Evaluation of Efgartigimod PH20 SC Efficacy and Safety in Adult Systemic Sclerosis: A Randomized, Double-Blind, Placebo-Controlled Phase 2 Study

The primary objective of this study is to evaluate the **efficacy** of efgartigimod PH20 SC, a subcutaneous formulation coformulated with rHuPH20, compared with placebo on skin sclerosis in participants with **Systemic Sclerosis** (SSc). This is clinically relevant as skin sclerosis is a significant manifestation of SSc, impacting patient quality of life and disease progression.

Secondary objectives include:

• Evaluating the efficacy of efgartigimod PH20 SC compared with placebo on skin sclerosis in participants with SSc.
• Assessing the safety and tolerability of efgartigimod PH20 SC compared with placebo in participants with SSc.
• Evaluating the response to efgartigimod PH20 SC versus placebo based on the Revised Composite Response Index in Systemic Sclerosis (CRISS-25).
• Evaluating the impact of efgartigimod PH20 SC versus placebo on functioning and disability.
• Evaluating the participant’s and the physician’s assessment of the participant’s overall health.
• Evaluating the impact of efgartigimod PH20 SC versus placebo on lung function.
• Evaluating the pharmacokinetics (PK) of efgartigimod PH20 SC.
• Evaluating the pharmacodynamics of efgartigimod PH20 SC.
• Evaluating the immunogenicity of efgartigimod and rHuPH20.

The clinical trial involves a total of **80 participants** diagnosed with **Systemic Sclerosis** (SSc). The study population includes both male and female subjects, aged 18 years and older, who meet the local legal age of consent for clinical studies. Participants were selected based on specific criteria, including a confirmed diagnosis of diffuse or limited SSc according to the 2013 ACR/EULAR classification criteria, and a positive antinuclear antibodies (ANA) test result with a titer of at least 1:160. The trial does not include a vulnerable population. Participants are required to have a Health Assessment Questionnaire–Disability Index (HAQ-DI) score of at least 0.5 or a Patient Global Assessment (PGA) score of at least 3, and a modified Rodnan Skin Score (mRSS) between 15 and 35. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The selection process ensures that participants have either uninvolved or mildly thickened skin areas suitable for injection sites. The study aims to evaluate the efficacy of efgartigimod for subcutaneous administration coformulated with rHuPH20 compared with placebo on skin sclerosis in participants with SSc.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, Phase 2 study to evaluate the efficacy, safety, tolerability, pharmacodynamics, pharmacokinetics, and immunogenicity of efgartigimod PH20 SC in adult participants with **systemic sclerosis**. The trial will involve a parallel-group design, with participants randomly assigned to receive either the investigational product, efgartigimod PH20 SC, or a placebo. The study is expected to commence recruitment on March 1, 2025, and conclude by March 22, 2027, with a total duration of approximately 48 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, diagnosis of systemic sclerosis, and specific laboratory test results. Following successful screening, participants will be enrolled and randomized into the study. The primary endpoint will be assessed at week 24, focusing on the change from baseline in the modified Rodnan Skin Score (mRSS). Secondary endpoints will be evaluated at both weeks 24 and 48, including changes in mRSS, incidence and severity of adverse events, and other clinical assessments.

Study visits will include regular follow-up assessments to monitor safety and efficacy, with specific evaluations of laboratory parameters, electrocardiograms, and vital signs. Participants will also be assessed for the presence of antidrug antibodies and changes in serum concentrations of efgartigimod. The end-of-study visit will occur at week 48, marking the completion of the participant's involvement in the trial.

Participant involvement is expected to last for the full 48-week duration unless early termination is warranted. Conditions that may lead to early termination include the occurrence of serious adverse events, significant protocol deviations, or withdrawal of consent by the participant. The trial aims to provide comprehensive data on the potential benefits and risks of efgartigimod PH20 SC in the treatment of systemic sclerosis.

The clinical trial involves the administration of **Efgartigimod**, an experimental medication formulated as a **solution for injection in pre-filled syringe**. The active substance, **efgartigimod alfa**, is a protein-based therapeutic agent classified under the category "Protein - Other". The medication is administered via the **subcutaneous** route. The maximum daily dose is set at 1000 mg, with a total maximum dose of 47000 mg over a treatment period of 48 weeks. The dosing schedule is designed to ensure optimal efficacy and safety, with participant compliance being closely monitored throughout the trial. The product is identified by the sponsor product code ARGX-113 and is developed by ARGENX BV.

The study also includes a **placebo** treatment, referred to as **placebo PH20 SC**. This non-experimental treatment serves as a comparator to evaluate the efficacy of the experimental medication. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial. The placebo does not contain any active pharmaceutical ingredients and is used to ensure that any observed effects can be attributed to the experimental medication.

The efficacy of **efgartigimod** PH20 SC in the treatment of systemic sclerosis will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the modified Rodnan Skin Score (mRSS) at week 24. This score is a validated measure used to evaluate skin thickness, which is a key indicator of disease severity in systemic sclerosis.

Secondary endpoints include a variety of measures to provide a comprehensive assessment of efficacy. These include the change from baseline in mRSS at week 48, the incidence and severity of treatment-emergent adverse events, and clinically meaningful changes in laboratory parameters, electrocardiograms, and vital signs. Additionally, the proportion of participants who show improvement in at least two or three of the five core items of the CRISS-25 at weeks 24 and 48 will be evaluated, along with changes from baseline in the Health Assessment Questionnaire—Disability Index (HAQ-DI), Patient Global Assessment (PGA), and Clinician’s Global Assessment (CGA) at weeks 24 and 48.

Further assessments include the annualized rate of decline in forced vital capacity in participants with interstitial lung disease, efgartigimod serum concentrations over time, percent change from baseline in total IgG levels in serum, and the incidence and prevalence of antidrug antibodies against efgartigimod and antibodies against recombinant human hyaluronidase PH20 over time. These endpoints will be measured at specified time points throughout the trial to ensure a thorough evaluation of the treatment's efficacy.