Anca Askanase’s research while affiliated with Aurinia Pharmaceuticals and other places

Introduction Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune disease with clinical manifestations that affects nearly every organ and induces myriad laboratory abnormalities. B-cell dysfunction is central to SLE pathophysiology, including autoantibody production and cytokine secretion. Treatment of SLE consists of immunosuppressive therapy to prevent organ damage and improve quality of life. Recently, CD19-directed chimeric antigen receptor (CAR) T-cell therapy has shown promising early results in patients with SLE and lupus nephritis (LN) via transient B-cell depletion and, possibly, immunologic reset to a more naïve B cell repertoire. More widespread use has been limited by cumbersome infrastructure requirements and treatment delays associated with bespoke manufacturing of CAR T cells, as well as concerns about side effects from chemotherapy used for lymphodepletion (LD). Allogeneic NK cell-based therapies allow off-the-shelf use, obviating the necessity to wait for manufacture of autologous T-cell therapies. NKX019 is a cryopreserved product, composed of expanded NK cells engineered to express a humanized CAR against CD19, fused to co-stimulatory (OX40) and signaling (CD3ζ) domains to enhance target cell killing. NKX019 also expresses a membrane-bound interleukin-15 (IL-15) to serve as an autocrine growth factor and thereby increase NKX019 persistence, with an in vivo half-life of up to 28 days without systemic IL-2 support. Whereas autologous CAR T cells depend on host cytokine surges induced by lymphodepletion, the membrane-bound IL-15 construct also enables the use of NKX019 without fludarabine-containing LD. Preclinical characterization has shown that NKX019, unlike non-engineered NK cells, effectively kills B cells from patients with various autoimmune diseases, including SLE. Lacking a T-cell receptor and the consequent clonal expansion, NKX019 has been safely administered to patients with B-cell malignancies with minimal elevations of inflammatory cytokines and without side effects typically associated with CAR T-cell therapies, such as severe cytokine release syndrome or neurotoxicity (Dickinson 2023). Hence, clinical evaluation of NKX019 is being undertaken in this Phase 1 study in subjects with refractory SLE with or without LN. Methods This is a single center, open-label, non-randomized Phase 1 study of NKX019 in adult (≥18 years) patients with SLE with or without LN (NCT06518668). Patients with SLE must have a score of 8 or more points on the Hybrid Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and those with SLE and LN must have biopsy-proven active LN (Class III or IV with or without Class V using the 2018 International Society of Nephrology and Renal Pathology Society criteria) with proteinuria after at least 2 prior lines of therapy. Patients with prior hematopoietic transplantation or cellular therapy (including CAR T or CAR NK), significant organ dysfunction or severe cytopenias are ineligible. The study will evaluate safety and tolerability, pharmacokinetics (PK), immunogenicity, and activity of NKX019, including changes in autoantibody levels and improvement in SLE disease-related activity. NKX019 is manufactured from NK cells obtained from healthy adult donors. The study will evaluate NKX019 dosed at 1 × 109 viable CAR+ NK cells administered on Days 0, 7, and 14 following single agent cyclophosphamide lymphodepletion. The primary endpoint is incidence of adverse events, dose-limiting toxicities, and clinically significant laboratory abnormalities. Secondary endpoints include standard cellular PK parameters and SLE responses. Subjects will be assessed for response based on SLEDAI or the European Alliance of Associations for Rheumatology (EULAR)/European Renal Association-European Dialysis and Transplantation Association (ERA-EDTA) criteria. Patient screening began in mid-2024. References: Dickinson M, Hamad N, Bryant C, et al. First in human data of NKX019, an allogeneic CAR NK for the treatment of relapsed/refractory (R/R) B-cell malignancies. Presented at: 2023 EHA Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S261.

Background The Manhattan Lupus Surveillance Program (MLSP), a population-based retrospective registry of patients with systemic lupus erythematosus (SLE), was used to investigate the prevalence of cardiovascular disease events (CVE) and compare rates among sex, age and race/ethnicity to population-based controls. Methods Patients with prevalent SLE in 2007 aged ≥ 20 years in the MLSP were included. CVE required documentation of a myocardial infarction or cerebrovascular accident. We calculated crude risk ratios and adjusted risk ratios (ARR) controlling for sex, age group, race and ethnicity, and years since diagnosis. Data from the 2009–2010 National Health and Nutrition Examination Survey (NHANES) and the 2013–2014 NYC Health and Nutrition Examination Survey (NYC HANES) were used to calculate expected CVE prevalence by multiplying NHANES and NYC HANES estimates by strata-specific counts of patients with SLE. Crude prevalence ratios (PRs) using national and NYC estimates and age standardized prevalence ratios (ASPRs) using national estimates were calculated. Results CVE occurred in 13.9% of 1,285 MLSP patients with SLE, and risk was increased among men (ARR:1.7, 95%CI:1.2–2.5) and older adults (age > 60 ARR:2.5, 95%CI:1.7–3.8). Compared with non-Hispanic Asian patients, CVE risk was elevated among Hispanic/Latino (ARR:3.1, 95%CI:1.4-7.0) and non-Hispanic Black (ARR:3.5, 95%CI1.6-7.9) patients as well as those identified as non-Hispanic and in another or multiple racial groups (ARR:4.2, 95%CI:1.1–15.8). Overall, CVE prevalence was higher among patients with SLE than nationally (ASPR:3.1, 95%CI:3.0-3.1) but did not differ by sex. Compared with national race and ethnicity-stratified estimates, CVE among patients with SLE was highest among Hispanics/Latinos (ASPR:4.3, 95%CI:4.2–4.4). CVE was also elevated among SLE registry patients compared with all NYC residents. Comparisons with age-stratified national estimates revealed PRs of 6.4 (95%CI:6.2–6.5) among patients aged 20–49 years and 2.2 (95%CI:2.1–2.2) among those ≥ 50 years. Male (11.3, 95%CI:10.5–12.1), Hispanic/Latino (10.9, 95%CI:10.5–11.4) and non-Hispanic Black (6.2, 95%CI:6.0-6.4) SLE patients aged 20–49 had the highest CVE prevalence ratios. Conclusions These population-based estimates of CVE in a diverse registry of patients with SLE revealed increased rates among younger male, Hispanic/Latino and non-Hispanic Black patients. These findings reinforce the need to appropriately screen for CVD among all SLE patients but particularly among these high-risk patients.

Background and Aims Voclosporin is a second generation calcineurin inhibitor (CNI) approved for the treatment of adults with active lupus nephritis (LN) in combination with immunosuppressive therapy. An integrated analysis of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies concluded that combining voclosporin with lower-dose mycophenolate mofetil (MMF, 2 g/day) and low-dose glucocorticoids (GCs) led to significantly greater and earlier reductions in proteinuria when compared to MMF and GCs alone. This is an important finding as early reduction in proteinuria is associated with improved long-term kidney survival and mortality. Yet, dual-immunosuppressive regimens consisting of high-dose glucocorticoids and either intravenous cyclophosphamide (IVC) or higher doses of MMF (>2 g/day) continue to be frequently used for the initial management of active LN despite their association with incomplete efficacy and dose-dependent toxicities. Method All three studies enrolled participants with active LN. In AURA-LV and AURORA 1, participants received voclosporin 23.7 mg BID in combination with MMF (target 2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (target 3 g/day) or IVC (0.5 to 1.0 g/m2/month × 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS [MMF and IVC] vs. AURA-LV/AURORA 1 [voclosporin]) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months. Results Propensity matching identified 179 pairs of participants with similar demographics and baseline disease characteristics. Mean cumulative exposure to GCs was more than 2-fold higher in the IVC and MMF cohorts of ALMS than AURA-LV/AURORA 1 participants over both 3 and 6 months. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS, although more participants in AURA-LV and AURORA 1 reported hypertension and anemia (Table 1). Due to the known hemodynamic effects of calcineurin inhibition, there was a small decrease in mean eGFR in the AURA-LV/AURORA 1 participants in the first few weeks of treatment after which mean eGFR remained stable; AURA-LV/AURORA 1 participants also had an increased rate of events of GFR decreased. The incidence of serious AEs was similar across treatments. In the first 3 months of treatment, significantly more AURA-LV/AURORA 1 participants achieved a reduction in UPCR >25% from baseline (91.6% vs 69.3%; odds ratio [OR] 4.75, 95% confidence interval [CI] 2.56, 8.84; p < 0.0001). Over six months of treatment, mean (SD) change from baseline in UPCR was −3.1 (2.9) g/g in voclosporin-treated patients in AURA-LV and AURORA 1 compared to −2.4 (3.3) g/g in IVC- or MMF-treated participants in ALMS (Fig. 1). Conclusion Voclosporin-based, triple immunosuppressive therapy was associated with an improved safety profile as well as greater and earlier reductions in proteinuria compared to more conventional dual immunosuppressive regimens. These data support treatment guidelines for active LN that recommend both minimizing patient exposure to GCs and use of a multi-targeted treatment regimen as initial therapy.

Objectives This study aims to determine the independent impact of definitions of remission/low disease activity (LDA) on direct/indirect costs (DCs, ICs) in a multicentre inception cohort. Methods Patients from 31 centres in 10 countries were enrolled within 15 months of diagnosis and assessed annually. Five mutually exclusive disease activity states (DAS) were defined as (1) remission off-treatment: clinical (c) SLEDAI-2K=0, without prednisone/immunosuppressants; (2) remission on-treatment: cSLEDAI-2K=0, prednisone ≤5 mg/day and/or maintenance immunosuppressants; (3) LDA-Toronto Cohort (TC): cSLEDAI-2K≤2, without prednisone/immunosuppressants; (4) modified lupus LDA state (mLLDAS): SLEDAI-2K≤4, no activity in major organs/systems, no new activity, prednisone ≤7.5 mg/day and/or maintenance immunosuppressants and (5) active: all remaining assessments. At each assessment, patients were stratified into the most stringent DAS fulfilled and the proportion of time in a DAS since cohort entry was determined. Annual DCs/ICs (2021 Canadian dollars) were based on healthcare use and lost workforce/non-workforce productivity over the preceding year. The association between the proportion of time in a DAS and annual DC/IC was examined through multivariable random-effects linear regressions. Results 1692 patients were followed a mean of 9.7 years; 49.0% of assessments were active. Remission/LDA (per 25% increase in time in a remission/LDA state vs active) were associated with lower annual DC/IC: remission off-treatment (DC −$C1372; IC −$C2507), remission on-treatment (DC −$C973; IC −$C2604,) LDA-TC (DC −$C1158) and mLLDAS (DC −$C1040). There were no cost differences between remission/LDA states. Conclusions Our data suggest that systemic lupus erythematosus patients who achieve remission, both off and on-therapy, and reductions in disease activity incur lower costs than those experiencing persistent disease activity.

Lay Summary Participation in clinical trials is part of treatment for many patients with chronic diseases. However, patients with systemic lupus erythematosus (SLE), especially those of African American and Hispanic descent, have been reluctant to participate in clinical trials. Here, we describe patients’ decisions to participate in a study that plans to enroll 200 patients in an engagement program modeled after the Lupus Research Alliance Patient Advocates for Lupus Studies (PALS) program. These data suggest that lupus patients’ intention to participate in clinical research is influenced by severity of disease, patient factors, and the study design. It is difficult to tell if racial and ethnic factors affect the current study enrollment. More data is needed to confirm the role of these factors and additional qualitative data will help identify factors that affect a patient’s decision at the individual level. Background/Purpose Participation in clinical trials is part of treatment for many patients with chronic diseases. However, patients with systemic lupus erythematosus (SLE), especially those of African American and Hispanic descent, have been reluctant to participate in clinical trials. Qualitative research identified patient, provider, community, and study design factors as the main reasons for this hesitancy. Concerted efforts to increase awareness of and engagement in SLE clinical trials are underway. We evaluated factors associated with challenges to clinical research enrollment in the Columbia University (CU) and Albert Einstein College of Medicine (AECOM) lupus cohorts in New York City (NYC) that serve the low socioeconomic status communities of Washington Heights and the Bronx. Methods This study sponsored by the U.S. Department of Health and Human Services, Office of Minority Health, plans to enroll 200 patients in an engagement program modeled after the Lupus Research Alliance Patient Advocates for Lupus Studies (PALS) program. SLE patients were invited to participate during routine clinic visits. Patients were apprised of the study in detail and their decision to participate or refuse was recorded. Socio-demographics and disease characteristics were collected. Data from recent therapeutic clinical trial participants was included for comparison. One-way ANOVA was used to detect differences among the 3 groups: enrolled in the study, refused participation and clinical trial participants. Results Of the 138 patients asked to participate, 103 (74.6%) agreed while 35 (25.4%) refused. Additionally, 25 clinical trial participants were included. Participants enrolled in the educational sessions, demonstrating willingness to engage in clinical trial education, were more likely to have been admitted during the past year (1.36 vs 1.09 vs 0.52, p=0.044) and have co-morbid fibromyalgia (17% vs 3% vs 0%, p=0.013). While there were more African American and Hispanic patients in the education study groups, these differences did not reach statistical significance. The major reasons for refusal were lack of interest in clinical trials (17, 49%), time constraints (14, 40%) and negative prior experiences relating to clinical trials (4, 11%). Clinical trial participants were more likely to have arthritis (84% vs 71% vs 96%, p=0.043), mucocutaneous manifestations (67% vs 69% vs 88%, p=NS) and be on steroids (26% vs 14% vs 56%, p=0.001) as required for inclusion in clinical trials. Also, the clinical trial group displayed a higher zip-code median income (54K vs 51K vs 77K, p=0.001) and more rheumatology office visits in the past year (2.99 vs 2.63 vs 4.76, p=0.001). Conclusion These data suggest that people’s intention to participate in clinical research is influenced by disease severity (admissions and office visits), patient factors (income and co-morbid fibromyalgia) and study design (arthritis, steroid use). It is difficult to ascertain if racial and ethnic factors affect the current study enrollment. More data is needed to confirm the role of these factors and additional qualitative data will help identify factors that affect a patient’s decision at the individual level.

Lay Summary Almost all patients with SLE experience joint problems and arthritis, 12% suffer permanent joint damage. The wide variability in SLE arthritis and the limitations of existing assessment tools make it difficult to identify joint involvement in clinical care and clinical trials. Here we describe preliminary data on comparisons between optical imaging that uses light to pass through the joint and ultrasound evaluations of lupus in affected and unaffected finger joints. OT imaging of 20 SLE patients were evaluated, 8 finger joints/patient were imaged, with a total of 160 images. Optical imaging correlated with ultrasound findings in 160 evaluated fingers affected by lupus arthritis. The system, which will take the form of an ergonomic glove, will allow the investigators to image lupus arthritis, both in the office and at home, to diagnose and monitor arthritis progress. Background/Purpose Almost all patients with SLE experience joint problems and arthritis, 12% suffer permanent joint damage. The wide variability in SLE arthritis and the limitations of existing assessment tools make it difficult to identify musculoskeletal involvement in clinical care and clinical trials. Identifying lupus arthritis based on physical exam remains challenging. Clinicians need a robust, easy-to-use imaging technique to diagnose and monitor arthritis in SLE. Ultrasound (US) and magnetic resonance (MRI) allow for more objective assessments but are plagued by operator dependence and high cost. With the support of a DoD award, we are developing a prototype imaging system that uses lasers and light detectors to evaluate finger joints in SLE. Here we describe preliminary data on comparisons between optical imaging and US evaluations of affected and unaffected proximal interphalangeal (PIP) joints. Methods 20 SLE patients were evaluated, 8 PIP joints (bilateral PIP 2–5)/patient were imaged, with a total of 160 images. A systematic multiplanar grey-scale (GS) and power doppler (PD) examination of PIP joints was performed using the Outcome Measures in Rheumatology (OMERACT) consensus definitions for joint pathologies, and a combined PDGS score was calculated. Immediately after the US, joints were examined using optical imaging. The instrumentation uses a 670nm, 8mW laser with a 1 mm diameter beam modulated at 300 MHz as light source. The laser beam is focused on the dorsal surface of each finger and scans across the PIP joints (as shown in figure 1a). The transmitted light is collected by an intensified charge-coupled device camera and the absorption and scattering distributions inside the finger are reconstructed (figure 1b shows absorption) using a radiative transfer equation model. Amplitude AUC divided by finger thickness (mm) was calculated and is displayed in figure 2. Results When comparing OT images of a total of 48 PIPs from healthy volunteers and 160 PIPs from SLE patients, an AUC of 0.79 is obtained (figure 3) with corresponding sensitivity and specificity of 77% and 71% respectively.The PDGS scored 34 joints 0, 44 – 1, 20 – 2 and 22 – 3 (120 joints). The absorption and scattering data were obtained from the reconstructed images. Figure 1c shows a cross section through an unaffected joint (PDGS=0) on the left and an affected joint (PDGS=3) on the right. The average absorption coefficient of joints with PDGS = 0 or 1 was 0.52±0.19 cm⁻¹, while joints with PDGS = 2 or 3 the absorption was 0.60±0.19 cm⁻¹, p < 0.05. Similarly, we found that the difference in the scattering coefficients between the two groups was also statistically significant (10.8±1.9 cm⁻¹ versus 11.8±2.1 cm⁻¹, p< 0.01). Conclusion Optical imaging correlated with PDGS findings in 120 evaluated lupus arthritis PIP joints. Further examination of SLE arthritis using the new US OMERACT criteria that includes a tenosynovitis score and MRI will allow for better definitions of PIP arthritis and improve the correlations with optical imaging.The system, which will take the form of an ergonomic glove (figure 4), will allow the investigators to image lupus arthritis, both in the office and at home, to diagnose and monitor arthritis progress. The goal is to create a portable, wearable, imaging device that permits real-time monitoring of SLE arthritis to improve patient care and outcomes. • Download figure • Open in new tab • Download powerpoint Abstract 616 Figure 1 Reconstruction of absorption and scattering distributions • Download figure • Open in new tab • Download powerpoint Abstract 616 Figure 2 Boxplot of Amplitude AUC divided by finger thickness • Download figure • Open in new tab • Download powerpoint Abstract 616 Figure 3 ROC Curve • Download figure • Open in new tab • Download powerpoint Abstract 616 Figure 4 OT Glove

Objective Early reduction in proteinuria after initial treatment has been associated with improved long-term kidney outcomes in lupus nephritis (LN). The addition of voclosporin, a second generation calcineurin inhibitor, to MMF and low-dose glucocorticoids (GC)s led to greater reductions in proteinuria compared to conventional therapy in the AURA-LV and AURORA 1 studies with an acceptable safety profile. Using propensity-matched participants from the voclosporin clinical trials and ALMS, we tested the hypothesis that a voclosporin-based, triple immunosuppressive regimen results in improved safety without compromising efficacy. Methods In AURA-LV and AURORA 1, voclosporin 23.7 mg BID was combined with MMF (2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (3 g/day) or intravenous cyclophosphamide (IVC; 0.5 to 1.0 g/m²/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate groups of matched participants (ALMS vs. AURA-LV/AURORA 1) based on demographic and disease characteristics. Safety and efficacy were assessed at 3 and 6 months. Results A total of 179 matched pairs were identified. As expected, cumulative GC exposure was 2-fold higher in ALMS at 3 and 6 months. The incidence of adverse events (AEs) was higher in IVC- and high-dose MMF-treated participants (table 1), although more voclosporin-treated participants reported AEs of GFR decrease and hypertension; the incidence of serious AEs was similar with all treatments. At 6 months, the proportion of participants achieving >50% UPCR reduction from baseline was significantly greater in the voclosporin arm (p=0.005). Conclusion A voclosporin-based triple immunosuppressive regimen (voclosporin, MMF, and low-dose GCs) has a better overall safety profile than double-therapy regimens, with specific AEs attributable to higher-dose GCs, higher-dose MMF and IVC in the latter. Triple therapy is also superior in achieving early proteinuria milestones. These data provide further support for use of combination therapy as initial treatment in patients with active LN and to minimizing patient exposure to GCs, as proposed by the 2023 EULAR guidelines. Acknowledgement This study was funded by Aurinia Pharmaceuticals Inc. View this table: • View inline • View popup Abstract P87 Table 1 Select safety outcomes In AURA-LV and AURORA 1, voclosporin 23.7 mg BID was combined with MMF (2 g/day) and oral GCs (25 mg/day tapered to 2.5 mg/day by Week 16). In ALMS, MMF (3 g/day) or intravenous cyclophosphamide (IVC; 0.5 to 1.0 g/m²/month x 6) was added to oral GCs initiated at a maximum dose of 60 mg/day, tapered every 2 weeks to 10 mg/day. Propensity score methodology was used to generate two groups of matched patients (n=179) from the ALMS (IVC and MMF) and AURA-LV/AURORA 1 (voclosporin) studies based on the following parameters: age, duration of lupus nephritis, duration of SLE, albumin, C3, C4, creatinine, anti-dsDNA, eGFR, UPCR, biopsy class, sex, and geographical region. Adverse events (AEs) occurred on or after the first dose of study drug up to either 3 or 6 months of treatment and coded by System Organ Class and Preferred Term using MedDRA v9.1 (ALMS), v17.0 (AURA-LV) and v20.0 (AURORA 1). AEs were selected for inclusion in this table to evaluate the impact of IVC, MMF, voclosporin, and glucocorticoids on these organ systems. Assignation of AEs of ‘GFR decreased’ were based on the clinical discretion of the study investigator and were not characterized by a specified drop in eGFR from baseline. GFR, glomerular filtration rate; IVC, intravenous cyclophosphamide; MMF, mycophenolate mofetil.