CARTIMMUNE: Study of Patients With Autoimmune Diseases Receiving KYV-101

Inclusion Criteria

• •Idiopathic inflammatory myopathy (including dermatomyositis, antisynthetase syndrome, immune mediated necrotizing myopathy, and polymyositis):
• •1. Diagnosis of probable or definite (\>55%) idiopathic inflammatory myopathy, including dermatomyositis, anti-synthetase myopathy, immune-mediated necrotizing myopathy (including anti-HMGCoR-myopathy, anti-SRP myopathy), polymyositis, according to the 2017 ACR/EULAR Classification Criteria for idiopathic inflammatory myopathies (Lundberg, Tjarnlund et al. 2017).
• •2. Disease severity and minimal core set measure criteria: MMT-8 score \<136/150, with at least 2 other abnormal core set measures (CSMs) from the following:
• •* Patient global VAS≥3 on a 1-10 scale (Appendix 3).
• •* Physician's global VAS ≥3 on a 1-10 scale (Appendix 4).
• •* Global extramuscular activity score ≥2 cm (Appendix 5).
• •* Elevation of at least one of the muscle enzymes (CK, AST, ALT, aldolase, LDH) \>1.5 times upper limit of normal (Appendix 6).
• •* HAQ-DI ≥0.25 (Appendix 7).
• •3. Active disease as per one of the following:
• •* Creatine kinase ≥4×ULN.
• •* Active rashes of dermatomyositis such that CDASI-activity ≥6 (Appendix 8).
• •* Evidence on MRI of active myositis within last 6 months.
• •* Evidence on EMG of active myositis within last 6 months.
• •* Muscle biopsy evidence of active myositis within last 6 months
• •4. Positive, at screening or by documented medical history, for one myositis-specific per pre specified list (Table 3), except for patients with DM who need not have a positive test for a myositis-specific antibody.
• •Table 3. Pre specified List of Autoantibodies
• •Myositis-specific: Target Antigen
• •* Anti-Jo-1: Histidyl-tRNA synthetase
• •* Anti-EJ: Glycyl-tRNA synthetase
• •* Anti-PL-7: Threonyl-tRNA synthetase
• •* Anti-OJ: Isoleucyl-tRNA synthetase
• •* Anti-PL-12: Alanyl-tRNA synthetase
• •* Anti-Mi-2: Nucleosome remodeling deacetylase complex
• •* Anti-TIF1 gamma; Transcription intermediary factor 1
• •* Anti-MDA5: Melanoma differentiation associated protein 5
• •* Anti-SAE: Small ubiquitin-like modifier activating enzyme
• •* Anti-NXP2: Nuclear matrix protein 2
• •* Anti-SRP: Signal recognition particle
• •* Anti-HMGCR: 3hydroxy-3methylglutaryl CoA reductase
• •5. Refractory disease: subject with previous failure (or intolerance) to glucocorticoids and at least two non-glucocorticoids immunosuppressive therapies. An adequate trial of medication defined as at least 12 weeks of therapy or intolerance/adverse reaction necessitating discontinuation.
• •Diffuse cutaneous systemic sclerosis:
• •1. Classified as systemic sclerosis according to the 2013 ACR/EULAR classification criteria, with a total score of ≥9.
• •2. Clinical disease as follows:
• •* Classified as diffuse cutaneous SSc.
• •* 6 years or less since first non-Raynaud's sign or symptom.
• •* Active disease defined as:
• •* MRSS ≥16 with, in the prior 6 months, one or more of the following:
• •* An increase in MRSS of ≥3 units
• •* Involvement of 1 new body area with ≥2 MRSS units
• •* 2 new body areas with ≥1 MRSS unit. OR
• •* Progressive ILD meeting all of the following criteria
• •* Inadequate response or intolerance to at least one treatment, including cyclophosphamide, methotrextate, MMF/mycophenolic acid, nintedanib, rituximab, or tocilizumab.
• •AND one of the following:
• •Evidence of progression on HRCT
• •FVC \<80%
• •DLCO \<80%
• •evidence of FVC decline of 10% (absolute decline)
• •FVC decline of 5% to 9% and DLCO 15%.
• •SLE-related nephritis:
• •1. Clinical diagnosis of SLE consistent with the 2019 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria.
• •2. Active, biopsy-proven, proliferative LN Class III or IV according to the revised ISN/RPS criteria (Krassanairawiwong, 2021: DOI: 10.1007/s11255-020-02732-3).
• •* Overlapping membranous changes are allowed.
• •* Biopsy must be within 12 months prior to screening or during screening.
• •* Further, the following subjects will be excluded:
• •* Significant chronicity defined as: \> 50% glomeruli with global sclerosis
• •* 50% interstitial fibrosis on renal biopsy
• •* 2018 revised International Society of Nephrology (ISN)/Renal Pathology Society (RPS) mNIH chronicity index (CI) ≥5.
• •3. Inadequate response (Urine Protein ≥1.0 g/24 hours - or equivalent value by spot uPCR but not \>7 g/24 hours or equivalent value by spot uPCR) after at least 6 months of treatment with two or more conventional therapies including, but not limited to, belimumab, a calcineurin inhibitor, CYC, mycophenolate mofetil/mycophenolic acid, obinutuzumab, or rituximab.
• •ANCA-associated vasculitis:
• •1. Diagnosis of GPA or MPA according to the 2022 ACR/EULAR Classification Criteria.
• •2. Positive serum PR3-ANCA or MPO-ANCA at screening or by documented medical history.
• •3. Disease activity/course as follows: Subject must fulfill either A or B
• •* A) BVAS/WG ≥3 within prior 60 days (not including the BVAS-WG items of "fever" or "purpura") (Appendix 9) and either:
• •* Failure to achieve sustained remission with glucocorticoids and either cyclophosphamide or rituximab given for at least 4 months, OR
• •* Intolerance or contraindication to alternative treatments
• •* B) Refractory disease defined as:
• •* A history of repeated (\>2) relapses of AAV despite treatment with immunosuppressive agents OR
• •* Requiring prolonged and/or repeated courses of unacceptable doses (as per investigator judgment) of glucocorticoids to maintain adequate control.
• •1. Subject must sign a written ICF prior to any screening procedures.
• •2. Subject must be ≥18 years of age.
• •3. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• •4. Adequate organ function as per table below.
• •Hematology
• •Hemoglobin ≥8.5 g/dL without any transfusion support\[a\]
• •Platelets ≥75,000/uL (without transfusion support within 7 days before the laboratory test).
• •Absolute Lymphocyte Count (ALC) ≥500/uL (with detectable circulating B cells: \>5 cells/mL)
• •Absolute Neutrophil Count (ANC) ≥1,200/µL (prior growth factor support is permitted but must be without support in the 7 days prior to the laboratory test)
• •Hepatic
• •AST and ALT ≤2.5×upper limit of normal (ULN)
• •Total bilirubin ≤1.5xULN, except in subjects with congenital bilirubinemia, such as Gilbert syndrome (in which case direct bilirubin ≤1.5×ULN is required)
• •Renal - Creatinine clearance Estimated glomerular filtration rate ≥30 mL/min/1.73 m2 (measured by CKD-EPI Creatinine Equation)
• •Cardiac
• •Left Ventricular Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA
• •1. Women of childbearing potential must have a negative pregnancy test at screening using a highly sensitive serum pregnancy test (β-human chorionic gonadotropin \[β-hCG\]) at screening and prior to lymphodepletion chemotherapy.
• •2. Female subjects of childbearing potential who have a fertile male sexual partner must agree to use highly effective methods of contraception (failure rate of \<1% per year when used consistently and correctly) specifically 2 forms of contraception, one of which must be a barrier method, from the time of signing the ICF until 1 year after the KYV-101 infusion. Examples of highly effective method of contraception include:
• •* Established use of hormonal methods of contraception associated with inhibition of ovulation (eg, oral, inserted, injected, implanted, transdermal), provided the subject or male subject's female partner plans to remain on the same treatment throughout the entire study and has been using that hormonal contraceptive for an adequate period of time to ensure effectiveness.
• •* Correctly placed copper containing- intrauterine device or intrauterine hormone-replacing system.
• •* Male sterilization with absence of sperm in the post-vasectomy ejaculate.
• •* Female sterilization (bilateral tubal ligation/bilateral salpingectomy or bilateral tubal occlusive procedure (provided that occlusion has been confirmed).
• •* Sexual abstinence, defined as completely and persistently refraining from all heterosexual intercourse (including during the entire period of risk associated with the study treatments) may obviate the need for contraception ONLY if this is the preferred and usual lifestyle of the subject.
• •3. Male subjects, if not surgically sterilized, must agree to use highly effective method of contraception from the time of signing the ICF until 1 year after the KYV-101 infusion.
• •4. Women and men must agree not to donate eggs (ova, oocytes) or sperm, respectively, from time of signing the ICF until at least 1 year after receiving a KYV-101 infusion.