Phase II Multicenter Study on Azacitidine Efficacy and Safety in VEXAS Syndrome Patients

The primary objective of this study is to evaluate the effectiveness of **Azacitidine** therapy in reducing the UBA1 Variant Allele Frequency (VAF) in patients with VEXAS Syndrome. This is clinically relevant as a reduction in UBA1 VAF may correlate with a decrease in disease activity and progression, potentially offering a therapeutic benefit for individuals affected by this condition.

Secondary objectives include:

• Determining the safety of Azacitidine by monitoring serious adverse events (SAEs), dose modifications, discontinuation rates, and the need for Granulocyte colony-stimulating factor (G-CSF) or prophylactic antibiotics, antifungals, or antivirals.
• Assessing the clinical efficacy of Azacitidine by evaluating dose modifications of systemic corticosteroids, anti-IL6R treatment, changes in symptoms, blood chemistry values, and the requirement for blood transfusions.
• Evaluating the potential of Azacitidine to improve patient-reported outcome measures (PROs), including health-related quality of life (HRQoL) and symptoms, using the EORTC QLQ-C30 questionnaire.
• Further assessing the molecular response rate and depth.
• In patients who respond to Azacitidine, assessing the duration of clinical response and frequency of relapse, as evaluated by a VEXAS expert council.
• Describing the mortality rate in responders and non-responders.
• Examining correlations between UBA1 VAF, changes in clinician-reported VEXAS organ involvement, and PROs.

The clinical trial focuses on evaluating the effectiveness of Azacitidine therapy in patients diagnosed with **VEXAS** syndrome. The study population includes both male and female participants, aged 18 years and older, who possess one of the currently described UBA1 mutations with a Variant Allele Frequency (VAF) greater than 10%. Participants must either present with any degree of cytopenia or exhibit inflammatory symptoms of VEXAS, with or without cytopenia. The trial does not involve a vulnerable population. Participants are required to have the cognitive capacity to provide informed consent. Male participants engaging in sexual activity with pre-menopausal women must use barrier contraceptives during and after treatment, while fertile female participants must adhere to strict contraceptive measures and undergo regular pregnancy testing. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **efficacy** and safety of **Azacitidine** in patients diagnosed with VEXAS syndrome. This is a single-arm, multicenter Phase II study, which will assess the primary endpoint of a 50% relative reduction in UBA1 Variant Allele Frequency (VAF) after six cycles of treatment. The trial is expected to commence recruitment on May 1, 2024, and conclude by November 1, 2033. Participants will receive Azacitidine administered via subcutaneous injection, with a maximum daily dose of 200 mg and a total dose not exceeding 10,000 mg over a treatment period of up to 10 cycles.

Study visits will follow a structured sequence, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as possessing a UBA1 mutation with a VAF greater than 10% and being at least 18 years old. Participants must also meet conditions related to cytopenia or inflammatory symptoms of VEXAS. Follow-up visits will be scheduled to monitor the treatment's impact and ensure participant safety. The end-of-study visit will evaluate the primary endpoint and gather final data on the treatment's efficacy and safety.

The expected duration of participant involvement is contingent upon the completion of six treatment cycles, with each cycle lasting approximately one month. Conditions that may lead to early termination from the study include adverse reactions to the treatment, withdrawal of consent, or failure to adhere to study protocols. The trial's design ensures rigorous monitoring and data collection to achieve its primary objective while maintaining participant safety and scientific integrity.

The clinical trial involves the administration of **Azacitidine**, a cytostatic agent, as the experimental medication. Azacitidine is provided in the form of a **powder for suspension for injection**. The active substance, azacitidine, is of chemical origin. The medication is administered via **subcutaneous injection**. The dosing regimen allows for a maximum daily dose of 200 mg, with a total maximum dose of 10,000 mg over the treatment period. The treatment duration is capped at 10 days. The trial aims to assess the efficacy and safety of Azacitidine in patients diagnosed with VEXAS Syndrome, specifically targeting the reduction of UBA1 Variant Allele Frequency (VAF).

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus remains solely on the administration of Azacitidine. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed as a single-arm, multicenter Phase II study, emphasizing the evaluation of Azacitidine's therapeutic potential in the specified patient population.

The efficacy of Azacitidine in treating VEXAS Syndrome will be assessed primarily by evaluating the reduction in **UBA1 Variant Allele Frequency (VAF)**. The primary endpoint is defined as the number and percentage of patients who achieve a 50% relative reduction in VAF after completing six cycles of Azacitidine treatment. This assessment will provide a quantitative measure of the drug's effectiveness in altering the genetic marker associated with the disease.