Evaluation of KYV-101 Anti-CD19 CAR T-Cell Therapy in Refractory Primary and Secondary Progressive Multiple Sclerosis: A Phase 2 Randomized Study

The primary objective of this study is to evaluate the **efficacy** of KYV-101, an autologous fully human anti-CD19 chimeric antigen receptor T cell (CD19 CAR T) therapy, in subjects with refractory primary and secondary progressive multiple sclerosis. This is clinically relevant as it aims to address the therapeutic needs of patients with limited treatment options due to the refractory nature of their condition.

Secondary objectives include: - Characterizing the safety and tolerability of KYV-101, which is crucial for understanding the risk-benefit profile of the therapy. - Further evaluating the efficacy of KYV-101 to provide additional insights into its therapeutic potential. - Characterizing the pharmacokinetics (PK) and pharmacodynamics (PD) of KYV-101 to understand its behavior and effects in the body. - Evaluating the immunogenicity (humoral) of KYV-101 to assess the potential for immune response against the therapy.

The clinical trial involves a total of **46 participants** diagnosed with **Primary or Secondary Progressive Multiple Sclerosis**. The study population includes both male and female subjects, aged between 18 to 60 years. Participants were selected based on a history of diagnosis with either PPMS or SPMS, and a history of treatment with anti-CD20 monoclonal antibodies, with evidence of worsening physical disability over a period of at least six months. Additionally, individuals with active SPMS must have shown an inadequate response or intolerance to another disease-modifying therapy, such as a sphingosine-1-phosphate receptor modulator. The trial includes a vulnerable population, and the selection criteria ensure that participants have documented evidence of clinical disability progression within the two years prior to inclusion. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed as a **Phase 2**, open-label, randomized, multicenter study to evaluate the efficacy and safety of **KYV-101**, an autologous fully human anti-CD19 chimeric antigen receptor T cell (CAR T) therapy, in subjects with refractory primary and secondary progressive multiple sclerosis. The trial will involve a series of study visits, beginning with an inclusion visit to screen participants based on specific criteria, including age between 18 to 60 years and a history of diagnosis of primary or secondary progressive multiple sclerosis. Participants must have shown evidence of worsening physical disability over a period of at least six months and have documented clinical disability progression within the two years prior to inclusion.

The trial will be conducted over an estimated duration from October 2024 to July 2028. Participants will be randomly assigned to receive the investigational product, KYV-101, and will be monitored through a series of follow-up visits to assess primary and secondary endpoints. The primary endpoint is confirmed disability progression, defined as an increase in the Expanded Disability Status Scale (EDSS). Secondary endpoints include the incidence and severity of adverse events, changes in clinical disability, annualized relapse rate, and MRI comparisons from baseline to the end of the study.

Study visits will include regular assessments of CAR-positive T-cell counts, CAR transgene levels, B-cell counts, and systemic cytokine concentrations. The presence of anti-KYV-101 antibodies will also be evaluated. The expected length of participant involvement is up to 24 months, with conditions for early termination including significant adverse events or withdrawal of consent. The trial aims to provide comprehensive data on the efficacy and safety of KYV-101 in the specified patient population.

The clinical trial involves the administration of **KYV-101**, an investigational therapy, which is a suspension form of a structurally diverse substance used in cell therapy. KYV-101 comprises lentiviral vector-transduced T-cells, specifically targeting CD19 through a chimeric antigen receptor (CAR) mechanism. The administration route is intravenous, with a maximum daily dose of 33,000,000 dosage forms and a total dose of up to 100,000,000 dosage forms. The treatment period is limited to a single administration.

**Kesimpta** (ofatumumab) is utilized as a comparator in the study. It is available as a 20 mg solution for injection in pre-filled pens or syringes. The pharmaceutical form is a solution for injection, administered subcutaneously. The maximum daily dose is 20 mg, with a total dose of up to 480 mg over a treatment period of 24 weeks.

**Ocrevus** (ocrelizumab) is another comparator used in the trial. It is provided as a 300 mg concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, administered intravenously. The maximum daily dose is 600 mg, with a total dose of up to 3 grams over a treatment period of 24 weeks.

**MabThera** (rituximab) is also included as a comparator. It is available in two concentrations: 100 mg and 500 mg, both as concentrates for solution for infusion. The pharmaceutical form is a solution for infusion, administered intravenously. The maximum daily dose is 1 gram, with a total dose of up to 5 grams over a treatment period of 42 weeks.

**Briumvi** (ublituximab) is used as a comparator in the study. It is provided as a 150 mg concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, administered intravenously. The maximum daily dose is 450 mg, with a total dose of up to 2.25 grams over a treatment period of 24 weeks.

Participant compliance is monitored through regular assessments and documentation of dosing schedules. The trial aims to evaluate the efficacy of KYV-101 in subjects with refractory primary and secondary progressive multiple sclerosis. The study is conducted in a randomized, open-label, multicenter format.

The efficacy of KYV-101 in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the confirmed disability progression, defined as an increase in the Expanded Disability Status Scale (EDSS). Secondary endpoints include a range of measures such as the incidence and severity of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs). Additionally, the trial will evaluate the composite confirmed disability progression (CCDP) as measured by EDSS, the impact on clinical disability by the number of days from randomization to the primary outcome, and the change in disability as measured by EDSS from pretreatment baseline to the end of the study.

Further secondary endpoints include the annualized relapse rate (ARR) in patients with active secondary progressive multiple sclerosis (SPMS), comparison of end-of-study brain MRI to baseline in terms of T2 burden of demyelinating disease, whole brain volume, and grey matter volume changes. For the cerebrospinal fluid (CSF) consenting subset, interval changes in unmatched intrathecal oligoclonal bands from baseline to the end of the study will be compared. Additional assessments involve CAR-positive T-cell counts, CAR transgene levels, B-cell counts over time, systemic cytokine concentrations, and the presence of anti-KYV-101 antibodies.