susceptibility to infection may persist for several weeks after the final dose of the drug.[37]

5.2 Required Risk Evaluation and Mitigation Strategy (REMS): Vaccination and Prophylaxis

Due to the serious risk of meningococcal infection, the use of pozelimab is governed by a comprehensive risk management plan that includes mandatory vaccination, prophylaxis in certain situations, and extensive patient education.

• Meningococcal Vaccination: It is mandatory for patients to be vaccinated against meningococcal serogroups A, C, W, and Y (using a MenACWY vaccine) and against serogroup B (using a MenB vaccine) at least two weeks prior to receiving their first dose of pozelimab. This is in accordance with the current recommendations from the Advisory Committee on Immunization Practices (ACIP) for patients receiving a complement inhibitor.[3] Patients must remain up-to-date with these vaccinations throughout treatment. It is critical to note that vaccination reduces, but does not eliminate, the risk of infection.[38]
• Other Vaccinations: In addition to meningococcal vaccines, vaccination against other encapsulated bacteria, specifically Streptococcus pneumoniae and Haemophilus influenzae type b (Hib), is also recommended per ACIP guidelines.[22]
• Antibiotic Prophylaxis: In cases where urgent treatment with pozelimab is required and a patient has not completed their vaccinations at least two weeks prior, they should receive prophylactic antibacterial drugs.[26]
• Patient Education and Safety Card: Prescribers must counsel patients on the signs and symptoms of meningococcal infection, which include headache with a stiff neck or back, fever, rash, nausea or vomiting, confusion, and muscle aches with flu-like symptoms.[13] Patients must be provided with a Patient Safety Card that describes these symptoms and instructs them to seek immediate medical care if any develop. Patients are required to carry this card with them at all times during treatment and for several weeks after their last dose.[26]

This comprehensive REMS program effectively transforms the act of prescribing pozelimab from a simple medication order into a proceduralized therapeutic process. It necessitates careful coordination between prescribing specialists, primary care providers (who may administer vaccinations), and patients. This operational complexity places a significant burden of education, tracking, and responsibility on the entire healthcare team and is a critical factor in the real-world implementation, cost, and market access for the entire class of terminal complement inhibitors.

5.3 Contraindications, Warnings, and Precautions

Beyond the boxed warning, the prescribing information includes several other important safety considerations:

• Contraindication: Pozelimab is strictly contraindicated for use in patients with an unresolved Neisseria meningitidis infection.[24]
• Other Bacterial Infections: Patients are at an increased risk for other bacterial infections, particularly those caused by encapsulated bacteria such as Neisseria gonorrhoeae.[3] Treatment with pozelimab should be interrupted in any patient undergoing treatment for a serious infection until that infection is resolved.[38]
• Systemic Hypersensitivity Reactions: As with any biologic therapy, allergic reactions, including anaphylaxis, can occur. If a severe hypersensitivity reaction occurs during the intravenous infusion, the healthcare provider may need to slow the rate of infusion or stop the treatment entirely.[3]
• Immune Complex Formation: This is a potential risk associated with monoclonal antibody therapies, though its clinical incidence with pozelimab has not been fully characterized.[3]

5.4 Analysis of the Adverse Reaction Profile Across Clinical Trials

The adverse event profile of pozelimab reveals a clear distinction between predictable, on-target effects and other events whose causality is less certain. The risk of infections is a direct and unavoidable consequence of the drug's pharmacology. In contrast, the other commonly reported adverse reactions from the pivotal CHAPLE trial—upper respiratory tract infection, fracture, urticaria (hives), and alopecia (hair loss)—are not all obviously linked to the mechanism of C5 inhibition.[2] While upper respiratory infections are consistent with immune modulation and urticaria can be a sign of hypersensitivity, events like alopecia and fractures have no clear biological link to C5 blockade. In a very small trial of 10 pediatric patients, observing an event in two or more individuals (the threshold for being listed as a "common" reaction) can occur by chance. Therefore, while the infectious risk must be managed proactively through the universal REMS, these other events require careful post-marketing surveillance to determine if they are causally related to the drug, a feature of the underlying disease, or simply statistical anomalies from a small patient sample.

5.5 Special Populations: Pregnancy and Lactation

There is limited information on the use of pozelimab in special populations.

• Pregnancy: It is not known if Veopoz can cause harm to an unborn baby.[37]
• Lactation: No clinical data are available on the use of pozelimab during breastfeeding. However, based on its molecular properties, the risk to a breastfed infant is considered theoretically low. As a large protein molecule with a molecular weight of approximately 145 kDa, the amount that would be secreted into breast milk is likely to be very low. Furthermore, any ingested antibody would likely be denatured and destroyed by proteases in the infant's gastrointestinal tract, leading to minimal systemic absorption. As a precaution, it has been suggested that waiting at least two weeks postpartum before resuming therapy may further minimize any potential transfer to the infant.[39]

Section 6: Clinical Administration and Dosing Regimen

The effective and safe use of pozelimab requires adherence to a specific dosing and administration schedule designed to rapidly achieve and then maintain therapeutic levels of the drug.

6.1 Recommended Dosing: Intravenous Loading and Subcutaneous Maintenance

Pozelimab employs a standard two-phase dosing strategy common for monoclonal antibodies to ensure rapid onset and sustained activity.

• Loading Dose: Treatment is initiated on Day 1 with a single loading dose of 30 mg/kg, which must be administered as an intravenous (IV) infusion after dilution.[3] This higher initial dose is designed to quickly saturate the system and achieve therapeutic drug concentrations.
• Maintenance Dosage: Beginning one week later on Day 8, treatment transitions to a maintenance phase. The standard maintenance dosage is 10 mg/kg, administered as a subcutaneous (SC) injection once weekly.[3]

6.2 Preparation, Administration, and Dose Adjustment Guidelines

Pozelimab is supplied as a sterile, preservative-free, colorless to light yellow solution for injection in a single-dose vial containing 400 mg in 2 mL (200 mg/mL).[38] The drug must be prepared and administered by a qualified healthcare provider.[11]

The prescribing information includes provisions for dose adjustment to optimize treatment for individual patients.

• Dose Escalation: If a patient demonstrates an inadequate clinical response after at least three weekly maintenance doses (i.e., starting from Week 4), the weekly subcutaneous dosage may be increased to 12 mg/kg.[15] This built-in flexibility is a direct acknowledgment of potential inter-patient variability in pharmacokinetics or disease severity. It provides clinicians with a formal, on-label pathway to tailor therapy to individual patient needs, optimizing the balance between efficacy and drug exposure without resorting to off-label dosing.
• Maximum Dose: The maximum recommended maintenance dosage is 800 mg once weekly. If a patient's weight-based dose exceeds 400 mg, it must be administered as two separate subcutaneous injections.[15]

6.3 Drug-Drug Interaction Profile

The prescribing information for pozelimab identifies one clinically significant potential drug-drug interaction.

• Intravenous Immunoglobulin (IVIg): Concomitant administration of IVIg may decrease pozelimab concentrations.[37] The mechanism for this interaction is not fully elucidated but may relate to saturation of the neonatal Fc receptor (FcRn), which is responsible for recycling IgG antibodies and extending their half-life. The prescribing information recommends avoiding concomitant use if possible. If co-administration is unavoidable, patients should be closely monitored for any worsening of clinical signs and symptoms of their disease, which might indicate suboptimal pozelimab levels.[38] This interaction is particularly relevant, as patients with severe immune-mediated diseases like CHAPLE (who can have hypogammaglobulinemia) or Myasthenia Gravis are often treated with IVIg as part of their standard of care. This creates a real-world management challenge that requires clinical vigilance to ensure that a common supportive therapy does not inadvertently compromise the efficacy of the primary treatment.

Section 7: Regulatory and Development Trajectory

The journey of pozelimab from laboratory invention to approved medicine is a case study in modern drug development for rare diseases, characterized by an expedited regulatory pathway in the United States and a distinct strategic approach in other global markets.

7.1 U.S. FDA Approval Pathway: A Case Study in Expedited Review for Rare Disease

Pozelimab, marketed as Veopoz, was approved by the U.S. Food and Drug Administration (FDA) on August 18, 2023.[2] This approval was a significant milestone, as it established pozelimab as the

first and only FDA-approved treatment for CHAPLE disease.[2]

The development and review process for the CHAPLE indication was significantly accelerated by Regeneron's successful leveraging of multiple FDA programs designed to facilitate the development of drugs for serious conditions with high unmet medical need. The specific characteristics of CHAPLE disease—being a serious, life-threatening, rare condition that primarily affects children and had no approved therapies—made it an ideal candidate for these pathways. The full suite of designations granted by the FDA included:

• Orphan Drug Designation: For diseases affecting fewer than 200,000 people in the U.S..[1]
• Rare Pediatric Disease Designation: For serious or life-threatening diseases primarily affecting individuals aged 18 years or younger.[13]
• Fast Track Designation: To facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.[2]
• Priority Review: Which directs overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions.[2]

Upon receiving approval, Regeneron was also awarded a Rare Pediatric Disease Priority Review Voucher.[13] This voucher is a valuable incentive that can be used to obtain a priority review for a subsequent drug application that would not otherwise qualify, or it can be sold to another pharmaceutical company for a substantial sum.

7.2 Current Regulatory Status in the European Union and Other Regions

As of early 2024, pozelimab has not yet received marketing authorization from the European Medicines Agency (EMA). However, regulatory processes are underway. On December 1, 2023, the EMA's Paediatric Committee (PDCO) agreed to a Paediatric Investigation Plan (PIP) for pozelimab (EMEA-003238-PIP02-22).[41] A PIP is a mandatory development plan for new medicines to ensure that necessary data are obtained through studies in children to support their authorization for use in pediatric populations.

Notably, the agreed-upon indication for the pozelimab PIP in Europe is the treatment of Paroxysmal Nocturnal Haemoglobinuria (PNH), not CHAPLE disease.[41] This divergent regulatory starting point between the U.S. (CHAPLE) and the EU (PNH) likely reflects a calculated global commercialization strategy. The approach in the U.S. focused on securing a rapid, clean approval for an ultra-rare indication with an absolute efficacy signal and no competition, which also yielded the valuable Priority Review Voucher. With this initial approval secured, the company can now approach the more complex and competitive European market with PNH as the lead indication. PNH has a larger patient pool but also established competitors, requiring the more robust and differentiated data package from the pozelimab-cemdisiran combination trials to establish its value proposition. Active Phase 3 clinical trials for PNH are currently recruiting across multiple EU member states to generate this data.[29]

7.3 Originator and Development History

Pozelimab was invented, developed, and is manufactured by Regeneron Pharmaceuticals, Inc., a leading biotechnology company based in Tarrytown, New York.[3]

For the development of the combination therapy, Regeneron is collaborating with Alnylam Pharmaceuticals, the pioneering company in RNA interference (RNAi) therapeutics and the developer of cemdisiran.[10] This strategic collaboration, initiated in 2019, involved a significant financial commitment from Regeneron, including an $800 million upfront payment to Alnylam, to gain access to its RNAi technology for diseases of the eye and central nervous system, with the pozelimab-cemdisiran combination being a central component of the partnership.[34]

Section 8: Conclusions

Pozelimab (Veopoz) emerges as a highly engineered, first-in-class therapeutic that exemplifies the power of precision medicine in the treatment of complement-mediated diseases. As a fully human, stabilized IgG4P monoclonal antibody, its design reflects a sophisticated approach to maximizing efficacy and durability while minimizing immunogenicity. Its mechanism of action—a potent and sustained blockade of complement C5 cleavage—is validated by both preclinical data and profound pharmacodynamic effects observed in clinical trials.

The landmark approval of pozelimab for CHAPLE disease represents a triumph for patients with this ultra-rare and life-threatening condition. The unprecedented 100% efficacy rate observed in the pivotal trial, while based on a small patient cohort, provided an unequivocal signal of benefit that justified its expedited approval. This success serves as a powerful model for a genetics-first approach to drug development, demonstrating that a clear understanding of a monogenic disease's pathophysiology can lead to the creation of a direct and transformative therapeutic countermeasure.

Beyond this initial indication, the future of pozelimab lies in its broad and ambitious clinical development pipeline. The strategic combination with the siRNA therapeutic cemdisiran creates a dual-mechanism C5 blockade designed to establish a best-in-class clinical profile in larger, more competitive indications such as PNH, Myasthenia Gravis, and Geographic Atrophy. This tiered expansion strategy, from an ultra-rare "proof-of-concept" to major disease markets, highlights a sophisticated approach to asset lifecycle management.

The clinical use of pozelimab is defined by the inseparable link between its profound efficacy and its primary, on-target safety risk: an increased susceptibility to serious meningococcal infections. Consequently, a comprehensive and mandatory Risk Evaluation and Mitigation Strategy (REMS), centered on vaccination and patient education, is not an adjunct to treatment but a core, proceduralized component of its administration. This reality underscores the responsibilities inherent in wielding powerful immunomodulatory therapies.

In summary, pozelimab is more than a novel drug; it is a testament to the progress in bioengineering, a beacon of hope for patients with rare genetic disorders, and a strategic asset poised to compete across a spectrum of complement-mediated diseases. Its continued development and real-world application will be closely watched as a benchmark for targeted biologic therapy.

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