Systemic Lupus Erythematosus Lupus Nephritis MedDRA version: 21.1 Level: PT Classification code 10042945 Term: Systemic lupus erythematosus System Organ Class: 10028395 - Musculoskeletal and connective tissue disorders
Conditions
Interventions
Product Code: YTB323
Pharmaceutical Form: Dispersion for infusion
INN or Proposed INN: Not estabilished
Other descriptive name: YTB323
Concentration unit: Other
Concentration type: not less then
Conce
Sponsors
Novartis Pharma AG
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: - Signed informed consent. - Adequate renal, hepatic, cardiac, hematological and pulmonary function. - Men and women with SLE, aged =18 years and =65 years at acreening, fulfilling the 2019 European League Against Rheumatism EULAR/ACR classification criteria for SLE. - 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). - Active (severe) disease as defined by SLEDAI-2K =8 (not including the SLEDAI-2K domains of lupus headache, cerebrovascular accident, organic brain syndrome*) AND at least one of the following significant SLE related organ involvements that can result in debilitating and permanent damage or may represent a life-threatening condition as judged by the investigator and defined by: - Renal**: histological diagnosis of proliferative lupus nephritis World Health Organization (WHO) ISN/RPS (Weening et al 2004) Class III or IV ("A" or "A/C") within 18 months of screening, AND at least one of the following at Screening (which must be fulfilled despite nephroprotective treatment, unless contraindicated and as per local standart of care): - First morning void UPCR: 0.7 to 4mg/mg (79.1 to 452 mg/mmol) or - Urine sediment consistent with active proliferative lupus nephritis such as presence of red blood cells, dysmorphic red blood cells, white blood cells, casts - At least moderate or severe peri/myocarditis - At least moderate or severe pleuritis or other lung involvement - Vasculitis - Failure to respond (i.e. having high disease activitiy as defined in criterion above despite the following therapy) to two or more standard immunosuppressive therapies (including one of mycophenolate or cyclophosphamide), unless contraindicated or having experienced documented adverse events or intolerance related to such immunosuppresive drugs not allowing their further use, in combination with glucocorticoids and failure to respond to at least on biological agent (unless contraindicated, the patient deemed ineligible by the Investigator or not available in a country). When country specific guidelines are in place pertaining to specific medications, these are to be followed by investigators unless otherwise clinically justified. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 24 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: - Clinically signficant active, opportunistic, chronic or recurrent infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, such as COVID-19 etc.) one month prior to or during screening. Patients who have had at least one severe infection that required prolonged hospitalization in the intensive care setting within 5 years prior to screening and/or at least one severe infection that required prolonged hospitalization within one year prior to screening. - Uncontrolled diabetes mellitus, lung diseases or any other illness that are not related to SLE that in the opinion of the Investigator would jeopardize the ability of the patient to tolerate lymphodepletion and CD19 CAR T cell therapy. - Prior history of malignancy except for localized basal cell or squamous skin cancer. Other malignancies for which the patient is judged to be cured for at least 5 years by local surgica therapy, such as head and neck cancer, or stage I breast cancer will be considered on an individual basis. - Any patients requiring medications probited by the protocol. - Any psychiatric condition or disability compliance with treatment or informed consent impossible. - Prior treatment with anti-CD19 therapy, adoptive T cell therapy or any prior gene therapy product (e.g. CAR-T cell therapy). - History o bone marrow/hematopoietic stem cell or solid organ transplantation. - Female participants who are pregnant or breastfeeding or intending to conceive during the course of the study. - Women of childbearing potential, defined as all womoen physiologically capable of becoming pregnant, unless they are using a highly effective method of contraception starting from the time of enrollment to at least 12 months after the YTB323 administration and until CAR-T cells are no longer present by qPCR on two consecutive tests. - Sexually active males unwilling to use a condom during intercourse from the time enrollment for at least 12 months after YTB323 administration and until CAR-T cells ar eno longer present by qPCR on two consecutive tests. - Any acute, severe lupus related flare during screening that needs immediate treatment and/or makes the immunosuppressive washout impossible; thus, makes the patient ineligibile for CD19 CAR-T therapy as judged by the Investigator, such as acute central nervous system (CNS) lupus (e.g. psychosis, epilespy) or catastrophic antiphospholipid syndrome. - Significant, likely irreversible organ damage related to SLE, including, end stage renal disease defined as glomerular filtration rate <15mL/min/body surface or need for hemodialysis, ii) heart disease defined as in Exclusion Criterion 11, severe valve insufficiency, or ejection fraction <20%; iii) end.stage liver disease defined as Child- Pugg class C; iv) severe lung disease defined as respiratory insufficiency requiring at least 1 l/min supplemental oxygen or as severe fibrotic changes at lung CT scan; v) any other severe condition that in the opinion of the Investigator renders CD19 CAR-T cell therapy as unlikely to benefit the patient.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess safety of YTB323 in participants with srSLE. ;Secondary Objective: •To characterize the in vivo cellular kinetics (pharmacokinetics, PK) of YTB323 in peripheral blood by quantitative polymerase chain reaction (qPCR) •To characterize the incidence and prevalence of pre-existing and treatment induced immunogenicity (cellular and humoral) of YTB323 •To evaluate feasibility of the manufacturing process in srSLE •Part A: To assess the effect of YTB323 on the following SLE disease activity scores •Part A: To evaluate effect of YTB323 for srSLE participants who also have active lupus nephritis;Primary end point(s): •Safety parameters include vital signs, adverse events, laboratory parameters and ECG evaluation;Timepoint(s) of evaluation of this end point: 720 days | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •YTB323 transgene concentration by qPCR over time in peripheral blood; cellular kinetics parameters (Cmax, AUC, Tmax, T1/2, Clast, Tlast) •Pre-existing and treatment induced immunogenecity (cellular, humoral) of YTB323. •Manufacture success (defined as meeting release specification and at or abiove the planned target dose) •At various timepoints: •SLEDAI-2K •Physician's global assessment •LLDAS •Remission (DORIS) •UPCR at various timepoints •Complete Renal Response (CRR) at various timepoints;Timepoint(s) of evaluation of this end point: 720 days | — |
Countries
Australia, France, Germany, Spain, United States
Contacts
Public ContactMedizinischer Infoservice (MCC)
Novartis Pharma GmbH
Outcome results
None listed