Faculty Bibliography

Background/Purpose: The efficacy and safety of anifrolumab (ANIFR), a type I IFN receptor antagonist, were assessed in a Phase II, randomized, double-blind, placebo-controlled study in SLE (NCT01438489). Methods: Three hundred and five adults with seropositive moderate to severe SLE despite standard of care medication were randomized and received intravenous (iv) ANIFR (300 mg, 1000 mg) or placebo (PBO) every 4 weeks for 48 weeks. Patients were stratified by SLEDAI score, oral corticosteroid (OCS) dose, and IFN gene signature (IFN high vs. IFN low) based on a 4-gene expression assay. Disease activity was assessed by SLEDAI-2K, BILAG 2004, Physician's Global Assessment, CLASI, BICLA, and 28-joint count. The primary endpoint was a composite of SRI(4) response at Day 169 with sustained reduction of OCS (<10 mg/day and 10 mg/day at baseline. Other efficacy measures of systemic and organ-specific disease activity and safety were also assessed at Day 365. Results: The primary endpoint at Day 169 was met by a greater proportion of ANIFR-treated patients vs. PBO (PBO: 17.6%; 300 mg: 34.3%, p=0.014; 1000 mg: 28.8%, p=0.063). At Day 365, the secondary SRI endpoint was met by 25.5% of PBO, 51.5% of 300 mg (p<0.001) and 38.5% of 1000 mg (p=0.048) patients. OCS reduction to <7.5 mg/day at Day 365 was achieved by 26.6% of PBO, 56.4% of 300 mg (p=0.001) and 31.7% of 1000 mg (p=0.595) patients. ANIFR demonstrated consistent benefit across multiple global and organ-specific measures at Day 365 (Table), as well as lower rates of BILAG moderate/severe flares/patient-year (PBO: 0.611; 300 mg: 0.266; 1000 mg: 0.391). 75% of patients were IFN high at baseline. The ANIFR efficacy observed in the entire cohort was similar or more pronounced in IFN high patients. Median suppression of 21 IFN-regulated genes was ~90% for both doses of ANIFR. Serious adverse events were reported in 18.8% of patients on PBO and 16.7% of patients in the pooled ANIFR groups. A higher frequency of influenza (most unconfirmed) (PBO: 1.0%; 300 mg: 6.1%; 1000 mg: 7.6%) and a dosage-dependent increase in Herpes zoster (PBO: 2.0%; 300 mg: 5.1%; 1000 mg: 9.5%) occurred in the ANIFR arms. Conclusion: Anifrolumab significantly reduced disease activity compared with PBO across multiple clinical endpoints. Enhanced effects in IFN high patients support the pathobiology of this treatment strategy. The lack of dose response can be explained by the nearly similar degrees of IFN gene signature inhibition achieved with the two anifrolumab doses. These data strongly support further development of anifrolumab. (Table Presented)

INTRODUCTION: Blisibimod is a potent B cell-activating factor (BAFF) antagonist that binds to both cell membrane-expressed and soluble BAFF. The goal of these first-in-human studies was to characterize the safety, tolerability, and pharmacokinetic and pharmacodynamic profiles of blisibimod in subjects with systemic lupus erythematosus (SLE). METHODS: SLE subjects with mild disease that was stable/inactive at baseline received either a single dose of blisibimod (0.1, 0.3, 1, or 3 mg/kg subcutaneous [SC] or 1, 3, or 6 mg/kg intravenous [IV]) or placebo (phase 1a; N = 54), or four weekly doses of blisibimod (0.3, 1, or 3 mg/kg SC or 6 mg/kg IV) or placebo (phase 1b; N = 63). Safety and tolerability measures were collected, and B cell subset measurements and pharmacokinetic analyses were performed. RESULTS: All subjects (93 % female; mean age 43.7 years) carried the diagnosis of SLE for >/= 1 year. Single- and multiple-dose treatment with blisibimod produced a decrease in the number of naive B cells (24-76 %) and a transient relative increase in the memory B cell compartment, with the greatest effect on IgD(-)CD27+; there were no notable changes in T cells or natural killer cells. With time, memory B cells reverted to baseline, leading to a calculated 30 % reduction in total B cells by approximately 160 days after the first dose. In both the single- and multiple-dosing SC cohorts, the pharmacokinetic profile indicated slow absorption, dose-proportional exposure from 0.3 through 3.0 mg/kg SC and 1 through 6 mg/kg IV, linear pharmacokinetics across the dose range of 1.0-6.0 mg/kg, and accumulation ratios ranging from 2.21 to 2.76. The relative increase in memory B cells was not associated with safety signals, and the incidence of adverse events, anti-blisibimod antibodies, and clinical laboratory abnormalities were comparable between blisibimod- and placebo-treated subjects. CONCLUSIONS: Blisibimod changed the constituency of the B cell pool and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1.0-6.0 mg/kg. The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases. TRIAL REGISTRATION: Clinicaltrials.gov NCT02443506 . Registered 11 May 2015. NCT02411136 Registered 7 April 2015.

Co-stimulatory molecules help to regulate interactions between T cells and antigen-presenting cells and may play an important role in the pathogenesis of lupus. Both work in murine models and some early studies in human lupus support further examination of these molecules as therapeutic targets. Complexities of lupus clinical trial variables may have hampered progress in this area but recent developments in the field may make interventional trials more feasible in the near future. To date biologics which provide direct blockade of interactions between CD40 and CD154, B7RP-1 and ICOS, and CD80 or CD86 with CD28 have been assessed in multicenter clinical trials. These data will be reviewed and critiqued.

Despite rapid accumulation of knowledge about complex immune dysregulation in systemic lupus erythematosus (SLE) and major primary lupus syndromes, and a plethora of promising new treatments reaching preclinical and early clinical studies, advanced-phase trials of new biologic agents have repeatedly failed to achieve their clinical end points. It is possible that none of these agents work, but the accuracy of this suggestion is as unclear as the case for efficacy, owing to issues in the design of studies and the opacity of the data that have resulted. Disease heterogeneity and complexity might be a hurdle that is simply too high to overcome by existing methodological approaches, and the way forward to interpretable trial results remains unclear. Nonetheless, well-characterized patterns of immune pathology are shared by substantial subsets of patients, and selective targeting of one or more relevant immune system molecules seems to offer the promise of safer and more effective treatments. Evolution dictates a more personalized approach to therapy and trial design, but this option seems challenging in the current economic, regulatory and scientific environment. This Review addresses these concerns by considering the progress of some of the investigational treatments targeting key physiological abnormalities in lupus.

OBJECTIVES: The efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE). METHODS: 431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. RESULTS: Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physician's Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index-2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment. CONCLUSIONS: Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity. TRIAL REGISTRATION NUMBER: NCT01283139; Results.

OBJECTIVES/OBJECTIVE:Systemic lupus erythematosus (SLE) remains a deadly disease, yet our ability to predict adverse outcomes is poor. Mitochondria are organelles recognised by the immune system when released from cells, and antimitochondrial antibodies (AMA) can be detected in people with SLE. We assessed AMA as markers of nephritis, arterial vascular events (AVE), and other outcomes including mortality. METHODS:We studied sera and data from 1114 participants of the Systemic Lupus International Collaborating Clinics inception cohort. We measured antiwhole mitochondria (AwMA), antimitochondrial DNA (AmtDNA), and antimitochondrial RNA (AmtRNA) antibodies by direct Enzyme-Linked ImmunoSorbent Assays (ELISAs). Separate multivariable Cox proportional hazards regression models estimated associations of either baseline or most recent measures of AMA with the outcomes, adjusted for biological sex, age, medications, and other clinical factors. Interactions of AMA with biological sex were tested for each outcome. RESULTS:All AMA titres were elevated in SLE vs healthy individuals. Higher AMA levels were associated with a higher hazard of nephritis, with the strongest associations for most recent AmtDNA (adjusted hazard ratio [aHR] =1.61 for increase of 1 SD, 95% CI 1.43-1.82) and AmtRNA (aHR =1.59, 1.46-1.73). Higher baseline AwMA levels predicted early mortality (aHR =1.19, 1.02-1.40). Most recent AmtDNA (aHR =1.68, 1.28-2.19) was associated with higher mortality throughout the follow-up. For AVE, the impact of higher AmtRNA was stronger in females. CONCLUSIONS:Baseline and most recent assessments of AMA levels may help identify individuals at higher risk of severe outcomes in SLE, including mortality. Integrating AMA into precision medicine strategies will allow deeper exploration of lupus heterogeneity.

BACKGROUND:Using hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring. METHODS:This observational study included patients (n=2010) across the Systemic Lupus International Collaborating Clinics (SLICC), Wisconsin, International, and French studies, who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross-sectional data, we first identified a HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for SLE Disease Activity Index 2000 (SLEDAI-2K ≥6). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels. RESULTS:Among 1842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ related toxicity. Odds of toxicity were 2.1-fold higher with blood levels ≥1150 ng/mL, and 1.7-fold higher with cumulative HCQ dose per 1000g increase. Blood levels ≥1150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage ≥3 had 2.3-fold higher odds of having supratherapeutic levels (≥1150 ng/mL). CONCLUSION/CONCLUSIONS:The therapeutic reference range for HCQ blood level monitoring is 750-<1150 ng/ml. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage ≥3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing.

OBJECTIVES/OBJECTIVE:This 1-year long-term extension (LTE) study (NCT04451772) followed the 48-week phase 2 SLEek study (NCT03978520) that evaluated upadacitinib (a Janus kinase inhibitor) alone or combined with elsubrutinib (a Bruton's tyrosine kinase inhibitor) in adults with moderately to severely active systemic lupus erythematosus (SLE). The objective was to evaluate the efficacy and safety of an additional 56 weeks of treatment. METHODS:Patients randomised to upadacitinib 30 mg one time per day (QD) or upadacitinib 30 mg/elsubrutinib 60 mg QD (upadacitinib/elsubrutinib) in the SLEek study continued their assigned treatment during the LTE. Patients originally receiving placebo switched to upadacitinib/elsubrutinib in the LTE. Assessments through week 104 included SLE Responder Index-4 (SRI-4), British Isles Lupus Assessment Group-based Combined Lupus Assessment (BICLA), Lupus Low Disease Activity State (LLDAS), change from baseline in glucocorticoid dose, flare events and adverse events. RESULTS:This LTE analysis included 127 patients. Efficacy responses for the groups receiving upadacitinib, upadacitinib/elsubrutinib and placebo to upadacitinib/elsubrutinib were maintained or increased from weeks 48 to 104 (week 104: SRI-4: 82.1%, 85.4% and 61.3%; BICLA: 69.2%, 78.0% and 54.8%; LLDAS: 60.0%, 78.0% and 34.4%). From weeks 48 through 104, the mean daily glucocorticoid dose was reduced, and the incidence of flares was maintained or further reduced in all treatment groups. Safety profiles were similar to those observed in the primary SLEek study. CONCLUSIONS:In this LTE study, upadacitinib monotherapy and upadacitinib/elsubrutinib combined were well tolerated and continued to demonstrate beneficial effects on SLE disease activity, glucocorticoid dose and flares through 104 weeks.

Clinical diagnosis typically incorporates physical examination, patient history, various laboratory tests, and imaging studies but makes limited use of the human immune system's own record of antigen exposures encoded by receptors on B cells and T cells. We analyzed immune receptor datasets from 593 individuals to develop MAchine Learning for Immunological Diagnosis, an interpretive framework to screen for multiple illnesses simultaneously or precisely test for one condition. This approach detects specific infections, autoimmune disorders, vaccine responses, and disease severity differences. Human-interpretable features of the model recapitulate known immune responses to severe acute respiratory syndrome coronavirus 2, influenza, and human immunodeficiency virus, highlight antigen-specific receptors, and reveal distinct characteristics of systemic lupus erythematosus and type-1 diabetes autoreactivity. This analysis framework has broad potential for scientific and clinical interpretation of immune responses.