Evaluation of Rapcabtagene Autoleucel Versus Standard of Care in Systemic Lupus Erythematosus Patients with Active, Refractory Lupus Nephritis

The primary objective of this study is to evaluate the effect of **rapcabtagene autoleucel** compared to Standard of Care (SOC) in patients with systemic lupus erythematosus (SLE) with active, refractory lupus nephritis (LN). This evaluation focuses on the clinical response at Week 52, with Part A estimating the effect and Part B demonstrating the superiority of rapcabtagene autoleucel following lymphodepletion. The clinical relevance of this objective lies in its potential to offer a more effective treatment option for patients with this challenging condition, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Part A: Assessing the efficacy of rapcabtagene autoleucel versus SOC.
• Part A: Evaluating the overall safety and tolerability of rapcabtagene autoleucel in the LN population.
• Part B: Demonstrating the superiority of rapcabtagene autoleucel following lymphodepletion compared to SOC.
• Part B: Assessing the overall safety and tolerability of rapcabtagene autoleucel.

The clinical trial involves a total of **75 participants** diagnosed with **systemic lupus erythematosus (SLE)** with active, refractory **lupus nephritis (LN)**. The study population includes both men and women aged between 18 and 65 years, who meet the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE. Participants were selected based on their positive status for specific autoantibodies and the presence of active lupus nephritis without significant chronicity. The trial includes individuals who have shown an inadequate response to at least two lupus nephritis treatment regimens. The selection process ensures a diverse representation of both genders, and the trial considers vulnerable populations. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, open-label, assessor-blinded, active-controlled study to evaluate the efficacy and safety of **rapcabtagene autoleucel** compared to standard of care in patients with systemic lupus erythematosus (SLE) with active, refractory lupus nephritis (LN). The trial is divided into two parts, Part A and Part B, each with specific objectives related to clinical response at Week 52. The trial is expected to commence recruitment on December 2, 2024, and conclude by June 4, 2030, with an estimated duration of 104 weeks for participant involvement.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis of SLE, and inadequate response to previous treatments. The screening will include laboratory tests to verify the presence of specific autoantibodies and assess renal function. Following successful screening, participants will be randomized to receive either the investigational product or standard of care. Study visits will occur at regular intervals to monitor safety, efficacy, and adherence to the treatment protocol.

Follow-up visits will be conducted to assess primary and secondary endpoints, including clinical response, renal response, and safety parameters. The primary endpoint is the proportion of participants achieving a clinical response at Week 52, defined by the Definition Of Remission In Systemic Lupus Erythematosus (DORIS) criteria. Secondary endpoints include complete renal response, disease activity scores, and safety assessments. The end-of-study visit will occur at the conclusion of the treatment period, where final evaluations will be conducted.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, with informed consent obtained from all participants prior to enrollment.

The clinical trial involves the administration of several experimental and non-experimental treatments to evaluate their efficacy and safety in patients with systemic lupus erythematosus (SLE) and active, refractory lupus nephritis (LN). The primary experimental treatment is **rapcabtagene autoleucel**, also known as YTB323, which is a dispersion for infusion. This treatment involves autologous T cells transduced with a lentiviral vector containing a chimeric antigen receptor directed against CD19. It is administered via **intravenous use** as a single infusion following lymphodepletion, with a maximum treatment period of 1 week.

**Mycophenolate mofetil** is used as a comparator treatment in the form of hard capsules. It is administered orally with a maximum daily dose of 3000 mg and a total dose of 3000 mg over a treatment period of 104 weeks. **Cyclophosphamide** is another comparator, provided as a powder for solution for infusion, administered via **intravenous infusion**. The maximum total dose is 3 g over a period of 6 weeks.

**Belimumab** is included as a comparator in the form of a solution for injection in a pre-filled syringe. The administration route is currently unspecified, with a maximum daily and total dose of 10 mg/kg over 104 weeks. **Fludarabine phosphate** is also used as a comparator, provided as a concentrate for solution for infusion, administered intravenously with a maximum treatment period of 3 weeks.

**Rituximab** is administered as a concentrate for solution for infusion via **intravenous infusion**. It is designated as an orphan drug and used as a comparator with a maximum daily dose of 1000 mg and a total dose of 4000 mg over 104 weeks. **Voclosporin** is another comparator, provided in capsule form for oral use, with a maximum daily and total dose of 47.4 mg over 104 weeks.

**Tocilizumab** is administered as a concentrate for solution for infusion via **intravenous infusion**. It is used as an auxiliary treatment with a maximum daily dose of 2400 mg and a total dose of 3200 mg over 2 weeks. **Tacrolimus** is provided in capsule form for oral use, with a maximum daily dose of 4 mg and a total dose of 2.9 g over 104 weeks.

Lastly, **mycophenolic acid** is used as a comparator in tablet form, administered orally with a maximum daily and total dose of 2160 mg over 104 weeks. Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint for Part A is the proportion of participants with a clinical response at Week 52, defined by the Definition Of Remission In Systemic Lupus Erythematosus (DORIS) and maintaining treatment with low-dose glucocorticoids. For Part B, the primary endpoint is the proportion of participants achieving a clinical response at Week 52, similarly defined as in Part A.

Secondary endpoints include the proportion of participants achieving complete renal response (CRR) at Week 52, the number of weeks where the Lupus Low Disease Activity Score (LLDAS) was achieved from Week 12 until Week 52, and the proportion of participants without flaring from Week 12 through Week 52. Additional secondary endpoints involve the annualized cumulative corticosteroids dose until Week 52, the proportion of participants who are negative for antinuclear antibodies (ANA), anti-dsDNA, and anti-Sm at Week 52, and the change in FACIT-Fatigue score from baseline at Week 52. The proportion of participants in sustained remission from Week 52 to Week 76 and safety parameters, including vital signs, adverse events, laboratory parameters, and ECG evaluation, will also be assessed.