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

A Phase 1/2 Study of NKX019, a CD19 Chimeric Antigen Receptor Natural Killer (CAR NK) Cell Therapy, in Subjects With Immune-Mediated Diseases

This is a Phase 1/2, open-label, multi-center, multi-cohort, non-randomized dose escalation and dose expansion basket study to determine the safety and tolerability of NKX019 (allogeneic CAR NK cells targeting CD19) in participants with autoimmune diseases.

Dose escalation of NKX019 will utilize a "3+3" design to determine the recommended dose(s) for expansion for enrolling additional participants across indications. The study will evaluate safety and tolerability, preliminary efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity in participants with autoimmune diseases. Participants will receive a cycle consisting of lymphodepletion with fludarabine and cyclophosphamide (Flu/Cy) followed by three doses of NKX019. Participants who are cytopenic may receive a modified lymphodepletion regimen of Cy alone.

General Inclusion Criteria:

1. Age ≥18 and ≤75
2. Signed informed consent form and ability to adhere to the study visit schedule and comply with other protocol requirements
3. Women of childbearing potential must have negative pregnancy tests at screening and baseline, and agree to abstinence or acceptable birth control from 2 weeks prior to the first dose through 1 year after the last dose
4. For participants taking corticosteroids, the prednisone (or equivalent) dose must be ≤20 mg/day at 2 weeks prior to Screening and stable for ≥ 14 days before start of Screening
5. For participants on immunosuppressives or immunomodulators (other than corticosteroids), all doses must be stable for ≥ 4 weeks prior to Screening
6. eGFR as calculated by the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation of ≥45 mL/min/1.73 m2 at screening

SSc Inclusion Criteria:

1. Meets the 2013 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) classification criteria for SSc

2. Meet criteria a and/or b:

   a. 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:

   i. An increase in mRSS of ≥ 3 units

   ii. Involvement of 1 new body area with ≥ 2 mRSS units

   iii. 2 new body areas with ≥ 1 mRSS unit

   b. 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 or alveolar volume 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:

   i. Worsening respiratory symptoms

   ii. Evidence of progression on HRCT, or

   iii. Evidence of absolute decline in FVC ≥ 5%

3. 10 years or less since the first non-Raynaud's sign or symptom

4. Inadequate response or intolerance to at least one treatment, including cyclophosphamide, methotrexate, MMF/mycophenolic acid, nintedanib, rituximab, or tocilizumab

IIM Inclusion Criteria:

1. Diagnosis for IIM as per 2017 ACR/EULAR Classification Criteria

2. One positive myositis antibody

3. Activity defined as manual muscle testing (MMT-8) score <136/150

4. Creatinine kinase or aldolase ≥ 1.5 x ULN 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 global assessment (CGA) using a visual analog scale (VAS) (0-100 mm)

   Note: Participants with DM or ASyS may be eligible despite CK or aldolase <1.5 × ULN, provided they have a Clinician Global Assessment ≥2 cm and meet at least one of criteria (a)-(d) above OR have a CDASI score of ≥20.

5. Inadequate response to treatment defined as ≥ 3 months failure (or intolerance) to at least 2 immunosuppressive therapies (including glucocorticoids)

AAV:

1. Meets the 2022 ACR/EULAR classification criteria for Granulomatosis with Polyangiitis (GPA) (Robson 2022) or Microscopic Polyangiitis (MPA) (Suppiah 2022)
2. 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
3. Positive test for anti-proteinase-3 (PR3-ANCA) or anti-myeloperoxidase (MPO-ANCA) at screening
4. Have at least one "major" item, or at least 3 other items, or at least 2 renal items on the BVAS version 3

RA Inclusion Criteria:

1. Documented diagnosis of RA, meeting the 2010 ACR/EULAR classification criteria

2. Rheumatoid Factor (RF) or Anti-Citrullinated Protein Antibody (ACPA) positive

3. CRP >3 mg/L

4. Inadequate response, defined as failure to achieve a clinically meaningful improvement (eg, ACR50 response or DAS28-low disease activity [ie, DAS28 >3.2]) after at least 12 weeks of therapy with the following:

   1. At least 1 conventional synthetic DMARD (csDMARD) (eg, methotrexate, leflunomide, sulfasalazine, hydroxychloroquine) AND
   2. Either of the following:

   i. At least 2 biologic (b) DMARDs (eg, TNF inhibitors, abatacept, anti-IL-6 or anti-IL-6R, rituximab) with distinct mechanisms of action (MoAs)

   OR

   ii. At least 1 bDMARD and at least 1 targeted synthetic DMARD (tsDMARD) (eg, JAK inhibitor)

   AND

   c. Have failed no more than 3 biologics or tsDMARDs with unique mechanisms of action

5. Minimum of 6 swollen joint counts (SJCs) and 6 tender joint counts (TJCs) according to joint assessment

General 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) with active pulmonary disease

7. Participants with ILD with any of the following:

   1. Requires supplemental oxygen therapy
   2. FVC <45% of predicted
   3. Diffusing capacity of the lung (DLCO) corrected for alveolar volume (AV) or Hemoglobin (Hgb) ≤ 40% of predicted at screening (per Investigator or Sponsor judgement)

   i. If the participant has a historical FVC value within the last year that exceeds the 45% threshold, discuss with the Medical Monitor should the Screening FVC be <45% predicted

8. Bone marrow insufficiency unrelated to active underlying autoimmune disease with white blood cell count < 3,000/mm^3; hemoglobin levels ≤ 9 g/dL; absolute neutrophil count (ANC) ≤ 1500/mm^3; platelet count ≤ 100,000/mm^3, and blood transfusion within 60 days prior to LD

9. 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

10. Active bleeding disorders

11. Any overlapping autoimmune condition for which the condition or the treatment of the condition may affect the study assessments or outcomes (eg, anti-GBM antibody glomerulonephritis or any condition for additional immunosuppression is indicated); clinically significant conditions that could cause a secondary nephropathy (eg, infections, liver disease, tumors or drugs); or kidney biopsy-confirmed significant renal disease other than disease under study (eg, diabetic nephropathy, hypertensive nephropathy). Overlapping conditions for which the condition or treatment is not expected to affect assessments or outcomes (eg, Sjögren's syndrome, rheumatoid arthritis) are not excluded

12. Pregnancy, breast feeding or, if of childbearing potential, not using adequate contraceptive precautions

13. Current infection requiring active systemic anti-infective therapy or recent acute infection requiring systemic therapy within 30 days of planned LD

14. History of positive HIV test at screening, Hepatitis B or C positive at screening, active tuberculosis (TB) or latent TB requiring suppressive therapy

15. Major surgery within 28 days prior to the first dose of NKX019 or any surgery from which the participant has not recovered or has ongoing complications

16. Malignancy within 5 years of screening, with the exception of basal and squamous cell carcinomas treated by complete excision. Participants 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

17. Prior cellular therapy including mesenchymal, CAR-T or CAR-NK cells

18. 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. Moderate-to-severe Pulmonary arterial hypertension (PAH) on right heart catheterization requiring PAH specific treatment. Those participants with mild PAH (as defined by the 2022 ECS/ERS Guidelines, [Humbert 2023]) well controlled on therapy can be enrolled
2. Gastrointestinal (GI) dysmotility requiring total parenteral nutrition (TPN)
3. Renal crisis or Pericardial tamponade within 6 months prior to enrollment
4. Current gangrene of a digit

IIM Exclusion Criteria:

1. Evidence of severe chronic proximal muscle involvement of upper or lower extremities, based on Magnetic Resonance Imaging (MRI) defined as:

   1. ≥15% fibro-fatty replacement in core muscle groups (including gluteus and vastus musculature), and/or
   2. ≥15% muscle atrophy in these regions Participants will also be excluded if the combined extent of fibro-fatty replacement and muscle atrophy exceeds 30% in aggregate

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. Generalized severe musculoskeletal or neuro-muscular conditions other than IIM

5. Immune-mediated necrotizing myopathy

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