Pharmacokinetic Evaluation of the CYP3A4 and CYP2C9 Drug-Drug Interaction of Avacopan in 2 Open-Label Studies in Healthy Participants.

Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30 mg of avacopan increased the area under the curve (AUC) of midazolam by 1.81-fold and celecoxib by 1.15-fold when administered without food, and twice-daily oral administration of 30 or 60 mg of avacopan increased the AUC of simvastatin by approximately 2.6-3.5-fold and the AUC of the active metabolite ß-hydroxy-simvastatin acid by approximately 1.4-1.7-fold when co-administered with food. Furthermore, the AUC of avacopan increased by approximately 2.19-fold when co-administered with itraconazole and decreased by approximately 13.5-fold when co-administered with rifampin. These findings provide critical insights into the potential drug-drug interactions involving avacopan, which could have significant implications for patient care and treatment planning. (NCT06207682).

Renal Recovery for Patients with ANCA-Associated Vasculitis and Low eGFR in the ADVOCATE Trial of Avacopan.

Introduction: In the 330-patient ADVOCATE trial of avacopan for the treatment of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which 81% of patients had renal involvement, estimated glomerular filtration rate (eGFR) increased on average 7.3 ml/min per 1.73 m2 in the avacopan group and 4.1 ml/min per 1.73 m2 in the prednisone group (P = 0.029) at week 52. This new analysis examines the results in the patient subgroup with severe renal insufficiency at enrollment into the trial, i.e., eGFR ≤20 ml/min per 1.73 m2. Methods: eGFR was determined at baseline and over the course of the trial. Changes in eGFR were compared between the 2 treatment groups. Results: In ADVOCATE, 27 of 166 patients (16%) in the avacopan group and 23 of 164 patients (14%) in the prednisone group had a baseline eGFR ≤20 ml/min per 1.73 m2. At week 52, eGFR increased on average 16.1 and 7.7 ml/min per 1.73 m2 in the avacopan and prednisone groups, respectively (P = 0.003). The last eGFR value measured during the 52-week treatment period was ≥2-fold higher than baseline in 41% of patients in the avacopan group compared to 13% in the prednisone group (P = 0.030). More patients in the avacopan group versus prednisone group had increases in eGFR above 20, 30, and 45 ml/min per 1.73 m2, respectively. Serious adverse events occurred in 13 of 27 patients (48%) in the avacopan group and 16 of 23 patients (70%) in the prednisone group. Conclusion: Among patients with baseline eGFR ≤20 ml/min per 1.73 m2 in the ADVOCATE trial, eGFR improved more in the avacopan group than in the prednisone group.

The Glucocorticoid Toxicity Index-Metabolic Domains, an abridged version of the Glucocorticoid Toxicity Index: post-hoc analysis of data from the ADVOCATE trial.

BACKGROUND: Quantifying glucocorticoid toxicity is crucial to efforts to reduce it. The Glucocorticoid Toxicity Index (GTI) measures toxicity effectively in clinical trials by calculating two scores: the cumulative worsening score (CWS) and the aggregate improvement score (AIS). However, in clinical practice, high patient volumes limit the time available for standardised assessments. We aimed to compare the GTI with an abbreviated version of the GTI, the GTI-Metabolic Domains (GTI-MD), which could help to address this issue by using data that are collected easily at routine visits and do not require additional effort from clinicians. METHODS: We did a post-hoc analysis of data from ADVOCATE, a randomised, double-blind, double-dummy, phase 3 trial in which avacopan replaced a standard prednisone taper in patients with antineutrophil cytoplasmic antibody-associated vasculitis. We calculated the cumulative worsening score (CWS) and aggregate improvement score (AIS) for each domain of the GTI-MD-comprising the BMI, glucose tolerance, blood pressure, and lipid metabolism domains of the GTI-to test its ability to differentiate the avacopan and prednisone groups by glucocorticoid toxicity. Data from two additional disease cohorts, one comprising patients with asthma and the other comprising patients with autoimmune blistering disease, constituted the validation set. FINDINGS: Complete data were available for 321 (97%) of the 330 participants comprising the intention-to-treat population in the ADVOCATE trial at week 13, and 307 (93%) at week 26; data from these individuals were included in our post-hoc analysis. In ADVOCATE, 98 (59%) of 166 participants in the avacopan group were men and 68 (41%) were women, 88 (54%) of 164 in the prednisone group were men and 76 (46%) were women; the mean age of participants was 61·2 years [SD 14·6] in the avacopan group and 60·5 years [14·5] in the prednisone group. The validation cohort included 159 patients (89 with glucocorticoid-dependent asthma, of whom 40 [45%] were men and 49 [55%] were women, and 70 with autoimmune blistering disease of the skin, of whom 30 [43%] were men and 40 [57%] were women). The Spearman's rank correlation coefficient in ADVOCATE for the GTI-MD CWS with the GTI CWS for the treatment groups combined was 0·78 (95% CI 0·75-0·81; p<0·0001). The corresponding correlation for the AIS was 0·73 (0·69-0·77, p<0·0001). The GTI-MD distinguished the groups by glucocorticoid toxicity at both 13 weeks and 26 weeks. The mean GTI-MD CWS was lower in the avacopan group than in the prednisone group, consistent with less toxicity (15·9 vs 23·0 at 13 weeks [p=0·0010]; 26·7 vs 31·7 at 26 weeks [p=0·0092]). The GTI-MD AIS values were also consistent with less toxicity in the avacopan group (2·5 vs 13·0 at 13 weeks [p=0·0003], 4·4 vs 10·1 at 26 weeks [p=0·027]). A GTI-MD score of 0 corresponded to a low likelihood of toxicity in the other GTI domains. In the validation set, the Spearman's rank correlation coefficient for the GTI-MD CWS with the GTI CWS was 0·61 (95% CI 0·50-0·70; p<0·0001) and the corresponding correlation for the AIS was 0·58 (0·47-0·68; p<0·0001). INTERPRETATION: The GTI-MD correlates well with the full GTI and could be incorporated readily into routine clinic workflows without additional input from the clinician. Using the GTI-MD on the background of electronic medical records systems could help clinicians to monitor glucocorticoid toxicity longitudinally, with the goals of preventing the burden of chronic, treatment-related harms and reducing long-term costs to health systems. FUNDING: ChemoCentryx.

The impact of treatment with avacopan on health-related quality of life in antineutrophil cytoplasmic antibody-associated vasculitis: a post-hoc analysis of data from the ADVOCATE trial.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterised by inflammation and destruction of small to medium sized blood vessels. In the previously reported ADVOCATE study, a phase 3 double-blind, double-dummy randomised controlled trial of patients with newly diagnosed or relapsing ANCA-associated vasculitis, the oral selective complement 5a receptor inhibitor avacopan was shown to be non-inferior with regard to remission induction at week 26 and superior with regard to sustained remission at week 52, compared with a prednisone taper in a standard of care regimen. In this Article, we report an in-depth analysis of prespecified and exploratory patient-reported outcomes from the ADVOCATE study, measuring health-related quality of life and health utilities. METHODS: We did a post-hoc analysis of patient-reported outcome data from the ADVOCATE study (NCT02994927) of patients with newly diagnosed or relapsing ANCA-associated vasculitis. We analysed summary scores and individual domain scores for the prespecified health-related quality of life outcomes from ADVOCATE, which were evaluated at weeks 26 and 52 by use of the Medical Outcomes Survey 36-Item Short Form Health Survey (SF-36) version 2, the EuroQol 5-Dimensions 5-Levels Questionnaire (EQ-5D-5L), and the EQ-5D health utility measure, assessed in the modified intention-to-treat population. We also calculated the Short Form 6 Dimension (SF-6D) score as an additional health utility measure. We evaluated the proportion of patients who reported scores that met or exceeded minimum clinically important differences in health-related quality of life, and we compared scores to normative values (age-specific and sex-specific scores from healthy populations from the USA matched to the protocol population). We also evaluated the proportion of patients who reported scores that met or exceeded minimum important difference in health utility scores. FINDINGS: 331 patients were enrolled in the ADVOCATE trial, of whom 166 were in the avacopan group and 165 were in the prednisone standard of care group. In the avacopan group, the mean age was 61·2 years (SD 14·6), 98 (59%) of 166 patients were men, 68 (41%) were women, and 138 (83%) were White; in the prednisone group, the mean age was 60·5 years (14·5), 88 (54%) of 164 patients were men, 76 (46%) were women, and 140 (85%) were White. Patients treated with avacopan received approximately 2500 mg less median total prednisone up to week 52. Least squares means difference from baseline in physical component summary scores were significantly greater in patients in the avacopan group compared with those in the prednisone group at weeks 26 and 52, as well as in five of eight SF-36 domains at week 26 and two of eight SF-36 domains at week 52. The proportion of patients reporting scores equal to or greater than normative values was higher in the avacopan group than in the prednisone group across all SF-36 domains at both week 26 and 52, although the differences were not statistically significant with the exception of the role physical and vitality domains at week 26. Least squares means change from baseline in EQ-5D-5L visual analogue scale, EQ-5D health utility scores, and SF-6D health utility scores were significantly greater at week 52 in the avacopan group compared with the prednisone group. INTERPRETATION: Patients with ANCA-associated vasculitis who received avacopan reported statistically significant and clinically meaningful improvements in health-related quality of life at 26 and 52 weeks and in health utility EQ-5D and SF-6D scores at 52 weeks. These patient-reported outcomes complement investigator assessments and support the efficacy of avacopan in patients with ANCA-associated vasculitis with use of lower prednisone doses. FUNDING: ChemoCentryx.

Glucocorticoid Toxicity Index scores by domain in patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with avacopan versus standard prednisone taper: post-hoc analysis of data from the ADVOCATE trial.

BACKGROUND: The ADVOCATE trial, in which the complement C5a receptor inhibitor avacopan was compared with a standard prednisone taper in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, used the Glucocorticoid Toxicity Index (GTI) to measure glucocorticoid toxicity change. We set out to do a post-hoc analysis of the ADVOCATE data to evaluate changes in individual GTI domains and their ability to differentiate treatment groups. METHODS: The ADVOCATE trial was a phase 3, double-blind, double-dummy, randomised trial comparing oral avacopan (30 mg) twice daily for 52 weeks plus a prednisone-matching placebo for 20 weeks with oral prednisone tapered over 20 weeks plus an avacopan-matching placebo for 52 weeks in patients with ANCA-associated vasculitis. GTI data were collected within each of the included domains (BMI, blood pressure, glucose tolerance, lipid metabolism, glucocorticoid myopathy, skin toxicity, neuropsychiatric effects, and infections) at baseline, 13 weeks, and 26 weeks. In this post-hoc analysis, we calculated the cumulative worsening score (CWS) and aggregate improvement score (AIS) for each GTI domain, assessed to what extend each domain contributed to the GTI score, and which domains differentiated between the avacopan and prednisone groups. Differences in domain scores between the two groups were compared using Mantel-Haenszel χ2 tests. FINDINGS: Among the 330 patients included in the intention-to-treat population of the ADVOCATE trial, 321 (97%) had complete data at week 13 (160 in the avacopan group, and 161 in the prednisone group), and 307 (93%) had complete data at week 26 (154 in the avacopan group, and 153 in the prednisone group) and were assessed in this post-hoc study. In ADVOCATE, mean age in both groups was 61 years (61·2 years [SD 14·6] in the avacopan group; 60·5 years [14·5] in the prednisone group); 98 (59%) of 166 patients in the avacopan group were men and 68 (41%) were women; 88 (54%) of 164 patients in the prednisone group were men and 76 (46%) were women. 278 (84%) of 330 patients were White. The mean glucocorticoid use over 26 weeks was lower in the avacopan group than the prednisone group (1073 mg [SD 1669] vs 3192 mg [1174]). Significantly less glucocorticoid toxicity was observed in the avacopan group than the prednisone group by week 13 in four domains of the GTI (BMI, glucose tolerance, lipid metabolism, and skin toxicity), based on both the CWS and AIS. CWS values in the BMI, lipid metabolism, and skin toxicity domains were significantly lower in the avacopan group than the prednisone group at 26 weeks. No domain favoured the prednisone group for glucocorticoid toxicity reduction. 280 (91%) of 307 patients had glucocorticoid toxicity at 26 weeks. Blood pressure (35% in the avacopan group vs 25% in the prednisone group), infection (22% vs 24%), and lipid metabolism (20% vs 15%) contributed the most weight toward CWS values at 26 weeks. 128 (42%) of 307 patients had combinations of improvement and worsening in different domains at 26 weeks. INTERPRETATION: Replacing a standard prednisone taper with avacopan in patients with ANCA-associated vasculitis reduced glucocorticoid toxicity in multiple GTI domains. For individual patients, glucocorticoid toxicity was often nuanced, improving in some domains while worsening in others. These findings emphasise the value of a composite measure of glucocorticoid toxicity that quantifies cumulative worsening and aggregate change directly. FUNDING: ChemoCentryx.

C5a receptor inhibitor avacopan in immunoglobulin A nephropathy-an open-label pilot study.

Background: Improvement of proteinuria as a marker for disease activity is associated with a better renal outcome in immunoglobulin A nephropathy (IgAN). Complement is an effector pathway in IgA-mediated kidney injury. Avacopan, a selective C5a receptor inhibitor, has previously shown efficacy in anti-neutrophil cytoplasmic antibody-associated vasculitis. The aim of this study was to evaluate the safety and efficacy of avacopan in patients with IgAN with persistent proteinuria despite a maximally tolerated dose of renin-angiotensin-aldosterone system blockade. The efficacy evaluation was based on the change in proteinuria. Methods: This open-label pilot trial enrolled adult patients with biopsy-proven IgAN, urinary protein:creatinine ratio (UPCR) >1 g/g creatinine and an estimated glomerular filtration rate (eGFR) >60 mL/min/1.73 m2 or >45 mL/min/1.73 m2 if eGFR has not declined >10 mL/min/1.73 m2 over the previous 24 weeks. If the UPCR remained at >1 g/g creatinine after an 8-week run-in period, patients started avacopan 30 mg twice daily. The primary efficacy endpoint was the change in the slope of the UPCR from the 8-week run-in period to the slope in the 12-week avacopan dosing period. Results: A total of 10 of 15 screened patients entered the run-in period. Seven patients with a UPCR >1 g/g creatinine received avacopan. Six of seven patients had numerical improvement in the UPCR during the avacopan treatment period, three of whom had a numerical improvement of ∼50% at week 12. At week 24, five of seven patients still showed numerical improvement in the UPCR compared with baseline. The urinary monocyte chemoattractant protein-1:creatinine ratio decreased numerically 30% by week 8, possibly reflecting the anti-inflammatory activity of avacopan. Avacopan was well tolerated. There was one serious adverse event of unstable angina, which was deemed to be unrelated to avacopan. Conclusions: This short-term pilot study showed an improvement in the slope of the UPCR, with ∼50% improvement in three of seven patients with IgAN. Longer avacopan treatment duration may be indicated for maximal benefit.

The glucocorticoid toxicity index: Measuring change in glucocorticoid toxicity over time.

Glucocorticoids (GCs) have been the cornerstone of treating dozens of inflammatory conditions for more than seven decades. GC toxicity is ubiquitous in both clinical trials and clinical practice, and toxicities associated with GC use are central to the experience of most patients being treated for immune-mediated conditions. These conditions span the full range of medical specialties, including rheumatology, nephrology, gastroenterology, neurology, pulmonology, ophthalmology, and others. One of the goals of novel therapies for inflammatory disease must be to diminish the effects of GC toxicity in clinically important ways, thereby differentiating these new treatments from existing approaches. Despite the importance of glucocorticoids in the treatment of inflammatory disease for more than 70 years, no reliable means of calculating the degree to which GC toxicity has worsened or improved over the course of treatment has been available. The Glucocorticoid Toxicity Index (GTI), developed by an international group of subspecialty physician experts as a clinician-facing clinical trials outcome measure, is a standardized, validated measure of the phenomenon known as GC toxicity. The purpose of the instrument is to measure change in GC toxicity between two points in time: for example, between the baseline visit and the time of the primary efficacy outcome assessment. The instrument is designed to quantify both worsening and improvement in GC toxicity. The GTI has been validated in both real-world experiences and clinical trials, including a phase 3, label-enabling trial in ANCA associated vasculitis. This article reviews the history and rationale for the development of the GTI, describes key data from validation studies, considers the minimum clinically important difference, and provides instructions for use of the instrument.

Avacopan for the Treatment of ANCA-Associated Vasculitis.

BACKGROUND: The C5a receptor inhibitor avacopan is being studied for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: In this randomized, controlled trial, we assigned patients with ANCA-associated vasculitis in a 1:1 ratio to receive oral avacopan at a dose of 30 mg twice daily or oral prednisone on a tapering schedule. All the patients received either cyclophosphamide (followed by azathioprine) or rituximab. The first primary end point was remission, defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 (on a scale from 0 to 63, with higher scores indicating greater disease activity) at week 26 and no glucocorticoid use in the previous 4 weeks. The second primary end point was sustained remission, defined as remission at both weeks 26 and 52. Both end points were tested for noninferiority (by a margin of 20 percentage points) and for superiority. RESULTS: A total of 331 patients underwent randomization; 166 were assigned to receive avacopan, and 165 were assigned to receive prednisone. The mean BVAS at baseline was 16 in both groups. Remission at week 26 (the first primary end point) was observed in 120 of 166 patients (72.3%) receiving avacopan and in 115 of 164 patients (70.1%) receiving prednisone (estimated common difference, 3.4 percentage points; 95% confidence interval [CI], -6.0 to 12.8; P<0.001 for noninferiority; P = 0.24 for superiority). Sustained remission at week 52 (the second primary end point) was observed in 109 of 166 patients (65.7%) receiving avacopan and in 90 of 164 patients (54.9%) receiving prednisone (estimated common difference, 12.5 percentage points; 95% CI, 2.6 to 22.3; P<0.001 for noninferiority; P = 0.007 for superiority). Serious adverse events (excluding worsening vasculitis) occurred in 37.3% of the patients receiving avacopan and in 39.0% of those receiving prednisone. CONCLUSIONS: In this trial involving patients with ANCA-associated vasculitis, avacopan was noninferior but not superior to prednisone taper with respect to remission at week 26 and was superior to prednisone taper with respect to sustained remission at week 52. All the patients received cyclophosphamide or rituximab. The safety and clinical effects of avacopan beyond 52 weeks were not addressed in the trial. (Funded by ChemoCentryx; ADVOCATE ClinicalTrials.gov number, NCT02994927.).

Adjunctive Treatment With Avacopan, an Oral C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: This study aimed to evaluate the safety of avacopan, an orally administered C5a receptor inhibitor, for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in addition to standard-of-care (SOC) treatment with glucocorticoids with cyclophosphamide or rituximab. METHODS: In this randomized 12-week study, twice daily avacopan (10 mg or 30 mg) plus SOC was assessed versus SOC only in patients with newly diagnosed/relapsing ANCA-associated vasculitis. Efficacy measurements included 50% or greater reduction in Birmingham Vasculitis Activity Score (BVAS) at day 85, rapid reduction (day 29) of BVAS to a score of 0 that was sustained through day 85, change in Vasculitis Damage Index (VDI), renal response (improvement in estimated glomerular filtration rate [eGFR], hematuria, and albuminuria), and health-related quality of life (HRQoL). RESULTS: Forty-two patients were randomized (n = 13 SOC, n = 13 avacopan 10 mg, and n = 16 avacopan 30 mg). Serious adverse events occurred in 15% and 17% of patients receiving SOC only and patients receiving avacopan with SOC, respectively. In the intent-to-treat population, BVAS response was high across arms (11 of 13 SOC, 11 of 12 avacopan 10 mg, and 12 of 15 avacopan 30 mg); increases in mean VDI were greater with SOC only than with avacopan plus SOC (0.3 versus 0.1). Avacopan 30 mg was numerically superior to placebo and avacopan 10 mg in early remission (15%, 8%, and 20% for SOC only, avacopan 10 mg, and avacopan 30 mg, respectively), improved eGFR (+2.0 ml/min/1.73m2 , +1.3 ml/min/1.73m2 , and +6.2 ml/min/1.73m2 , respectively), renal response (17%, 40%, and 63%, respectively), and measures of HRQoL. CONCLUSION: Avacopan in addition to SOC for ANCA-associated vasculitis was well tolerated, and at the higher study dose, it appeared to improve time to remission (ClinicalTrials.gov identifier NCT02222155).

Evaluation of the Safety and Efficacy of Avacopan, a C5a Receptor Inhibitor, in Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis Treated Concomitantly With Rituximab or Cyclophosphamide/Azathioprine: Protocol for a Randomized, Double-Blind, Active-Controlled, Phase 3 Trial.

BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a serious, often life-threatening disease. In new-onset disease or a relapse, the standard treatment is immunosuppressive therapy with glucocorticoids; these therapies are associated with substantial short- and long-term toxicity. Complement component 5a (C5a) binding to C5a receptor (C5aR) may play a central role in the pathogenesis of ANCA-associated vasculitis. Avacopan is a novel, orally bioavailable, and highly selective antagonist of human C5aR. Avacopan does not interfere with the production of C5b or the membrane attack complex (ie, terminal complement complex) and does not block C5a binding to a second receptor, C5L2 (also called C5aR2), shown to be protective in antimyeloperoxidase glomerulonephritis. This trial will evaluate if avacopan replaces the need for chronic glucocorticoids in the treatment of ANCA-associated vasculitis. OBJECTIVE: The aim of this study is to determine the proportions of patients in remission at week 26 and with sustained remission at week 52, defined as Birmingham Vasculitis Activity Score=0, and not taking glucocorticoids within the 4 weeks before week 26 and week 52, respectively. METHODS: The Avacopan Development in Vasculitis to Obtain Corticosteroid elimination and Therapeutic Efficacy study is a randomized, double-blind, active-comparator (prednisone), 2-arm study evaluating the safety and efficacy of avacopan versus prednisone, administered in combination with other immunosuppressive therapy. Eligible subjects will have active disease requiring induction of remission. Subjects are stratified based on the type of immunosuppressive therapy, ANCA subtype, and new or relapsing disease. Target sample size is 300 patients, enrolled at over 200 sites globally. All authors and local ethics committees approved the study design. All patients will provide informed consent. RESULTS: Enrollment of patients was completed in Q4 2018. Topline results are anticipated to be published by Q3 2020. CONCLUSIONS: Results will be released irrespective of whether the findings are positive or negative. TRIAL REGISTRATION: ClinicalTrials.gov NCT02994927; https://clinicaltrials.gov/ct2/show/NCT02994927. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/16664.

Correction: Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

[This corrects the article DOI: 10.1371/journal.pone.0164646.].

Effect of Disease Activity at Three and Six Months After Diagnosis on Long-Term Outcomes in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

OBJECTIVE: The treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) aims to suppress disease activity and prevent subsequent disease flare. This study sought to explore the association of early disease control with long-term outcomes to validate early disease control as an end point for future clinical trials in AAV. METHODS: Data from 4 European Vasculitis Society inception clinical trials in AAV (1995-2002) and subsequent data on long-term outcomes from the trial data registry were studied. Clinical parameters in patients with AAV at baseline and at 3 and 6 months after diagnosis were assessed to study the long-term risk of death and end-stage renal failure (ESRF). At 6 months, outcomes were defined based on a disease status of either sustained remission (remission by 3 months, sustained to 6 months), late remission (remission after 3 months and by 6 months), relapsing disease (remission by 3 months but relapse by 6 months), or refractory disease (no remission by 6 months). RESULTS: Of the 354 patients with AAV who were followed up for a median of 5.7 years, 46 (13%) developed ESRF, 66 (18.6%) died, and 89 (25.1%) had either died or developed ESRF. At 6 months, predictors of the composite end point of death or ESRF were as follows: age (hazard ratio [HR] 1.02, 95% confidence interval [95% CI] 1-1.05; P = 0.012), estimated glomerular filtration rate (HR 0.94, 95% CI 0.92-0.95; P < 0.001), and disease status at 6 months (late remission, HR 2.94, 95% CI 1.1-7.85 [P = 0.031]; relapsing disease, HR 8.21, 95% CI 2.73-24.65 [P < 0.001]; refractory disease, HR 4.89, 95% CI 1.96-12.18 [P = 0.001]). Similar results were observed when these analyses were performed separately for death and for ESRF. CONCLUSION: The results of this study suggest that disease status at 3 and 6 months following the diagnosis of AAV may be predictive of the long-term risk of mortality and ESRF, and therefore these may be valid end points for induction trials in AAV. The current findings need to be validated in a larger data set.

Randomized Trial of C5a Receptor Inhibitor Avacopan in ANCA-Associated Vasculitis.

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.

Characterization of Pharmacologic and Pharmacokinetic Properties of CCX168, a Potent and Selective Orally Administered Complement 5a Receptor Inhibitor, Based on Preclinical Evaluation and Randomized Phase 1 Clinical Study.

The complement 5a receptor has been an attractive therapeutic target for many autoimmune and inflammatory disorders. However, development of a selective and potent C5aR antagonist has been challenging. Here we describe the characterization of CCX168 (avacopan), an orally administered selective and potent C5aR inhibitor. CCX168 blocked the C5a binding, C5a-mediated migration, calcium mobilization, and CD11b upregulation in U937 cells as well as in freshly isolated human neutrophils. CCX168 retains high potency when present in human blood. A transgenic human C5aR knock-in mouse model allowed comparison of the in vitro and in vivo efficacy of the molecule. CCX168 effectively blocked migration in in vitro and ex vivo chemotaxis assays, and it blocked the C5a-mediated neutrophil vascular endothelial margination. CCX168 was effective in migration and neutrophil margination assays in cynomolgus monkeys. This thorough in vitro and preclinical characterization enabled progression of CCX168 into the clinic and testing of its safety, tolerability, pharmacokinetic, and pharmacodynamic profiles in a Phase 1 clinical trial in 48 healthy volunteers. CCX168 was shown to be well tolerated across a broad dose range (1 to 100 mg) and it showed dose-dependent pharmacokinetics. An oral dose of 30 mg CCX168 given twice daily blocked the C5a-induced upregulation of CD11b in circulating neutrophils by 94% or greater throughout the entire day, demonstrating essentially complete target coverage. This dose regimen is being tested in clinical trials in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis. Trial Registration ISRCTN registry with trial ID ISRCTN13564773.

CCR9 Antagonists in the Treatment of Ulcerative Colitis.

While it has long been established that the chemokine receptor CCR9 and its ligand CCL25 are essential for the movement of leukocytes into the small intestine and the development of small-intestinal inflammation, the role of this chemokine-receptor pair in colonic inflammation is not clear. Toward this end, we compared colonic CCL25 protein levels in healthy individuals to those in patients with ulcerative colitis. In addition, we determined the effect of CCR9 pharmacological inhibition in the mdr1a(-/-) mouse model of ulcerative colitis. Colon samples from patients with ulcerative colitis had significantly higher levels of CCL25 protein compared to healthy controls, a finding mirrored in the mdr1a(-/-) mice. In the mdr1a(-/-) mice, CCR9 antagonists significantly decreased the extent of wasting and colonic remodeling and reduced the levels of inflammatory cytokines in the colon. These findings indicate that the CCR9:CCL25 pair plays a causative role in ulcerative colitis and suggest that CCR9 antagonists will provide a therapeutic benefit in patients with colonic inflammation.

The effect of CCR2 inhibitor CCX140-B on residual albuminuria in patients with type 2 diabetes and nephropathy: a randomised trial.

BACKGROUND: Patients with type 2 diabetes and nephropathy have high cardiorenal morbidity and mortality despite optimum treatment including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). Residual risk is related to residual albuminuria. We assessed whether CCX140-B, a selective inhibitor of C-C chemokine receptor type 2 (CCR2), could further reduce albuminuria when given in addition to standard care, including ACE inhibitors or ARBs. METHODS: In this randomised, double-blind, placebo-controlled clinical trial, we recruited patients from 78 research centres in Belgium, Czech Republic, Germany, Hungary, Poland, and the UK. We enrolled patients with type 2 diabetes aged 18-75 years with proteinuria (first morning void urinary albumin to creatinine ratio [UACR] 100-3000 mg/g), estimated glomerular filtration rate of 25 mL/min per 1·73 m(2) or higher, and taking stable antidiabetic treatment and ACE inhibitors or ARBs, for at least 8 weeks before study entry. Patients were stratified based on baseline UACR and renal function (estimated glomerular filtration rate), and then randomly assigned (1:1:1) via an interactive web response system with a minimisation algorithm to oral placebo, 5 mg CCX140-B, or 10 mg CCX140-B once a day. The 12-week dosing period in the initial protocol was extended to 52 weeks by protocol amendment. The primary efficacy measure was change from baseline in UACR during 52 weeks in the modified intention-to-treat population (all patients with uninterrupted dosing, excluding patients who stopped dosing at week 12 either permanently under the original protocol, or temporarily because of delay in approval of the protocol amendment). We did safety analyses on all randomly assigned patients who received at least one dose of study drug. According to a prespecified analysis plan, we analysed the primary endpoint with one-sided statistical testing with calculation of upper 95% confidence limits of the differences between active and control. This trial is registered with ClinicalTrials.gov, number NCT01447147. FINDINGS: The study ran from Dec 7, 2011 (first patient enrolled), until Aug 4, 2014. We enrolled 332 patients: 111 were assigned to receive placebo, 110 to 5 mg CCX140-B, and 111 to 10 mg CCX140-B. Of these, 192 were included in the modified intention-to-treat population. UACR changes from baseline during 52 weeks were -2% for placebo (95% CI -11% to 9%), -18% for 5 mg CCX140-B (-26% to -8%), and -11% for 10 mg CCX140-B (-20% to -1%). We recorded a -16% difference between 5 mg CCX140-B and placebo (one-sided upper 95% confidence limit -5%; p=0·01) and a -10% difference between 10 mg CCX140-B and placebo (upper 95% confidence limit 2%; p=0·08). Adverse events occurred in 81 (73%) of 111 patients in the placebo group versus 71 (65%) of 110 patients in the CCX140-B 5 mg group and 68 (61%) of 111 patients in the CCX140-B 10 mg group; there were no renal events during the study. INTERPRETATION: Our data suggest that CCR2 inhibition with CCX140-B has renoprotective effects on top of current standard of care in patients with type 2 diabetes and nephropathy. FUNDING: ChemoCentryx.