1. AstraZeneca’s Anifrolumab Shows Promise with CD163 Biomarker Improvements in Lupus Nephritis Phase II Trial (Abstract # POS0409)

SAPHNELO (anifrolumab-fnia), a human monoclonal antibody that binds to the type I interferon receptor subunit 1 (IFNAR1), thus blocking the biological activity of type I IFNs.  It has been approved in the US for the treatment of adult patients with moderate to severe systemic lupus erythematosus (SLE) who are receiving standard therapy.

Results presented in 2021 showed that while anifrolumab IR did not meet the primary endpoint, it did show numerical improvements over placebo in various endpoints, including CRR, in patients with active lupus nephritis. Recent findings from the EULAR 2024 conference revealed that CD163 protein levels decreased over time in all treatment groups (anifrolumab BR, IR, and placebo) from baseline to Week 48. Anifrolumab IR treatment led to a significantly greater reduction in CD163 levels from baseline to Week 12 compared to placebo. By Week 48, CD163 levels were similar across all groups. Patients achieving CRR experienced more significant reductions in mean CD163 levels from baseline than nonresponders at Weeks 12 and 48, irrespective of treatment. Among nonresponders, those on anifrolumab IR had a larger decrease in CD163 levels from baseline to Week 12 than those on placebo. Additionally, there was a correlation between urine CD163 levels and blood IFNGS within individual patients. These findings suggest that CD163 could serve as a valuable biomarker for renal response to therapy. However, further research is needed to fully understand how anifrolumab treatment affects this urinary biomarker of renal inflammation and histologic activity. 

2. Obinutuzumab Benefits Patients with Active Lupus Nephritis Irrespective of Baseline Proteinuria Severity and Longitudinal Assessment of Biomarkers in the Phase II NOBILITY Trial (Abstract# POS0529 and OP0077)

Obinutuzumab, a glycoengineered type II anti-CD20 humanized monoclonal antibody, demonstrated better clinical responses through Week 104 compared to mycophenolate mofetil (MMF) alone in patients with lupus nephritis.

Baseline CD19+ B cell and serum biomarker levels were similar between the treatment groups. By Week 4, 89% of patients treated with obinutuzumab had total B cells and all B cell subsets below the lower limit of quantitation (LLOQ). By Week 104, 92% had total B cells above the LLOQ. At Week 104, the mean memory B cells in obinutuzumab-treated patients remained low compared to baseline (3.5 vs. 65 cells/µL), while the mean naïve B cells were repopulated (127 vs. 229 cells/µL). Of the 51 patients in the obinutuzumab arm with B-cell measurements at Weeks 24 and 52, 30 had sustained B-cell depletion. In contrast, no patients in the placebo arm achieved sustained B-cell depletion. A significant difference in the complete renal response rate at Week 76 was observed between obinutuzumab-treated patients with sustained B-cell depletion and those receiving placebo (50% vs. 18%, respectively). In patients who were positive for anti-dsDNA antibodies at baseline (>30 IU/mL), median anti-dsDNA antibodies at Week 104 were reduced by 84% in the obinutuzumab group and 39% in the placebo group; anti-C1q antibodies were reduced by 61% and 7%, respectively. Patients with lupus nephritis who achieved sustained B cell depletion following obinutuzumab treatment were more likely to reach complete renal response compared to those receiving placebo. This supports the therapeutic hypothesis that deep and durable B cell depletion leads to improved clinical outcomes. Obinutuzumab is currently undergoing further evaluation in patients with active proliferative lupus nephritis in the global, registrational, Phase III REGENCY trial.

3. Comparison of Voclosporin-Based Triple-Immunosuppressive Regimen and High-Dose Glucocorticoid with Mycophenolate Mofetil Therapy for Lupus Nephritis: A Propensity Analysis of the ALMS, AURA-LV, and AURORA 1 Studies

LUPKYNIS (voclosporin) is a novel, structurally modified calcineurin inhibitor (CNI) with a dual mechanism of action, acting as an immunosuppressant through inhibition of T-cell activation and cytokine production and promoting podocyte stability in the kidney. 

Propensity matching identified 179 participant pairs with similar demographics and baseline disease characteristics. The mean cumulative exposure to glucocorticoids (GCs) was over twice as high in the intravenous cyclophosphamide (IVC) and MMF cohorts of the ALMS study compared to the AURA-LV and AURORA 1 participants over both 3 and 6 months. The overall incidence of adverse events (AEs) was higher in the IVC- and MMF-treated participants in ALMS over the 6 months, while more participants in AURA-LV and AURORA 1 reported hypertension and anemia. Due to the known hemodynamic effects of calcineurin inhibition, there was a small decrease in the mean estimated glomerular filtration rate (eGFR) in the AURA-LV/AURORA 1 participants during the initial weeks of treatment, after which mean eGFR remained stable. A greater number of eGFR decrease events were reported by AURA-LV/AURORA 1 participants. The incidence of serious AEs was similar across all groups.

Notably, 52% of voclosporin-treated participants achieved a urine protein-to-creatinine ratio (UPCR) of ≤0.5 mg/mg compared to 41.1% of IVC- or MMF-treated participants in ALMS. The median time to this endpoint for the voclosporin group was 142 days, while it was not determinable for ALMS participants as less than 50% achieved the endpoint within the study period. Additionally, more voclosporin-treated participants achieved a 50% reduction in UPCR from baseline at any point during the study, meeting this endpoint significantly earlier than the other groups.

Conclusion

“The landscape of lupus nephritis treatment is transforming, marked by an increasing number of available drugs. The total market size in the 7MM for lupus nephritis is expected to show positive growth and reach ~USD 3,200 million by 2032. There is a notable shift from the current sequential therapy paradigm to combined regimens involving a targeted add-on alongside standard immunosuppression right from the initiation of lupus nephritis treatment. This not only alters the challenge from a lack of drug availability to the strategic selection of the most suitable drug for each patient. In the current array of options, it is expected that patients with lupus nephritis presenting extra-renal manifestations may be prioritized for BENLYSTA over LUPKYNIS. At the same time, those with high-grade proteinuria might lean towards LUPKYNIS. LUPKYNIS is expected to generate ~USD 600 million by 2032 in the United States.  Roche's obinutuzumab is anticipated to be the first to enter the market among the upcoming therapies, giving it a competitive edge over other emerging assets.”