Phase 2 Multicenter Study of KYV-101 Anti-CD19 CAR T-Cell Therapy in Refractory Generalized Myasthenia Gravis
- Trial ID
- 2023-509892-17-00
- Protocol
- KYV101-006
- Sponsor
- Kyverna Therapeutics Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 2, open-label, multicentre study is to **characterize the safety and tolerability** and 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 generalized myasthenia gravis. This objective is clinically relevant as it aims to determine the potential of KYV-101 to provide a therapeutic option for patients with this challenging condition, where current treatments may be insufficient.
Secondary objectives include:
- Further evaluating the efficacy of KYV-101.
- Evaluating disease-related antibodies.
- Characterizing the pharmacokinetics (PK) and pharmacodynamics (PD) of KYV-101 in blood.
- Evaluating the immunogenicity (humoral response) of KYV-101.
- Assessing patient-reported outcomes (PRO) after infusion of KYV-101.
Participants
The clinical trial involves a total of **10 participants** diagnosed with **refractory generalized myasthenia gravis**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically represent adults and older adults. Participants were selected based on specific criteria, including the presence of autoantibodies to AChR and MuSK, and classification within the Myasthenia Gravis Foundation of America (MGFA) Class IIB-IV. The trial population includes a vulnerable group, indicating careful consideration of ethical standards in participant selection. Lifestyle factors such as diet, physical activity, and habits were not specified by the sponsor. The trial aims to assess the safety, tolerability, and efficacy of KYV-101 in this specific patient group.
Plans and Procedures
The clinical trial is a Phase II, open-label, multicenter study designed to evaluate the safety, tolerability, and efficacy of **KYV-101**, an autologous fully human anti-CD19 chimeric antigen receptor T-cell therapy, in subjects with refractory generalized myasthenia gravis. The trial will involve the administration of KYV-101 via **intravenous infusion**. The study is expected to commence recruitment on July 31, 2024, and conclude by December 31, 2027. Participants will be involved in the study for a maximum treatment period of one year.
The trial will include several key visits: an initial screening visit to confirm eligibility based on criteria such as the presence of autoantibodies to AChR and MuSK and classification within the Myasthenia Gravis Foundation of America (MGFA) Class IIB-IV. Following the screening, participants will undergo baseline assessments before receiving the investigational product. Subsequent follow-up visits will occur at regular intervals to monitor the incidence and severity of adverse events (AEs), laboratory abnormalities, and changes in clinical scores such as the MG-ADL, QMG, and MGC scores at 12, 24, and 52 weeks. The end-of-study visit will assess the primary and secondary endpoints, including the presence of anti-KYV-101 antibodies and changes in antibody levels over time.
Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The primary endpoints focus on the incidence and severity of AEs and laboratory abnormalities, as well as the MG-ADL score at 24 weeks. Secondary endpoints include various clinical and laboratory measures over the course of the study. The trial is not classified as a low-intervention study and is not intended for pediatric populations.
Treatment
The clinical trial involves the administration of **KYV-101**, an experimental medication developed by Kyverna Therapeutics Inc. KYV-101 is an autologous engineered anti-CD19 Chimeric Antigen Receptor (CAR+) T-cell therapy, specifically designed for the treatment of refractory generalized **myasthenia gravis**. The pharmaceutical form of KYV-101 is a suspension, and it is administered via **intravenous infusion**. The maximum daily dose and total dose amount are both set at 100,000,000 units, with a maximum treatment period of one day. The active substance, KYV-101, is classified as a structurally diverse substance used in cell therapy, and it is genetically modified to enhance its therapeutic efficacy.
In this study, KYV-101 is the sole investigational product, and no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is designed to evaluate the safety, tolerability, and efficacy of KYV-101 in the specified patient population. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol. The trial does not include any pediatric formulations, and KYV-101 is not classified as an orphan drug. The study is conducted under an open-label design, allowing for direct observation of the treatment effects in the participants.
Efficacy
The efficacy of KYV-101 in the treatment of **refractory generalized myasthenia gravis** will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence and severity of adverse events (AEs) and laboratory abnormalities, as well as the Myasthenia Gravis Activities of Daily Living (MG-ADL) score at 24 weeks. Secondary endpoints will evaluate the Quantitative Myasthenia Gravis (QMG) score and the Myasthenia Gravis Composite (MGC) score at 12, 24, and 52 weeks. Additionally, changes in anti-acetylcholine receptor (anti-AChR), anti-muscle-specific kinase (anti-MuSK), and anti-low-density lipoprotein receptor-related protein 4 (anti-LRP4) antibodies over time will be measured.
Further assessments will include CAR-positive T-cell counts, CAR transgene levels, B-cell counts over time, and systemic cytokine concentrations. The presence of anti-KYV-101 antibodies will also be monitored. Patient-reported outcomes will be evaluated through changes from baseline in the Myasthenia Gravis Quality of Life 15-item revised scale (MGQOL15r), the Myasthenia Gravis Foundation of America Post-Intervention Status (MGFA-PIS), the Neuro-QOL Fatigue Scale, and the EQ-5D. These efficacy parameters will be collected and analyzed at specified timepoints throughout the study to determine the therapeutic impact of KYV-101.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patients must be ≥ 18 to ≤ 75 years of age with a diagnosis of generalized MG
- No use of IVIG (or subcutaneous or intramuscular Ig) or plasmapheresis (PLEX) within 4 weeks of screening or pre-dose baseline (unless this is part of their SOC treatment regimen).
- Presence of autoantibodies to AChR or MuSK at screening (not just historical). Patients receiving an FcRn inhibitor at screening who have a negative autoantibody result at screening may be considered eligible if they have documented historical autoantibody positivity. Note: In such a case, the presence of autoantibodies must be confirmed prior to baseline to be eligible for randomization.
- Myasthenia Gravis Foundation of America (MGFA) Class IIb-IV (in Germany only, Class IIb-IV).
- MG-ADL total score of ≥6 at screening and confirmed at baseline visit.
- QMG total score of ≥11 at screening and confirmed at baseline visit.
- Failed treatment with 2 or more immunosuppressive/immunomodulatory therapies, or failed at least 1 immunosuppressive therapy and required chronic plasmapheresis, or intravenous immune globulin (IVIG )(or subcutaneous or intramuscular Ig) (>4 times/year over ≥12 months) to control symptoms. a. Failed treatment may consist of either lack of sufficient efficacy with an adequate trial, intolerable adverse effects, or contraindications to therapy, as determined by the investigator.
- In Germany only, failed standard-of-care immunosuppressive and immunomodulatory therapies including complement inhibitors and FcRn modulators. a. Failed treatment may consist of either lack of sufficient efficacy with an adequate trial, intolerable adverse effects, or contraindication to therapy, as determined by the investigator. b. Failure of chronic plasmapheresis or IVIG (or subcutaneous or intramuscular Ig) is defined as requiring >4 times/year over ≥12 months to control symptoms.
- On a stable dose of glucocorticoids and/or other immunotherapies for ≥1 month prior to screening. For azathioprine, being on a stable dose for ≥2 months prior to screening is required.
- No change in dose of acetylcholinesterase inhibitors for ≥2 weeks prior to screening
- No use of rituximab (or any other anti-CD20 or CD19 monoclonal antibody) within 12 weeks prior to screening.
- Able and willing to attend the necessary visits to the study site.
Exclusion Criteria
- Unable to washout or interrupt autoimmune disease therapy prior to apheresis and/or baseline if required, as specificed in protocol
- Patients requiring chronic anticoagulation therapy that cannot be discontinued for medical procedures (such as apheresis
- Prior treatment with gene therapy product or cellular immunotherapy (eg, CAR T) requiring vector integration and directed at any target.
- Plan to receive live, attenuated vaccine after signing ICF (inactive vaccines, such as the flu vaccine, are allowed).
- Contraindications or life-threatening allergies, hypersensitivity, or intolerance to KYV-101 or its excipients, including dimethyl sulfoxide; or to CYC, FLU, or tocilizumab.
- Have evidence of latent or active TB infection, as documented by a positive QuantiFERON-TB Gold test at screening. Patients with a positive QuantiFERON-TB Gold test at screening can be considered for enrollment if: 1) a history of active TB infection is accompanied by a subsequent, medically documented “cured” status per WHO guidelines or 2) a history of latent TB infection (LTBI) is accompanied by a subsequent, medically documented completion of a full course of LTBI treatment prior to screening per WHO guidelines (WHO 2025).
- Positive hepatitis B surface antigen (HBsAg) at screening. Patients who are HBsAg negative but hepatitis B core antibody (HBcAb) positive must have negative hepatitis B virus (HBV) DNA testing.
- Positive hepatitis C serology confirmed by polymerase chain reaction (PCR).
- Positive serology for human immunodeficiency virus (HIV).
- Positive screening test for SARS-CoV-2, by PCR or rapid antigen testing (not antibody testing). Note: Patients with a positive SARS-CoV-2 at screening can be enrolled if the patient has all 3 of the following: no active signs or symptoms of SARS-Cov-2 infection after 10 days, a negative repeat PCR or rapid antigen test, and no sequelae or complications of SARS-CoV-2 infection.
- In Brazil only, confirmed current infection with malaria, syphilis, human T cell lymphotropic virus (HTLV), or Chagas disease.
- Co-occurring neurological autoimmune disease (ie, Lambert-Eaton Myasthenic Syndrome [LEMS]) or any disease affecting the neuromuscular junction or muscle causing weakness (eg, myositis, myopathy, motor neuropathy). Anti-voltage-gated calcium channel (VGCC) antibody testing may be conducted as part of a larger clinical work up to help rule out LEMS, if clinically warranted by neurological examination or electromyography findings.
- Any laboratory, imaging, or physiologic testing values at screening meeting the cutoff ranges in this table
- Any of the following vital sign parameters at rest: • Systolic Blood Pressure (mmHg) <95 or >160 • Diastolic Blood pressure (mmHg) <55 or >95 • Heart Rate <50 or >100 bpm • Temperature > 37.7° C • Respiratory rate <12 or >20 bpm (Note: Up to 3 assessments of blood pressure, heart rate, and respiratory rate may be made within a 24-hour period)
- History of stroke (with residual sequalae and/or risk for recurrence), seizure (even if well controlled on antiepileptics), neurodegenerative disease, altered mental status (unexplained and/or recent/current), or uncontrolled/severe psychiatric disease
- Any serious and/or uncontrolled medical condition that, in the investigator’s judgment, would cause unacceptable safety risk, interfere with study procedures or results, or compromise compliance with the protocol, including but not limited to, clinically significant cardiac or pulmonary disease.
- History of primary immunodeficiency, organ or allogeneic bone marrow transplant, or splenectomy.
- Active, uncontrolled, viral, bacterial, or systemic fungal infection or recent history of repeated infections.
- Previous or concurrent malignancy with the following exceptions: a. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to screening). b. In situ carcinoma (eg, of the cervix or breast), treated curatively and without evidence of recurrence for at least 3 years prior to screening. c. A primary malignancy which has been completely resected, or treated, and is in complete remission for at least 5 years prior to screening.
- Major surgery within 4 weeks prior to apheresis or planned within 4 weeks after KYV-101 administration. For surgery planned after 4 weeks post KYV-101 administration, discuss with the sponsor
- Thymectomy ≤ 12 months of screening or planned during the study.
- Pregnant or breastfeeding, plans to become pregnant/breastfeed or father a child, risk of unintentional pregnancy/fathering, or plans to donate eggs/sperm in the timeframe provided in the protocol
- Unlikely to comply with the study protocol OR those who would not be suitable candidates for participation in the opinion of the investigator including any reason which, in the opinion of the investigator, would prevent the subject from completing all study procedures and complying with study restrictions.
- Employed by the sponsor or any contract research organizations responsible for the conduct of the study, or who are immediate family members (eg, spouse, parent, child, sibling) of said employees responsible for the conduct of the study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Germany | Recruiting | 31 Jul 2024 | 17 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Methotrexate 2.5 mg Tablets | Comparator | TABLETS | ORAL | 50 | 40 | PRD11534406 |
CellCept 250 mg capsules | Comparator | CAPSULES | ORAL | 2.5 | 40 | PRD2153965 |
Privigen 100 mg/ml solution for infusion | Comparator | SOLUTION FOR INFUSION | INTRAVENOUS INFUSION | 1000 | 40 | PRD339234 |
Prograf 1 mg Hartkapseln | Comparator | HARTKAPSELN | ORAL | 4 | 40 | PRD11855448 |
KYV-101 | Test | SUSPENSION | INTRAVENOUS INFUSION | 100000000 | 1 | PRD9974051 |
Methotrexate 2.5 mg Tablets | Comparator | TABLETS | ORAL | 50 | 40 | PRD11534405 |
Methotrexate 2.5 mg Tablets | Comparator | TABLETS | ORAL | 50 | 40 | PRD11534408 |
NEORAL® Soft Gelatin Capsules 100mg | Comparator | SOFT GELATIN CAPSULES | ORAL | 3.5 | 40 | PRD11355207 |
NEORAL® Soft Gelatin Capsules 50mg | Comparator | SOFT GELATIN CAPSULES | ORAL | 3.5 | 40 | PRD11355215 |
Zilbrysq 23 mg solution for injection in pre-filled syringe | Comparator | SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE | SUBCUTANEOUS INJECTION | 0.3 | 40 | PRD10984301 |