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CC-97540

CC-97540 (also known as BMS-986353) is an innovative CD19-targeted NEX-T Chimeric Antigen Receptor (CAR) T cell therapy currently being investigated in clinical trials for various autoimmune conditions. These trials, collectively known as the “Breakfree” series, are evaluating this therapy in patients with severe or refractory autoimmune diseases including multiple sclerosis, myasthenia gravis, systemic lupus erythematosus, idiopathic inflammatory myopathy, and systemic sclerosis. The studies aim to assess the safety, tolerability, efficacy, and drug levels of CC-97540, offering potential new treatment options for patients who haven’t responded adequately to conventional therapies.

Table of Contents

What is CC-97540?

CC-97540 (also known as BMS-986353) is an investigational treatment being studied for various autoimmune diseases[1][2][3]. It belongs to a specialized class of therapies called CD19-targeted NEX-T Chimeric Antigen Receptor (CAR) T cells. This is a type of cell therapy where immune cells (T cells) are modified in a laboratory to recognize and target specific cells in the body that may be contributing to autoimmune diseases.

CAR T-cell therapy was first developed for cancer treatment, but researchers are now exploring its potential for treating autoimmune conditions where the immune system mistakenly attacks healthy tissues[1]. CC-97540 specifically targets CD19, a protein found on the surface of B cells, which play a significant role in many autoimmune diseases.

How CC-97540 Works

In autoimmune diseases, B cells (a type of white blood cell) can produce harmful antibodies that attack the body’s own tissues. CC-97540 works by targeting cells that have the CD19 protein on their surface, primarily B cells[1][2].

The treatment process involves:

  1. Collecting T cells from the patient’s blood
  2. Modifying these T cells in a laboratory to create CAR T cells that can recognize CD19
  3. Growing these modified cells in large numbers
  4. Infusing them back into the patient where they can find and eliminate B cells that may be causing the autoimmune response

By reducing the number of problematic B cells, this therapy aims to decrease autoimmune activity and improve symptoms of various autoimmune conditions[2].

Conditions Treated with CC-97540

Based on the ongoing clinical trials, CC-97540 is being investigated for several autoimmune conditions[1][2][3]:

Multiple Sclerosis (MS)

Multiple Sclerosis is a condition where the immune system attacks the protective covering of nerve fibers, causing communication problems between the brain and the rest of the body. CC-97540 is being studied for two types of MS[1]:

  • Relapsing Forms of Multiple Sclerosis (RMS) – characterized by clearly defined attacks of new or increasing neurological symptoms followed by periods of recovery
  • Progressive Forms of Multiple Sclerosis (PMS) – characterized by steadily worsening neurological function over time

Myasthenia Gravis (MG)

Myasthenia Gravis is a chronic autoimmune disorder that causes muscle weakness. The condition specifically affects refractory cases, which means patients who haven’t responded well to conventional treatments[1]. In MG, antibodies block or destroy receptors for acetylcholine, a neurotransmitter that stimulates muscle contractions.

Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus, commonly known as lupus, is a disease that occurs when the immune system attacks its own tissues and organs. Symptoms include fatigue, joint pain, rash, and fever. CC-97540 is being studied for SLE, including a specific complication called lupus nephritis, which affects the kidneys[2][3].

Idiopathic Inflammatory Myopathy

Idiopathic Inflammatory Myopathy is a group of rare disorders that cause muscle inflammation and weakness. This includes conditions like dermatomyositis, which also affects the skin[2].

Systemic Sclerosis

Systemic Sclerosis, also known as scleroderma, is a group of rare diseases that involve hardening and tightening of the skin and connective tissues. It can affect blood vessels, internal organs, and the digestive tract[2].

Current Clinical Trials

CC-97540 is currently being evaluated in several clinical trials[1][2][3]:

Breakfree-1

This is a Phase 1 study evaluating the safety, preliminary effectiveness, and how the drug moves through the body (pharmacokinetics) in patients with severe, refractory autoimmune diseases including Systemic Lupus Erythematosus, Idiopathic Inflammatory Myopathy, or Systemic Sclerosis[2].

Breakfree-2

This Phase 1 study focuses on evaluating the safety, tolerability, efficacy, and drug levels of CC-97540 in patients with Relapsing Forms of Multiple Sclerosis, Progressive Forms of Multiple Sclerosis, or Refractory Myasthenia Gravis[1].

Breakfree-SLE

This is a Phase 2 study specifically evaluating CC-97540 in patients with active Systemic Lupus Erythematosus (including Lupus Nephritis) who have not responded adequately to glucocorticoids and at least 2 immunosuppressant medications[3].

These clinical trials are designed to determine the optimal dose, safety profile, and effectiveness of CC-97540 across these different autoimmune conditions.

How CC-97540 is Administered

Based on the clinical trial information, the administration of CC-97540 involves several steps[1][2][3]:

  1. Preparation with conditioning chemotherapy: Before receiving CC-97540, patients are given preparatory medications including:
    • Fludarabine – a chemotherapy medication that helps reduce the number of existing immune cells to make room for the new CAR T cells
    • Cyclophosphamide – another chemotherapy medication that works similarly
  2. Infusion of CC-97540: The modified CAR T cells are then infused into the patient at a specified dose on specified days
  3. Additional supportive medications: In some trials, medications like Tocilizumab may be given to manage potential side effects of the CAR T cell therapy

The exact dosing schedule and amounts are being determined through these clinical trials, with researchers looking for what’s called the “Recommended Phase 2 Dose” (RP2D) – the optimal dose that balances effectiveness with manageable side effects[1][2].

How Effectiveness is Measured

The effectiveness of CC-97540 is being measured differently depending on the condition being treated[1][2][3]:

For Multiple Sclerosis:

  • No Evidence of Disease Activity (NEDA) – a comprehensive measure that looks for the absence of relapses, disability progression, and new MRI lesions
  • Expanded Disability Status Scale (EDSS) – measures changes in disability
  • Annualized relapse rate – how frequently relapses occur
  • MRI metrics – changes in brain lesions visible on MRI scans

For Myasthenia Gravis:

  • Myasthenia Gravis activities of daily living (MG-ADL) score – measures how the disease affects daily activities
  • Myasthenia Gravis composite (MG-C) score – a comprehensive measure of disease severity
  • Quantitative Myasthenia Gravis (QMG) score – an objective measure of muscle strength

For Systemic Lupus Erythematosus:

  • Definition of Remission in SLE (DORIS) remission – a standardized definition of disease remission
  • Lupus Low Disease Activity State (LLDAS) – measures when the disease is under good control
  • Changes in proteinuria – measures protein in urine, important for lupus nephritis
  • SLE Responder Index (SRI-4) – a composite measure of disease improvement

For Other Autoimmune Conditions:

  • Health Assessment Questionnaire – Disability Index (HAQ-DI) – measures physical function
  • Myositis Response Criteria (MRC) – for inflammatory myopathies
  • Modified Rodnan Skin Score (mRSS) – for systemic sclerosis
  • Pulmonary function tests – measures lung function in patients with interstitial lung disease

These various measurements help researchers determine whether CC-97540 is effectively treating the target conditions and improving patients’ quality of life[2][3].

Safety Monitoring

Safety is a primary focus in all the clinical trials of CC-97540. Researchers are closely monitoring[1][2][3]:

  • Adverse events (AEs) – any undesirable experience associated with the drug
  • Serious adverse events (SAEs) – adverse events that result in hospitalization, disability, or are life-threatening
  • Adverse events of special interest (AESIs) – specific side effects that are being particularly monitored
  • Laboratory test abnormalities – changes in blood tests that might indicate safety concerns
  • Imaging abnormalities – changes on scans that might indicate problems
  • Dose-limiting toxicities (DLTs) – side effects severe enough to prevent increasing the dose further

CAR T cell therapies like CC-97540 can have unique side effects, including cytokine release syndrome (a systemic inflammatory response) and neurological effects. These are carefully monitored and managed during treatment[1].

The safety monitoring continues for up to 2 years after CC-97540 infusion in some trials, highlighting the importance of long-term safety follow-up for this type of therapy[2].

Study Name Target Conditions Phase Key Medications Primary Outcomes
Breakfree-1 Systemic Lupus Erythematosus, Idiopathic Inflammatory Myopathy, Systemic Sclerosis Phase 1 CC-97540, Fludarabine, Cyclophosphamide, Tocilizumab Safety, tolerability, dose-limiting toxicities, recommended Phase 2 dose
Breakfree-2 Relapsing and Progressive Forms of Multiple Sclerosis, Refractory Myasthenia Gravis Phase 1 CC-97540, Fludarabine, Cyclophosphamide Safety, tolerability, dose-limiting toxicities, recommended Phase 2 dose
Breakfree-SLE Systemic Lupus Erythematosus including Lupus Nephritis Phase 2 CC-97540, Fludarabine, Cyclophosphamide Proportion of participants achieving drug-free DORIS remission

FAQ

  • What is CC-97540 and how does it work? CC-97540 (also known as BMS-986353) is a type of CD19-targeted NEX-T Chimeric Antigen Receptor (CAR) T cell therapy. This means it uses specially modified immune cells that are designed to target cells with CD19 proteins on their surface. In autoimmune diseases, this therapy aims to reset the immune system by targeting and eliminating B cells (which have CD19 on their surface) that are involved in the abnormal immune response causing the disease.
  • What conditions is CC-97540 being tested for? CC-97540 is currently being tested in clinical trials for several autoimmune conditions. These include relapsing and progressive forms of multiple sclerosis (MS), refractory myasthenia gravis (MG), systemic lupus erythematosus (SLE) including lupus nephritis, idiopathic inflammatory myopathy, and systemic sclerosis. These are all conditions where the immune system attacks the body's own tissues.
  • What are the 'Breakfree' clinical trials? The 'Breakfree' trials are a series of clinical studies investigating CC-97540 for different autoimmune conditions. Breakfree-1 is studying the therapy in patients with systemic lupus erythematosus, idiopathic inflammatory myopathy, or systemic sclerosis. Breakfree-2 focuses on patients with multiple sclerosis and myasthenia gravis. Breakfree-SLE specifically targets patients with active systemic lupus erythematosus, including those with lupus nephritis, who haven't responded adequately to conventional treatments.
  • What other medications are used along with CC-97540 in these trials? In the clinical trials, CC-97540 is administered along with other medications as part of the treatment protocol. These typically include fludarabine and cyclophosphamide, which are used to prepare the patient's body for the CAR T cell therapy. In some trials, like Breakfree-1, tocilizumab may also be used. These medications help to create the right conditions in the body for the CAR T cells to work effectively.
  • How is success being measured in these clinical trials? Success in these trials is being measured in several ways. For safety, researchers track adverse events, serious adverse events, and laboratory abnormalities. For effectiveness, they use disease-specific measures. For example, in MS trials, they look at disease activity, disability progression, and MRI results. In lupus trials, they measure disease remission, kidney function, and quality of life scores. The trials also measure how the drug moves through the body (pharmacokinetics) by looking at concentration levels in the blood over time.

Ongoing Clinical Trials on CC-97540

  • Long-Term Follow-Up Study for Patients Treated with Idecabtagene Vicleucel or Lisocabtagene Maraleucel for Cancer

    Recruiting

    1 1 1
    Investigated drugs:
    Austria Belgium Czechia Denmark Finland France +11

  • Study of CC-97540 CD19-targeted CAR T cells in patients with systemic lupus erythematosus who did not respond to previous immunosuppressive treatment

    Not yet recruiting

    1 1 1
    Investigated drugs:
    Austria Belgium Denmark France Germany Italy +3

Glossary

  • CAR T Cell Therapy: A type of treatment in which a patient's T cells (a type of immune cell) are changed in the laboratory so they will attack cancer cells or, in the case of autoimmune diseases, abnormal immune cells. CAR stands for Chimeric Antigen Receptor.
  • CD19: A protein found on the surface of B cells (a type of white blood cell). In autoimmune diseases, targeting CD19 can help eliminate B cells that are causing the abnormal immune response.
  • NEX-T: Next-generation Engineered X-linked CAR T cells, a newer form of CAR T cell technology with potentially improved function.
  • Multiple Sclerosis (MS): A disease in which the immune system eats away at the protective covering of nerves, causing communication problems between the brain and the rest of the body.
  • Relapsing Forms of Multiple Sclerosis (RMS): A type of MS characterized by clearly defined attacks of new or increasing neurologic symptoms, followed by periods of partial or complete recovery.
  • Progressive Forms of Multiple Sclerosis (PMS): Types of MS in which there is a gradual, continuous worsening of neurologic function over time, with or without occasional relapses.
  • Myasthenia Gravis (MG): A chronic autoimmune disorder that causes muscle weakness that typically worsens after periods of activity and improves after periods of rest.
  • Systemic Lupus Erythematosus (SLE): A chronic autoimmune disease that can affect various parts of the body, including the skin, joints, kidneys, brain, and other organs.
  • Lupus Nephritis: Kidney inflammation caused by systemic lupus erythematosus (SLE). It can lead to kidney damage and kidney failure if not treated effectively.
  • Idiopathic Inflammatory Myopathy: A group of disorders characterized by inflammation of the muscles used for movement, leading to weakness.
  • Systemic Sclerosis: A rare autoimmune disorder characterized by hardening and tightening of the skin and connective tissues, affecting blood vessels and internal organs.
  • Fludarabine: A chemotherapy medication used in preparation for CAR T cell therapy to help create space in the body for the modified T cells to grow.
  • Cyclophosphamide: A medication that suppresses the immune system, used in preparation for CAR T cell therapy to help reduce the number of existing immune cells.
  • Tocilizumab: A medication that blocks the activity of interleukin-6 (IL-6), a protein involved in immune responses. It may be used to manage side effects of CAR T cell therapy.
  • Adverse Events (AEs): Any unfavorable and unintended sign, symptom, or disease that develops during treatment, whether or not it is considered related to the treatment.
  • Serious Adverse Events (SAEs): Adverse events that result in death, are life-threatening, require hospitalization, cause persistent or significant disability, or lead to birth defects.
  • Dose-Limiting Toxicities (DLTs): Side effects that are severe enough to prevent an increase in the dose of a medication during a clinical trial.
  • Recommended Phase 2 Dose (RP2D): The dose of a medication determined from Phase 1 trials that is recommended for further testing in Phase 2 trials.
  • No Evidence of Disease Activity (NEDA): A treatment goal in multiple sclerosis where patients show no relapses, no disability progression, and no new or enlarging lesions on MRI scans.
  • Expanded Disability Status Scale (EDSS): A method of quantifying disability in multiple sclerosis and monitoring changes over time.
  • Magnetic Resonance Imaging (MRI): A medical imaging technique that uses a magnetic field and radio waves to create detailed images of the organs and tissues within the body.
  • Pharmacokinetics: The study of how drugs move through the body, including how they are absorbed, distributed, metabolized, and excreted.
  • Cmax: The maximum concentration of a drug in the blood after it has been administered.
  • Tmax: The time it takes for a drug to reach its maximum concentration in the blood.
  • AUC(0-28D): Area Under the Curve from time zero to 28 days, a measure of the total exposure to a drug over a specific time period.
  • DORIS Remission: Definition Of Remission In Systemic lupus erythematosus, a standardized definition for disease remission in lupus.
  • Lupus Low Disease Activity State (LLDAS): A state where lupus disease activity is present but at a low level that is considered acceptable.
  • SLE Responder Index (SRI): A composite measure used to determine treatment response in systemic lupus erythematosus clinical trials.
  • Proteinuria: The presence of excess protein in the urine, which can be a sign of kidney damage in lupus nephritis.
  • Estimated Glomerular Filtration Rate (eGFR): A test that measures how well the kidneys are filtering blood, used to detect kidney disease and monitor kidney function.

References

  1. https://clinicaltrials.gov/study/NCT06220201
  2. https://clinicaltrials.gov/study/NCT05869955
  3. https://clinicaltrials.gov/study/NCT07015983