A Phase 2, Multi-Center Study Consisting of a Randomized, Double-Blind, Placebo-Controlled Period, Followed by an Open-Label Extension Period, to Assess the Efficacy, Safety, and Tolerability of Tibulizumab in Adults with Systemic Sclerosis

This Phase 2 study evaluates tibulizumab in adults with systemic sclerosis. The primary objective in Period 1 is to assess the effect of tibulizumab on skin thickness in patients with systemic sclerosis. The primary objective in Period 2 is to evaluate the safety and tolerability of tibulizumab in patients with systemic sclerosis. Skin thickening represents a cardinal manifestation of systemic sclerosis and serves as a clinically relevant endpoint for assessing disease progression and therapeutic response.

The secondary objectives include:

• To assess the effect of tibulizumab on lung involvement in patients with systemic sclerosis-associated interstitial lung disease during Period 1 and Period 2

• To assess the effect of tibulizumab on lung function in patients with systemic sclerosis-interstitial lung disease during Period 1

• To assess the effect of tibulizumab on systemic sclerosis-related function and quality of life in patients with systemic sclerosis during Period 1

• To assess the safety and tolerability of tibulizumab when administered to patients with systemic sclerosis during Period 1

• To assess the effect of tibulizumab on skin thickness in patients with systemic sclerosis during Period 2

This clinical trial enrolled a total of **43 participants** diagnosed with **systemic sclerosis**. The study population included both **male and female subjects** aged **18 to 75 years**. Participants were required to have a **body mass index (BMI)** between 18.0 and 38.0 kg/m². Key selection criteria included fulfillment of the **ACR and EULAR 2013 classification criteria** for systemic sclerosis, presence of **diffuse cutaneous systemic sclerosis**, and disease duration of 7 years or less from the first non-Raynaud's phenomenon symptom. Participants were required to have a **modified Rodnan Skin Score (mRSS)** between 15 and 45 at screening. Regarding pulmonary function, participants needed to demonstrate **forced vital capacity (FVC)** greater than 50% predicted and **diffusing capacity of the lungs for carbon monoxide (DLCO)** of at least 40% predicted when corrected for hemoglobin. The trial population was categorized as patients and included vulnerable populations. All participants were required to agree to specific contraception requirements as defined in the clinical protocol.

This is a Phase 2, multi-center clinical trial designed to evaluate the efficacy, safety, and tolerability of **tibulizumab** in adults with **systemic sclerosis**. The study follows a two-period design: Period 1 consists of a **randomized**, **double-blind**, **placebo-controlled** phase, followed by Period 2, which is an **open-label extension** period. The investigational medicinal product, tibulizumab, is a biological product of protein origin administered as a **solution for injection** via **subcutaneous injection**, with a maximum treatment period of 48 weeks. The placebo comparator is also included in the study design. The trial is classified as a Category 2 intervention trial in accordance with Regulation EU No 536/2014.

The primary objective of Period 1 is to assess the effect of tibulizumab on skin thickness in patients with systemic sclerosis, while Period 2 aims to assess the safety and tolerability of tibulizumab in this patient population. The **primary endpoint** for Period 1 is the change from baseline at Week 24 in **modified Rodnan Skin Score** (mRSS). For Period 2, the primary endpoint includes the incidence of all **treatment-emergent adverse events** and changes from baseline in vital signs, **electrocardiogram** parameters, and clinical laboratory results. Secondary endpoints encompass changes from baseline at Week 24 in quantitative **interstitial lung disease** obtained with high-resolution quantitative tomography in the whole lung, changes in **forced vital capacity** (mL), and changes in the **Health Assessment Questionnaire Disability Index** during Period 1. Period 2 secondary endpoints include the change from baseline at Week 52 in modified Rodnan Skin Score.

Eligible participants must be adults aged 18 to 75 years with a **body mass index** between 18.0 and 38.0 kg/m², who fulfill the classification of systemic sclerosis according to ACR and EULAR 2013 criteria. Participants must have **diffuse cutaneous** systemic sclerosis with disease duration of 7 years or less from the first non-Raynaud's phenomenon symptom or sign attributed to systemic sclerosis. At screening, participants must have a modified Rodnan Skin Score between 15 and 45, **forced vital capacity** greater than 50% predicted at screening and Day 1, and **diffusing capacity of the lungs for carbon monoxide** of 40% or greater predicted (corrected for hemoglobin) at screening. All participants must provide signed and witnessed written informed consent, understand the protocol requirements, and agree to adhere to the contraception requirements defined in the clinical protocol.

The study involves a structured sequence of visits beginning with a screening visit to assess eligibility criteria. Following enrollment, participants will undergo baseline assessments and randomization. Study visits are scheduled at regular intervals throughout the 24-week double-blind period (Period 1), with key assessments occurring at Week 24. Participants who complete Period 1 may continue into the open-label extension (Period 2), with follow-up visits extending to Week 52. The end-of-study visit marks the completion of participant involvement. The estimated recruitment start date is January 2, 2026, with an estimated study end date of May 7, 2027. Participant involvement is expected to last up to 52 weeks for those completing both study periods. Conditions that may lead to early termination from the study include withdrawal of consent, protocol violations, adverse events requiring discontinuation, or investigator decision based on safety or efficacy concerns.

The experimental medicinal product in this clinical trial is **Tibulizumab**, a biological agent of protein origin. Tibulizumab is formulated as a **solution for injection** and is administered via **subcutaneous injection**. The active substance is tibulizumab, and the product is manufactured by ZURA BIO INC. The maximum treatment period for tibulizumab administration is 48 weeks. The study is designed to assess the efficacy, safety, and tolerability of tibulizumab in adults with **systemic sclerosis**.

The comparator treatment used in the randomized, double-blind, placebo-controlled period of the study is **Tibulizumab Placebo**. The placebo is matched to the experimental product to maintain blinding during the controlled phase of the trial. Following the placebo-controlled period, the study includes an open-label extension period during which all participants receive the active investigational product.

Efficacy will be assessed through multiple parameters measured during two distinct study periods. During Period 1, the primary efficacy endpoint is the change from baseline at Week 24 in modified Rodnan Skin Score (mRSS), which evaluates skin thickness in patients with systemic sclerosis. Secondary efficacy endpoints for Period 1 include the change from baseline at Week 24 in quantitative interstitial lung disease obtained with high-resolution quantitative tomography in the whole lung, the change from baseline at Week 24 in forced vital capacity measured in milliliters, and the change from baseline at Week 24 in Health Assessment Questionnaire Disability Index. During Period 2, efficacy assessment focuses on the change from baseline at Week 52 in modified Rodnan Skin Score (mRSS). Additionally, both periods will evaluate the change from baseline at Week 24 in quantitative interstitial lung disease obtained with high-resolution quantitative tomography in the whole lung. Safety parameters, including the incidence of all treatment-emergent adverse events and changes from baseline in vital signs, electrocardiogram parameters, and clinical laboratory results, will be monitored throughout both study periods.