Comparative Efficacy, Safety, and Immunogenicity of Intravenous AVT16 Versus Vedolizumab in Adults with Moderate to Severe Active Ulcerative Colitis

The primary objective of this study is to demonstrate the equivalent **efficacy** of AVT16, a proposed biosimilar to Entyvio, in subjects with moderate to severe active **ulcerative colitis**. Establishing biosimilarity is clinically relevant as it may provide an alternative therapeutic option with potentially reduced costs, thereby increasing accessibility for patients requiring treatment for this chronic inflammatory bowel disease.

Secondary objectives include:

• Comparing the efficacy of AVT16 with Entyvio.
• Assessing the safety profile of AVT16 in comparison to Entyvio.
• Evaluating the immunogenicity of AVT16 relative to Entyvio.
• Comparing the pharmacokinetics (PK) of AVT16 with Entyvio.

The clinical trial involves a total of **370 participants** diagnosed with **Moderate to Severe Active Ulcerative Colitis**. The study population includes both male and female subjects, aged between 18 to 80 years. Participants were selected based on their ability to provide informed consent and their diagnosis of ulcerative colitis, with a focus on those with moderate to severe activity of the disease. The trial includes individuals who may be considered part of a vulnerable population. Participants' general health status allows for the inclusion of those who have demonstrated an inadequate response, loss of response, or intolerance to certain therapeutic agents over the past five years. Lifestyle considerations such as diet and physical activity are not specified, but participants may be receiving treatments like oral 5-aminosalicylic acid compounds, oral corticosteroid therapy, probiotics, antidiarrheals, azathioprine, or 6-mercaptopurine. The selection criteria ensure a diverse representation of individuals affected by the condition, while maintaining a focus on safety and efficacy in the context of the trial's objectives.

The clinical trial is designed to evaluate the **efficacy**, safety, and immunogenicity of AVT16, a proposed biosimilar to Entyvio, in subjects with moderate to severe active **ulcerative colitis**. This is a randomized, double-blind, controlled study involving two parallel groups. Participants will be randomly assigned to receive either AVT16 or Entyvio, both administered as a solution for infusion. The trial is expected to last approximately 46 weeks, with the estimated recruitment start date in August 2024 and an estimated end date in June 2026.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific inclusion criteria, such as age, diagnosis of ulcerative colitis, and previous treatment history. Following successful screening, participants will be enrolled and randomized into one of the two treatment arms. Study visits will occur at regular intervals, including key assessments at Weeks 6, 14, 22, 30, 38, 46, and 52. These visits will involve clinical evaluations, laboratory tests, and monitoring for adverse events. The primary endpoint is the clinical response at Week 6, with secondary endpoints including clinical remission and mucosal healing at various time points, as well as safety assessments.

The expected length of participant involvement is approximately 52 weeks, including follow-up. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or non-compliance with study procedures. Participants will conclude their involvement with an end-of-study visit, where final assessments will be conducted to ensure participant safety and collect final data for analysis. The trial aims to provide robust data on the comparative efficacy and safety of AVT16 and Entyvio in the treatment of moderate to severe active ulcerative colitis.

The clinical trial involves the administration of **Vedolizumab**, a **solution for infusion** provided by ALVOTECH SWISS AG. This investigational medicinal product is administered via **intravenous infusion**. The dosage is set at a maximum of 300 mg per administration, with a total treatment period not exceeding 46 weeks. Vedolizumab is a protein-based therapeutic agent, specifically classified under the ATC code L04AA33. The administration schedule and participant compliance are monitored to ensure adherence to the protocol.

The comparator treatment in this study is **Entyvio 300 mg powder for concentrate for solution for infusion**, manufactured by TAKEDA PHARMA A/S. This product is also administered as a **solution for infusion** through **intravenous infusion**. The maximum dosage is 300 mg, consistent with the investigational product, and the treatment duration is similarly capped at 46 weeks. Entyvio has been repackaged and relabelled for blinding purposes to maintain the integrity of the double-blind study design. The active substance in Entyvio is also **Vedolizumab**, ensuring a direct comparison between the investigational product and the marketed comparator.

An auxiliary treatment used in the trial is **Isotonische Kochsalzlösung Fresenius**, a **solution for infusion** containing **sodium chloride**. This product, provided by FRESENIUS KABI DEUTSCHLAND GMBH, serves as a diluent for both the investigational medicinal product and the comparator. It is administered intravenously, with a maximum daily dose of 250 ml. The sodium chloride solution is relabelled for central distribution, ensuring consistency and compliance with trial protocols. The use of this auxiliary treatment is essential for the preparation and administration of the primary and comparator treatments.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the **Clinical Response** at Week 6, which is defined by a reduction in the complete Mayo Clinic score in the rectal bleeding subscore or an absolute rectal bleeding subscore at Week 6. Secondary endpoints include Clinical Response at Weeks 14, 22, 30, 38, and 46, as well as Clinical Remission at Week 6 and Week 52. Additional secondary endpoints involve mucosal healing at Week 6 and Week 52, glucocorticoid-free remission at Week 52, and albumin and CRP levels at Baseline, Week 6, and Week 52.

Data collection will occur at specified timepoints throughout the trial, including Weeks 0, 2, 6, 14, 22, 30, 38, 46, and 52. The trial will also monitor the incidence, nature, and severity of adverse events (AEs), graded according to the current version of the CTCAE. Clinical laboratory assessments will include hematology, clinical biochemistry, coagulation, inflammatory markers such as the erythrocyte sedimentation rate, urinalysis, and urine microscopy. Vital signs, ECG, physical examination findings, infusion drug-related reactions, and injection site reactions will also be evaluated. Additionally, the titer and frequency of anti-drug antibodies (ADA), frequency of neutralizing antibodies (NAb), and serum trough concentration of AVT16 and Entyvio will be measured at the specified timepoints.