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David Jayne, Annette Bruchfeld, Lorraine Harper, Matthias Schaier, Michael Venning, Patrick Hamilton, Volker Burst, Franziska Grundman, Michel Jadoul, Istvan Szombati, Vladimir Tesar, Mårten Segelmark, Antonia Potarca, Thomas J Schall, Pirow Bekker, MO039
SUCCESSFUL STEROID REPLACEMENT IN ANCA-ASSOCIATED VASCULITIS WITH C5A RECEPTOR INHIBITOR CCX168 IN PHASE 2 RANDOMISED TRIAL (CLEAR), Nephrology Dialysis Transplantation, Volume 31, Issue suppl_1, May 2016, Page i45, https://doi.org/10.1093/ndt/gfw137.01Close - Share Icon Share
Introduction and Aims: To investigate the potential of the orally administered complement 5a receptor inhibitor CCX168 to substantially or completely replace steroids while maintaining or improving efficacy in patients with active ANCA-associated vasculitis (AAV) receiving cyclophosphamide (CYC) or rituximab (RTX).
Methods: This randomised, double-blind, placebo-controlled Phase 2 trial (CLEAR) in 11 European countries included 3 groups: (1) High dose steroids standard of care (SOC) control: Placebo + CYC or RTX + 60 mg starting dose of prednisone, (2) CCX168 30 mg b.i.d. + CYC or RTX + 20 mg starting dose of prednisone, or (3) CCX168 30 mg b.i.d. + CYC or RTX + no prednisone. The CYC regimen was 15 mg/kg IV q2 to 4 weeks. The RTX regimen was 375 mg/m2 IV weekly for 4 weeks. The primary endpoint compared each CCX168 group to SOC control, based on Birmingham Vasculitis Activity Score (BVAS) response, defined as BVAS decrease from baseline of ≥50% and no worsening in any body system. Eligible patients had GPA, MPA, or renal limited vasculitis and PR3 or MPO-ANCA positivity.
Results: 67 patients were enrolled. The table shows baseline characteristics and efficacy results at Week 12. Groups were well balanced. The study met its primary endpoint: BVAS response at week 12 was numerically superior and statistically non-inferior to SOC control (P = 0.002 and P = 0.01 for each CCX168 group vs. control). Three of 22 (14%) and 6 of 21 (29%) patients in the low and no steroids CCX168 groups, respectively, and 1 of 20 (5%) on SOC had BVAS remission at Week 4 and 12, showing a more rapid and sustained response with CCX168. The CCX168 treatment groups performed better than SOC for most of the secondary endpoints (see table). Health-related quality of life measurements improved more with CCX168 vs. SOC. CCX168 was well tolerated. One serious adverse reaction of pneumonia (SOC), one of hepatic and pancreatic enzyme elevations in a patient with a history of alcohol abuse who also received CYC, cotrimoxazole, and pantoprazole (CCX168), and one of worsening renal function in a patient who had rapidly declining renal function prior to study entry (CCX168) were observed.
Conclusions: CCX168 successfully replaced chronic steroids suggesting a new treatment paradigm for AAV, with the same or better efficacy compared to SOC. These results provide a clear path to Phase 3 and suggest that the well-known serious side effects of chronic steroid treatment can likely be avoided in AAV treatment.
| . | CCX168 + CYC/RTX + Low-Dose Steroids . | CCX168 + CYC/RTX + No Steroids . | High Dose Steroids + CYC/RTX SOC . |
|---|---|---|---|
| Demographics and baseline characteristics in Safety Population | N = 22 | N = 22 | N = 23 |
| Age, mean ± SD; Male % | 57 ± 14; 64% | 57 ± 14; 73% | 59 ± 14; 74% |
| Newly diagnosed/relapsing disease | 68%/32% | 73%/27% | 78%/22% |
| MPO+/PR3+/Both MPO+ and PR3+ ANCA (%) | 45%/36%/14% | 41%/36%/14% | 26%/48%/22% |
| BVAS, mean ± SD | 14.3 ± 6.0 | 13.8 ± 6.4 | 13.2 ± 5.8 |
| Efficacy results (at 12 Weeks) in Intent-to-Treat Population | N = 22 | N = 21 | N = 20 |
| BVAS Response, n (%) 1 | 19 (86%) ** | 17 (81%) * | 14 (70%) |
| BVAS Total, % Change from baseline, mean ± SEM | -79 ± 14 % | -73 ± 7 % | -57 ± 14 % |
| BVAS Renal, % Change from baseline, mean ± SEM | -77 ± 6 % | -62 ± 9 % | -53 ± 14 % |
| BVAS Non-Renal, % Change from baseline, mean ± SEM | -87 ± 9 % | -92 ± 5 % # | -54 ± 19 % |
| BVAS Remission, n (%) 2 | 10 (46%) | 7 (33%) | 8 (40%) |
| BVAS Remission at Week 4 and 12 | 3 (14%) | 6 (29%) | 1 (5%) |
| U-ACR, mean % change 3,4 | -56% ## | -44% | -21% |
| eGFR, mean ± SEM 5 Baseline, Week 12 (mL/min/1.73 m2) | 52.5 ± 5.7 , 56.2 ± 4.3 | 54.8 ± 4.4 , 56.1 ± 5.2 | 47.2 ± 3.5 , 52.8 ± 3.6 |
| U-RBC count, mean % change 4,6 | -83% | -85% | -92% |
| Urinary MCP-1/creatinine, mean % change 4,7 | -70% ## | -49% | -43% |
| EuroQOL-5D-5L VAS, mean ± SEM 8 Baseline, Week 12 | 65 ± 5 , 75 ± 5 † | 69 ± 6 , 78 ± 4 | 69 ± 5 , 66 ± 5 |
| SF-36 v2 Physical Functioning, mean ± SEM 9 Baseline, Week 12 | 68 ± 8 , 84 ± 4 | 74 ± 11 , 93 ± 3 † | 67 ± 7 , 72 ± 4 |
| SF-36 v2 Mental Health, mean ± SEM Baseline, Week 12 | 62 ± 5 , 79 ± 6 †† | 82 ± 7 , 89 ± 4 †† | 66 ± 5 , 65 ± 5 |
| . | CCX168 + CYC/RTX + Low-Dose Steroids . | CCX168 + CYC/RTX + No Steroids . | High Dose Steroids + CYC/RTX SOC . |
|---|---|---|---|
| Demographics and baseline characteristics in Safety Population | N = 22 | N = 22 | N = 23 |
| Age, mean ± SD; Male % | 57 ± 14; 64% | 57 ± 14; 73% | 59 ± 14; 74% |
| Newly diagnosed/relapsing disease | 68%/32% | 73%/27% | 78%/22% |
| MPO+/PR3+/Both MPO+ and PR3+ ANCA (%) | 45%/36%/14% | 41%/36%/14% | 26%/48%/22% |
| BVAS, mean ± SD | 14.3 ± 6.0 | 13.8 ± 6.4 | 13.2 ± 5.8 |
| Efficacy results (at 12 Weeks) in Intent-to-Treat Population | N = 22 | N = 21 | N = 20 |
| BVAS Response, n (%) 1 | 19 (86%) ** | 17 (81%) * | 14 (70%) |
| BVAS Total, % Change from baseline, mean ± SEM | -79 ± 14 % | -73 ± 7 % | -57 ± 14 % |
| BVAS Renal, % Change from baseline, mean ± SEM | -77 ± 6 % | -62 ± 9 % | -53 ± 14 % |
| BVAS Non-Renal, % Change from baseline, mean ± SEM | -87 ± 9 % | -92 ± 5 % # | -54 ± 19 % |
| BVAS Remission, n (%) 2 | 10 (46%) | 7 (33%) | 8 (40%) |
| BVAS Remission at Week 4 and 12 | 3 (14%) | 6 (29%) | 1 (5%) |
| U-ACR, mean % change 3,4 | -56% ## | -44% | -21% |
| eGFR, mean ± SEM 5 Baseline, Week 12 (mL/min/1.73 m2) | 52.5 ± 5.7 , 56.2 ± 4.3 | 54.8 ± 4.4 , 56.1 ± 5.2 | 47.2 ± 3.5 , 52.8 ± 3.6 |
| U-RBC count, mean % change 4,6 | -83% | -85% | -92% |
| Urinary MCP-1/creatinine, mean % change 4,7 | -70% ## | -49% | -43% |
| EuroQOL-5D-5L VAS, mean ± SEM 8 Baseline, Week 12 | 65 ± 5 , 75 ± 5 † | 69 ± 6 , 78 ± 4 | 69 ± 5 , 66 ± 5 |
| SF-36 v2 Physical Functioning, mean ± SEM 9 Baseline, Week 12 | 68 ± 8 , 84 ± 4 | 74 ± 11 , 93 ± 3 † | 67 ± 7 , 72 ± 4 |
| SF-36 v2 Mental Health, mean ± SEM Baseline, Week 12 | 62 ± 5 , 79 ± 6 †† | 82 ± 7 , 89 ± 4 †† | 66 ± 5 , 65 ± 5 |
1 Primary endpoint; BVAS response: ≥ 50% decrease from baseline and no worsening in any body system; 4 patients were excluded from the ITT population since they had no post baseline on-treatment BVAS measurements; 2 BVAS remission defined as BVAS of zero; 3 U-ACR = first morning urinary albumin:creatinine ratio; 4 percentage change based on ratio of geometric means, Week 12/Baseline; 5 estimated glomerular filtration rate from MDRD equation based on serum creatinine; 6 based on microscopic count of urinary RBC; 7 First morning urinary monocyte chemoattractant protein-1:creatinine ratio; 8 Euro Quality-of-Life 5-Domain 5-Level visual analogue scale; 9 Short Form-36 version 2 health survey; ** P = 0.002, * P = 0.01 for test of non-inferiority vs. control; ## P < 0.01, # P < 0.05 for superiority vs control; †† P < 0.01, † P < 0.05 for % change from baseline vs control.
| . | CCX168 + CYC/RTX + Low-Dose Steroids . | CCX168 + CYC/RTX + No Steroids . | High Dose Steroids + CYC/RTX SOC . |
|---|---|---|---|
| Demographics and baseline characteristics in Safety Population | N = 22 | N = 22 | N = 23 |
| Age, mean ± SD; Male % | 57 ± 14; 64% | 57 ± 14; 73% | 59 ± 14; 74% |
| Newly diagnosed/relapsing disease | 68%/32% | 73%/27% | 78%/22% |
| MPO+/PR3+/Both MPO+ and PR3+ ANCA (%) | 45%/36%/14% | 41%/36%/14% | 26%/48%/22% |
| BVAS, mean ± SD | 14.3 ± 6.0 | 13.8 ± 6.4 | 13.2 ± 5.8 |
| Efficacy results (at 12 Weeks) in Intent-to-Treat Population | N = 22 | N = 21 | N = 20 |
| BVAS Response, n (%) 1 | 19 (86%) ** | 17 (81%) * | 14 (70%) |
| BVAS Total, % Change from baseline, mean ± SEM | -79 ± 14 % | -73 ± 7 % | -57 ± 14 % |
| BVAS Renal, % Change from baseline, mean ± SEM | -77 ± 6 % | -62 ± 9 % | -53 ± 14 % |
| BVAS Non-Renal, % Change from baseline, mean ± SEM | -87 ± 9 % | -92 ± 5 % # | -54 ± 19 % |
| BVAS Remission, n (%) 2 | 10 (46%) | 7 (33%) | 8 (40%) |
| BVAS Remission at Week 4 and 12 | 3 (14%) | 6 (29%) | 1 (5%) |
| U-ACR, mean % change 3,4 | -56% ## | -44% | -21% |
| eGFR, mean ± SEM 5 Baseline, Week 12 (mL/min/1.73 m2) | 52.5 ± 5.7 , 56.2 ± 4.3 | 54.8 ± 4.4 , 56.1 ± 5.2 | 47.2 ± 3.5 , 52.8 ± 3.6 |
| U-RBC count, mean % change 4,6 | -83% | -85% | -92% |
| Urinary MCP-1/creatinine, mean % change 4,7 | -70% ## | -49% | -43% |
| EuroQOL-5D-5L VAS, mean ± SEM 8 Baseline, Week 12 | 65 ± 5 , 75 ± 5 † | 69 ± 6 , 78 ± 4 | 69 ± 5 , 66 ± 5 |
| SF-36 v2 Physical Functioning, mean ± SEM 9 Baseline, Week 12 | 68 ± 8 , 84 ± 4 | 74 ± 11 , 93 ± 3 † | 67 ± 7 , 72 ± 4 |
| SF-36 v2 Mental Health, mean ± SEM Baseline, Week 12 | 62 ± 5 , 79 ± 6 †† | 82 ± 7 , 89 ± 4 †† | 66 ± 5 , 65 ± 5 |
| . | CCX168 + CYC/RTX + Low-Dose Steroids . | CCX168 + CYC/RTX + No Steroids . | High Dose Steroids + CYC/RTX SOC . |
|---|---|---|---|
| Demographics and baseline characteristics in Safety Population | N = 22 | N = 22 | N = 23 |
| Age, mean ± SD; Male % | 57 ± 14; 64% | 57 ± 14; 73% | 59 ± 14; 74% |
| Newly diagnosed/relapsing disease | 68%/32% | 73%/27% | 78%/22% |
| MPO+/PR3+/Both MPO+ and PR3+ ANCA (%) | 45%/36%/14% | 41%/36%/14% | 26%/48%/22% |
| BVAS, mean ± SD | 14.3 ± 6.0 | 13.8 ± 6.4 | 13.2 ± 5.8 |
| Efficacy results (at 12 Weeks) in Intent-to-Treat Population | N = 22 | N = 21 | N = 20 |
| BVAS Response, n (%) 1 | 19 (86%) ** | 17 (81%) * | 14 (70%) |
| BVAS Total, % Change from baseline, mean ± SEM | -79 ± 14 % | -73 ± 7 % | -57 ± 14 % |
| BVAS Renal, % Change from baseline, mean ± SEM | -77 ± 6 % | -62 ± 9 % | -53 ± 14 % |
| BVAS Non-Renal, % Change from baseline, mean ± SEM | -87 ± 9 % | -92 ± 5 % # | -54 ± 19 % |
| BVAS Remission, n (%) 2 | 10 (46%) | 7 (33%) | 8 (40%) |
| BVAS Remission at Week 4 and 12 | 3 (14%) | 6 (29%) | 1 (5%) |
| U-ACR, mean % change 3,4 | -56% ## | -44% | -21% |
| eGFR, mean ± SEM 5 Baseline, Week 12 (mL/min/1.73 m2) | 52.5 ± 5.7 , 56.2 ± 4.3 | 54.8 ± 4.4 , 56.1 ± 5.2 | 47.2 ± 3.5 , 52.8 ± 3.6 |
| U-RBC count, mean % change 4,6 | -83% | -85% | -92% |
| Urinary MCP-1/creatinine, mean % change 4,7 | -70% ## | -49% | -43% |
| EuroQOL-5D-5L VAS, mean ± SEM 8 Baseline, Week 12 | 65 ± 5 , 75 ± 5 † | 69 ± 6 , 78 ± 4 | 69 ± 5 , 66 ± 5 |
| SF-36 v2 Physical Functioning, mean ± SEM 9 Baseline, Week 12 | 68 ± 8 , 84 ± 4 | 74 ± 11 , 93 ± 3 † | 67 ± 7 , 72 ± 4 |
| SF-36 v2 Mental Health, mean ± SEM Baseline, Week 12 | 62 ± 5 , 79 ± 6 †† | 82 ± 7 , 89 ± 4 †† | 66 ± 5 , 65 ± 5 |
1 Primary endpoint; BVAS response: ≥ 50% decrease from baseline and no worsening in any body system; 4 patients were excluded from the ITT population since they had no post baseline on-treatment BVAS measurements; 2 BVAS remission defined as BVAS of zero; 3 U-ACR = first morning urinary albumin:creatinine ratio; 4 percentage change based on ratio of geometric means, Week 12/Baseline; 5 estimated glomerular filtration rate from MDRD equation based on serum creatinine; 6 based on microscopic count of urinary RBC; 7 First morning urinary monocyte chemoattractant protein-1:creatinine ratio; 8 Euro Quality-of-Life 5-Domain 5-Level visual analogue scale; 9 Short Form-36 version 2 health survey; ** P = 0.002, * P = 0.01 for test of non-inferiority vs. control; ## P < 0.01, # P < 0.05 for superiority vs control; †† P < 0.01, † P < 0.05 for % change from baseline vs control.
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