AVT-80: An Investigational Biosimilar to Vedolizumab for Inflammatory Bowel Disease

I. Executive Summary

AVT-80 is an investigational monoclonal antibody currently under development by Alvotech Swiss AG.[1] It is engineered as a biosimilar to the approved biologic drug vedolizumab, which is marketed under the brand name Entyvio®. The development program for AVT-80 is strategically positioned within the growing landscape of biosimilar therapies, aiming to offer a comparable alternative for the treatment of inflammatory bowel diseases (IBD).

Currently, AVT-80 is advancing through Phase I clinical development.[3] The cornerstone of this phase is a clinical trial (NCT06732804) meticulously designed to establish pharmacokinetic (PK) similarity, as well as comparable safety and immunogenicity, between AVT-80 and its reference product, vedolizumab. This initial human study is being conducted in healthy volunteers.

The mechanism of action of AVT-80 is expected to mirror that of vedolizumab. This involves the specific targeting of the α4β7 integrin, a protein predominantly found on the surface of gut-homing T helper lymphocytes.[5] By binding to α4β7 integrin, AVT-80 is anticipated to inhibit its interaction with Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1) on endothelial cells within the gastrointestinal tract. This blockade is designed to prevent the migration of pathogenic lymphocytes into the gut tissue, thereby exerting a gut-selective anti-inflammatory effect.[7]

The potential therapeutic indications for AVT-80 will align with those for which vedolizumab has established efficacy and regulatory approval, primarily moderate to severe Crohn's disease (CD) and ulcerative colitis (UC).[5] The development of AVT-80 is significant as it holds the potential to increase patient access to effective biologic therapies for IBD. By introducing a biosimilar competitor, AVT-80 could contribute to a more cost-effective treatment landscape, benefiting both patients and healthcare systems. The successful progression of AVT-80 through the rigorous clinical and regulatory pathway is contingent upon demonstrating a high degree of similarity to vedolizumab with no clinically meaningful differences. This development is indicative of a broader pharmaceutical industry trend focusing on biosimilars to enhance the accessibility and affordability of treatments for complex chronic conditions. Should AVT-80 successfully navigate its clinical trials and gain regulatory approval, it could notably influence the market dynamics for IBD therapies, fostering competition and potentially expanding therapeutic options for patients.

II. Introduction to AVT-80 and the Landscape of Vedolizumab Biosimilars

A. AVT-80: An Investigational Biosimilar

AVT-80 is an investigational biological product being developed by Alvotech Swiss AG, a company specializing in the development and manufacture of biosimilar medicines.[1] It is specifically designed as a biosimilar candidate to the reference product vedolizumab, marketed globally as Entyvio®.[5] Alternative designations for this investigational drug include AVT 80 or AVT80, which are consistent with Alvotech's internal product coding system.[4] Pharmaceutical companies commonly employ such alphanumeric codes for their investigational compounds during development. Alvotech's broader pipeline reveals a series of "AVTxx" designations for its various biosimilar candidates, such as AVT02 (adalimumab biosimilar) and AVT04 (ustekinumab biosimilar).[10] The use of AVT80 (or AVT16, another code noted in some Alvotech pipeline documentation for a vedolizumab biosimilar [10], possibly representing an earlier or alternative internal identifier) fits this established pattern, signifying its formal inclusion within their strategic development program.

The term "biosimilar" denotes a biological product that is highly similar to an already approved original biologic (the "reference product") and has been shown to have no clinically meaningful differences in terms of safety, purity, and potency (i.e., efficacy) from the reference product. The development of a biosimilar like AVT-80 is a complex and resource-intensive endeavor. It requires substantial investment to meticulously demonstrate this high degree of similarity through a comprehensive series of analytical studies, non-clinical evaluations, and comparative clinical trials. This rigorous pathway is mandated by regulatory authorities such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to ensure that biosimilars meet the same high standards of quality, safety, and efficacy as their reference products.[11] The ongoing Phase I clinical trial for AVT-80, NCT06732804, represents the initial clinical stage in this demanding process, with a primary focus on comparing its pharmacokinetic profile, safety, and immunogenicity against vedolizumab in human subjects.[3]

B. The Reference Product: Vedolizumab (Entyvio®) - A Foundation for Understanding AVT-80

A thorough understanding of AVT-80 necessitates a foundational knowledge of its reference product, vedolizumab (Entyvio®). Vedolizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that has transformed the treatment landscape for certain inflammatory bowel diseases.[6]

Mechanism of Action: The therapeutic effect of vedolizumab is derived from its highly specific mechanism of action. It selectively binds to the α4β7 integrin, a heterodimeric protein preferentially expressed on the surface of a subset of T helper lymphocytes known as gut-homing lymphocytes.[6] This α4β7 integrin plays a crucial role in mediating the trafficking of these lymphocytes to the gastrointestinal (GI) tract by interacting with its ligand, the Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1). MAdCAM-1 is primarily expressed on the endothelial cells of post-capillary venules within the gut and gut-associated lymphoid tissue.[5] By binding to α4β7 integrin, vedolizumab effectively blocks its interaction with MAdCAM-1.[14] This blockade inhibits the adhesion and subsequent migration of these pathogenic T lymphocytes across the vascular endothelium and into the inflamed parenchymal tissue of the GI tract. Consequently, vedolizumab reduces the accumulation of these inflammatory cells in the gut, leading to a decrease in gastrointestinal inflammation. A key characteristic of vedolizumab is its gut-selectivity; it does not bind to α4β1 or αEβ7 integrins, nor does it significantly interfere with systemic immune surveillance mechanisms, particularly those within the central nervous system (CNS). This distinguishes it from broader integrin inhibitors, such as natalizumab, which targets α4β1 integrin (also binding VCAM-1) and has been associated with an increased risk of progressive multifocal leukoencephalopathy (PML).[6] This gut-selective mechanism is a paramount feature that AVT-80 must accurately emulate to achieve biosimilarity and replicate the favorable safety profile of vedolizumab.

Approved Indications: Vedolizumab is approved by major regulatory agencies worldwide, including the FDA and EMA, for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) and Crohn's disease (CD).[13] It is typically indicated for patients who have demonstrated an inadequate response to, have lost response to, or were intolerant to conventional therapies (such as corticosteroids or immunomodulators) or a tumor necrosis factor-alpha (TNF-α) antagonist.[6] In some jurisdictions, vedolizumab is also approved for the treatment of chronic pouchitis, an inflammatory condition that can occur after proctocolectomy with ileal pouch-anal anastomosis in patients with UC.[12]

Administration: Vedolizumab is available in formulations for both intravenous (IV) infusion and subcutaneous (SC) injection.[12] The IV formulation is typically used for induction therapy and can also be used for maintenance, while the SC formulation is approved for maintenance therapy, offering patients a more convenient administration option.[12] AVT-80 is being investigated as a subcutaneous injection from its initial Phase I trial.[5]

Efficacy and Safety Overview: Clinical trials have demonstrated the efficacy of vedolizumab in inducing and maintaining clinical remission and mucosal healing in patients with both UC and CD.[11] Its safety profile is generally considered favorable. Common adverse events include nasopharyngitis, headache, and arthralgia.[13] Infusion-related reactions (for IV administration) or injection-site reactions (for SC administration) can occur. While infections are a potential risk with any immunomodulatory therapy, vedolizumab's gut-selective action appears to mitigate the risk of systemic opportunistic infections. Critically, and in stark contrast to natalizumab, no confirmed cases of PML have been reported in association with vedolizumab treatment to date, which is a significant safety advantage.[18] The established efficacy and safety profile of vedolizumab sets a high benchmark for AVT-80. Regulatory approval for AVT-80 will be contingent upon a comprehensive demonstration of "no clinically meaningful differences" from vedolizumab, encompassing all aspects of its performance and safety.

Table 1: Comparative Overview of AVT-80 and Vedolizumab (Entyvio®)

Attribute	AVT-80	Vedolizumab (Entyvio®)
Developer/Originator	Alvotech Swiss AG 1	Takeda Pharmaceuticals (Originator)
Drug Class	Monoclonal Antibody, Integrin Antagonist 5	Monoclonal Antibody, Integrin Antagonist 6
Target	α4β7 integrin 5	α4β7 integrin 6
Mechanism of Action	Inhibition of α4β7 integrin binding to MAdCAM-1, reducing gut inflammation (Expected) 5	Inhibition of α4β7 integrin binding to MAdCAM-1, reducing gut inflammation 6
Potential/Approved Indications	Crohn's disease, Ulcerative colitis (Investigational) 5	Crohn's disease, Ulcerative colitis, Pouchitis (Approved) 6
Administration Route	Subcutaneous (Investigational) 4	Intravenous, Subcutaneous (Approved) 12
Development/Approval Status	Phase I Clinical Trial (Recruiting) 3	Approved (FDA, EMA, and other regulatory authorities) 12

This table serves to provide a succinct, side-by-side comparison, clearly positioning AVT-80 as a biosimilar candidate to vedolizumab by highlighting shared fundamental characteristics such as target and mechanism of action, while contrasting their current developmental or approval status and originators. This comparative view is essential for understanding the context and objectives of AVT-80's development program.

III. Clinical Development Program of AVT-80

A. Rationale for Development

The primary impetus behind the development of AVT-80 is to introduce a biosimilar version of vedolizumab to the market. This strategic objective aims to broaden therapeutic options for patients suffering from inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, and to potentially alleviate the economic burden associated with biologic therapies.[5] Vedolizumab has proven its efficacy and established α4β7 integrin inhibition as a valuable and distinct therapeutic strategy in IBD management. However, biologic medicines are often associated with high treatment costs, which can limit access for some patients and strain healthcare budgets.

Biosimilars, such as AVT-80, are intended to foster competition within the pharmaceutical market upon the expiration of patents and other market exclusivities held by the originator biologic. This competition typically leads to price reductions, thereby enhancing the affordability and accessibility of these important treatments.[11] Alvotech's decision to invest in the development of AVT-80 reflects a strategic evaluation of the significant clinical need for vedolizumab, the commercial opportunity presented by its market size, and the societal benefit of providing a potentially more cost-effective alternative. This aligns with Alvotech's broader corporate strategy, which is heavily focused on the development of a diverse portfolio of biosimilar candidates across various therapeutic areas.[10]

B. Phase I Clinical Trial: AVT80-GL-P01 (NCT06732804)

The initial and critical step in the clinical development of AVT-80 is the Phase I study, designated AVT80-GL-P01 and registered under the clinical trial identifier NCT06732804.[1] This study is pivotal for establishing the foundational data required for further development and potential regulatory submission.

• Study Title and Identifier: The official title of the study is "A Randomised, Parallel Group Treatment, Double-blind, 3-arm Study to Investigate the Comparative PK, Safety, Immunogenicity, and Tolerability Between AVT80 and Entyvio® in Healthy Male and Female Participants Aged 18 to 55 Years Inclusive" (NCT06732804).[1]
• Sponsor: The trial is sponsored by Alvotech Swiss AG.[1]
• Phase: This is a Phase I clinical trial.[1]
• Study Objectives: The primary objective is to compare the pharmacokinetic (PK) profiles of AVT-80 with those of Entyvio® sourced from different geographical regions.[3] Secondary objectives are comprehensive and include the evaluation and comparison of the safety, tolerability, and immunogenicity of AVT-80 relative to Entyvio®.[3] The study will specifically measure the concentration of AVT-80 in the blood over various time points to derive key PK parameters and assess its effects on certain immune system cells and proteins, which may form part of the immunogenicity assessment.[5]
• Design and Methodology: The study employs a robust randomized, parallel-group, double-blind, 3-arm design.[1] The double-blind nature, where neither the participants nor the investigators are aware of the specific treatment assigned to each participant, is crucial for minimizing potential bias in the assessment of outcomes, particularly for safety and tolerability endpoints.[8] The selection of healthy volunteers for this initial Phase I biosimilar trial is a standard and scientifically sound approach. It allows for a clear and direct comparison of PK profiles and an initial assessment of safety and tolerability without the confounding variables often present in patient populations, such as active disease, concomitant medications, or heterogeneous disease states. This homogeneity in the study population enhances the ability to detect any true differences in PK between the biosimilar and the reference product.
• Participant Population: The trial is enrolling healthy male and female volunteers between the ages of 18 and 55 years, inclusive.[1] Specific eligibility criteria include a body weight ranging from 50.0 kg to 90.0 kg and a Body Mass Index (BMI) between 17.0 kg/m² and 32.0 kg/m².[1] Key exclusion criteria are designed to ensure participant safety and data integrity, and include a history of relevant drug or food allergies, known hypersensitivity to vedolizumab, AVT-80, or their constituents, and any past or concurrent medical conditions that could increase participant risk or interfere with study evaluations, such as demyelinating disorders.[1]
• Intervention Arms: Participants are randomized to one of three treatment arms, each receiving a single dose of the investigational product:

1. AVT-80
2. Entyvio® (sourced from the USA, e.g., US-Entyvio®)
3. Entyvio® (sourced from Australia, e.g., AU-Entyvio®, or another major regulatory region).[1] This 3-arm design, comparing AVT-80 against Entyvio® sourced from two distinct major markets, is a strategically important element for global biosimilar development. Reference biologic products can occasionally exhibit minor, approved variations in their manufacturing processes or sourcing across different geographical regions. Regulatory authorities in key markets (such as the FDA in the US, EMA in Europe, and TGA in Australia) may require or prefer comparability data generated against the reference product that is marketed and sourced locally. By demonstrating similarity to Entyvio® from multiple regions, Alvotech aims to build a comprehensive data package that can support regulatory submissions across a broader range of international markets, potentially streamlining the global approval process and facilitating wider market access for AVT-80.

• Route of Administration: The investigational medicinal products are administered via subcutaneous (SC) injection.[4] Specifically, AVT-80 is delivered as an injection under the skin of the upper arm.[5] The decision to investigate a subcutaneous formulation of AVT-80 from the outset of Phase I clinical development aligns with a significant trend in the biopharmaceutical market towards more convenient, patient-centric administration options for chronic therapies. Subcutaneous formulations, which can often be self-administered by patients at home, offer greater flexibility and reduce the burden on healthcare systems and patients associated with intravenous infusions that require clinic visits. This approach mirrors the evolution of Entyvio® itself, for which a subcutaneous formulation has gained regulatory approval for maintenance therapy [16], positioning AVT-80 to compete effectively with all available formulations of its reference product.
• Current Status and Timelines: As of February 2025, the AVT80-GL-P01 trial was actively recruiting participants.[1] The target enrollment for the study is 351 participants.[9] Timelines for study completion can vary, but some sources estimate the primary completion date around October 2025 [4], while others suggest an overall study completion date around April 2025.[1] Given the complexities of clinical trial execution, it is reasonable to anticipate primary completion by late 2025.

Table 2: Summary of Phase I Clinical Trial NCT06732804 (AVT80-GL-P01)

Parameter	Details
Trial Identifier	NCT06732804 1
Trial Title	A Randomised, Parallel Group Treatment, Double-blind, 3-arm Study to Investigate the Comparative PK, Safety, Immunogenicity, and Tolerability Between AVT80 and Entyvio® in Healthy Male and Female Participants Aged 18 to 55 Years Inclusive 1
Phase	Phase I 3
Status	Recruiting (as of February 2025) 3
Sponsor	Alvotech Swiss AG 1
Primary Objectives	Compare the pharmacokinetics (PK) of AVT-80 and Entyvio® 3
Secondary Objectives	Evaluate and compare safety, tolerability, and immunogenicity 3
Study Design	Randomized, parallel-group, double-blind, 3-arm 1
Population	Healthy male and female volunteers, 18-55 years, with specific BMI (17.0-32.0 kg/m²) and body weight (50.0-90.0 kg) criteria 1
Interventions	Single subcutaneous dose of AVT-80 vs. Entyvio® (US-sourced) vs. Entyvio® (AU-sourced or other designated region) 1
Key Endpoints	PK parameters (e.g., AUC, Cmax, T1/2​), incidence and severity of adverse events, formation of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs).
Target Enrollment	351 participants 9
Estimated Primary Completion	Approximately October 2025 4 (Study completion timelines may vary, with some sources indicating April 2025 1)

This table consolidates the critical parameters of the AVT80-GL-P01 trial, offering a structured overview of its design, objectives, and operational details. Understanding this initial human study is fundamental, as its outcomes will significantly shape the subsequent development strategy and regulatory interactions for AVT-80.

IV. Pharmacology of AVT-80 (Anticipated and Investigational)

A. Expected Mechanism of Action (based on biosimilarity to vedolizumab)

As a biosimilar candidate to vedolizumab, AVT-80 is fundamentally designed to replicate the therapeutic mechanism of its reference product. Therefore, AVT-80 is expected to function as a humanized monoclonal antibody that specifically targets the α4β7 integrin.[5] This integrin is a key adhesion molecule expressed predominantly on the surface of gut-homing T lymphocytes, which are implicated in the pathogenesis of inflammatory bowel diseases.

The anticipated mechanism involves AVT-80 binding with high affinity and specificity to the α4β7 integrin. This binding is expected to sterically hinder or otherwise block the interaction between the α4β7 integrin on these lymphocytes and its cognate ligand, MAdCAM-1, which is expressed on endothelial cells lining the blood vessels within the gastrointestinal tract.[6] By preventing this crucial cell-cell adhesion step, AVT-80 is designed to inhibit the transendothelial migration of these pathogenic lymphocytes from the bloodstream into the inflamed tissues of the gut. This reduction in lymphocyte infiltration into the lamina propria and epithelium of the GI tract is expected to lead to a decrease in local inflammatory processes, ultimately ameliorating the signs and symptoms of UC and CD.[7]

A critical aspect of this mechanism, which AVT-80 must faithfully replicate, is its gut-selectivity. Vedolizumab's specificity for the α4β7/MAdCAM-1 pathway, which is primarily operative in the GI tract, means it does not significantly interfere with lymphocyte trafficking to other organs, such as the brain (mediated by α4β1/VCAM-1 interactions). This selectivity is believed to contribute to vedolizumab's favorable safety profile, particularly the absence of PML risk.[6] The successful demonstration that AVT-80 possesses an indistinguishable binding affinity for α4β7, exhibits comparable functional activity in inhibiting α4β7-MAdCAM-1 mediated cell adhesion, and maintains this gut-selectivity is paramount. These characteristics are rigorously assessed during pre-clinical analytical and functional comparability studies, which form the bedrock for advancing to clinical trials.

B. Pharmacokinetics (Focus of current comparative studies)

The pharmacokinetic (PK) properties of AVT-80 are a central focus of its current clinical development program, particularly within the Phase I trial, AVT80-GL-P01.[3] A primary objective of this study is to meticulously compare the PK profile of AVT-80 with that of its reference product, Entyvio®, following subcutaneous administration in healthy volunteers.[3]

This comparative PK assessment involves the collection of serial blood samples from participants at predefined time points after a single subcutaneous dose of either AVT-80 or Entyvio®. These samples are then analyzed to determine the concentration of the drug in the bloodstream over time. From these concentration-time data, key PK parameters are calculated and compared between the AVT-80 and Entyvio® groups. These parameters typically include:

• Cmax (Maximum Plasma Concentration): The peak concentration of the drug achieved in the plasma.
• AUC (Area Under the Plasma Concentration-Time Curve): Represents the total exposure to the drug over time. This can be measured from time zero to the last quantifiable concentration (AUC0−t​) or extrapolated to infinity (AUC0−inf​).
• Tmax​ (Time to Maximum Plasma Concentration): The time taken to reach Cmax after administration.
• t1/2​ (Elimination Half-Life): The time required for the plasma concentration of the drug to decrease by half.

Demonstrating PK equivalence is a cornerstone of biosimilar development and approval. Regulatory agencies establish predefined equivalence margins (typically 80% to 125% for the 90% confidence intervals of the ratio of geometric means for Cmax and AUC) within which the biosimilar's PK parameters must fall relative to the reference product. Achieving this PK equivalence is a critical milestone, as it suggests that the biosimilar is absorbed, distributed, metabolized, and eliminated in a manner comparable to the reference product. This, in turn, supports the extrapolation of efficacy and safety data from the reference product to the biosimilar, assuming high analytical and functional similarity have also been established. The positive outcome of these PK bridging studies in the AVT80-GL-P01 trial would therefore represent a significant step forward for the AVT-80 development program.

C. Immunogenicity (A critical aspect for biosimilar evaluation)

The evaluation of immunogenicity, defined as the propensity of a therapeutic protein to elicit an immune response in the recipient, is a critical component in the development and regulatory assessment of all biologic drugs, including biosimilars like AVT-80.[3] The Phase I trial, AVT80-GL-P01, includes specific objectives to compare the immunogenicity profile of AVT-80 with that of Entyvio®.[3]

This assessment involves monitoring participants for the development of anti-drug antibodies (ADAs) against AVT-80 or Entyvio®. If ADAs are detected, further characterization is typically performed to determine their titers, persistence, and, importantly, their neutralizing capacity (i.e., whether they are neutralizing antibodies, NAbs, that can inhibit the biological activity of the drug). The study protocol details that the effect of AVT-80 on specific immune system cells and proteins will be measured, which could encompass assays for ADA detection and characterization.[5]

Even minor differences in the manufacturing process, formulation, or impurities between a biosimilar and its reference product can potentially lead to alterations in the immunogenic profile. Differences in immunogenicity could have significant clinical consequences, potentially affecting the drug's safety (e.g., hypersensitivity reactions, infusion/injection-site reactions, or other immune-mediated adverse events) or efficacy (e.g., by altering PK through enhanced clearance or by neutralizing the drug's therapeutic effect). Therefore, regulatory authorities mandate robust comparative immunogenicity studies. The FDA's historical scrutiny regarding the sensitivity and drug tolerance of the immunogenicity assays used for the originator vedolizumab [15] underscores the technical complexities and the high bar for demonstrating comparable immunogenicity. Alvotech will need to employ validated, sensitive, and drug-tolerant assays to reliably compare the immunogenicity of AVT-80 and Entyvio®. Demonstrating a similar immunogenicity profile to Entyvio® is essential for the successful development and approval of AVT-80.

V. Safety and Tolerability Profile (Emerging and Anticipated)

A. Expected Safety Profile (based on vedolizumab)

As AVT-80 is being developed as a biosimilar to vedolizumab, its safety and tolerability profile is anticipated to be highly similar to that of its reference product, Entyvio®. The extensive clinical experience and post-marketing surveillance of vedolizumab provide a well-characterized safety database that serves as a benchmark for AVT-80.

Common adverse events (AEs) reported with vedolizumab treatment include nasopharyngitis (common cold), headache, arthralgia (joint pain), nausea, pyrexia (fever), fatigue, cough, and various infections such as sinusitis, bronchitis, and upper respiratory tract infections.[13] For subcutaneously administered formulations, injection-site reactions (e.g., pain, erythema, swelling at the injection site) may occur, analogous to infusion-related reactions observed with intravenous administration.

Serious adverse events with vedolizumab are generally infrequent. While infections are a monitored risk, clinical trial data have not shown a significantly increased risk of serious infections overall compared to placebo.[19] A crucial aspect of vedolizumab's safety profile, and a key differentiator from some other integrin antagonists like natalizumab, is the absence of reported cases of progressive multifocal leukoencephalopathy (PML).[12] This favorable CNS safety profile is attributed to its gut-selective mechanism of action, which AVT-80 aims to replicate. The incidence of malignancies in patients treated with vedolizumab has been reported to be consistent with that observed in the broader IBD patient population.[18]

The Phase I clinical trial for AVT-80 (AVT80-GL-P01) is designed to meticulously monitor and record all AEs, allowing for a direct comparison of the safety and tolerability of AVT-80 with Entyvio® in healthy volunteers.[1] While major deviations in safety are not anticipated if biosimilarity is established, even subtle differences in the frequency or nature of AEs could emerge and would require careful evaluation. The gut-selective mechanism of vedolizumab is fundamental to its favorable risk-benefit balance, and any indication that AVT-80 deviates from this selectivity would be a significant concern. The initial safety data from healthy volunteers in Phase I will provide a preliminary assessment; however, more comprehensive safety data will be gathered if AVT-80 progresses to studies in patient populations.

B. Monitoring in Clinical Trials

The AVT80-GL-P01 study incorporates comprehensive safety monitoring protocols to protect participants and gather robust data.[5] This includes the systematic collection and assessment of all adverse events, regardless of severity or perceived relationship to the study drug. Regular physical examinations, vital sign measurements, and laboratory safety tests (e.g., hematology, clinical chemistry, urinalysis) are conducted at specified intervals throughout the study.

Prior to enrollment and administration of the investigational product, participants undergo rigorous screening. This includes tests for recreational drug use and screening for specific infections such as Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and Tuberculosis (TB).[5] Such screening is a standard and critical safety measure in clinical trials involving immunomodulatory agents like vedolizumab (and by extension, AVT-80). Administering a drug that affects the immune system to individuals with active or certain latent infections (e.g., TB) could lead to severe complications, such as reactivation of the infection.[12] Therefore, these pre-treatment screenings are essential to ensure a suitable and safe study population and to minimize risks. All changes in participants' health status are carefully documented and monitored by the clinical trial investigators.[5]

Table 3: Known Clinically Significant Adverse Events and Drug Interactions of Vedolizumab (Entyvio®) (Anticipated for AVT-80)

Category	Details
Common Adverse Events (Reported in ≥5% of Vedolizumab-treated patients)	Nasopharyngitis, Headache, Arthralgia, Nausea, Pyrexia, Upper respiratory tract infection, Fatigue, Cough, Bronchitis, Influenza, Sinusitis, Back pain, Rash, Pruritus, Pain in extremities.13
Serious Adverse Events (Vedolizumab)	- Serious infections (overall risk not significantly increased versus placebo in pivotal trials 19). <br> - Hypersensitivity reactions and infusion-related reactions (or injection-site reactions for SC formulation).13 <br> - Progressive Multifocal Leukoencephalopathy (PML): No cases reported with vedolizumab.12 <br> - Malignancies (incidence rates consistent with the IBD patient population).18
Key Drug Interactions (Vedolizumab)	- Live Vaccines: Concurrent use should be avoided. Patients should be brought up to date with all immunizations per current immunization guidelines prior to initiating vedolizumab. If live vaccines are administered, it should be if benefits outweigh risks. There are no data on secondary transmission of infection by live vaccines in patients receiving vedolizumab.20 <br> - Natalizumab: Concomitant use is contraindicated or strongly advised against due to the potential for increased risk of PML and other serious infections.21 <br> - TNF-blockers: Concomitant use is generally avoided due to a potential increased risk of infections.20 <br> - Other Immunosuppressants (e.g., ifosfamide, lomustine, ozanimod, ponesimod): Use with caution due to the potential for additive immunosuppressive effects and an increased risk of infections.21
Contraindications (Vedolizumab)	Active severe infections, such as tuberculosis (TB).12

This table provides a summary of the established safety profile and interaction considerations for vedolizumab. Given that AVT-80 is developed as a biosimilar, this information is crucial for anticipating its safety characteristics and for guiding monitoring during its clinical development and potential post-marketing use. It underscores important safety advantages, such as the absence of PML risk, and highlights necessary precautions, particularly concerning concomitant medications and vaccinations. This forms a baseline against which the emerging safety data for AVT-80 will be compared and interpreted.

VI. Regulatory Considerations and Future Outlook

A. The Pathway for Biosimilar Approval

The development and approval of AVT-80 as a biosimilar to vedolizumab are governed by stringent regulatory pathways established by health authorities such as the FDA in the United States and the EMA in Europe.[11] These pathways, while potentially abbreviated compared to those for entirely novel biologics, demand a comprehensive demonstration of biosimilarity. This involves a stepwise approach that begins with extensive analytical characterization. Sophisticated laboratory techniques are used to compare the structural and functional attributes of AVT-80 with those of Entyvio® at a molecular level. This includes assessing protein structure, post-translational modifications, purity, and biological activity (e.g., binding to α4β7 integrin and inhibition of MAdCAM-1 interaction).

Following successful analytical similarity, preclinical studies are conducted to compare pharmacodynamics and toxicology. If these foundational stages demonstrate a high degree of similarity, the biosimilar candidate progresses to comparative clinical studies. The current Phase I trial for AVT-80 (AVT80-GL-P01) is a critical part of this clinical comparison, focusing on pharmacokinetics, safety, and immunogenicity in healthy volunteers.[1] The overarching goal of this entire exercise is to provide a "totality of evidence" demonstrating that AVT-80 is "highly similar" to Entyvio® and that there are "no clinically meaningful differences" between the two products in terms of safety, purity, and potency (efficacy).

Depending on the robustness of the data from these earlier stages, regulatory agencies may sometimes waive the requirement for large-scale comparative Phase III efficacy and safety trials in patients. However, this is determined on a case-by-case basis, and often at least one confirmatory efficacy and safety study in a relevant patient population (e.g., patients with UC or CD) is required. The regulatory burden for biosimilars, therefore, remains substantial, necessitating meticulous planning and execution of all comparative studies. The 3-arm design of the AVT80-GL-P01 trial, comparing AVT-80 against Entyvio® sourced from two different major markets [1], indicates Alvotech's proactive approach to generating data suitable for stringent reviews by multiple international regulatory bodies.

B. Potential Impact of AVT-80 on Treatment Landscape

The successful development and subsequent regulatory approval of AVT-80 have the potential to significantly impact the treatment landscape for inflammatory bowel diseases. As a biosimilar to vedolizumab, AVT-80 would introduce direct competition into a market segment currently dominated by the originator product, Entyvio®. Historically, the entry of biosimilars into the market has led to a reduction in the price of biologic therapies. This price competition can improve the affordability of treatment, thereby increasing patient access to these highly effective medicines. For healthcare systems, the availability of lower-cost biosimilars can lead to substantial cost savings, allowing for the reallocation of resources to other areas of patient care or the treatment of a larger number of patients within existing budgets.

Furthermore, the development of AVT-80 with a subcutaneous formulation from an early stage [4] is a strategic move that could enhance its competitiveness. Subcutaneous administration offers greater convenience for patients compared to intravenous infusions, allowing for self-administration at home and reducing the need for frequent clinic visits. This aligns with patient preferences and the broader trend towards more patient-friendly treatment regimens for chronic conditions. The introduction of AVT-80 and potentially other vedolizumab biosimilars may also stimulate further innovation, not only in drug development but also in patient support programs and value-added services offered by both originator and biosimilar manufacturers as they compete for market share and strive to meet patient needs comprehensively.

C. Anticipated Next Steps in Development

Upon the completion of the ongoing Phase I trial (AVT80-GL-P01), Alvotech will undertake a detailed analysis of the pharmacokinetic, safety, and immunogenicity data. The outcomes of this study are critical: if the results demonstrate that AVT-80 meets the predefined criteria for PK similarity to Entyvio® and exhibits a comparable safety and immunogenicity profile, this will represent a major positive milestone for the program.

Following positive Phase I results, the typical next steps in a biosimilar development program involve engaging with regulatory agencies (such as the FDA and EMA) to discuss the existing data and to agree on the requirements for the subsequent phases of development. Depending on these discussions and the strength of the "totality of evidence" gathered from analytical, preclinical, and Phase I studies, Alvotech may proceed to a Phase III comparative clinical trial. Such a trial would be designed to confirm similar efficacy and safety between AVT-80 and Entyvio® in a relevant patient population (i.e., adults with moderately to severely active UC or CD). In some instances, if the degree of similarity demonstrated in earlier stages is exceptionally high and well-justified, regulatory agencies might consider waiving the need for a dedicated Phase III efficacy trial.

The drug development process is inherently associated with risk. A probability of success (PoS) of 23% has been noted for AVT-80 at its current Phase I stage, based on general industry data for assets at this phase.[4] This figure underscores the early stage of development and the challenges that lie ahead. However, successful completion of the Phase I study with positive PK bridging data would significantly de-risk the AVT-80 program and likely lead to an upward revision of its PoS for subsequent development phases and eventual regulatory approval.

VII. Conclusion

AVT-80 is an investigational monoclonal antibody being developed by Alvotech Swiss AG as a biosimilar to the established biologic therapy, vedolizumab (Entyvio®). It is currently progressing through Phase I clinical trials, with the AVT80-GL-P01 study (NCT06732804) actively recruiting healthy volunteers to meticulously compare its pharmacokinetic profile, safety, and immunogenicity against Entyvio® sourced from multiple major markets.[1]

The anticipated mechanism of action for AVT-80 is identical to that of vedolizumab: the gut-selective antagonism of the α4β7 integrin. This targeted approach is designed to inhibit the migration of pathogenic lymphocytes into gastrointestinal tissue, thereby reducing inflammation in conditions such as Crohn's disease and ulcerative colitis, which are the primary therapeutic targets for AVT-80.[5] The commitment to developing a subcutaneous formulation from an early clinical phase suggests a focus on patient convenience and market competitiveness.[4]

The journey of AVT-80 from concept to potential market availability exemplifies the complex, multi-stage, and scientifically rigorous process required to develop and gain approval for a biosimilar medicine. This process emphasizes comprehensive analytical comparability, robust preclinical assessment, and meticulously designed comparative clinical trials to satisfy the stringent requirements of global regulatory authorities. The ultimate value and success of AVT-80 will be determined not only by its demonstrated similarity to Entyvio® in terms of quality, safety, and efficacy but also by factors such as manufacturing consistency and reliability, the confidence of prescribing physicians, and acceptance by payers within an increasingly competitive IBD therapeutic landscape.

The successful development and approval of AVT-80 hold the promise of providing a valuable and potentially more affordable therapeutic alternative for patients with inflammatory bowel diseases. The outcomes of the ongoing Phase I study and any subsequent clinical trials will be critical in defining AVT-80's path towards potential regulatory approval and its eventual role in clinical practice. If successful, AVT-80 could contribute significantly to enhancing patient access to effective biologic treatments and fostering a more sustainable healthcare environment for the management of these chronic and debilitating conditions.

Works cited

1. Study to Investigate Comparative Pharmacokinetics, Safety, Immunogenicity and Tolerability Between AVT80 and Entyvio | Clinical Research Trial Listing ( Healthy Male and Female Subjects ) ( NCT06732804 ) - TrialX, accessed May 14, 2025, https://www.trialx.com/clinical-trials/listings/297245/study-to-investigate-comparative-pharmacokinetics-safety-immunogenicity-and-tolerability-between-avt80-and-entyvio/
2. Alvotech hf - Drug pipelines, Patents, Clinical trials - Patsnap Synapse, accessed May 14, 2025, https://synapse.patsnap.com/organization/2bd14d8f2f5b9b377c933388ce210dee
3. A Randomised, Parallel Group Treatment, Double-blind, 3-arm ..., accessed May 14, 2025, https://adisinsight.springer.com/trials/700378896
4. AVT-80 Drug Profile - Ozmosi, accessed May 14, 2025, https://pryzm.ozmosi.com/product/33740
5. www.nzcr.co.nz, accessed May 14, 2025, https://www.nzcr.co.nz/wp-content/uploads/2025/02/AVT80-GL-P01-NZCR-PISCF_v1.1_17Jan2025_clean_CTMS-1.pdf
6. Efficacy and safety of vedolizumab in the treatment of ulcerative colitis | Gastroenterología y Hepatología (English Edition) - Elsevier, accessed May 14, 2025, https://www.elsevier.es/es-revista-gastroenterologia-hepatologia-english-edition--382-articulo-efficacy-safety-vedolizumab-in-treatment-S2444382416301298
7. Researchers Are a Step Closer to Understanding How a Highly Successful IBD Drug Works - Mount Sinai, accessed May 14, 2025, https://reports.mountsinai.org/article/gastro2025-vedolizumab-study
8. Study to Investigate Comparative Pharmacokinetics - ClinConnect, accessed May 14, 2025, https://clinconnect.io/trials/NCT06732804
9. vedolizumab biosimilar (AVT-80) / Alvotech - Larvol Delta, accessed May 14, 2025, https://delta.larvol.com/Products/?ProductId=4ba8a96b-281b-41d5-ab19-67eb39dbeb28
10. Pipeline - Alvotech - Better Access Better Lives, accessed May 14, 2025, https://www.alvotech.com/pipeline
11. Are there any biosimilars available for Vedolizumab? - Patsnap Synapse, accessed May 14, 2025, https://synapse.patsnap.com/article/are-there-any-biosimilars-available-for-vedolizumab
12. entyvio-epar-product-information_en.pdf - EMA, accessed May 14, 2025, https://www.ema.europa.eu/en/documents/product-information/entyvio-epar-product-information_en.pdf
13. Vedolizumab - ECCO E-Guide, accessed May 14, 2025, https://www.e-guide.ecco-ibd.eu/interventions-therapeutic/vedolizumab
14. Top 7 Breakthrough Drugs for Ulcerative Colitis Treatment - DelveInsight, accessed May 14, 2025, https://www.delveinsight.com/blog/emerging-drugs-for-ulcerative-colitis-treatment
15. 125476Orig1s000 | FDA, accessed May 14, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/125476Orig1s000ODMemo.pdf
16. FDA Approves Subcutaneous Administration of ENTYVIO - Takeda Pharmaceuticals, accessed May 14, 2025, https://www.takeda.com/newsroom/newsreleases/2024/fda-approves-subcutaneous-administration-of-entyvio/
17. Entyvio | European Medicines Agency (EMA), accessed May 14, 2025, https://www.ema.europa.eu/en/medicines/human/EPAR/entyvio
18. The safety of vedolizumab for ulcerative colitis and Crohn's disease | Gut, accessed May 14, 2025, https://gut.bmj.com/content/66/5/839
19. The safety of vedolizumab for ulcerative colitis and Crohn's disease - PubMed, accessed May 14, 2025, https://pubmed.ncbi.nlm.nih.gov/26893500/
20. Entyvio (Vedolizumab): Uses & Side Effects - Cleveland Clinic, accessed May 14, 2025, https://my.clevelandclinic.org/health/drugs/18357-vedolizumab-injection
21. Entyvio, Entyvio Pen (vedolizumab) dosing, indications, interactions, adverse effects, and more - Medscape, accessed May 14, 2025, https://reference.medscape.com/drug/entyvio-vedolizumab-999901