Evaluation of Axatilimab (INCA034176) and Corticosteroids in Initial Treatment of Moderate to Severe Chronic Graft-Versus-Host Disease: A Phase 3 Randomized Study

The primary objective of this Phase 3, randomized, double-blind, placebo-controlled study is to compare the **efficacy** of axatilimab versus placebo in combination with corticosteroids as initial treatment for moderate or severe chronic graft-versus-host disease (cGVHD). This objective is clinically relevant as it aims to determine the potential of axatilimab to improve treatment outcomes in cGVHD, a condition that can significantly impact patient quality of life and survival.

Secondary objectives include evaluating the clinical benefit of axatilimab in combination with corticosteroids in participants with cGVHD. This assessment is crucial for understanding the broader therapeutic impact of axatilimab beyond its primary efficacy, potentially informing future treatment protocols and improving patient management strategies.

The clinical trial involves a total of **39 participants** diagnosed with **chronic graft-versus-host disease** (cGVHD). The study population includes both male and female subjects, aged **12 years and older**, with a history of allogeneic hematopoietic cell transplantation (allo-HCT) from any donor HLA type. Participants were selected based on their new-onset moderate or severe cGVHD, as defined by the 2014 NIH Consensus Development Project Criteria for Clinical Trials in cGVHD, requiring systemic therapy. The trial includes individuals with adequate hematologic function and a Karnofsky Performance Status (KPS) score of 60% or higher for those aged 16 and older, or a Lansky Play-Performance Scale (LPS) score of 60% or higher for those younger than 16. The study population is characterized by a willingness to adhere to pregnancy prevention measures, with male participants agreeing to avoid fathering children and female participants of childbearing potential required to have negative pregnancy tests and agree to effective contraception. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the treatment's efficacy across a diverse group of individuals.

The clinical trial is a **Phase 3**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy of **axatilimab** in combination with corticosteroids as an initial treatment for moderate or severe **chronic graft-versus-host disease** (cGVHD). The trial aims to compare the outcomes of axatilimab versus placebo when used alongside corticosteroids. The study is expected to commence recruitment on January 1, 2025, and conclude by March 31, 2030. Participants will be randomly assigned to receive either axatilimab or a placebo, both in combination with corticosteroids, with the treatment administered over a maximum period of 24 weeks.

Study visits are structured to ensure comprehensive monitoring and data collection. The initial visit, known as the inclusion or screening visit, will determine participant eligibility based on specific criteria, including age, ability to provide informed consent, and the presence of new-onset moderate or severe cGVHD. Following the screening, participants will undergo regular follow-up visits to assess treatment efficacy and safety. These visits will include evaluations of the primary endpoint, which is event-free survival (EFS), defined as the time from randomization to the first EFS event, such as the initiation of new systemic therapy for cGVHD or death. Secondary endpoints include overall response at six months and EFS2.

The expected duration of participant involvement in the trial is up to 24 weeks, with additional follow-up for safety assessments. Conditions that may lead to early termination from the study include the addition or initiation of new systemic therapy for cGVHD, treatment failure, or any adverse events that compromise participant safety. The trial is designed to ensure rigorous adherence to protocol, with all procedures conducted in accordance with ethical standards and regulatory requirements.

The clinical trial involves the administration of **Axatilimab (INCA034176)**, a protein-based investigational drug, formulated as a solution for infusion. Axatilimab is administered either intravenously (IV) or subcutaneously (SC) at a maximum dose of 0.3 mg/kg. The treatment period extends up to 24 weeks. Axatilimab is provided by INCYTE CORPORATION and is utilized as the test product in this study.

**Prednisone**, a corticosteroid, is used as a comparator in the trial. It is administered orally in tablet form. The maximum daily dose is 1 mg/kg, with a total treatment duration of 24 weeks. Prednisone is a chemically synthesized steroid, and its role in the trial is to serve as a standard-of-care therapy in combination with the investigational drug.

**Methylprednisolone**, another corticosteroid, is also employed as a comparator. It is available as a solution for injection or infusion and is administered intravenously. The maximum daily dose is 1.0 mg/kg, with a treatment period of up to 24 weeks. Like prednisone, methylprednisolone is chemically synthesized and serves as a standard-of-care therapy in the study.

A **placebo** is included in the trial as a control. It is not associated with any active pharmaceutical ingredient and is used to maintain the double-blind nature of the study. The placebo is administered in a manner consistent with the investigational drug to ensure blinding is maintained throughout the trial.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Event-Free Survival (EFS)**, defined as the time from the date of randomization to the date of the first EFS event. Events include the addition or initiation of new systemic therapy for chronic Graft-Versus-Host Disease (cGVHD), death due to any cause, or treatment failure (non-Complete Response (CR) or non-Partial Response (PR) by Month 6).

Secondary endpoints include Overall Response (OR) at 6 months, defined for each treatment group as CR or PR at 6 months in the absence of new systemic therapy for cGVHD. The response assessment will be based on the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in cGVHD, utilizing the refined NIH response algorithm for cGVHD disease in joints and fascia. Additionally, response is defined as the proportion of participants with a ≥ 7-point improvement in the modified Lee Symptom Scale (mLSS) total score. Another secondary endpoint is EFS2, which is defined similarly to EFS but includes progression based on the best prior organ status as an event.