Abstract
Objective
This study aimed to report the safety of avacopan, an oral selective complement C5a receptor antagonist, using pooled data from clinical trials in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (granulomatosis with polyangiitis [GPA] or microscopic polyangiitis [MPA]).
Methods
Data were included from two phase 2 (CLEAR [NCT01363388] and CLASSIC [NCT02222155]) and one phase 3 (ADVOCATE [NCT02994927]) double‐blind randomized controlled trials comparing the safety and efficacy of avacopan with active non‐avacopan control regimens to induce remission in patients with GPA or MPA. In CLEAR and ADVOCATE, avacopan‐treated patients received either no or lower doses of study‐supplied prednisone than the control groups; in CLASSIC, all groups received the same dose of study‐supplied prednisone. Assessments included rates of exposure‐adjusted adverse events (AEs), serious AEs (SAEs), and AEs of special interest.
Results
Overall, 439 patients with GPA or MPA (avacopan: n = 239; non‐avacopan: n = 200) were included. The exposure‐adjusted rates of AEs, SAEs, white blood cell (WBC) count reductions, and infections were lower with avacopan versus control (between‐group differences in rate per 100 patient‐years −151.9 [95% confidence interval (CI) −218.6 to −85.3], −20.8 [95% CI −38.3 to −3.3], −11.6 [95% CI −22.2 to −1.2], and −24.3 [95% CI −48.5 to −0.1], respectively). SAEs associated with hepatic function abnormalities occurred in 4.4% of the avacopan group and 2.8% of the control group.
Conclusion
In clinical trials of GPA or MPA, use of avacopan was associated with fewer AEs, SAEs, and WBC count reductions and fewer infections than non‐avacopan treatment. Safety data support the use of avacopan in patients with GPA or MPA.
INTRODUCTION
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is a complex, systemic, organ‐ or life‐threatening relapsing autoimmune disorder characterized by inflammation of small‐ to medium‐sized blood vessels affecting multiple organ systems. 1 AAV encompasses the three clinical syndromes of granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis. 1
The standard treatment for patients with new‐onset or relapsing AAV involves the use of high‐dose glucocorticoids with rituximab (RTX) or cyclophosphamide (CYC) to achieve and sustain remission, limit further organ damage, and reduce mortality rates. 1 , 2 , 3 Although effective, the toxic effects of these treatments can have a profound impact on patients with AAV, especially during the first year of treatment. 4 , 5 , 6 Adverse events (AEs) include short‐term complications, such as hyperglycemia and infection (a major cause of early mortality in people with AAV 5 , 6 , 7 ), and long‐term complications, including hypogammaglobulinemia and infertility. 1 , 4 , 5 , 8 , 9 , 10 In some patients, the risk of AEs is increased by frequent relapses that necessitate the re‐introduction of glucocorticoids and other immunosuppressive drugs. 11 The unmet need for treatment strategies for AAV that reduce the risk of AEs by reducing glucocorticoid exposure has led to multiple clinical trials. 11 , 12 , 13 , 14 , 15 , 16 , 17
The alternative complement pathway is an important component of the pathogenesis underlying the autoimmune dysregulation associated with AAV. 18 , 19 Avacopan is a first‐in‐class, small molecule, selective C5a receptor antagonist. 20 Avacopan does not interfere with the formation of the terminal complement complex or the membrane attack complex, C5b‐9, which is necessary for the clearance of pathogenic encapsulated bacteria, such as Neisseria meningitidis. 20 , 21 , 22 , 23 The phase 2 CLASSIC trial demonstrated that avacopan was well tolerated and improved time to remission when used as adjunctive therapy to standard care in patients with GPA and MPA. 15 In the phase 2 CLEAR trial 14 and the phase 3 ADVOCATE trial, 16 avacopan improved remission rates, sustained remission over time, and improved kidney function (albuminuria and/or estimated glomerular filtration rate) in patients with GPA and MPA treated with RTX or CYC and reduced glucocorticoid exposure. The aim of this integrated analysis was to evaluate the safety of avacopan using pooled data from the CLEAR, CLASSIC, and ADVOCATE trials.
PATIENTS AND METHODS
Trial designs
This integrated analysis includes data from patients with GPA or MPA treated with an avacopan or non‐avacopan active control‐based regimen in two phase 2 trials (CLEAR [NCT01363388 14 ] and CLASSIC [NCT02222155 15 ]) and one phase 3 trial (ADVOCATE [NCT02994927 16 ]). Characteristics of these trials are published 14 , 15 , 16 and are summarized in Figure 1.
Figure 1.
Study characteristics for the CLEAR, 14 CLASSIC, 15 and ADVOCATE 16 trials. aExcludes patients who were randomized but did not receive treatment. AE, adverse event; ANCA, antineutrophil cytoplasmic antibody; BID, twice daily; BVAS, Birmingham Vasculitis Activity Score; eGFR, estimated glomerular filtration rate; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PR3, proteinase‐3.
Briefly, CLEAR was a randomized, double‐blind, placebo‐controlled, phase 2 clinical trial designed to evaluate the safety and efficacy of avacopan in 67 patients with newly diagnosed or relapsing GPA or MPA from 11 countries in Europe. 14 Patients received CYC or RTX at doses consistent with the current standard of care and were randomized to receive one of the following treatments for 12 weeks: avacopan 30 mg twice daily (BID) with a prednisone placebo (n = 22), avacopan 30 mg BID with a prednisone taper starting at 20 mg/day (n = 22), or non‐avacopan treatment (active control) with a prednisone taper starting at 60 mg/day (n = 23). Patients were observed for a further 12 weeks.
The randomized, double‐blind, placebo‐controlled, phase 2 CLASSIC trial evaluated the safety and efficacy of avacopan in addition to standard therapy in 42 patients with newly diagnosed or relapsing GPA or MPA in the United States or Canada. 15 Patients were randomized to receive either avacopan 30 mg BID (n = 16) or 10 mg BID (n = 13) as an add‐on to standard therapy or standard therapy alone (n = 13) for 12 weeks with an additional 12 weeks of observation. Standard therapy consisted of a prednisone taper starting at 60 mg/day plus CYC or RTX.
ADVOCATE was a 52‐week randomized, double‐blind, double‐dummy, active‐controlled, phase 3 trial conducted in 331 patients with newly diagnosed or relapsing GPA or MPA in the United States, Canada, Europe, New Zealand, Australia, and Japan. 16 The study design was based on the findings from the two phase 2 trials. 14 , 15 Patients received oral avacopan 30 mg BID (n = 166) or oral prednisone on a tapering schedule (60 mg/day tapered to discontinuation by week 21; n = 165). Per protocol, open‐label glucocorticoid treatment during the screening period was tapered to ≤20 mg of prednisone equivalent before the start of the trial and was further tapered to discontinuation by the end of week 4. All patients received RTX without maintenance therapy or CYC followed by azathioprine (AZA) or mycophenolate mofetil.
The total systemic glucocorticoid dose of study‐ and non–study‐supplied glucocorticoids varied across trials. This was partly because of differences in the per‐protocol dosing of glucocorticoids and partly because some patients received non–study‐supplied glucocorticoids during the screening period, as premedication for RTX, as tapering doses during the study period to reduce the risk of adrenal crisis, and/or as short‐term rescue therapy for flares of AAVGPA/MPA.
All three trials adhered to the tenets of the Declaration of Helsinki and were conducted in accordance with the International Conference on Harmonization E6 for Good Clinical Practice. Trial sites received institutional review board approval before trial initiation, and all patients (or a parent or guardian) provided written informed consent.
Efficacy outcomes
The primary efficacy endpoint for the CLEAR and CLASSIC trials was the proportion of patients achieving a ≥50% reduction in Birmingham Vasculitis Activity Score (BVAS) by week 12 and no worsening in any body system component (Figure 1). 14 , 15 For the ADVOCATE trial, the first primary endpoint was the proportion of patients achieving remission (BVAS 0) at week 26 with no use of glucocorticoid in the previous 4 weeks for the treatment of GPA/MPA, and the second primary endpoint was the proportion achieving sustained remission at week 52 with no use of glucocorticoid in the previous 4 weeks for the treatment of GPA/MPA. 16 Additional efficacy endpoints for each of the trials have been previously described. 14 , 15 , 16
Safety outcomes
Safety outcomes for each of the three trials included AEs, serious AEs (SAEs), AEs leading to study drug discontinuation, hospitalizations, deaths, and AEs of special interest. AEs and SAEs were defined according to International Conference on Harmonization guidelines, and the reported AEs were assigned preferred terms using the Medical Dictionary for Regulatory Activities (version 19.1). AEs of special interest were identified as AEs related to hepatic abnormalities, infections, white blood cell (WBC) count reductions (neutropenia and/or lymphopenia), and hypersensitivity events, including angioedema. Hepatic abnormalities were identified by an abnormal liver function test result, the presence of a hepatobiliary disorder, and/or elevations in liver enzymes above the normal range (6–41 U/L for alanine aminotransferase [ALT], 9–34 U/L for aspartate aminotransferase [AST], 37–116 U/L for alkaline phosphatase [ALP], and 0.1–1.1 mg/dL for bilirubin). Infections were identified using the AE System Organ Class (SOC) of “Infections and Infestations.” Neutropenia and lymphopenia were defined as WBC counts below the normal range (1 to 8 × 103/μL for neutrophils and 1 to 5 × 103/μL for lymphocytes). Pre‐existing conditions worsening during a trial were reported as AEs. For the phase 2 trials, AE summaries included all events in the 24‐week study period (including the 12‐week treatment period and the 12‐week follow‐up period).
Statistical analysis
Details of the sample size calculations and statistical analyses for each of the three trials are published. 14 , 15 , 16 Efficacy outcomes were analyzed for the intention‐to‐treat populations, defined as all patients with at least one post‐baseline on‐treatment BVAS assessment in the CLEAR and CLASSIC trials and all randomized patients receiving at least one dose of study medication in the ADVOCATE trial. Safety data were analyzed for the safety populations, which included all patients receiving at least one dose of study medication.
Safety data for the phase 3 trial and the pooled phase 2 trials were summarized descriptively by treatment group, phase of the study, and overall. For continuous variables, numbers, means, medians, ranges, SDs, and SEMs were calculated. Categorical variables were described using frequency counts and percentages.
The integrated analyses of pooled safety data from the phase 2 and 3 trials were conducted according to the methodology outlined by the Pharmaceuticals User Software Exchange (https://phuse.global/Working_Groups). Exposure‐adjusted event rates and exposure‐adjusted first incidence rates of AEs and SAEs were presented as point estimates and 95% confidence intervals (CIs) for the between‐group differences in rates per 100 patients. Exposure‐adjusted event rates were calculated based on the total number of events experienced for each Medical Dictionary for Regulatory Activities–preferred term divided by the total duration of follow‐up (on or off treatment) for all patients. Exposure‐adjusted first incidence rates were calculated based on the number of patients with a specific event divided by the total time at risk (the time to the first event for patients who experienced the event and the time during the study for patients who did not experience the event).
RESULTS
Demographics and baseline characteristics
A total of 440 patients were randomized to treatment in the CLEAR, CLASSIC, and ADVOCATE trials. 14 , 15 , 16 Of these, 439 (239 receiving avacopan and 200 not receiving avacopan) were included in the safety population, and 1 (a patient in the ADVOCATE trial control group) was excluded after a renal biopsy failed to confirm the presence of vasculitis. Patient demographics and baseline characteristics for the pooled phase 2 trials, the phase 3 trial, and the pooled phase 2 and 3 trials are described in Table 1.
Table 1.
Demographics and baseline characteristics of patients with GPA and MPA treated with avacopan‐ versus non‐avacopan‐based regimens in the phase 2 CLEAR 14 and CLASSIC 15 trials and the phase 3 ADVOCATE 16 trial
| Characteristic | Avacopan‐based regimen | Non‐avacopan‐based regimen | Combined (3) trials (n = 439/440) | ||
|---|---|---|---|---|---|
| Pooled phase 2 (n = 73) | Phase 3 (n = 166) | Pooled phase 2 (n = 36) | Phase 3 (n = 164/165) a | ||
| Age at screening, mean (SD), y | 57.5 (13.2) | 61.2 (14.6) | 59.2 (14.4) | 60.6 (14.5) | 60.2 (14.3) |
| Duration of AAV, mean (SD), mo | 27.1 (60.0) | 22.9 (52.5) | 16.4 (34.4) | 20.1 (40.5) | 22.0 (48.3) |
| Male patients, n (%) | 45 (61.6) | 98 (59.0) | 21 (58.3) | 89 (53.9) | 253 (57.5) |
| Race, b n (%) | |||||
| Asian | 0 | 17 (10.2) | 0 | 15 (9.1) | 32 (7.3) |
| Black or African American | 3 (4.1) | 3 (1.8) | 0 | 2 (1.2) | 8 (1.8) |
| White | 69 (94.5) | 138 (83.1) | 36 (100.0) | 141 (85.5) | 384 (87.3) |
| Other | 1 (1.4) | 8 (4.8) | 0 (0.0) | 7 (4.2) | 16 (3.6) |
| Baseline eGFR, mean (SD), mL/min/1.73 m2 |
CLEAR: 53.6 (23.2) CLASSIC: 59.1 (28.8) |
44.6 (2.4) |
CLEAR: 47.6 (15.1) CLASSIC: 60.1 (24.3) |
45.6 (2.4) | 52.5 (30.0) |
| Disease history, n (%) | |||||
| Newly diagnosed | 50 (68.5) | 115 (69.3) | 26 (72.2) | 114 (69.5) | 305 (69.3) |
| Relapsed | 23 (31.5) | 51 (30.7) | 10 (27.8) | 50 (30.5) | 134 (30.5) |
| Type of AAV, n (%) | |||||
| GPA | 43 (58.9) | 91 (54.8) | 19 (52.8) | 90 (54.9) | 243 (55.4) |
| MPA | 26 (35.6) | 75 (45.2) | 13 (36.1) | 74 (45.1) | 188 (42.8) |
| Renal limited vasculitis | 4 (5.5) | 0 (0.0) | 3 (8.3) | 0 (0.0) | 7 (1.6) |
| Other | 0 (0.0) | 0 (0.0) | 1 (2.8) | 0 (0.0) | 1 (0.1) |
| ANCA type, n (%) | |||||
| Anti‐MPO | 39 (53.4) | 94 (56.6) | 17 (47.2) | 94 (57.3) | 244 (55.6) |
| Anti‐PR3 | 33 (45.2) | 72 (43.4) | 17 (47.2) | 70 (42.7) | 192 (43.7) |
| Anti‐MPO and anti‐PR3 | 0 (0.0) | 0 (0.0) | 1 (2.8) | 0 (0.0) | 1 (0.2) |
| ANCA equivocal | 1 (1.4) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.2) |
| ANCA negative | 0 (0.0) | 0 (0.0) | 1 (2.8) | 0 (0.0) | 1 (0.2) |
| Prior medications, n (%) | |||||
| Cyclophosphamide | 1 (1.4) | 4 (2.4) | 0 | 2 (1.2) | 7 (1.6) |
| Rituximab | 0 | 1 (0.5) | 0 | 4 (2.4) | 5 (1.1) |
| Other immunosuppressive drugs | 14 (19.2) | 26 (15.7) | 4 (8.1) | 26 (15.9) | 70 (15.9) |
| Glucocorticoids | 52 (71.2) | 125 (75.3) | 21 (58.3) | 135 (82.3) | 333 (75.9) |
| Induction treatment, n (%) | |||||
| Rituximab | 37 (50.7) | 107 (64.5) | 15 (41.7) | 107 (65.2) | 266 (60.6) |
| Intravenous cyclophosphamide | 36 (49.3) | 51 (30.7) | 21 (58.3) | 51 (31.1) | 159 (36.2) |
| Oral cyclophosphamide | 0 | 8 (4.8) | 0 | 6 (3.7) | 14 (3.2) |
| Avacopan | Non‐avacopan | Combined (2) trials (n = 398) | |||
|---|---|---|---|---|---|
| Organ involvement, n (%) | Phase 2 c (n = 44) | Phase 3 (n = 166) | Phase 2 c (n = 23) | Phase 3 (n = 165) | |
| Pulmonary | 15 (34.1) | 71 (42.8) | 9 (39.1) | 71 (43.3) | 166 (41.7) |
| Neurologic | 7 (15.9) | 38 (22.9) | 3 (13.0) | 31 (18.9) | 79 (19.8) |
| Cardiovascular | 3 (6.8) | 6 (3.6) | 0 | 3 (1.8) | 12 (3.0) |
| Ear, nose, and throat | 13 (29.5) | 75 (45.2) | 9 (39.1) | 69 (42.1) | 166 (41.7) |
| Mucous membranes and eye | 5 (11.4) | 26 (15.7) | 1 (4.3) | 40 (24.4) | 72 (18.1) |
| Cutaneous | 5 (11.4) | 24 (14.5) | 4 (17.4) | 23 (14.0) | 56 (14.1) |
| Kidney | 42 (95.5) | 134 (80.7) | 23 (100.0) | 134 (81.7) | 333 (83.7) |
AAV, antineutrophil cytoplasmic antibody–associated vasculitis; ANCA, antineutrophil cytoplasmic antibody; eGFR, estimated glomerular filtration rate; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; MPO, myeloperoxidase; PR3, proteinase 3.
n = 164 for age at screening, duration of AAV, male patients, race, baseline eGFR, and prior medications received. n = 165 for disease history, type of AAV, ANCA type, and induction treatment.
Race was identified by the patient using a fixed set of categories.
Organ involvement data are only provided for the CLEAR trial. Data are not available for the CLASSIC trial.
Exposure to glucocorticoids and avacopan
The total doses and durations of use of study‐ and non–study‐supplied systemic glucocorticoids varied across the three trials (Table 2). In the combined trials, the total exposure to avacopan treatment was 212.3 patient‐years, and the total exposure to the non‐avacopan treatment regimen was 195.7 patient‐years (Table 3).
Table 2.
Total systemic glucocorticoid dose and treatment duration in patients with granulomatosis with polyangiitis and microscopic polyangiitis treated with avacopan‐based versus non‐avacopan‐based regimens in the CLEAR, 14 CLASSIC, 15 and ADVOCATE 16 trials (intention‐to‐treat populations)
| Treatment regimen group | CLEAR | CLASSIC | ADVOCATE | |||||
|---|---|---|---|---|---|---|---|---|
| 84 days | 84 days | 12 months | ||||||
| Avacopan 30 mg BID (n = 21) | Avacopan + low‐dose prednisone (n = 22) | Placebo + full‐dose prednisone (n = 20) | Avacopan 30 mg BID + prednisone (n = 14) a | Avacopan 10 mg BID + prednisone (n = 12) | Non‐avacopan + prednisone (n = 13) | Avacopan 30 mg BID (n = 166) | Non‐avacopan + prednisone (n = 164) | |
| Mean/median dose of study‐supplied GCs, mg | 0/0 | 701/721 | 2,092/2,100 | 2,015/2,093 | 1,900/2,050 | 2,109/2,090 | 0/0 | 2,389/2,448 |
| Mean/median dose of GC received, mg | 698 b /500 b | 1,064/743 | 2,414/2,108 | 2,397/2,490 | 2,532/2,455 | 2,484/2,435 | 1,676/600 | 3,847/3,098 |
BID, twice daily; GC, glucocorticoid.
Data from 14 of the 15 patients who took study‐supplied prednisone during the designated study period.
Seven patients used non–study‐supplied GCs.
Table 3.
Exposure‐adjusted adverse event/serious adverse event rates per 100 patient‐years in patients with granulomatosis with polyangiitis and microscopic polyangiitis treated with avacopan‐based versus non‐avacopan‐based regimens in the CLEAR, 14 CLASSIC, 15 and ADVOCATE 16 trials
| Exposure‐adjusted rate/100 patient‐years | Avacopan (n = 239) | Non‐avacopan (n = 200) | Difference in rate (95% CI) |
|---|---|---|---|
| Total exposure to avacopan/non‐avacopan treatment, patient‐years a | 212.3 | 195.7 | – |
| Overall AEs | |||
| First incidence rate b | 1,328.5 | 1,626.5 | −298 (−583.0 to −13.0) |
| AE rate c | 1,099.8 | 1,251.7 | −151.9 (−218.6 to −85.3) d |
| Overall SAEs | |||
| First incidence rate b | 61.6 | 60.1 | 1.5 (−16.5 to 19.6) |
| SAE rate c | 70.7 | 91.5 | −20.8 (−38.3 to −3.3) d |
| Discontinuation of study medication owing to AEs | |||
| First incidence rate b | 18.2 | 18.0 | 0.2 (−8.4 to 8.9) |
| Event rate c | 21.7 | 21.5 | 0.2 (−8.8 to 9.2) |
| Infections e | |||
| First incidence rate b | 139.1 | 148.5 | −9.4 (−42.6 to 23.7) |
| AE rate c | 142.2 | 166.6 | −24.3 (−48.5 to −0.1) d |
| Hepatic function AEs e | |||
| First incidence rate b | 14.7 | 12.3 | 2.3 (−5.2 to 9.8) |
| AE rate c | 18.4 | 17.4 | 1.0 (−7.2 to 9.2) |
| WBC count decrease AEs e | |||
| First incidence rate b | 18.9 | 25.0 | −6.1 (−16.0 to 3.8) |
| AE rate c | 22.6 | 34.2 | −11.6 (−22.0 to −1.2) d |
| Hypersensitivity AEs e | |||
| First incidence rate b | 57.7 | 58.0 | −0.3 (−18.1 to 17.5) |
| AE rate c | 68.8 | 61.8 | 6.9 (−8.7 to 22.6) |
AE, adverse event; CI, confidence interval; SAE, serious AE; WBC, white blood cell.
Exposure is calculated as the follow‐up time for all patients in the treatment group (irrespective of whether an event occurred).
First incidence rate calculated as the number of patients with at least one event divided by the total follow‐up time per 100 patient‐years. Follow‐up time is the total time at risk (in years), defined as the sum of (1) the follow‐up time of patients who did not have an AE and (2) the time to first occurrence of the event in patients who had a treatment‐emergent AE.
The rate was calculated as the total number of events divided by real follow‐up time per 100 patient‐years; it thus included multiple events per patient.
P < 0.05 based on 95% CI.
Prespecified AE of special interest; AE‐preferred terms identified before unblinding.
Exposure‐adjusted rates of adverse events
Exposure‐adjusted rates of AEs (1,099.8 vs 1,251.7; difference −151.9 [95% CI −218.6 to −85.3]), infection (142.2 vs 166.6; −24.3 [95% CI −48.5 to −0.1]), and neutropenia/lymphopenia (22.6 vs 34.2; −11.6 [95% CI −22.0 to −1.2]) per 100 patient‐years were significantly lower in the avacopan group than in the non‐avacopan group (Table 3). Although not statistically significant, rates of first infection were slightly lower in the avacopan group (139.1 vs 148.5; difference −9.4 [95% CI −42.6 to 23.7]), whereas rates of AEs related to hepatic abnormalities (18.4 vs 17.4; 1.0 [95% CI −7.2 to 9.2]) and hypersensitivity reactions (68.8 vs 61.8; 6.9 [−8.7 to 22.6]) were slightly higher. The rates of AEs leading to study drug discontinuation (21.7 vs 21.5; 0.2 [95% CI −8.8 to 9.2]) were similar between treatment groups.
Exposure‐adjusted rates of seroius adverse events
Although the exposure‐adjusted rate of SAEs was lower in the avacopan group than in the non‐avacopan group (70.7 vs 91.5; difference −20.8 [95% CI −38.3 to −3.3]), rates of first incidence SAEs were similar between treatments (61.6 vs 60.1; 1.5 [95% CI −16.5 to 19.6]) (Table 3). Overall, the exposure‐adjusted rates of SAEs by SOC were similar for the phase 3 trial and the integrated phase 2 and 3 trials.
Serious adverse events related to hepatic abnormalities
Across the three trials, SAEs associated with hepatic abnormalities occurred in 4.4% of patients in the avacopan group versus 2.8% of patients in the non‐avacopan group (difference 1.7 [95% CI −1.8 to 5.1]) (Table 4). Trial medication was interrupted or discontinued because of hepatic abnormalities in 7 of the 10 patients with liver‐related SAEs in the avacopan group versus three of six patients in the non‐avacopan group (all issues resolved). None of the patients with liver abnormalities met the Hy's law criteria for potentially fatal drug‐induced liver injury (ALT or AST ≥3 times the upper limit of normal [ULN], total bilirubin ≥2 times the ULN, and ALP <2 times the ULN with no obvious cause 24 ), with all patients having either confounding factors (other hepatotoxic drugs, viral etiology, or alcohol abuse), bilirubin levels within the normal range, and/or evidence of cholestasis. In the ADVOCATE trial, there was a higher incidence of grade 1 (ALP >1 to 2.5 times the ULN if baseline levels were normal or 2.0–2.5 times the baseline if baseline levels were abnormal) and grade 2 ALP elevation (>2.5 to 5.0 times the ULN or >2.5 to 5.0 times baseline, respectively) in the avacopan group compared with the non‐avacopan group and a greater mean decrease in ALP in the non‐avacopan versus the avacopan group over the first 20 weeks of the study. Grade 3 ALP elevations (ALP >5.0 to 20.0 times the ULN or >5.0 to 20.0 times the baseline) were observed in one patient in the non‐avacopan group and none in the avacopan group.
Table 4.
Patient incidence of serious adverse events associated with hepatic abnormalities in patients with granulomatosis with polyangiitis and microscopic polyangiitis treated with avacopan‐based versus non‐avacopan‐based regimens in the CLEAR, 14 CLASSIC, 15 and ADVOCATE 16 trials
| Serious Adverse Events | Avacopan (n = 239), n (%) a | Non‐avacopan (n = 200), n (%) a | Difference in rate (95% CI), % |
|---|---|---|---|
| Any treatment‐emergent SAE associated with hepatic function abnormalities | 10 (4.4) | 6 (2.8) | 1.7 (−1.8 to 5.1) |
| Hepatobiliary disorders | 5 (2.3) | 1 (0.5) | 1.8 (−0.3 to 4.0) |
| Hepatic function abnormal | 2 (0.9) | 0 (0.0) | 0.9 (−0.3 to 2.2) |
| Drug‐induced liver injury b | 1 (0.5) | 0 (0.0) | 0.5 (−0.4 to 1.3) |
| Hepatitis cholestatic | 1 (0.5) | 0 (0.0) | 0.5 (−0.4 to 1.3) |
| Hepatocellular injury | 1 (0.5) | 1 (0.5) | −0.0 (−1.3 to 1.3) |
| Investigations | 5 (2.2) | 5 (2.3) | −0.1 (−2.9 to 2.6) |
| Hepatic enzyme increased | 3 (1.2) | 3 (1.4) | −0.1 (−2.2 to 2.0) |
| AST increased | 1 (0.5) | 1 (0.5) | −0.0 (−1.3 to 1.3) |
| Liver function test increased | 1 (0.5) | 0 (0.0) | 0.5 (−0.4 to 1.3) |
| ALT increased | 0 (0.0) | 1 (0.5) | −0.5 (−1.4 to 0.4) |
| Transaminases increased | 0 (0.0) | 1 (0.5) | −0.5 (−1.4 to 0.4) |
ALT, alanine aminotransaminase; AST, aspartate aminotransaminase; CI, confidence interval.
The number of patients with at least one event. Patient incidence of SAEs is reported as the study‐size adjusted percentage.
The reported term is azathioprine‐induced liver toxicity.
Infection‐related seroius adverse events
In the phase 3 ADVOCATE trial, 25 infection‐related SAEs were reported in 22 patients (13.3%) in the avacopan group compared with 31 events in 25 patients (15.2%) in the non‐avacopan group. In the phase 2 trials, 12 serious infections were reported by seven patients (9.6%) in the avacopan group, and four events were reported by three patients (8.3%) in the non‐avacopan group. Three patients (0.7%) died because of infection across the three trials, with all three deaths occurring in the ADVOCATE trial (one in the avacopan group and two in the non‐avacopan group).
In the ADVOCATE trial, the most common infection‐related SAE in both treatment groups was pneumonia (8 of 166 patients [4.8%] in the avacopan group versus 6 of 164 [3.7%] in the non‐avacopan group). Infections in the avacopan group included pneumonia, sepsis, infective exacerbation of chronic obstructive pulmonary disease, Campylobacter gastroenteritis, and hepatitis B. The distribution of individual infections was similar during the first 20 weeks of the trial and from weeks 21 to 52. Six patients (3.6%) in the avacopan group and 11 (6.7%) in the non‐avacopan group had serious opportunistic infections. No infections caused by Neisseria meningitidis have been observed in clinical trials with avacopan.
Neutropenia or lymphopenia
In the ADVOCATE trial, a lower proportion of patients in the avacopan group had serious neutropenia or lymphopenia compared with those in the non‐avacopan group (2.4% vs 4.9%). One case of neutropenic sepsis was reported on day 59 (neutrophil count 1.4 × 103/μL on day 50) in a patient in the avacopan group receiving oral CYC. The patient was treated with antibiotics and recovered without interruption of avacopan.
The distribution of individual WBC‐related SAEs was similar throughout the ADVOCATE trial. The incidence of grade 3 lymphopenia (lymphocyte counts 0.2 to <0.5 × 103/μL) in the ADVOCATE trial was similar between treatment groups (28.3% in the avacopan group and 30.1% in the non‐avacopan group), whereas the incidence of grade 4 lymphopenia (<0.2 × 103/μL) was lower in the avacopan than in the non‐avacopan group (2.4% vs 8.0%). The integrated analysis of data from the phase 2 trials reported one case of grade 4 neutropenia (neutrophils <0.5 × 103/μL) in the avacopan group and no grade 3 neutropenia (0.5 to <1.0 × 103/μL) in either group. One SAE of neutropenia was reported in one patient (also treated with RTX) in the avacopan group in the CLASSIC study. No grade 4 lymphopenia events were observed in the phase 2 trials, and the incidence of grade 3 lymphopenia was 23.3% in the avacopan group and 5.9% in the non‐avacopan group.
Hypersensitivity
Across the three trials, AEs related to hypersensitivity occurred in 37.3% of patients in the avacopan group versus 36.9% in the non‐avacopan group. Most cases of hypersensitivity occurred in the skin and subcutaneous tissues, with rash affecting 21.5% of the avacopan group versus 22.7% of the non‐avacopan group. No cases of angioedema were observed in the phase 2 trials. In the phase 3 ADVOCATE trial, two cases of angioedema were observed in two patients treated with avacopan, with a negative re‐challenge in one of the two patients. No cases of angioedema were reported in the non‐avacopan group.
All‐cause hospitalizations
The rates of SAEs resulting in hospitalizations were similar across groups (Table 5). The mean duration of hospitalization was 11.7 days in the avacopan group and 17.6 days in the non‐avacopan group.
Table 5.
Exposure‐adjusted rate of serious treatment‐emergent adverse events leading to hospitalizations while receiving treatment in patients with granulomatosis with polyangiitis and microscopic polyangiitis treated with avacopan‐based versus non‐avacopan‐based regimens in the CLEAR, 14 CLASSIC, 15 and ADVOCATE 16 trials
| Category | Avacopan (N = 239), n/time a (rate b ) | Non‐avacopan (N = 200), n/time a (rate b ) | Difference in rate b (95% CI) |
|---|---|---|---|
| Any SAE resulting in hospitalization while on treatment c | 73/148.7 (49.1) | 70/157.9 (44.3) | 4.8 (−10.6, 20.1) |
| Hospitalization due to glucocorticoid‐related SAE | 13/157.0 (8.3) | 9/152.3 (5.9) | 2.4 (−3.6, 8.3) |
| Hospitalization due to infection SAE | 28/151.9 (18.4) | 25/144.2 (17.3) | 1.1 (−8.5, 10.7) |
| Summary of hospitalizations d | Avacopan (N = 239) | Non‐avacopan (N = 200) | Difference between treatment groups |
|---|---|---|---|
| Number of patients hospitalized | 73 | 70 | 3 |
| Number of events | 106 | 119 | −13 |
| Mean (SD) duration of hospitalization d | 11.7 (13.0) | 17.6 (28.3) | −5.9 |
Time = total time at risk (in years), defined as the sum of (1) treatment duration in patients who did not have a treatment‐emergent occurrence of the adverse event and (2) time to first occurrence of the event in patients who had a treatment‐emergent occurrence of the adverse event.
Rate = incidence per 100 patient‐years ([n/time] × 100).
Treatment‐emergent SAEs resulting in a hospitalization with a start date between first and last dose date of the study drug.
Hospitalization length of stay is calculated from treatment‐emergent serious adverse events resulting in hospitalization with a start date between first and last dose date of study drug.
CI, confidence interval; GPA, granulomatosis with polyangiitis; MPA, microscopic polyangiitis; n, number of patients with at least one incidence in specified category; SAE, serious adverse event; SD, standard deviation.
Deaths
Seven deaths were reported across the three trials, all of which occurred in the phase 3 ADVOCATE trial. Of these, one death occurred during the screening period and six after randomization (two in the avacopan group and four in the non‐avacopan group). Causes of death in the avacopan group were serious infection (pneumonia) and worsening GPA; both the patients had been without avacopan treatment for ≥79 days at the time of death. Two patients in the non‐avacopan group died from serious infection (fungal sepsis and infectious pleural effusion), one from acute myocardial infarction, and one from unknown causes.
DISCUSSION
Previous studies demonstrated that C5a receptor inhibition using avacopan improved remission rates, sustained remission over time, and, in the subset of patients with ANCA‐associated glomerulonephritis, improved kidney function in patients with GPA and MPA treated with RTX or CYC and reduced exposure to glucocorticoids. 14 , 16 This report presents an integrated analysis of safety data from the CLEAR, CLASSIC, and ADVOCATE trials, 14 , 15 , 16 which included 239 patients with GPA or MPA and a total of 212.3 patient‐years of avacopan exposure. Results suggest that, compared with standard (non‐avacopan) treatment, the use of avacopan with a reduced‐dose glucocorticoid regimen was associated with a lower incidence of AEs, SAEs, and infections without increasing the rates of neutropenia or lymphopenia. These benefits were likely due to the reduced exposure to glucocorticoids in the avacopan versus non‐avacopan group. Together, these results suggest a favorable benefit‐risk profile for avacopan and support the EULAR (2022) and KDIGO (2024) recommended the use of avacopan to reduce glucocorticoid exposure in patients with GPA or MPA. 3 , 25
Overall, 4.4% of patients treated with avacopan had SAEs related to hepatic abnormalities compared with 2.8% of patients treated with a non‐avacopan regimen. This, together with recent reports of hepatic toxicities in a small proportion of patients treated with avacopan in case studies, 26 , 27 suggests that patients receiving avacopan should be closely monitored for changes in liver function.
The 52‐week phase 3 ADVOCATE trial reported 25 cases of infection‐related SAEs in 22 patients (13.3%) in the avacopan group versus 31 cases in 25 patients (15.2%) in the non‐avacopan group, with similar rates reported by the 24‐week combined phase 2 trials (12 cases in seven patients [9.6%] versus four cases in three patients [8.3%], respectively). In comparison, the RITAZAREM trial (in which patients with relapsed GPA or MPA received RTX and glucocorticoids to reinduce remission followed by RTX or AZA for ≥36 months in patients achieving remission within 4 months) identified 19 severe infections in 15 patients (18%) in the RTX group compared with 27 cases in 19 patients (22%) in the AZA group. 28
Although rates of infection in the avacopan trials were lower in patients receiving avacopan than in those not receiving avacopan, the risk of infection was substantial in both groups despite a much lower cumulative exposure to glucocorticoids in patients receiving avacopan. This is likely because many patients in the avacopan group received some glucocorticoids, albeit at a lower dose, and because AAV itself, comorbidities, and other non‐glucocorticoid immunosuppressive drugs are key contributors to infections. Importantly, both the PEXIVAS 13 and LoVAS 17 trials demonstrated that substantial reductions in total early dosing of glucocorticoids are associated with a significantly reduced risk of serious infection in patients with AAV. Additional studies may be warranted to establish whether avacopan‐based regimens can reduce the rates of infection‐related SAEs compared with other treatment options in patients with GPA and MPA.
Overall rates of neutropenia or lymphopenia were lower in patients receiving avacopan than in those not receiving avacopan. Two severe events of neutropenia were noted in the avacopan group. However, there is no known method for establishing whether neutropenia was caused by avacopan or by RTX or CYC and no scientific rationale for a relationship between avacopan and neutropenia. Notably, the US Food and Drug Administration does not deem neutropenia to be an AE of concern for avacopan, whereas the European Union recommends monitoring patients treated with avacopan for changes in WBC counts.
This integrated safety analysis has several limitations, including differences between trials in glucocorticoid dosing and reported safety outcomes. Compared with the phase 3 ADVOCATE trial, 16 the phase 2 CLEAR and CLASSIC trials 14 , 15 had smaller sample sizes and shorter durations of therapy, both of which were accounted for using exposure‐adjusted rates per 100 patients. Nonetheless, the study provides important information about the safety profile of avacopan among the large numbers of patients with GPA and MPA in randomized controlled trials.
Overall, avacopan represents an advancement in the treatment of GPA and MPA, providing potential improvements in remission rates, sustained remission, and improved kidney function while reducing the need for glucocorticoids. 14 , 16 In this integrated analysis of safety data from the CLEAR, CLASSIC, and ADVOCATE trials, 14 , 15 , 16 avacopan demonstrated a favorable safety profile compared with standard treatment with a prednisone taper. No new safety signals have been identified since avacopan became commercially available, and its safety continues to be closely monitored. Additional studies, including the postauthorization AvacoStar safety study (NCT05897684) and a phase 4 randomized, double‐blind, placebo‐controlled clinical trial (NCT06072482) will provide a greater understanding of the long‐term safety of avacopan in patients with GPA or MPA.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Merkel confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.
ROLE OF THE STUDY SPONSOR
Data for the pooled analysis were provided by ChemoCentryx (a wholly owned subsidiary of Amgen). Writing and editing support for this manuscript was funded by Vifor Fresenius Medical Care Renal Pharma Ltd.
Supporting information
Supporting Information.
ACKNOWLEDGMENTS
The authors thank Martin Guppy, PhD, of Prescript Communications and Jackie Read, PhD, of Bright Red Fox Creative Ltd for writing and editing support.
ClinicalTrials.Gov identifiers NCT01363388, NCT02222155, and NCT02994927.
Supported by ChemoCentryx (a wholly owned subsidiary of Amgen). Data for the pooled analysis were provided by ChemoCentryx.
1Peter A. Merkel, MD, MPH, Michael D. George, MD, MSCE: University of Pennsylvania, Philadelphia; 2Huibin Yue, PhD: Amgen Inc., Thousand Oaks, California; 3Tamara Popov, MD: CSL Vifor, Glattbrugg, Switzerland; 4Andreas Kronbichler, MD, PhD: Medical University of Innsbruck, Innsbruck, Austria, and University of Cambridge, Cambridge, United Kingdom; 5Mark A. Little, MB BCh, PhD: Trinity College Dublin, Dublin, Ireland; 6David R.W. Jayne, MD, FRCP, FRCP(Ed), FMedSci: University of Cambridge, Cambridge, United Kingdom.
Qualified researchers may request data from Amgen Clinical Trials. Complete details are available at: https://wwwext.amgen.com/science/clinical-trials/clinical-data-transparency-practices/clinical-trial-data-sharing-request/.
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/acr2.70001.
REFERENCES
- 1. Qasim A, Patel JB. ANCA positive vasculitis. In: StatPearls. StatPearls Publishing; 2024. [Google Scholar]
- 2. Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation guideline for the management of antineutrophil cytoplasmic antibody‐associated vasculitis. Arthritis Rheumatol 2021;73(8):1366–1383. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Hellmich B, Sanchez‐Alamo B, Schirmer JH, et al. EULAR recommendations for the management of ANCA‐associated vasculitis: 2022 update. Ann Rheum Dis 2024;83(1):30–47. [DOI] [PubMed] [Google Scholar]
- 4. Xu T, Chen Z, Jiang M, et al. Association between different infection profiles and one‐year outcomes in ANCA‐associated vasculitis: a retrospective study with monthly infection screening. RMD Open 2022;8(2):e002424. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Little MA, Nightingale P, Verburgh CA, et al; European Vasculitis Study (EUVAS) Group. Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis. Ann Rheum Dis 2010;69(6):1036–1043. [DOI] [PubMed] [Google Scholar]
- 6. Odler B, Riedl R, Gauckler P, et al; RAVE−ITN Research Group. Risk factors for serious infections in ANCA‐associated vasculitis. Ann Rheum Dis 2023;82(5):681–687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Haris Á, Polner K, Arányi J, et al. Incidence and clinical predictors of infections in patients treated with severe systemic ANCA‐associated vasculitis. Physiol Int 2021;108:66–79. [DOI] [PubMed] [Google Scholar]
- 8. Neumann I. Immunosuppressive and glucocorticoid therapy for the treatment of ANCA‐asssociated vasculitis. Rheumatology (Oxford) 2020;59(suppl 3):iii60–iii67. [DOI] [PubMed] [Google Scholar]
- 9. King C, Harper L. Avoidance of harm from treatment for ANCA‐associated vasculitis. Curr Treatm Opt Rheumatol 2017;3(4):230–243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Habibi MA, Alesaeidi S, Zahedi M, et al. The efficacy and safety of rituximab in ANCA‐associated vasculitis. Biology (Basel) 2022;11(12):1767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Stone JH, Merkel PA, Spiera R, et al; RAVE‐ITN Research Group . Rituximab versus cyclophosphamide for ANCA‐associated vasculitis. N Engl J Med 2010;363(3):221–232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Jones RB, Tervaert JW, Hauser T, et al; European Vasculitis Study Group. Rituximab versus cyclophosphamide in ANCA‐associated renal vasculitis. N Engl J Med 2010;363(3):211–220. [DOI] [PubMed] [Google Scholar]
- 13. Walsh M, Merkel PA, Peh CA, et al; PEXIVAS Investigators . Plasma exchange and glucocorticoids in severe ANCA‐associated vasculitis. N Engl J Med 2020;382(7):622–631. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Jayne DRW, Bruchfeld AN, Harper L, et al; CLEAR Study Group . Randomized trial of C5a receptor inhibitor avacopan in ANCA‐associated vasculitis. J Am Soc Nephrol 2017;28(9):2756–2767. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Merkel PA, Niles J, Jimenez R, et al; CLASSIC Investigators . Adjunctive treatment with avacopan, an oral C5a receptor inhibitor, in patients with anti‐neutrophil cytoplasmic antibody–associated vasculitis. ACR Open Rheumatol 2020;2(11):662–671. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Jayne DRW, Merkel PA, Schall TJ, et al; ADVOCATE Study Group . Avacopan for the treatment of ANCA‐associated vasculitis. N Engl J Med 2021;384(7):599–609. [DOI] [PubMed] [Google Scholar]
- 17. Furuta S, Nakagomi D, Kobayashi Y, et al; LoVAS Collaborators . on behalf of the LoVAS trial investigators . Effect of reduced‐dose vs high‐dose glucocorticoids added to rituximab on remission induction in ANCA‐associated vasculitis: a randomized clinical trial. JAMA 2021;325(21):2178–2187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Jennette JC, Falk RJ, Gasim AH. Pathogenesis of antineutrophil cytoplasmic autoantibody vasculitis. Curr Opin Nephrol Hypertens 2011;20(3):263–270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Kallenberg CGM, Heeringa P. Complement is crucial in the pathogenesis of ANCA‐associated vasculitis. Kidney Int 2013;83(1):16–18. [DOI] [PubMed] [Google Scholar]
- 20. Hoy SM. Avacopan in granulomatosis with polyangiitis and microscopic polyangiitis: a profile of its use. Drugs Ther Perspect 2023;39(2):48–56. [Google Scholar]
- 21. Trivioli G, Vaglio A. The rise of complement in ANCA‐associated vasculitis: from marginal player to target of modern therapy. Clin Exp Immunol 2020;202(3):403–406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Gerard NP, Gerard C. The chemotactic receptor for human C5a anaphylatoxin. Nature 1991;349(6310):614–617. [DOI] [PubMed] [Google Scholar]
- 23. Bekker P, Dairaghi D, Seitz L, et al. 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. PLoS One 2016;11(10):e0164646. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf 2006;15(4):241–243. [DOI] [PubMed] [Google Scholar]
- 25. Floege J, Jayne DRW, Sanders JF, et al. Executive summary of the KDIGO 2024 clinical practice guideline for the management of ANCA‐associated vasculitis. Kidney Int 2024;105(3):447–449. [DOI] [PubMed] [Google Scholar]
- 26. Kataoka H, Tomita T, Nakanowatari M, et al. Gradual increase of avacopan dose with concomitant ursodeoxycholic acid use may help avoid the risk of C5a receptor inhibitor‐induced liver injury in antineutrophil cytoplasmic antibody‐associated vasculitis. Mod Rheumatol Case Rep 2023;7(2):444–447. [DOI] [PubMed] [Google Scholar]
- 27. Kojima K, Fukui S, Tanigawa M, et al. Severe prolonged liver abnormality with jaundice during treatment for granulomatosis with polyangiitis with rituximab and avacopan. Rheumatology (Oxford) 2024;63(3):e101–e103. [DOI] [PubMed] [Google Scholar]
- 28. Smith RM, Jones RB, Specks U, et al; RITAZAREM co‐investigators . Rituximab versus azathioprine for maintenance of remission for patients with ANCA‐associated vasculitis and relapsing disease: an international randomised controlled trial. Ann Rheum Dis 2023;82(7):937–944. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information.