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

Inclusion Criteria

• Age ≥18 and ≤70
• 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 ≤40 mg/day at 6 weeks prior to Screening and stable for ≥ 14 days before start of Screening
• Negative SARS-CoV-2 test
• For subjects 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 with or without Class V using the 2018 International Society of Nephrology and Renal Pathology Society (ISN/RPS) criteria (Bajema 2018) as evidenced on kidney biopsy during screening or within 6 months before screening. For subjects with primarily Class III or Class IV LN, the biopsy must have at least mild to moderate activity score (≥4/24) and no more than moderate chronicity index (≤ 6/12) 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
• Positive antinuclear antibodies (ANA) ≥ 1:80 OR anti-dsDNA OR 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
• Positive anti-PLA2R antibodies
• Refractory or intolerant to at least one 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
• White blood cell count < 3,000/mm^3; hemoglobin levels < 9 gm/dL absolute neutrophil count < 2,000/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 blood pressure > 160mmHg and diastolic > 90mmHg) despite therapy
• Active bleeding disorders
• Any overlapping autoimmune condition for which the condition itself or the treatment of that condition may affect the study assessments or outcomes; clinically significant conditions that could cause a secondary nephropathy; or kidney biopsy-confirmed significant renal disease other than disease under study
• 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
• 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
• Prior cellular therapy
• 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
• Disease-modifying therapies for disease under study or investigational agents within 14 days or 5 half-lives of the drug (whichever is shorter), prior to LD. a. For those subjects on B-cell-depleting or -modulating drugs (ie, rituximab, belimumab), the subject must have received first dose ≥ 6 months prior to LD
• 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