NKX019, Intravenous Allogeneic Chimeric Antigen Receptor Natural Killer Cells (CAR NK), in Participants With Immune-Mediated Diseases (Ntrust-2)

Overview

This is an open-label, multi-center, multi-cohort, non-randomized Phase 1 study to determine the safety and tolerability of NKX019 (allogeneic CAR NK cells targeting CD19) in participants with Immune-Mediated Diseases (IMD) including systemic sclerosis [SSc], idiopathic inflammatory myopathies [IIM], and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [AAV].

Description

This is a dose-finding study of NKX019 and will be conducted in 2 parts:

Part 1 dose escalation will utilize a "3+3" design to determine the recommended dose for expansion for Part 2. The study will evaluate safety and tolerability, preliminary activity, cellular kinetics, pharmacodynamics, and immunogenicity in participants with IMD. Participants will receive a cycle consisting of single-agent lymphodepletion with cyclophosphamide followed by three doses of NKX019.

Eligibility

Inclusion Criteria:

1. Age ≥18 and ≤65

   SSc

2. Meets the 2013 American College of Rheumatology (ACR)/European Alliance of

   Associations for Rheumatology (EULAR) classification criteria for SSc

3. Meet criteria a and/or b:
   1. Severe skin involvement defined as mRSS ≥ 30 or active skin disease defined as mRSS ≥ 15 at screening and one or more of the following within the prior 6 months of screening:
      • 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
   2. Moderate to severe Interstitial Lung Disease (ILD) defined by evidence of ILD

      on High-resolution computed tomography (HRCT) and FVC < 70% of predicted or DLCO (hemoglobin corrected) < 70% of predicted or ILD on HRCT and progressive ILD meeting at least 2 of the following 3 criteria within the prior 6 months of

      screening

      • Worsening respiratory symptoms
      • Evidence of progression on HRCT, or
      • Evidence of absolute decline in FVC ≥ 5% (Raghu et al 2022)

4. Presence of anti-nuclear antibody ≥ 2 x upper limit of normal (ULN)
5. 10 years or less since the first non-Raynaud's sign or symptom
6. Inadequate response or intolerance to at least one treatment, including cyclophosphamide, methotrexate, MMF/mycophenolic acid, nintedanib, rituximab, or tocilizumab

   IIM

7. Diagnosis for IIM as per 2017 ACR/EULAR Classification Criteria
8. One positive myositis antibody
9. Activity defined as manual muscle testing (MMT-8) score <136/150
10. Creatinine kinase or aldolase ≥ 1.5 x ULN (except for DM) and Clinician Global Assessment ≥ 2 cm with at least one of the following:
    1. Evidence on magnetic resonance imaging (MRI) of active myositis within the last 6 months
    2. Electromyography (EMG) with active myositis within the last 6 months
    3. Muscle Biopsy of active myositis within last 6 months
    4. Global extramuscular activity score ≥ 2 cm per Clinician Visual Analog Scale (VAS) (0-10 cm)
11. Refractory disease defined as ≥ 6 months failure (or intolerance) to at least two

    immunosuppressive therapies (including glucocorticoids)

    AAV

12. Meets the 2022 ACR/EULAR classification criteria for Granulomatosis with

    Polyangiitis (GPA) (Robson 2022) or Microscopic Polyangiitis (MPA) (Suppiah 2022)

13. Relapsed or refractory AAV despite repeated treatment with immunosuppressive agents or requiring prolonged and/or repeated courses of unacceptable doses of glucocorticoids to maintain disease control
14. Positive test for anti-proteinase-3 (PR3-ANCA) or anti-myeloperoxidase (MPO-ANCA) at screening
15. Have at least one "major" item, or at least 3 other items, or at least 2 renal items on the BVAS version 3

Exclusion Criteria:

1. eGFR < 45 ml/min/1.73m2
2. Currently requiring renal dialysis or expected to require dialysis during the study period
3. Previous solid organ or hematopoietic cell transplant or planned transplant within study treatment period
4. Congenital or acquired immunodeficiency resulting in severe infection or those receiving chronic immunoglobulin replacement therapy
5. Liver disease or dysfunction, including cirrhosis and/or bilirubin ≥ 3 times the upper limit of normal
6. Pulmonary comorbidity including chronic obstructive pulmonary disease or asthma requiring daily oral steroids, resting hypoxemia (<92% oxygen saturation via pulse oximetry) on room air, or significant smoking history (i.e. >10 pack/year)
7. White blood cell count < 3,000/mm^3; hemoglobin levels ≤ 9 g/dL; absolute neutrophil count (ANC) ≤ 2,000/mm^3; platelet count ≤ 100,000/mm^3, and blood transfusion within 60 days prior to LD
8. Major cardiac disease, abnormalities, or interventions as defined by, but not limited to:
   1. Uncontrolled angina or unstable life-threatening arrhythmias
   2. History of myocardial infarction within 12 weeks prior to the first dose of NKX019
   3. Any prior coronary artery bypass graft surgery
   4. ≥ Class III New York Heart Association (NYHA) congestive heart failure (CHF), significantly decreased ejection fraction (EF ≤ 40%), or severe cardiac insufficiency
   5. Prolongation of the QT interval corrected for heart rate (QTc) (Fridericia) interval of > 480 msec
   6. Peripheral artery bypass graft surgery, pulmonary embolism, or other ≥ Grade 2 thrombotic or embolic events within 12 weeks prior to the first dose of NKX019
9. Active bleeding disorders
10. Pregnancy, breast feeding or, if of childbearing potential, not using adequate contraceptive precautions
11. Current infection requiring active systemic anti-infective therapy or recent acute infection requiring systemic therapy within 30 days of planned LD
12. History of positive HIV test at screening, Hepatitis B or C positive at screening, active tuberculosis (TB) or latent TB requiring suppressive therapy
13. Major surgery within 28 days prior to the first dose of NKX019
14. Malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision. Subjects with cervical dysplasia that is cervical intraepithelial neoplasia but have been treated with conization or loop electrosurgical excision procedure and have had a normal repeat Papanicolaou test are allowed
15. Prior cellular therapy
16. Central nervous system (CNS) comorbidity or any autoimmune disease with CNS involvement within 90 days prior to the first dose of NKX019 as well as evidence of CNS related autoimmune manifestations within 1 year prior to screening

SSc Exclusion Criteria:

1. Patients with ILD requiring supplemental oxygen therapy or FVC ≤ 45% of predicted or diffusing capacity of the lung for CO (DLCO) ≤ 40% of predicted at screening
2. Pulmonary arterial hypertension (PAH) on right heart catheterization requiring PAH specific treatment
3. Gastrointestinal (GI) dysmotility requiring total parenteral nutrition (TPN)
4. Anti-centromere Ab positive
5. Renal crisis or Pericardial tamponade within 6 months prior to enrollment
6. Current gangrene of a digit

IIM Exclusion Criteria:

1. Severe proximal muscle atrophy of upper or lower extremity on Magnetic resonance imaging (MRI) or clinical exam
2. MMT-8 of ≤ 80
3. Findings of muscular inflammation or myopathy due to another cause, such as inclusion body myositis, cancer-associated myositis (myositis diagnosed within 2 years of cancer), amyloid myopathy, muscular dystrophy, metabolic myopathies, or myositis in the context of significant overlap with another systemic IIM rheumatologic disease (overlap myositis), except with Sjögren's syndrome
4. Patients with ILD requiring O2 therapy and/or FVC ≤ 45% of predicted
5. Generalized severe musculoskeletal or neuro-muscular conditions other than IIM

AAV Exclusion Criteria:

1. Alveolar hemorrhage requiring invasive pulmonary ventilation support
2. Required dialysis or plasma exchange within 12 weeks prior to screening
3. Any other known disease that may interfere with the assessments including eosinophilic GPA (Churg-Strauss), anti-glomerular basement membrane, systemic lupus erythematosus, IgA vasculitis (Henoch Schönlein), rheumatoid vasculitis, or cryoglobulinemic vasculitis