NKX019, Intravenous Allogeneic Chimeric Antigen Receptor Natural Killer Cells (CAR NK), in Adults With Autoimmune Disease (Ntrust-1)

Phase 1

Recruiting

• Conditions: Lupus Nephritis; Glomerulonephritis; Primary Membranous Nephropathy
• Interventions: Drug: NKX019; Drug: Fludarabine, Cyclophosphamide

• Registration Number: NCT06557265
• Lead Sponsor: Nkarta, Inc.

Brief Summary

This is an open-label, multi-center, non-randomized Phase 1 study to determine the safety and tolerability of NKX019 (allogeneic CAR NK cells targeting CD19) in participants with active lupus nephritis (LN) or primary membranous nephropathy (pMN).

Detailed 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 in participants with active LN or pMN. 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.

Study Timeline

• Study Start: 2024-06-13
• Study First Submitted: 2024-07-10
• Study First Submitted QC: 2024-08-13
• Study First Posted: 2024-08-16
• Status Verified: 2025-05
• Last Update Submitted: 2025-06-25
• Last Update Posted: 2025-06-27
• Primary Completion: 2027-04
• Study Completion: 2027-04-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 48

Inclusion Criteria

1. Age ≥18 and ≤65
2. Progression despite maximal tolerated doses of renin-angiotensin system (RAS) blockade agents
3. For participants taking chronic corticosteroids for management of the disease under study, stable dose for ≥ 14 days before the screening visit with planned reduction to ≤ 5 mg prednisone by the time of LD start
4. Negative SARS-CoV-2 test

LN-specific Inclusion Criteria:

1. Score of 10 or more points on the American College of Rheumatology (ACR) 2019 classification criteria for SLE
2. Active nephritis Class III, IV, and/or 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. Per NIH indices, subjects must have at least moderate activity score and no more than moderate chronicity index
3. Active renal disease as defined by urinary protein:creatinine ratio (UPCR) ≥ 1.5 g/g or proteinuria ≥1.5 g/day and ≤ 7 g/day
4. Positive antinuclear antibodies (ANA) ≥ 1:80 OR anti-dsDNA OR anti-Smith (anti-Sm)
5. Refractory LN defined as having received ≥ 2 prior therapies for LN

pMN-specific Inclusion Criteria:

1. Evidence of pMN by renal biopsy during screening or within 6 months before screening
2. Active renal disease at screening defined by UPCR ≥ 3.5 g/g or proteinuria ≥ 3.5 g/day
3. Positive anti-PLA2R antibodies
4. Refractory or intolerant to either B cell-depleting agents and/or cyclophosphamide and/or calcineurin inhibitors defined as not achieving a complete remission after 180 days, or partial remission after 90 days

General

Exclusion Criteria

1. eGFR < 45 ml/min/1.73 m^2

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 aspartate aminotransferase, alanine aminotransferase, 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 gm/dL absolute neutrophil count < 2,000/mm^3; platelet count < 100,000/mm^3

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
   7. Uncontrolled hypertension (systolic blood pressure > 160mmHg and diastolic > 90mmHg) despite therapy

9. Active bleeding disorders

10. Any overlapping autoimmune condition for which the condition itself or the treatment of that condition may affect the study assessments or outcomes; conditions that could cause a secondary nephropathy; or kidney biopsy-confirmed significant renal disease other than disease under study

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

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

13. 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

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 active CNS lupus within 1 year prior to screening

17. 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

18. Prior immunosuppressive/immunomodulating therapies, including investigational agents, within 14 days or 5 half-lives of the drug (whichever is shorter), prior to LD. Note: Prior antibody therapies not allowed within 90 days of LD

19. Currently taking or known need for any of the medications prohibited in the study protocol

20. 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:

1. Known antiphospholipid antibody syndrome (APS); or high-risk profile

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
NKX019 - CAR NK cell therapy	NKX019	Phase 1: NKX019 plus fludarabine and cyclophosphamide
NKX019 - CAR NK cell therapy	Fludarabine, Cyclophosphamide	Phase 1: NKX019 plus fludarabine and cyclophosphamide

Primary Outcome Measures

Name	Time	Method
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	From the first administration of NKX019 until the last administration of any study treatment + 30 days	Incidence and severity of treatment-emergent adverse events will be evaluated
Incidence of dose-limiting toxicities (DLTs) [Safety and Tolerability]	The first 29 days after the first NKX019 dose	Incidence of DLTs will be evaluated

Secondary Outcome Measures

Name	Time	Method
LN only: Number of participants who achieved complete renal response (CRR) and partial renal response (PRR)	Up to 2 years after NKX019 infusion	Complete renal response and partial renal response to treatment will be assessed based on European Alliance of Associations for Rheumatology (EULAR)/European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA) criteria (Bertsias 2012)
LN only: Change from baseline in titer of anti-double-stranded DNA (anti-dsDNA) antibodies levels	Up to 2 years after NKX019 infusion
Time to Cmax (Tmax) of NKX019 in peripheral blood	Up to 2 years after NKX019 infusion
LN only: Change from baseline in complement levels	Up to 2 years after NKX019 infusion
LN only: Assessment of Lupus Low Disease Activity State (LLDAS) and Definition of Remission in SLE (DORIS) remission	Up to 2 years from NKX019 infusion
LN only: Change from baseline in Systemic Lupus Erythematosus (SLE) Disease Activity Index 2000 (SLEDAI-2K) score	Up to 2 years from NKX019 infusion	The SLEDAI-2K score falls between 0 and 105. A higher score represents greater disease activity
pMN only: Number of participants who achieved complete remission (CR) and partial remission (PR) (Couser 2017)	Up to 2 years from NKX019 infusion
pMN only: Change from baseline in serum albumin	Up to 2 years after NKX019 infusion
pMN only: % change from baseline in estimated glomerular filtration rate (eGFR)	Up to 2 years after NKX019 infusion
Maximum Concentration (Cmax) of NKX019 in peripheral blood	Up to 2 years after NKX019 infusion
Area Under the Concentration-time Curve (AUC) of NKX019 in peripheral blood	Up to 2 years after NKX019 infusion
Half-life (t1/2) of NKX019 in peripheral blood	Up to 2 years after NKX019 infusion
Duration of Persistence of NKX019 in peripheral blood	Up to 2 years after NKX019 infusion
Incidence of positive anti-NKX019 antibodies to assess immunogenicity of NKX019 over time	Up to 2 years after NKX019 infusion
pMN only: Change from baseline in titer of anti-phospholipase A2 receptor (PLA2R) antibodies	Up to 2 years after NKX019 infusion

Trial Locations

Locations (1)

Nkarta Investigational Site; 🇵🇷 Manatí, Puerto Rico