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Background and Aims Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is a life- or organ-threatening condition in which patients experience severe inflammation of small arteries. Renal involvement is common in ANCA-associated vasculitis and is correlated with high morbidity and mortality. Current treatment regimens have limited efficacy for renal disease in patients presenting with organ- or life-threatening ANCA-associated vasculitis. Avacopan, a novel orally-administered antagonist of the complement fragment C5a receptor (C5aR), was evaluated through a Phase 3 trial in patients with ANCA vasculitis. Efficacy and safety results have been previously reported; this abstract provides details of the effects on renal function in patients with renal involvement. Method The ADVOCATE trial was a randomized, double-blind, active controlled, double-dummy, 52-week treatment Phase 3 trial of 331 patients with ANCA-associated vasculitis. Patients were randomized 1:1 and received either a standard daily prednisone dosing with taper (i.e., starting at 60 mg / day tapered to 0 mg by Week 21), or daily avacopan. Background therapy included either: a) cyclophosphamide (oral or IV) followed by azathioprine, or, b) rituximab (four IV infusions). Patients with active glomerulonephritis at baseline were included in this analysis. Kidney function was analyzed based on the following parameters, which were assessed at pre-specified time-points: changes in the urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and Urinary Monocyte Chemoattractant Protein-1 (MCP-1):Creatinine ratio. Results At the baseline visit, 265 patients had renal disease. eGFR improved more in the avacopan group (n=131) compared to the prednisone group (n=134). At Week 26, eGFR increased 5.8 mL/min/1.73 m2 (from a baseline of 44.6 mL/min/1.73 m2), compared to 2.9 mL/min/1.73 m2 in the prednisone group (from a baseline of 45.6 mL/min/m2), P=0.046. At Week 52, the increases in eGFR were 7.3 mL/min/1.73 m2 and 4.1 mL/min/1.73 m2, respectively, P=0.029. The improvement was most prominent in subjects with Stage 4 kidney disease at baseline (eGFR Conclusion Treatment with avacopan in patients with ANCA-associated vasculitis with renal disease led to greater recovery in eGFR when compared to standard prednisone therapy, especially in patients with Stage 4 kidney disease (eGFR

Background and Aims Primary Focal Segmental Glomerulosclerosis (FSGS) is the most common primary glomerular disease in patients with end stage renal disease in the United States. Current treatment regimens target reduction in proteinuria, but may have limited response or exhibit disease recurrence. CCX140 is an orally-administered selective small molecule inhibitor of the C-C chemokine receptor 2 (CCR2) under investigation for the treatment reduction of proteinuria in patients with FSGS. The primary objectives of this study were to evaluate the safety and efficacy of CCX140 in patients with FSGS and a urine protein to creatinine ratio (UPCR) of ≥1 g/g. Efficacy was assessed by the change in UPCR. Method Forty-six adult patients with primary or genetic FSGS were randomized into a double-blind, placebo-controlled Phase 2 dose-ranging study designed to evaluate the safety and efficacy of CCX140. Changes of urinary protein excretion estimation (UPCR) from baseline to Week 12 were measured in four blinded treatment groups (three active CCX140 doses of 5 mg once daily, 10 mg and 15 mg twice-daily (BID) vs placebo). Starting at Week 12, all subjects including those in the placebo group received the CCX140, 15 mg BID for an additional 12 weeks, and UPCR changes from Week 12 to Week 24 were assessed. There was a 4-week follow-up period from Week 24 to Week 28 where no CCX140 was administered. Results In the intent to treat (ITT) analysis of UPCR changes at Week 12 relative to baseline, the 15 mg BID CCX140 group exhibited the greatest reduction of UPCR (median reduction from baseline 0.9 g/g or approximately 30%, and approximately 25% reduction from baseline for the geometric mean), but that did not differ significantly from the placebo group (median reduction from baseline 0.45 g/g; or approximately 22%, and approximately 23% reduction from baseline for the geometric mean). Also, after crossover of the blinded portion of the trial to 15 mg BID active dosing, the previous placebo group did not appear to exhibit an additional reduction of UPCR. CCX140 at all doses was well-tolerated, with no serious adverse events (SAEs) during the blinded trial and a numerically lower rate of treatment-emergent adverse events in the CCX140 treatment groups. Conclusion In the study, CCX140 did not demonstrate a therapeutically meaningful reduction in proteinuria relative to the control group after 12 weeks of blinded treatment. The study provides insights into the natural disease progression of patients with primary or genetic FSGS as part of a clinical trial setting.

Background and Aims Diabetic nephropathy (DN) is a syndrome characterized by pathological levels of proteinuria, glomerular lesions and reduction in the glomerular filtration rate (GFR) in diabetic patients. Several lines of evidence support a role of CCR2 in the pathogenesis of DN. Recent studies have demonstrated that existing small molecule CCR2 antagonists can be placed in two classes, distinguished by their interaction with one of two distinct binding sites on CCR2: an extracellular site for which antagonists compete directly with native ligands (the orthosteric site), or an intracellular allosteric binding site. To better understand the functional differences between these antagonists we compared an example of each class in a murine model of DN. Our results revealed that the allosteric, but not the orthosteric CCR2 inhibitors ameliorated the proteinuria and improved glomerular histopathology in this model of DN. Method We used db/db mice to model DN. Several structurally distinct CCR2 inhibitors with that bind to either the allosteric (CCR2-RA-[R] and CCX872) or orthosteric (MK-0812 and CCX598) sites were compared. Pharmacokinetic (PK) properties and renal functional parameters were assessed, including trough drug levels and proteinuria (urinary albumin excretion rate UAER; urine albumin creatinine ratio UACR). Histopathology and electron microscopy (EM) were performed to assess any potential tissue-protective effects of the antagonists. Results Both the allosteric inhibitors (CCR2-RA-[R] and CCX872) and the orthosteric inhibitors (MK-0812 and CCX598) were potent CCR2 antagonists with desirable PK in mouse in so far as both classes effectively blocked CCR2-mediated monocyte migration into the peritoneal cavity in the thioglycollate-induced peritonitis model. At comparable drug coverage levels, CCR2-RA-[R] and CCX872 rapidly and significantly reduced UAER/UACR (CCX872: 70 % at day 7 vs vehicle, p Conclusion Allosteric antagonists of CCR2 provide significant and rapid renal protection in the db/db murine model of DN, as evidenced by improvements in renal function and histological parameters, while potent orthosteric CCR2 antagonists were not effective in the model. Our data suggest that targeting the effectiveness of CCR2 antagonists in DN are directly dependent on binding to the allosteric site of CCR2.

Background and Aims Complement fragment C5a is strongly linked to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The C5a receptor (C5aR), is a G protein-coupled receptor present on neutrophils. Avacopan (previously CCX168) is an orally-administered selective antagonist of C5aR which blocks C5a-induced cell activation. Two previous Phase 2 clinical trials provided evidence of effectiveness of avacopan in AAV. This Phase 3 study evaluated the efficacy and safety of avacopan for the treatment of AAV as well as the potential of avacopan to eliminate extensive use of glucocorticoids (GC) and GC-related toxicities. Method Eligible subjects were randomized 1:1 to receive either prednisone or avacopan in combination with either a) cyclophosphamide (oral or IV) followed by azathioprine or b) rituximab (four IV infusions). Randomization was stratified by the treatment regimen (rituximab, IV cyclophosphamide, or oral cyclophosphamide), ANCA serotype, and newly-diagnosed or relapsing disease. Treatment period was 52 weeks; primary efficacy endpoints were the proportion of subjects achieving disease remission at Week 26, and sustained disease remission at Week 52. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of zero and not taking glucocorticoids for AAV within 4 weeks prior to Week 26. Sustained remission was defined as being in remission at Week 26 and sustained through Week 52 without relapse. Change in estimated glomerular filtration rate (eGFR) from baseline to week 52 was a pre-specified secondary endpoint. Results 330 subjects were randomized and dosed: 166 in the avacopan and 164 in the prednisone groups. At Week 26, 72.3% subjects achieved remission in the avacopan compared to 70.1% in the prednisone group (p The avacopan arm had a significant reduction in glucocorticoid-related toxicity compared to the prednisone arm as measured by the Glucocorticoid Toxicity Index of Cumulative Worsening Score (p=0.0002) and Aggregate Improvement Score (p=0.0082). In subjects with renal disease at baseline, the avacopan group (n=134) showed a mean increase in eGFR of 7.3 mL/min/1.73 m2 from baseline to week 52 as compared to 4.1 mL/min/1.73 m2 increase in the prednisone group (n=132) (p=0.029). A pre-specified sub-group analysis showed a greater difference in the avacopan sub-group with a baseline eGFR Conclusion Treatment with avacopan resulted in remission in patients with AAV receiving rituximab or cyclophosphamide/azathioprine at a rate that was non-inferior to the active comparator prednisone at Week 26 and superior to prednisone in sustained remission at Week 52. A significant reduction in glucocorticoid-related toxicity was observed in the avacopan vs. prednisone arms. The increase in eGFR seen with avacopan was marked among subjects with more severe renal disease. The safety profile of avacopan was acceptable for use in patients with AAV. The ADVOCATE trial demonstrated avacopan is an effective treatment for patients with AAV.

Background and Aims We have recently demonstrated that small molecule inhibitors of CCR2 rapidly reduced proteinuria and preserved renal structure in animal models of diabetic nephropathy (DN) and focal segmental glomerular sclerosis (FSGS). Similar beneficial effects of CCR2 inhibition were also observed in DN patients in a large diabetic nephropathy Phase 2 clinical trial. Despite its rapid and robust effects in these kidney diseases, the mechanism by which CCR2 inhibition affords such renal protection remains unclear. CCR2 is well-known to be expressed on cells of the immune system, where it mediates inflammation and immunological functions by controlling the trafficking of monocytes and T cells. However, immune cell expression of CCR2 may not adequately explain the rapid pharmacologic benefits of CCR2 inhibitors in DN and FSGS because these diseases do not exhibit appreciable kidney inflammation. To better understand the protective mechanism(s) of CCR2 inhibition in renal diseases, we have used a variety of in vivo nephropathy models to determine if CCR2 is expressed on kidney parenchymal cells. Our results suggest that a subset of CD45 negative, renal parietal epithelial cells express CCR2. Method To characterize CCR2 expression in the kidney we used CCR2 RFP heterozygous mice (CCR2RFP/+) in which one copy of CCR2 was replaced by red fluorescent protein (RFP), whose expression is under the control of the endogenous CCR2 promoter. This approach provided a highly sensitive method for CCR2 detection by both flow cytometry and immunofluorescence, and compensated for the lack of validated, commercially available anti-CCR2 antibodies. Enriched glomerular cells were obtained by a non-enzymatic disruption of kidneys, followed by centrifugation at low speed (80gs), and sieving through 300µm and 150µm meshes. The Adriamycin (ADR)-nephropathy model with CCR2 RFP heterozygous mice was used to determine CCR2 expression on renal cells. 5/6 nephrectomy models of FSGS, as well as the db/db diabetic nephropathy model were used to access the change of activated parietal epithelial cells and proteinuria, both in the presence and absence of a CCR2 inhibitor in the setting of kidney injury. Results We observed dramatic increases in the number of activated parietal epithelial cells (PECs, identified as CD133+CD24+CD44hi cells by flow cytometry) in all three renal disease models. In the ADR nephropathy model, we found that in 30-40% of activated PEC cells within an enriched population of glomerular cells expressed CCR2/RFP. CD44hi RFP+ increased much more dramatically than CD44hi RFP- cells in response to ADR, and this was highly correlated with proteinuria, suggesting that CCR2 plays an important role in PEC cell activation and kidney pathology in ADR induced kidney injury. Furthermore, we found that blocking CCR2 with the CCR2-specific antagonist CCX872 significantly reduced both proteinuria and the number of activated PECs in the 5/6 nephropathy and db/db diabetic nephropathy models. Conclusion This is the first report that CCR2 is present on a subset of activated renal PECs. This population is markedly upregulated during kidney injury in a variety of murine models of nephropathy. Changes in the abundance CCR2+ activated PECs in the glomerular enriched preparations in response to CCR2 inhibition suggests that CCR2 antagonism may represent a novel approach for the treatment of chronic kidney disease.