A Phase 1/2 Study of NKX019 in Subjects With Autoimmune Disease (Ntrust-1)

Dose escalation of NKX019 will utilize a "3+3" design to determine the recommended dose(s) for enrolling additional participants across indications. The study will evaluate safety and tolerability, preliminary efficacy, pharmacokinetics, pharmacodynamics 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 LD regimen of Cy alone.

General Inclusion Criteria:

• Age ≥18 and ≤75
• Signed informed consent form 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 prior to the first dose through 1 year after the last dose
• Progression despite maximal tolerated doses of renin-angiotensin system (RAS) blockade agents
• . For participants taking chronic corticosteroids for management of the disease under study, 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
• For participants on immunosuppressives or immunomodulators (other than corticosteroids), all doses must be stable for ≥ 4 weeks prior to Screening

LN-specific Inclusion Criteria:

• Score of 10 or more points on the American College of Rheumatology (ACR) 2019 classification criteria for SLE
• Active biopsy proven lupus nephritis Class III or Class IV without Class V overlap using the 2018 International Society of Nephrology and Renal Pathology Society (ISN/RPS) criteria as evidenced on kidney biopsy during consent or within 6 months before screening. The biopsy must have at least mild to moderate activity score and no more than moderate chronicity index per NIH indices
• Active renal disease as defined by urinary protein:creatinine ratio (UPCR) ≥ 1.5 g/g or proteinuria ≥1.5 g/day on a 24-hour collection and ≤ 7 g/day by either measure
• One or more of the following: positive antinuclear antibodies (ANA) ≥ 1:80 at screening OR positive anti-dsDNA OR positive anti-Smith (anti-Sm)
• Refractory LN defined as having received ≥ 2 prior therapies for LN (immunosuppressant and corticosteroid/or immunomodulatory agent, and corticosteroid at therapeutic range for at least 90 days), and had an inadequate response to therapy despite being on a therapeutic dose for ≥ 90 days

pMN-specific Inclusion Criteria:

• Evidence of pMN by renal biopsy during screening or within 6 months before screening
• Active renal disease at screening defined by spot UPCR ≥ 3.5 g/g or proteinuria ≥ 3.5 g/day on a 24-hour collection
• Presence of primary membranous nephropathy autoantibodies
• Refractory or intolerant to at least 1 induction therapy for pMN (immunosuppressant and corticosteroid or immunomodulatory agent and/corticosteroid) and defined as not achieving a complete remission after 180 days, or partial remission after 90 days

General Exclusion Criteria:

• eGFR < 45 ml/min/1.73 m^2
• Currently requiring renal dialysis or expected to require dialysis during the study period
• Previous solid organ or hematopoietic cell transplant or planned transplant within study treatment period
• Congenital or acquired immunodeficiency resulting in severe infection or those receiving chronic immunoglobulin replacement therapy
• Liver disease or dysfunction, including cirrhosis and/or aspartate aminotransferase, alanine aminotransferase, or bilirubin ≥ 3 times the upper limit of normal
• 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
• Bone marrow insufficiency unrelated to active underlying autoimmune disease with white blood cell count < 3,000/mm^3; hemoglobin levels < 9 gm/dL absolute neutrophil count < 1500/mm^3; platelet count < 100,000/mm^3
• Major cardiac disease, abnormalities, or interventions as defined by, but not limited to:

• Uncontrolled angina or unstable life-threatening arrhythmias
• History of myocardial infarction within 12 weeks prior to the first dose of NKX019
• Any prior coronary artery bypass graft surgery
• ≥ Class III New York Heart Association (NYHA) congestive heart failure (CHF), significantly decreased ejection fraction (EF ≤ 40%), or severe cardiac insufficiency.
• Prolongation of the QT interval corrected for heart rate (QTc) (Fridericia) interval of > 480 msec
• 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
• Uncontrolled hypertension (systolic BP > 160mmHg and/or diastolic BP > 90mmHg) despite therapy
• Active bleeding disorders
• 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
• Pregnancy, breast feeding or, if of childbearing potential, not using adequate contraceptive precautions
• Current infection requiring active systemic anti-infective therapy or recent acute infection requiring systemic therapy within 30 days of planned LD
• History of positive HIV antibody or test positive at screening, Hepatitis B or C positive at screening, active tuberculosis (TB) or latent TB requiring suppressive therapy
• 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
• 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
• Prior cellular therapy including mesenchymal, CAR-T or CAR-NK cells
• 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 active CNS lupus within 1 year prior to screening
• Any other acute or chronic medical or psychiatric condition, or known laboratory abnormality that, in the Investigator's opinion, is expected to interfere or impact study participation
• Current participation in another interventional clinical trial

a. Potential participants can be considered for enrollment after investigational product washout period of 5 half-lives or 30 days, whichever is longer

• Currently taking or known need for any of the medications prohibited in the study protocol
• Known hypersensitivity or contraindications to the study treatment including LD; or other components such as human serum albumin or dimethyl sulfoxide

LN-specific Exclusion Criteria:

• Known clinically active antiphospholipid antibody syndrome (APS); or high-risk profile