YTB323 for Lupus

Not currently recruiting at 18 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Novartis Pharmaceuticals

Disqualifiers: Infections, Uncontrolled diabetes, Malignancy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1 day

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called YTB323 to determine its safety and effectiveness for people with severe lupus that hasn't improved with other treatments. Lupus is an autoimmune disease where the immune system mistakenly attacks the body, causing inflammation and damage to various organs. Participants will receive a single infusion of YTB323, an anti-CD19 CAR-T cell therapy. Suitable candidates have severe lupus affecting major organs and have not responded to at least two standard treatments and one biological agent. As a Phase 1 trial, this research aims to understand how YTB323 works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I need to stop my current medications for the YTB323 trial?

The trial protocol does not specify if you need to stop your current medications, but it mentions an 'immunosuppressive washout' period, which suggests you might need to stop certain medications. It's best to discuss this with the trial team.

Is there any evidence suggesting that YTB323 is likely to be safe for humans?

Research has shown that YTB323 appears safe so far. Early results from a recent study indicated that patients tolerated the treatment well. The study also found good growth of CAR T-cells, a positive sign for the treatment's potential effectiveness. No major safety problems emerged, which is encouraging for prospective trial participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for lupus, which typically include immunosuppressants and corticosteroids, YTB323 is unique because it involves a single infusion of engineered T-cells. This approach offers a potentially groundbreaking mechanism of action by harnessing the body's own immune system to target and manage lupus more effectively. Researchers are excited about YTB323 because it could provide a more targeted treatment, potentially reducing the side effects and long-term complications associated with current therapies.

What evidence suggests that YTB323 might be an effective treatment for lupus?

Research shows that YTB323, the treatment under study in this trial, may help treat severe refractory systemic lupus erythematosus (srSLE). Earlier studies found YTB323 to be safe and effective in increasing the number of CAR T-cells, which can locate and destroy harmful cells in the body. Initial results suggest that YTB323 can effectively reduce B-cells, which are linked to lupus symptoms. This treatment is a type of CAR-T cell therapy, using modified immune cells to target and eliminate specific disease-causing cells. Early evidence indicates that YTB323 might help reset the B-cell system, potentially easing lupus symptoms. ^{1 2 3 6 7}

Who Is on the Research Team?

Novartis Pharmaceuticals

Principal Investigator

Novartis Pharmaceutical

Are You a Good Fit for This Trial?

This trial is for adults aged 18-65 with severe, treatment-resistant systemic lupus erythematosus (SLE). Participants must meet specific SLE criteria and have certain autoantibodies. They should have tried at least two immunosuppressive therapies without success and may also have kidney, heart, lung or blood vessel involvement. Major organ functions need to be adequate.

Inclusion Criteria

Signed informed consent

My kidney, liver, heart, blood, and lung functions are all within normal ranges.

Patient must be positive for at least one of the following autoantibodies at screening: antinuclear antibodies (ANA) at a titer of ≥1:80, or anti dsDNA (above the ULN), or anti-Sm (above the ULN)

Exclusion Criteria

Any psychiatric condition or disability making compliance with treatment or informed consent impossible

My condition is B cell aplasia.

I do not have any serious or recurring infections.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single infusion of YTB323

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Regular visits (in-person and virtual) for monitoring

Long-term safety follow-up

Long term safety follow-up to monitor adverse events and efficacy

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• YTB323

Trial Overview The study tests YTB323's safety, effectiveness, and how it affects immune cells in patients with severe refractory SLE. It aims to see if this new treatment can help where others failed.

How Is the Trial Designed?

Group I: YTB323 Experimental Treatment 1 Intervention

Single infusion of YTB323

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

In a study involving six patients with systemic lupus erythematosus (SLE), researchers successfully produced functional anti-CD19 CAR T cells from their T cells, demonstrating that leukapheresis can yield sufficient T-cell numbers for clinical-scale production despite the challenges posed by autoimmune conditions.

The generated CAR T cells exhibited high expansion rates, viability, and specific cytotoxicity against CD19+ cell lines in vitro, indicating that CAR T-cell therapy can be effectively developed for patients with autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Generation of CD19 Chimeric Antigen Receptor T Cells from Patients with Advanced Systemic Lupus Erythematosus. Kretschmann, S., Völkl, S., Reimann, H., et al.[2023]

Using CAR T cells to continuously deplete B cells leads to remission of lupus symptoms in mice that are genetically predisposed to the disease, suggesting a potential therapeutic strategy for lupus.

This study highlights the effectiveness of targeted cell therapy in managing autoimmune diseases, demonstrating that manipulating the immune system can result in significant health improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Slamming the brakes on lupus with CAR T cells. Clark, RA.[2019]

In the updated ZUMA-3 study with a median follow-up of 26.8 months, brexucabtagene autoleucel (KTE-X19) achieved a 71% complete remission rate in adults with relapsed or refractory B-precursor acute lymphoblastic leukemia, indicating its efficacy as a treatment option.

Patients treated with KTE-X19 had a median overall survival of 25.4 months, significantly longer than the 5.5 months observed in matched historical controls, demonstrating a meaningful survival benefit with manageable safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-year follow-up of KTE-X19 in patients with relapsed or refractory adult B-cell acute lymphoblastic leukemia in ZUMA-3 and its contextualization with SCHOLAR-3, an external historical control study. Shah, BD., Ghobadi, A., Oluwole, OO., et al.[2023]

In a study involving five patients with severe systemic lupus erythematosus (SLE), treatment with CAR T cells targeting CD19 led to complete remission of the disease in all participants after 3 months, demonstrating high efficacy.

The CAR T cell therapy was well tolerated, with only mild side effects, and patients maintained drug-free remission for an average of 8 months, even after B cells reappeared, indicating a durable response to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Mackensen, A., Müller, F., Mougiakakos, D., et al.[2023]

In a small study of five treatment-resistant patients with systemic lupus erythematosus (SLE), CD19 CAR T cell therapy led to significant clinical improvements and remission in all participants after 3 months, demonstrating its potential efficacy.

The treatment was well tolerated, with only mild cytokine release syndrome reported, suggesting a favorable safety profile for this innovative therapy in seriously ill SLE patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Journal Club: Anti-CD19 Chimeric Antigen Receptor T Cell Therapy for Refractory Systemic Lupus Erythematosus. Boulougoura, A., Gendelman, H., Surmachevska, N., et al.[2023]

Yescarta (axicabtagene ciloleucel) is an engineered T-cell therapy that showed a 66% overall response rate and a 47% complete response rate in treating relapsed or refractory diffuse large B-cell lymphoma, based on a phase II study with a median follow-up of 15.1 months.

The therapy was associated with manageable adverse events, including cytokine release syndrome and neurological issues, making it a promising option for patients with limited treatment alternatives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

EMA Review of Axicabtagene Ciloleucel (Yescarta) for the Treatment of Diffuse Large B-Cell Lymphoma. Papadouli, I., Mueller-Berghaus, J., Beuneu, C., et al.[2022]

CAR T therapy, known for its success in treating blood cancers, has been applied to systemic lupus erythematosus in a small study involving five patients, indicating its potential beyond cancer treatment.

The findings from Mackensen et al. suggest that CAR T therapy could be a promising new approach for autoimmune diseases, warranting further research in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T therapy extends its reach to autoimmune diseases. Baker, DJ., June, CH.[2023]

Anti-CD19 CAR-T cell therapy demonstrated effective B-cell depletion in a mouse model of systemic lupus erythematosus (SLE), showing both preventive and therapeutic benefits against the disease.

CAR-T cells using the 4-1BB costimulatory motif were found to be more effective than those using the CD28 motif, suggesting a promising strategy for optimizing treatment in SLE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic efficacy of anti-CD19 CAR-T cells in a mouse model of systemic lupus erythematosus. Jin, X., Xu, Q., Pu, C., et al.[2022]

Two CAR T cell therapies, Tisagenlecleucel and Axicabtagene ciloleucel, have been approved for treating specific types of blood cancers, including B-cell acute lymphoblastic leukemia and large B-cell lymphoma, in patients who have not responded to other treatments.

This review emphasizes the importance of recognizing and managing the toxicities associated with CAR T cell therapies, while also suggesting future strategies to reduce these side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CAR T Cell Toxicity: Current Management and Future Directions. Yáñez, L., Sánchez-Escamilla, M., Perales, MA.[2020]

Anti-CD19-directed CAR T cell therapy has shown significant efficacy in treating relapsed or refractory B-cell malignancies, leading to the approval of tisagenlecleucel (Kymriah) for B-ALL in 2018 and for aggressive B-cell lymphoma shortly thereafter.

The review highlights ongoing research into resistance mechanisms and the exploration of new target antigens, indicating a continued effort to improve treatment outcomes for patients with CD19 positive B-cell lymphomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[CAR T-cell therapy for malignant B-cell lymphoma : A new treatment paradigm]. Balke-Want, H., Borchmann, P.[2021]

Systemic lupus erythematosus (SLE) patients exhibit abnormal T cell receptor (TCRbeta) gene repertoires characterized by oligoclonal expansions, which are linked to the disease's pathogenesis.

After autologous peripheral blood stem cell transplantation (APBSCT), T cell clones in SLE patients showed a recovery towards normal distribution, suggesting that the transplantation may help suppress disease-related T cell populations and contribute to remission.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The variation of T-cell clonal repertoire in patients with systemic lupus erythematosus (SLE) following autologous peripheral blood hematopoietic stem cell transplantation]. Fu, YW., Zhu, P., Zhao, XW., et al.[2006]

Complete and sustained depletion of CD19+ B cells using CD19-targeted CAR T cells was shown to be a highly effective therapy in lupus models, significantly reversing disease symptoms and extending lifespan in mouse models of lupus.

This approach demonstrated long-lasting effects, with CAR T cells remaining active for up to one year, suggesting that sustained B cell depletion could be a promising strategy for treating lupus in humans, warranting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus. Kansal, R., Richardson, N., Neeli, I., et al.[2021]

Chimeric antigen receptor (CAR) T-cell therapy, specifically anti-CD19 CAR T-cell therapies like axicabtagene ciloleucel and tisagenlecleucel, have been approved for treating relapsed or refractory aggressive B-cell lymphoma, marking a significant advancement after decades of limited treatment options.

These therapies have shown promising efficacy in clinical trials, but they also come with potential toxicities, highlighting the need for ongoing research to enhance their safety and effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The promise of CAR T-cell therapy in aggressive B-cell lymphoma. Nair, R., Neelapu, SS.[2021]

Citations

1. ard.bmj.com ard.bmj.com/content/83/Suppl_1/327.1

pos0046 preliminary results of an open-label, multicentre ... Preliminary data from this clinical trial suggest favourable safety, CAR T-cell expansion, B-cell depletion and initial efficacy of YTB323 in srSLE.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05798117

NCT05798117 | An Open-label, Study to Assess Safety ... The study is intended to assess safety, efficacy and cellular kinetics of YTB323 treatment in participants with severe refractory systemic lupus erythematosus.

3. novartis.com novartis.com/news/media-releases/novartis-showcases-significant-immunology-advancements-acr-congress-new-data-complex-autoimmune-diseases

Novartis showcases significant immunology advancements ... Additional presentations include data for rapcabtagene autoleucel, a novel one-time investigational CAR-T cell therapy being evaluated across ...

4. acrabstracts.org acrabstracts.org/abstract/biomarker-data-from-an-open-label-phase-1-2-study-for-ytb323-rapcabtagene-autoleucel-a-rapidly-manufactured-cd19-car-t-therapy-suggest-reset-of-the-b-cell-compartment-in-severe-refractory-sle/

Biomarker Data From an Open-Label, Phase 1/2 Study ... Methods: This ongoing open-label, single-arm, multicenter phase 1/2 study (NCT05798117) assesses the safety, efficacy and cellular kinetics of YTB323 in ...

5. novartis.com novartis.com/clinicaltrials/study/nct06581198

A Study of Rapcabtagene Autoleucel in Active, Refractory ... The purpose of this study is to evaluate the efficacy and safety of rapcabtagene autoleucel (administered once following lymphodepletion) in patients with ...

6. acrabstracts.org acrabstracts.org/abstract/an-open-label-multicenter-phase-1-2-study-to-assess-safety-efficacy-and-cellular-kinetics-of-ytb323-a-rapid-manufacturing-car-t-cell-therapy-targeting-cd19-on-b-cells-for-severe-refractory-system/

An Open-label, Multicenter, Phase 1/2 Study to Assess ... This is the first clinical trial to evaluate the preliminary safety and efficacy of anti-CD19 CAR-T cell therapy in patients with srSLE. YTB323 ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT06581198

NCT06581198 | A Study of Rapcabtagene Autoleucel in ... The purpose of this study is to evaluate the efficacy and safety of rapcabtagene autoleucel (administered once following lymphodepletion) in patients with ...