Efficacy and Safety Evaluation of HZN-1116 in Moderate-to-Severe Sjögren’s Syndrome: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this Phase 2 study is to evaluate the effect of **HZN-1116** on systemic manifestations of **Sjӧgren’s Syndrome** (SS) in participants with moderate-to-severe systemic disease activity, as well as on patient-reported symptoms in participants with an unsatisfactory symptom state. This is clinically relevant as it aims to address both the systemic and symptomatic burden of SS, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• For Population #1: Evaluating the effect of HZN-1116 on measures of systemic activity and patient-reported outcomes (PRO) in participants with SS.
• For Population #2: Assessing the effect of HZN-1116 on patient-reported symptoms of SS and PROs in participants with SS.
• For both Populations #1 and #2: Characterizing the pharmacokinetics (PK) of HZN-1116 and assessing the immunogenicity of multiple doses of HZN-1116 in participants with SS.

The clinical trial involves a total of **161 participants** diagnosed with **Sjögren’s Syndrome**, focusing on those with moderate-to-severe systemic disease activity and those with unsatisfactory symptom states. The study population includes adults aged **18 to 75 years**, encompassing both male and female participants. Participants were selected based on their ability to provide informed consent and meeting the 2016 ACR/EULAR Classification Criteria for Sjögren’s Syndrome. The trial includes individuals with positive anti-Ro autoantibodies or rheumatoid factor, and those with residual salivary or lacrimal gland function. Participants are required to be fully vaccinated against SARS-CoV-2 according to local guidelines. Lifestyle considerations such as the use of contraception for females of childbearing potential and nonsterilized males are mandated. The trial does not specifically exclude any vulnerable populations, ensuring a comprehensive evaluation of the treatment's effects across a diverse group of individuals.

The clinical trial is a **Phase 2**, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of HZN-1116 in participants with **Sjögren’s Syndrome**. The trial aims to assess the effect of HZN-1116 on systemic manifestations and patient-reported symptoms in two distinct populations: those with moderate-to-severe systemic disease activity and those with unsatisfactory symptom states. The study is expected to commence recruitment on January 1, 2025, and conclude by July 30, 2027, with a maximum treatment period of 48 weeks for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and specific disease activity scores. Following successful screening, participants will be randomized to receive either HZN-1116 or a placebo, administered as a **solution for injection** via subcutaneous use. The trial will include regular follow-up visits to monitor safety, efficacy, and any adverse events. These visits will also involve assessments of primary and secondary endpoints, such as changes in the European Alliance of Associations for Rheumatology Sjögren’s Syndrome Disease Activity Index (ESSDAI) and Patient Reported Index (ESSPRI).

The end-of-study visit will mark the completion of the participant's involvement, during which final assessments will be conducted. Participants are expected to remain in the study for the entire duration unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial will ensure that all participants provide informed consent and adhere to contraceptive guidelines if applicable. The study's design and procedures are structured to maintain scientific rigor and ensure the collection of reliable data on the investigational product's safety and efficacy.

The clinical trial involves the administration of **HZN-1116**, a **solution for injection** developed by Horizon Therapeutics Ireland DAC. The active substance in HZN-1116 is **VIB1116**, classified as a protein of other origin. The pharmaceutical form of HZN-1116 is a solution intended for **subcutaneous use**. The maximum daily dose is 300 mg, with a total maximum dose of 3600 mg over a treatment period of up to 48 weeks. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

In addition to the experimental treatment, a **commercially available 0.9% (w/v) saline solution** is used as a placebo. This saline solution is also intended for **subcutaneous administration**. The use of a placebo is integral to maintaining the double-blind nature of the study, allowing for an unbiased evaluation of the efficacy and safety of HZN-1116 in participants with Sjögren’s Syndrome. The saline solution serves as a control to compare against the effects observed with the active treatment.

The efficacy of HZN-1116 in the treatment of **Sjögren’s Syndrome** will be assessed through a series of primary and secondary endpoints. For Population #1, the primary endpoint is the change from baseline in the European Alliance of Associations for Rheumatology Sjögren’s Syndrome Disease Activity Index (ESSDAI) at specified time points. For Population #2, the primary endpoint is the change from baseline in the European Alliance of Associations for Rheumatology Sjögren’s Syndrome Patient Reported Index (ESSPRI) at specified time points.

Secondary endpoints for Population #1 include the change from baseline in ESSDAI, the proportion of participants achieving an ESSDAI[5] response, and changes in ESSPRI and Diary for Assessing Sjögren’s Patient Reported Index (DASPRI) domains such as pain, fatigue, and dryness. Additionally, changes in tender joint count (TJC), swollen joint count (SJC), and scores from the 36-item Short Form Survey (SF-36) and PROMIS-Fatigue SF-10a will be evaluated. For Population #2, secondary endpoints include changes in DASPRI, the proportion of participants achieving an ESSPRI[1.5] response, and changes in SF-36 and PROMIS-Fatigue SF-10a scores.

Both populations will be assessed for pharmacokinetics (PK) of HZN-1116 and the development of anti-drug antibodies (ADA) over time. These efficacy parameters will be measured and collected at various time points throughout the trial, ensuring a comprehensive evaluation of the treatment's impact on the systemic manifestations and patient-reported symptoms of Sjögren’s Syndrome.