A Phase 1/2 Study of NKX019 in Subjects With Immune-Mediated Diseases (Ntrust-2)

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• General Inclusion Criteria:
• Age ≥18 and ≤75 years
• Signed informed consent and ability to adhere to the study visit schedule and comply with other protocol requirements
• Women of childbearing potential must have negative pregnancy tests at screening and baseline and agree to abstinence or acceptable birth control from 2 weeks before the first dose through 1 year after the last dose
• Participants taking corticosteroids must be at a stable prednisone (or equivalent) dose ≤20 mg/day for ≥14 days before Screening
• Participants on immunosuppressives or immunomodulators (other than corticosteroids) must have stable dosing for ≥4 weeks before Screening
• eGFR (2021 CKD-EPI equation) ≥45 mL/min/1.73 m² at screening
  • For Subjects with Systemic Sclerosis (SSc):
• Meets the 2013 ACR/EULAR classification criteria for SSc
• Severe skin involvement defined as modified Rodnan skin score (mRSS ≥30) or active skin disease (mRSS ≥15 with, within the prior 6 months, an mRSS increase ≥3 units, 1 new body area with ≥2 mRSS units, or 2 new body areas with ≥1 mRSS unit each), OR moderate-to-severe interstitial lung disease (ILD) on HRCT with FVC <70% predicted or DLCO <70% predicted (or ILD on HRCT with progression per protocol-defined criteria)
• 10 years or less since the first non-Raynaud's sign or symptom
• Inadequate response or intolerance to at least one prior treatment, including cyclophosphamide, methotrexate, MMF/mycophenolic acid, nintedanib, rituximab, or tocilizumab
  • For Subjects with Idiopathic Inflammatory Myopathies (IIM):
• Diagnosis of IIM per the 2017 ACR/EULAR Classification Criteria
• One positive myositis antibody (historical)
• Disease activity defined as manual muscle testing (MMT-8) score <136/150
• Creatine kinase or aldolase ≥1.5×ULN and Clinician Global Assessment ≥2 cm, with evidence of active myositis (MRI, EMG, or biopsy within 6 months) or MDAAT Global Extramuscular Activity Score ≥2 cm; participants with DM, JDM, or ASyS may qualify with CK/aldolase <1.5×ULN if Clinician Global Assessment ≥2 cm and either of the above is met or CDASI ≥15, pending discussion with the medical monitor
• Inadequate response to ≥3 months of at least 2 immunosuppressive therapies (including glucocorticoids)
  • For Subjects with ANCA-Associated Vasculitis (AAV):
• Meets the 2022 ACR/EULAR classification criteria for Granulomatosis with Polyangiitis (GPA) or Microscopic Polyangiitis (MPA)
• Relapsed or refractory AAV despite repeated immunosuppressive treatment, or requiring prolonged/repeated unacceptable glucocorticoid doses to maintain disease control
• Positive anti-proteinase-3 (PR3-ANCA) or anti-myeloperoxidase (MPO-ANCA) at screening
• Meets BVAS version 3 activity threshold (≥1 major item, ≥3 other items, or ≥2 renal items)
  • For Subjects with Rheumatoid Arthritis (RA):
• Documented diagnosis of RA, meeting the 2010 ACR/EULAR classification criteria
• Rheumatoid Factor (RF) or Anti-Citrullinated Protein Antibody (ACPA) positive
• CRP >3 mg/L
• Inadequate response, defined as failure to achieve a clinically meaningful improvement (eg, ACR50 response or DAS28 remaining >3.2) after ≥12 weeks of therapy with: ≥1 conventional synthetic DMARD (eg, methotrexate, leflunomide, sulfasalazine, hydroxychloroquine) plus either: ≥2 biologic DMARDs with distinct mechanisms of action (eg, TNF inhibitors, abatacept, anti-IL-6/IL-6R, rituximab) or ≥1 biologic DMARD and ≥1 targeted synthetic DMARD (eg, a JAK inhibitor), having failed no more than 4 biologics or targeted synthetic DMARDs with unique mechanisms of action
• Minimum of 6 swollen joint counts (based on the 66-joint count) and 6 tender joint counts (based on the 68-joint count) at Screening (28-joint counts used at Baseline and thereafter)
  • General Exclusion Criteria:
• Currently requiring or expected to require renal dialysis during the study
• Previous solid organ or hematopoietic cell transplant, or planned transplant during the study treatment period
• Congenital or acquired immunodeficiency resulting in severe infection, or receiving chronic immunoglobulin replacement therapy
• Liver disease or dysfunction, including cirrhosis and/or bilirubin ≥3× the upper limit of normal
• Pulmonary comorbidity (eg, COPD or asthma requiring daily oral steroids), resting hypoxemia (<92% oxygen saturation on room air), or significant smoking history (>10 pack-years) with active pulmonary disease
• ILD requiring supplemental oxygen therapy, FVC <45% predicted, or DLCO ≤40% predicted at screening
• White blood cell count <3,000/mm³, hemoglobin levels ≤9 g/dL, absolute neutrophil count ≤1,500/mm³, platelets ≤100,000/mm³, or blood transfusion within 60 days before lymphodepletion (LD)
• Major cardiac disease, abnormalities, or interventions (eg, uncontrolled angina, myocardial infarction within 12 weeks, prior coronary artery bypass graft surgery, ≥Class III congestive heart failure (CHF), significantly decreased ejection fraction (EF) ≤40%, prolongation of the QT interval corrected for heart rate (QTc) >480 msec, or a ≥Grade 2 thrombotic/embolic event within 12 weeks of the first dose
• Active bleeding disorder
• Overlapping autoimmune condition for which the condition or its treatment may affect study assessments or outcomes
• Pregnancy, breastfeeding, or, if of childbearing potential, not using adequate contraception
• Current infection requiring active systemic anti-infective therapy, or a recent acute infection treated systemically within 30 days of planned LD; participants who are asymptomatic and being treated for a non-systemic infection (eg, urinary tract infection) are not excluded on this basis and may be eligible after discussion with the Sponsor Medical Monitor
• History of positive human immunodeficiency virus (HIV) antibody or PCR test, or a positive test at screening, Hepatitis B or C positive at screening, or active or latent tuberculosis requiring suppressive therapy
• Major surgery within 28 days before the first dose of NKX019, or any surgery from which the participant has not recovered or has ongoing complications
• Malignancy within 5 years of screening, except treated basal/squamous cell carcinoma or treated cervical dysplasia with a normal repeat Pap test
• Prior cellular therapy, including mesenchymal, CAR-T, or CAR-NK cells or CD19 directed therapy
• Central nervous system (CNS) comorbidity, including history or presence of seizure disorder, cerebrovascular ischemia/hemorrhage (including transient ischemic attack), dementia, cerebellar disease, or any immune-mediated disease with CNS involvement within 90 days before the first dose of NKX019, or evidence of CNS-related autoimmune manifestations within 1 year before screening (eg, aseptic meningitis, ataxia, CNS vasculitis, cranial neuropathy, demyelinating syndrome, optic neuritis, psychosis, seizures, or transverse myelitis)
• Any other acute or chronic medical or psychiatric condition, or laboratory abnormality, that in the Investigator's or Sponsor's opinion would increase the risk of participation, interfere with informed consent, study compliance, or interpretation of results, or make the participant inappropriate for the study, including clinically significant drug or alcohol abuse within 2 years before screening
• Current participation in another interventional clinical trial; participants may be considered after an investigational product washout of 5 half-lives or 30 days, whichever is longer
• Known hypersensitivity or contraindication to the study treatment, including lymphodepletion, or to other components such as human serum albumin or dimethyl sulfoxide
  • SSc Exclusion Criteria:
• Moderate-to-severe pulmonary arterial hypertension (PAH) on right heart catheterization requiring PAH-specific treatment (well-controlled mild PAH is permitted)
• Gastrointestinal dysmotility requiring total parenteral nutrition
• Renal crisis or pericardial tamponade within 6 months before enrollment
• Current gangrene of a digit
• Extensive, advanced fibrotic ILD on screening HRCT involving >50% of the total lung parenchyma, or other HRCT findings indicative of end-stage fibrotic lung disease with limited potentially reversible parenchyma
  • IIM Exclusion Criteria:
• Severe chronic proximal muscle involvement on MRI (≥15% fibro-fatty replacement or ≥15% muscle atrophy in core muscle groups, or a combined extent >30%)
• MMT-8 ≤80
• Muscular inflammation or myopathy due to another cause (eg, inclusion body myositis, cancer-associated myositis, amyloid myopathy, muscular dystrophy, metabolic myopathies, or overlap myositis other than with Sjögren's syndrome)
• Generalized, severe musculoskeletal or neuro-muscular condition other than IIM
• Immune-mediated necrotizing myopathy
• Clinically significant calcinosis (cutaneous or subcutaneous) that, in the Investigator's judgment, could confound assessment of muscle strength, physical function, or cutaneous disease
  • AAV Exclusion Criteria:
• Alveolar hemorrhage requiring invasive pulmonary ventilation support
• Required dialysis or plasma exchange within 12 weeks before screening
• Any other known disease that may interfere with assessments, including eosinophilic GPA (Churg-Strauss), anti-glomerular basement membrane disease, systemic lupus erythematosus, IgA vasculitis (Henoch-Schönlein), rheumatoid vasculitis, or cryoglobulinemic vasculitis