Evaluation of Synovial Biomarkers for Predicting Response to Ixekizumab in Refractory Psoriatic Arthritis Patients

The primary objective of this study is to evaluate whether modifications in **synovial biomarkers** in culture supernatants and cellular homogenates, following in vitro administration of **ixekizumab** (IXE) in assays of different cells or tissues obtained from patients with refractory **psoriatic arthritis** (PsA), can predict the clinical response to systemic IXE at 12 weeks. This is clinically relevant as it may provide insights into the potential of synovial biomarkers as predictive tools for treatment efficacy in PsA, thereby aiding in personalized treatment strategies.

Secondary objectives include:

• Evaluating if relevant biomarker modifications after in vitro administration of IXE relate to ultrasonography response at 12 weeks.
• Assessing if baseline histopathological data, based on Krenn’s score and specific cell markers evaluated using immunohistochemistry, relate to clinical response to systemic IXE at 12 weeks.
• Determining if synovial biomarker modifications after in vitro administration of IXE predict clinical response to systemic IXE at 24 weeks.
• Exploring the synovial effect of IXE in synovial explant cultures and fibroblast-like synoviocytes (FLS)/peripheral blood mononuclear cells (PBMCs) co-cultures.
• Establishing if a concentration-dependent effect of IXE could be responsible for relevant results obtained.
• Confirming the safety and reliability of ultrasound-guided synovial biopsy procedures in collecting adequate synovial tissue for FLS cultures.
• Establishing a reliable and reproducible method of co-culture system using PBMCs and FLS.

The clinical trial involves participants diagnosed with **psoriatic arthritis**, a condition characterized by joint inflammation and skin lesions. The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on specific criteria, including a confirmed diagnosis of psoriatic arthritis according to the Classification Criteria for Psoriatic Arthritis (CASPAR) and the presence of active disease, defined by three or more swollen and tender joints. Additionally, participants must have shown refractoriness to at least one conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy and be naïve to biologic or targeted synthetic DMARDs. The trial does not provide information on the total number of participants, as the sponsor has not disclosed this data. Lifestyle considerations include the allowance of oral prednisone at doses of 10 mg/day or less, provided it has been stable for at least four weeks, and the requirement for any concomitant csDMARDs to be stable for the same duration. Participants must also provide written informed consent to partake in the study.

The clinical trial is designed to evaluate the efficacy of **ixekizumab** in patients with refractory **psoriatic arthritis**. This is a Phase IV, randomized, double-blind, controlled study. The trial aims to identify synovial biomarkers that predict clinical response to ixekizumab at 12 weeks. The study is expected to commence on April 1, 2025, and conclude by April 1, 2027. Participants will be involved for a maximum treatment period of 4 months, with the primary endpoint being the ACR20 response at 12 weeks. Secondary endpoints include ultrasonographic responses and other clinical measures such as ACR50, ACR70, and DAPSA scores.

The trial will begin with a screening visit to confirm eligibility based on criteria such as a confirmed diagnosis of psoriatic arthritis, age of 18 years or older, and active disease. Participants must have a potential indication for biologic DMARD therapy with ixekizumab and be refractory to previous csDMARDs therapies. The inclusion visit will involve obtaining informed consent and ensuring stability of any concomitant medications. Following the inclusion visit, participants will receive subcutaneous injections of ixekizumab, with follow-up visits scheduled to monitor response and safety.

Study visits will occur at baseline, 12 weeks, and potentially at 24 weeks for secondary endpoint assessments. The end-of-study visit will evaluate the overall response to treatment and collect final data. Participants may be withdrawn from the study if they experience adverse events, fail to comply with the study protocol, or withdraw consent. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity.

The clinical trial involves the administration of **Taltz**, a pharmaceutical product containing the active substance **ixekizumab**. Taltz is formulated as a **solution for injection** in a pre-filled syringe, specifically designed for subcutaneous administration. Each syringe contains 80 mg of ixekizumab. The maximum daily dose is set at 160 mg, with a total maximum dose of 880 mg over the course of the treatment period. The treatment duration is limited to a maximum of four weeks. The administration schedule and dosage are determined based on the study protocol, ensuring adherence to the specified dosing regimen.

Ixekizumab, the active substance in Taltz, is a protein-based therapeutic agent classified under the ATC code L04AC13. It is not designated as an orphan drug and is not formulated for pediatric use. The substance is derived from a protein of other origins, and its administration is intended to evaluate synovial biomarker modifications in patients with refractory **psoriatic arthritis**. The study aims to predict clinical response to systemic ixekizumab at 12 weeks, following in vitro administration in assays of different cells and tissues obtained from the patients.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. Participant compliance with the dosing schedule is monitored according to the study protocol, ensuring accurate assessment of the treatment's efficacy and safety. The trial is conducted under the authorization of ELI LILLY AND COMPANY (IRELAND) LIMITED, with the product holding a marketing authorization number EU/1/15/1085/004.

Efficacy in this clinical trial will be assessed through a combination of clinical and laboratory endpoints. The primary clinical endpoint is the response to treatment at 12 weeks, measured by the **ACR20** response. Laboratory endpoints will evaluate the sensitivity, specificity, positive predictive values (PPV), negative predictive values (NPV), and accuracy of tests predicting treatment response at the same time point.

Secondary endpoints include patient-level ultrasonographic response using the multi-joint PsASon22 US score, with a 20% variation in the inflammatory subscore, and joint-level ultrasonographic response using the single-joint PsASon22 US score, both assessed at 12 weeks. Additional clinical endpoints such as **ACR50**, **ACR70**, **DAPSA**, **MDA**, **HAQ-DI** score, **PGA**, pain, **PhGA**, and the number of swollen/tender joints, as well as **BSA**, will be evaluated at 12 and 24 weeks.