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Abstract
Alternative C activation is involved in the pathogenesis of ANCA-associated vasculitis. However, glucocorticoids used as treatment contribute to the morbidity and mortality of vasculitis. We determined whether avacopan (CCX168), an orally administered, selective C5a receptor inhibitor, could replace oral glucocorticoids without compromising efficacy. In this randomized, placebo-controlled trial, adults with newly diagnosed or relapsing vasculitis received placebo plus prednisone starting at 60 mg daily (control group), avacopan (30 mg, twice daily) plus reduced-dose prednisone (20 mg daily), or avacopan (30 mg, twice daily) without prednisone. All patients received cyclophosphamide or rituximab. The primary efficacy measure was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score by week 12 and no worsening in any body system. We enrolled 67 patients, 23 in the control and 22 in each of the avacopan groups. Clinical response at week 12 was achieved in 14 of 20 (70.0%) control patients, 19 of 22 (86.4%) patients in the avacopan plus reduced-dose prednisone group (difference from control 16.4%; two-sided 90% confidence limit, −4.3% to 37.1%; P=0.002 for noninferiority), and 17 of 21 (81.0%) patients in the avacopan without prednisone group (difference from control 11.0%; two-sided 90% confidence limit, −11.0% to 32.9%; P=0.01 for noninferiority). Adverse events occurred in 21 of 23 (91%) control patients, 19 of 22 (86%) patients in the avacopan plus reduced-dose prednisone group, and 21 of 22 (96%) patients in the avacopan without prednisone group. In conclusion, C5a receptor inhibition with avacopan was effective in replacing high-dose glucocorticoids in treating vasculitis.
ANCA-associated vasculitis (AAV) is a serious, often life-threatening disease linked to autoantibodies to proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA). Despite the current standard treatment with high-dose glucocorticoids and either cyclophosphamide or rituximab, patients have a nine-fold increased mortality risk in the first year compared with healthy controls, attributed to infection, vasculitis activity, and renal disease.1 Current therapies, rather than the underlying disease itself, contribute more than half of this increased risk.2 Fifteen to 38% of patients develop ESRD within 5 years.3–7 Glucocorticoids are associated with increased infection risk8–10 and progressive organ damage.11
C5a and C5a receptor (C5aR, or CD88) play a central role in the pathogenesis of AAV.12–14 C5a can prime and activate neutrophils,15 which release C5a when stimulated by inflammatory cytokines such as TNFα.16 C5a, acting on C5aR, is a potent neutrophil chemoattractant and agonist17 and can decrease neutrophil deformability, slowing their ability to traverse small blood vessels, particularly in the presence of ANCA.18 C5a also activates vascular endothelial cells, promoting their retraction and increased vascular permeability.19,20
Avacopan, previously called CCX168, is an orally administered small-molecule C5aR antagonist that blocks the effects of C5a,21 and prevented the development of GN induced by anti-myeloperoxidase antibodies in a murine model of AAV.22 We therefore tested the efficacy and safety of avacopan in patients with active AAV, treated concomitantly with cyclophosphamide or rituximab.
Results
The study ran from October 12, 2011 (first patient enrolled) until January 18, 2016. Patient disposition is shown in Figure 1. The demographics and baseline characteristics were statistically similar among the three groups (no P values <0.05 for comparisons across groups), except for high baseline serum creatinine on the Birmingham Vasculitis Activity Score (BVAS), with 15 of 23 subjects in the control group compared with 6 of 22 in the avacopan plus no prednisone group (Table 1).
Consort diagram of patient flow through the study. Of 87 patients screened, 67 were enrolled. The main reasons for study exclusion were insufficient disease activity, low white blood cell count, and severe disease activity. AE, adverse event; PT, prothrombin time; PTT, partial thromboplastin time; WBC, white blood cell count.
Demographics and baseline characteristicsa
Treatment responses occurred in 86% and 81% of the avacopan with reduced-dose, and avacopan with no prednisone groups, respectively, and in 70% in the high-dose glucocorticoid (control) group. Both avacopan groups met noninferiority criteria (P=0.002 for avacopan with reduced-dose prednisone versus control and P=0.01 for avacopan with no prednisone versus control; Table 2). The avacopan treatment response was observed across subgroups (Supplemental Table 1), and individual patient BVAS data showed a more consistent response in the two avacopan groups compared with control (Figure 2A); P=0.04 at week 4 and P=0.09 at week 12 for all avacopan compared with prednisone control. Remission (BVAS 0) at week 4 that was sustained to week 12 occurred in 9 of 43 (21%) patients on avacopan compared with 1 of 20 (5%) in the control group (Figure 2A, Table 2); P=0.10 for all avacopan compared with prednisone control and P=0.04 for avacopan with no prednisone compared with prednisone control. Secondary end point results are summarized in Figure 2, B–G, and in Table 2. The mean percent decrease in BVAS at week 4 in the avacopan groups was comparable to the control group change at week 12. The mean increase in vasculitis damage index between entry and week 12 was 0.3 and 0.2 in the two avacopan groups, respectively, compared with 0.7 in the control group (not statistically different).
Efficacy results for 12-wk treatment perioda
Changes in disease activity, urinary abnormalities and quality of life indices in the three treatment groups during the study. (A) BVAS percent change from baseline for each patient, presented by treatment group. (B) BVAS mean±SEM percent change from baseline for placebo plus high-dose prednisone, n=20 (♦); avacopan plus reduced-dose prednisone, n=22 (■); and avacopan without prednisone, n=21 (▲). (C) First morning UACR percent change from baseline, calculated as 100 × (geometric mean at the study visit)/(geometric mean at baseline) for placebo plus high-dose prednisone, n=20 (♦); avacopan plus reduced-dose prednisone, n=22 (■); and avacopan without prednisone, n=20 (▲); *P<0.05, **P<0.01, and ***P<0.001 for avacopan compared with control by mixed-effects model for repeated measures analysis with treatment group, study visit, treatment-by-visit interaction, and randomization strata as factors, and baseline as covariate. (D) First morning urinary MCP-1–to-creatinine ratio percent change from baseline, calculated as 100 × (geometric mean at the study visit)/(geometric mean at baseline) for placebo plus high-dose prednisone, n=20 (♦); avacopan plus reduced-dose prednisone, n=22 (■); and avacopan without prednisone, n=21 (▲); **P<0.01, and ***P<0.001 for avacopan compared with control by mixed-effects model for repeated measures analysis with treatment group, study visit, treatment-by-visit interaction, and randomization strata as factors, and baseline as covariate. (E) And (F) health-related quality-of-life measurement Medical Outcomes Study SF-36 version 2 Physical Functioning and Role Emotional components, respectively, expressed as mean±SEM over the course of the treatment period for placebo plus high-dose prednisone, n=10 (♦); avacopan plus reduced-dose prednisone, n=14 (■); and avacopan without prednisone, n=9 (▲); the scale ranges from 0 to 100, from low to high functioning; *P<0.05 for avacopan compared with control regarding change or percent change from baseline by mixed-effects model for repeated measures analysis with treatment group, study visit, treatment-by-visit interaction, and randomization strata as factors, and baseline as covariate. (G) Health-related quality-of-life measurement EQ-5D-5L visual analog scale expressed as mean±SEM for placebo plus high-dose prednisone, n=10 (♦); avacopan plus reduced-dose prednisone, n=14 (■); and avacopan without prednisone, n=9 (▲); the scale is measured from 0 to 100, from low to high self-perception of health status; *P<0.05 for avacopan compared with control regarding change from baseline by mixed-effects model for repeated measures analysis with treatment group, study visit, treatment-by-visit interaction, and randomization strata as factors, and baseline as covariate.
Albuminuria improved early in both avacopan groups and the improvements were statistically greater than control at week 4 for both avacopan groups, and in the avacopan with reduced prednisone group versus control group at week 12 (Table 2). eGFR and hematuria improved similarly across all three groups. Urinary creatinine-corrected monocyte chemoattractant protein–1 (MCP-1) improved more in the avacopan compared with the control group at weeks 4 and 12, and C-reactive protein levels decreased similarly across groups (Table 2).
Health-related quality of life, including physical and mental components, improved more with avacopan compared with control on the basis of the Medical Outcomes Survey Short Form-36 (SF-36) and EuroQol-5D-5L (EQ-5D-5L) instruments (Supplemental Table 2, Table 2).
Three patients received rescue glucocorticoids during the treatment period, one in the control group and two in the avacopan without prednisone group.
At the end of the 12-week treatment period, three, three, and two patients in the control, avacopan plus reduced-dose prednisone, and avacopan without prednisone groups, respectively, were ANCA-negative.
The control and avacopan plus reduced prednisone groups continued to receive prednisone for the first 8 and 2 weeks, respectively, of the 12-week follow-up period, whereas the avacopan without prednisone group received no prednisone (Supplemental Table 3). Sixteen of 20 (80%), 17 of 22 (77%), and 15 of 21 (71%) patients in the control, avacopan plus reduced-dose prednisone, and avacopan without prednisone groups, respectively, had a BVAS decrease of at least 50% at week 24. The BVAS mean change at week 24 was −83%, −87%, and −85%, respectively. eGFR at week 24 was 54, 59, and 55 ml/min per 1.73 m2, respectively. The urinary albumin-to-creatinine ratio (UACR) mean change at week 24 was −48%, −61%, and −30%, respectively. At the end of the 12-week follow-up period, two, five, and six patients, respectively, were ANCA-negative.
The incidence of all adverse events and grade 3 or greater adverse events was similar across groups (Table 3). There were no deaths during the study. Adverse events were consistent with the underlying medical conditions and concomitant therapies. Four of 23 (17%) patients in the control group and 11 of 44 (25%) patients receiving avacopan had serious adverse events. When all adverse events are taken into account, two, one, and three patients in the control, avacopan plus reduced-dose prednisone, and avacopan without prednisone groups, respectively, reported vasculitis (worsening): two of relapse of renal vasculitis in the control group, one of vasculitis worsening in the avacopan plus low-dose prednisone group, and three of relapse of microscopic polyangiitis, flare of joint vasculitis, and relapse of renal vasculitis, respectively, in the avacopan plus no prednisone group. One patient in each group had a serious infection: pneumonia, febrile infection (no source identified), and respiratory infection in the control, avacopan plus reduced-dose prednisone, and avacopan without prednisone groups, respectively. No events of sepsis were reported. One patient, in the avacopan without prednisone group, with a medical history of alcohol abuse and concomitant treatment with cyclophosphamide, cotrimoxazole, and pantoprazole had hepatic and pancreatic enzyme elevations. Study drug was discontinued in this patient, who recovered. Another patient in this group had worsening of a preexisting skin rash.
Safety results for 12-week treatment period
There was a lower incidence of adverse effects potentially related to glucocorticoid use in patients receiving avacopan, 15 of 44 (34%), compared with control, 15 of 23 (65%); P=0.02. This difference was primarily driven by a lower incidence of psychiatric disorders and new-onset or worsening diabetes (Table 3).
More patients in the avacopan without prednisone group, but not the avacopan plus reduced-dose prednisone group, had grade 2 or 3 lymphopenia during the 12-week treatment period compared with control (Table 3). One patient in the avacopan plus reduced-dose prednisone group had an increase in creatine phosphokinase. This was not accompanied by any signs or symptoms of muscle injury, and the values returned to normal with uninterrupted avacopan treatment. Treatment was stopped in the patient with elevated liver and pancreatic enzymes (in the avacopan without prednisone group), who also had an elevated bilirubin level, which recovered.
Discussion
High-dose glucocorticoids have for half a century been considered indispensable in the treatment of AAV, despite their well documented toxicities.2,8–11,23 In this study we show that inhibition of C5aR may be an alternative to the use of oral glucocorticoids, and that C5a is an important inflammatory mediator in AAV.
Vasculitis activity is inadequately controlled in many patients. In a clinical trial comparing rituximab and cyclophosphamide, the primary outcome measure of disease remission at 6 months was not achieved in 42% of patients24 due to disease flares (36%), uncontrolled disease, discontinuation due to adverse events, or inability to completely taper glucocorticoids.25
This clinical trial met its primary end point, indicating that the orally administered C5aR inhibitor avacopan can replace high-dose glucocorticoids effectively and safely in patients with AAV. Several lines of evidence suggest that avacopan might also add benefit. In addition to avoiding glucocorticoid side effects, individual patient BVAS data suggest a rapid, consistent clinical response in patients receiving avacopan. Early efficacy with avacopan was further substantiated by a rapid improvement in albuminuria, which is common in patients with AAV and is a prognostic factor for poor renal outcome.26,27 Therefore, the avacopan benefit on albuminuria may translate into improved preservation of renal function. Results from the 12-week follow-up period indicate that there was no immediate rebound effect after withdrawal of avacopan treatment.
A high level of the renal inflammation marker, urinary MCP-1, also correlates with poorer outcomes in patients with active renal vasculitis and other renal diseases.28–31 Baseline urinary MCP-1–to-creatinine ratio was three- to five-fold higher than the upper limit of the reference range for healthy subjects32 and renal inflammation improved rapidly and to a greater extent with avacopan compared with control, which may lead to less glomerular and renal tubular damage. eGFR and hematuria improved similarly in all three groups over the 12-week treatment period, indicating that improvement in renal function in patients receiving avacopan did not require high-dose glucocorticoids.
Patients with AAV may present with symptoms such as fatigue, fever, headache, arthralgia, and myalgia, which negatively affect quality of life. Results showed that avacopan broadly improved various aspects of patients’ wellbeing, albeit from a small sample of patients. This may translate into less work absenteeism, fewer visits to the doctor, and ultimately reduced health care costs.
Avacopan appeared to be well tolerated and safe in this trial. There was a lower incidence of adverse effects related to glucocorticoid use, such as new-onset diabetes, psychiatric disorders, weight gain, fracture, and cataract in the avacopan treatment groups compared with control, indicating that using avacopan instead of glucocorticoids may avoid these side effects. Curiously, lymphopenia was observed more commonly in the avacopan without prednisone group, but not the avacopan plus reduced-dose prednisone group, compared with control. This argues against a detrimental avacopan effect. A more plausible explanation is that the absence of prednisone in the avacopan without prednisone group is unmasking the known lymphopenic effect of cyclophosphamide and rituximab, because, in the short term, glucocorticoids cause an increase in lymphocyte count.33
The study has limitations. It is relatively small and the treatment duration was short. The 12-week treatment period was driven by the available toxicology data at the time of study launch. By necessity, the trial was performed in three sequential steps, rather than as a concurrent, parallel group trial, because glucocorticoids could not be replaced completely without having some evidence of the efficacy of avacopan. A relatively small number of patients received rituximab rather than cyclophosphamide concomitant treatment; rituximab was not yet approved at the time of study launch. Treatment response instead of remission on the basis of BVAS was used as the primary end point in this study because of the short treatment duration. There is precedence for using such a response (or partial remission) end point on the basis of BVAS.34,35 The glucocorticoid tapering schedule is relatively rapid compared with the Rituximab in ANCA vasculitis study,24 but is consistent with the Rituximab versus cyclophosphamide in ANCA-associated vasculitis study conducted in Europe at the same time.36 There is no consensus glucocorticoid-tapering schedule in AAV, and the current European League Against Rheumatism/European Renal Association-European Dialysis and Transplant association guidance is to taper glucocorticoids more rapidly (7.5–10 mg prednisone by 3 months) to avoid side effects.37 Because this was the first study with avacopan in AAV, patients with severe end-organ manifestations needed to be excluded; this may limit the generalizability of the findings.
On the basis of the very promising results from this study, avacopan development was advanced to phase 3.
Concise Methods
Study Design and Patients
We performed a randomized, double-blind, placebo-controlled trial at 32 centers in Europe. (The study was registered with ClinicalTrials.gov, identifier NCT01363388.) The aim was to reduce or replace glucocorticoid treatment with avacopan without compromising efficacy in treating AAV. Because there were no available data before the study regarding the ability of avacopan to safely replace glucocorticoids, the original primary objective of the study was to assess the safety of avacopan. Therefore, the study was done in a stepwise manner with three sequential steps. In step 1, we tested whether avacopan permitted a reduced oral prednisone dose. If there were no unexpected serious adverse events or an excess of glucocorticoid rescue events, step 2 would be performed. In step 2, we tested whether avacopan could replace oral prednisone entirely. If successful, step 3 would follow, which was to be an expansion of the study size. After successful completion of the first two steps, an efficacy end point on the basis of treatment response was added. Twelve weeks’ treatment with avacopan was followed by 12 weeks without study drug. The prednisone-tapering schedule is shown in Supplemental Table 3.
The inclusion and exclusion criteria are provided in the Supplemental Material.
The trial was performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Ethics committees and institutional review boards approved the research protocol. All patients gave written informed consent before entry.
Randomization and Treatment
After screening, patients were stratified on the basis of having newly diagnosed or relapsing disease (all three steps), and by PR3 or MPO-ANCA, and cyclophosphamide or rituximab treatment (step 3). In step 1, 12 patients were enrolled and randomly assigned in a 2:1 ratio to receive 30 mg avacopan twice daily plus 20 mg prednisone, or placebo avacopan plus 60 mg prednisone. In step 2, 14 patients were enrolled and randomly assigned in a 2:1 ratio to receive 30 mg avacopan twice daily without prednisone or placebo avacopan plus 60 mg prednisone. All patients in steps 1 and 2 received cyclophosphamide intravenously at 15 mg/kg up to 1.2 g on day 1 and weeks 2, 4, 8, and 12, followed by oral azathioprine at a target dose of 2 mg/kg per day from weeks 14–24. Rituximab was not allowed in steps 1 and 2, because it was not approved at the time of study launch. The cyclophosphamide dose was adjusted on the basis of age, eGFR, and white blood cell count (see Supplemental Material). In step 3, 41 patients were randomly assigned (1:1:1) to receive 30 mg avacopan twice daily plus 20 mg prednisone, 30 mg avacopan twice daily plus placebo prednisone, or placebo avacopan plus 60 mg prednisone. All patients in step 3 received either cyclophosphamide followed by azathioprine as described above, or intravenous rituximab 375 mg/m2 per week for 4 weeks.
Stratification and randomization were performed centrally via an interactive voice response system using a minimization algorithm to maintain balance among the treatment groups with respect to strata and study center.38
Patients and all study personnel were masked to treatment allocation. All study drugs had matching active and placebo capsules, and identical bottles and boxes.
Study assessments are provided in the Supplemental Material.
End Points
The primary efficacy end point was the proportion of patients with a treatment response at week 12 defined as a BVAS decrease from baseline of at least 50% plus no worsening in any body system. Patients receiving rescue glucocorticoids were considered nonresponders. Secondary end points included the proportion of patients with a renal response, defined as an improvement in eGFR calculated using the Modified Diet in Renal Disease equation (see Supplemental Material), hematuria, and albuminuria at week 12; the proportion of patients with disease remission (BVAS 0); and change from baseline in BVAS, eGFR, UACR, urinary red blood cell count, urinary MCP-1–to-creatinine ratio, vasculitis damage index, SF-36 version 2, EQ-5D-5L, and rescue glucocorticoid use. The week 24 follow-up data were summarized.
Statistical Analyses
The planned study size was 60 patients. This study size was on the basis of feasibility given that AAV is an orphan disease. Efficacy analyses were conducted on the intention-to-treat population, defined as all patients with at least one postbaseline on-treatment BVAS assessment. The safety population included all randomized patients who received at least one dose of study drug.
For the primary efficacy end point, the proportion of patients achieving disease response was calculated for the comparison between each avacopan group against control. If the lower bound of the one-sided 95% confidence interval for the difference (avacopan minus control) was >−0.20, the respective avacopan group would be considered not inferior to control. A 20% noninferiority boundary and a one-sided 95% confidence interval were considered appropriate in the context of a relatively small phase 2 clinical trial in an orphan disease setting. There is also precedent for selecting a 20% noninferiority boundary in AAV.24 If the lower bound was >0.0, the respective avacopan group would be considered superior to control. As prespecified, results from all three study steps were combined for the primary analysis.
Continuous variables were analyzed using a mixed-effects model for repeated measures with treatment group, study visit, treatment-by-visit interaction, and randomization strata as factors, and baseline as covariate. Patients were considered as repeated measure units over visits. Data that were not normally distributed, e.g., UACR, were log-transformed before analysis.
Disclosures
D.R.W.J. received consulting and investigator fees from ChemoCentryx, research grants and consulting fees from Roche/Genentech, a grant from Sanofi/Genzyme, and investigator and consulting fees from Boehringer Ingelheim and Medimmune. A.N.B. received consulting and investigator fees from ChemoCentyx and Merck. V.B. received investigator fees from Roche and ChemoCentryx. The Department of Nephrology of M.J. has received research grants from Amgen, Baxter, Fresenius, Janssen-Cilag, and Roche, and M.J. received speaking fees from Amgen, Bellco, GSK, Menarini, MSD, Sanofi, and ZS-Pharma, and investigator fees from ChemoCentryx. L.H., M.S., M.C.V., and V.T. received consulting and investigator fees from ChemoCentryx. Recruitment by L.H. was carried out at the National Institute for Health Research (NIHR)/Wellcome Trust Birmingham Clinical Research Facility. The views expressed are those of the authors(s) and not necessarily those of the National Health Service, the NIHR of the Department of Health. P.H. and I.S. received investigator fees from ChemoCentryx. F.G. received investigator fees from ChemoCentryx and travel support from Otsuka, Astellas, Shire, Koeln Fortune, and DFG. P.B., A.P., and T.J.S. are employees and shareholders of ChemoCentryx, the sponsor of this study.
Acknowledgments
We thank all study coordinators, investigators, and patients for their valuable contribution. Jeffrey Vest (Medpace) and his team performed the statistical analysis.
This study was funded by ChemoCentryx, Inc., Mountain View, California.
Results from this clinical trial were presented at the American College of Rheumatology meeting, November 6–11, 2015, Boston, Massachusetts; the meetings of the European Renal Association–European Dialysis and Transplant Association, May 31 to June 3, 2014, Amsterdam, The Netherlands and May 21–24, 2016, Vienna, Austria; and the American Society of Nephrology meeting, November 15–20, 2016, Chicago, Illinois.
Footnotes
Published online ahead of print. Publication date available at www.jasn.org.
This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2016111179/-/DCSupplemental.
- Copyright © 2017 by the American Society of Nephrology
References
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