Phase 2 Open-Label Study on the Efficacy and Safety of Rilzabrutinib in Adult Patients with Graves' Disease

The primary objective of this open-label Phase 2 study is to explore the treatment effect of **rilzabrutinib** in reducing thyroid activity in adult participants with **Graves' disease**. This is clinically relevant as Graves' disease is an autoimmune disorder that leads to hyperthyroidism, and effective management of thyroid activity is crucial for improving patient outcomes.

Secondary objectives include:

• Exploring the treatment effect of rilzabrutinib in reducing thyroid activity in participants with Graves' disease.
• Evaluating the safety of rilzabrutinib.

The clinical trial involves a total of **20 participants** diagnosed with **Graves' disease**, an **immune system disease** characterized by active hyperthyroidism. The study population includes both male and female subjects, with an age range spanning from 18 to 64 years. Participants were selected based on a confirmed diagnosis of Graves' disease, with or without active Graves' orbitopathy, as determined by an ophthalmic exam and a clinical activity score of 3 or higher for the most severely affected eye. The trial also considers lifestyle factors such as contraceptive use, which must align with local regulations for clinical study participants. The study includes a vulnerable population, ensuring comprehensive representation within the trial. Participants' general health status is consistent with the presence of active hyperthyroidism, and the trial does not specify any particular dietary or physical activity requirements.

The clinical trial is designed to evaluate the **efficacy** and safety of **rilzabrutinib** in adult participants diagnosed with **Graves' disease**, an immune system disorder. This open-label, Phase 2 study aims to explore the treatment effect of rilzabrutinib in reducing thyroid activity. The trial will involve a randomized, controlled design, ensuring that participants are assigned to treatment groups in a manner that minimizes bias. The study is expected to commence recruitment on July 16, 2025, and conclude by August 13, 2026, with a maximum treatment period of 16 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 a confirmed diagnosis of Graves' disease with active hyperthyroidism. A subset of participants will also be assessed for active Graves' orbitopathy. The screening will include an ophthalmic exam and a clinical activity score evaluation. Following the screening, participants will attend regular follow-up visits to monitor the percent change from baseline in FT4 and FT3 levels, as well as the proportion of participants achieving normal limits for these thyroid function tests. The incidence of treatment-emergent adverse events, serious adverse events, and withdrawals due to adverse events will also be recorded throughout the study period.

The expected length of participant involvement is up to 16 weeks, with conditions for early termination including the occurrence of significant adverse events or withdrawal of consent. The study will ensure that contraceptive use by participants aligns with local regulations. The primary endpoint is the percent change from baseline in FT4 levels, while secondary endpoints include changes in FT3 levels and the incidence of adverse events. The trial will be conducted in compliance with regulatory standards to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **Rilzabrutinib**, an investigational medication, to evaluate its efficacy and safety in adult participants with **Graves' disease**. The experimental medication is provided in two pharmaceutical forms: a **film-coated tablet** and a **tablet**. The film-coated tablet is manufactured by Sanofi Aventis Recherche et Développement (SAR) and is identified by the sponsor product code SAR444671. The maximum daily dose for this formulation is 1200 mg, with a total maximum dose of 268800 mg over a treatment period of 16 weeks. The route of administration is oral, and the active substance is a synthetic mixture.

The second formulation, a tablet, is produced by Principia Biopharma, Inc. and is identified by the sponsor product code PRN1008. This formulation has a maximum daily dose of 800 mg and a total maximum dose of 89600 mg over the same 16-week treatment period. The route of administration is also oral, and the active substance is a synthetic chemical. Both formulations of Rilzabrutinib are not pediatric formulations and are not classified as orphan drugs.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to explore the treatment effect of Rilzabrutinib in reducing thyroid activity in participants with Graves' disease.

The efficacy of **rilzabrutinib** in the treatment of Graves' disease will be assessed through a series of primary and secondary endpoints. The primary endpoint is the percent change from baseline in free thyroxine (FT4) levels. Secondary endpoints include the percent change from baseline in free triiodothyronine (FT3) levels, the proportion of participants with FT4 and FT3 levels within normal limits, and the incidence of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs), and withdrawals due to TEAEs during the study period.