Background
Methods
Study design and patient population
Study endpoints and analysis
Type/Severity | Criteria |
---|---|
Laboratory values changea | The occurrence of a change in ≥ 2 laboratory valuesb: • Platelet count decrease ≥ 25%c and < LLN • Increase in SCr ≥ 25%c and > ULN • Increase in LDH ≥ 25%c and > ULN |
Clinical signs and symptoms of TMAd | Clinical signs and symptoms considered definitely related to aHUS, including: • Thrombosis • Seizure • Reduction in renal function • Proteinuria (new or worsec and > 1+ or > 30 mg/dL) • Hematuria (new or worsec and > 50 RBCs/HPF) • Increased hemolytic anemia • Biopsy-proven TMA • Other (eg, extrarenal TMA manifestations, including confusion, cardiovascular abnormalities, pericarditis, gastrointestinal symptoms/diarrhea) |
Interventiond | The patient required PE/PI, dialysis, blood transfusions, or renal transplant due to a TMA manifestation |
Results
Patient disposition
Patient characteristics
Characteristic | Never Discontinued (n = 51) | Discontinued (n = 42) | All Patients (N = 93) | |
---|---|---|---|---|
Reinitiated (n = 21) | Not Reinitiated (n = 21) | |||
Age, at first eculizumab dose, median (range), years | 23.0 (0.0, 63.0) | 21.0 (0.0, 65.0) | 30.0 (0.0, 80.0) | 21.0 (0.0, 80.0) |
Age < 12 years, n (%) | 15 (29) | 5 (24) | 6 (29) | 26 (28) |
Female, n (%) | 30 (59) | 11 (52) | 16 (76) | 57 (61) |
Genetic or autoimmune complement abnormality, n (%)a | 31 (61) | 14 (67) | 10 (48) | 55 (59) |
No. of TMA manifestations prior to first eculizumab dose, n (%) | ||||
1 | 30 (59) | 13 (62) | 16 (76) | 59 (63) |
≥ 2 | 21 (41) | 8 (38) | 5 (24) | 34 (37) |
Time from most recent TMA manifestation to the first eculizumab dose, median (range), months | 1.8 (0.0, 47.4) | 0.4 (0.1, 37.8) | 0.6 (0.0, 19.2) | 0.9 (0.0, 47.4) |
Time from aHUS diagnosis to first eculizumab dose, median (range), months | 18.0 (0.0, 313.3) | 3.0 (0.0, 191.4) | 0.5 (0.0, 178.1) | 4.0 (0.0, 313.3) |
No. of PE/PI sessions at latest TMA manifestation before the first eculizumab dose, median (range) | 13.0 (0.0, 230.0) | 7.0 (0.0, 121.0) | 7.0 (0.0, 64.0) | 10.5 (0.0, 230.0) |
Patients with dialysis at baseline of parent study, n (%) | 18 (35) | 11 (52) | 9 (43) | 38 (41) |
Patients with renal transplant prior to first eculizumab dose, n (%) | 14 (28) | 4 (19) | 5 (24) | 23 (25) |
Complement Abnormality by Risk Level,a n (%) | Never Discontinued (n = 51) | Discontinued (n = 42) | |
---|---|---|---|
Reinitiated (n = 21) | Not Reinitiated (n = 21) | ||
High risk | 25 (49) | 8 (38) | 6 (29) |
CFH | 14 (27)b | 6 (29) | 3 (14)c |
C3 | 6 (12) | 1 (5) | 1 (5)d |
CFH autoantibodies | 5 (10) | 1 (5) | 1 (5) |
CFB | 0 (0) | 0 (0) | 1 (5) |
Low/moderate risk | 6 (12) | 6 (29) | 3 (14) |
CD46 (MCP) | 3 (6)e | 3 (14) | 2 (10) |
CFI | 3 (6)f | 3 (14) | 1 (5) |
Deletions | 0 (0) | 0 (0) | 1 (5) |
CFHR1, CHFR3 | 0 (0) | 0 (0) | 1 (5) |
No identified abnormality | 20 (39) | 7 (33) | 11 (52) |
Follow-up and eculizumab exposure
TMA manifestations
Patient Group/Subgroup | On-Treatment Period | Off-Treatment Period | Fold Change in Ratea | Percent Decrease on Versus off Treatment |
---|---|---|---|---|
Overall | ||||
Patients | n = 82 | n = 42 | ||
Patients with TMA, n (%) | 2 (2) | 10 (24) | ||
Manifestations | 3 | 14 | ||
Total patient-years | 292.5 | 103.8 | ||
Rate per 100 patient-years | 1.0 | 13.5 | 13.5 | 93% |
Patients who never discontinued | ||||
Patients | n = 51 | N/A | ||
Patients with TMA, n (%) | 2 (4) | N/A | ||
Manifestations | 3 | N/A | ||
Total patient-years | 218.2 | N/A | ||
Rate per 100 patient-years | 1.4 | N/A | N/A | N/A |
Patients who discontinued eculizumab | ||||
Patients | n = 31 | n = 42 | ||
Patients with TMA, n (%) | 0 (0) | 10 (24) | ||
Manifestations | 0 | 14 | ||
Total patient-years | 74.2 | 103.8 | ||
Rate per 100 patient-years | 0.0 | 13.5 | N/A | 100% |
Genetic or autoimmune complement abnormality status | ||||
Patients with complement abnormality | n = 51 | n = 24 | ||
Patients with TMA, n (%) | 1 (2) | 7 (29) | ||
Manifestations | 2 | 9 | ||
Total patient-years | 188.3 | 50.1 | ||
Rate per 100 patient-years | 1.1 | 18.0 | 16.4 | 94% |
Patients without identified complement abnormality | n = 31 | n = 18 | ||
Patients with TMA, n (%) | 1 (3) | 3 (17) | ||
Manifestations | 1 | 5 | ||
Total patient-years | 104.1 | 53.7 | ||
Rate per 100 patient-years | 1.0 | 9.3 | 9.3 | 89% |
Age at diagnosis | ||||
Adult patients | n = 41 | n = 22 | ||
Patients with TMA, n (%) | 0 (0) | 3 (14) | ||
Manifestations | 0 | 5 | ||
Total patient-years | 140.5 | 56.2 | ||
Rate per 100 patient-years | 0.0 | 8.9 | N/A | 100% |
Pediatric patientsb | n = 41 | n = 20 | ||
Patients with TMA, n (%) | 2 (5) | 7 (35) | ||
Manifestations | 3 | 9 | ||
Total patient-years | 152.0 | 47.6 | ||
Rate per 100 patient-years | 2.0 | 18.9 | 9.5 | 89% |
History of TMA events | ||||
Single TMA | n = 51 | n = 29 | ||
Patients with TMA, n (%) | 2 (4) | 6 (21) | ||
Manifestations | 3 | 8 | ||
Total patient-years | 192.7 | 70.4 | ||
Rate per 100 patient-years | 1.6 | 11.4 | 7.1 | 86% |
Multiple TMA prior to initiation of eculizumab | n = 31 | n = 13 | ||
Patients with TMA, n (%) | 1 (3) | 4 (31) | ||
Manifestations | 1 | 6 | ||
Total patient-years | 99.8 | 33.4 | ||
Rate per 100 patient-years | 1.0 | 18.0 | 18.0 | 94% |
Transplant status | ||||
Transplanted kidney | n = 21 | n = 9 | ||
Patients with TMA, n (%) | 0 (0) | 0 (0) | ||
Manifestations | 0 | 0 | ||
Total patient-years | 76.0 | 24.3 | ||
Rate per 100 patient-years | 0.0 | 0.0 | N/A | N/A |
Native kidney | n = 61 | n = 33 | ||
Patients with TMA, n (%) | 2 (3) | 10 (30) | ||
Manifestations | 3 | 14 | ||
Total patient-years | 216.5 | 79.5 | ||
Rate per 100 patient-years | 1.4 | 17.6 | 12.6 | 92% |
Kidney function and long-term renal outcomes
Never Discontinued (n = 51) | Discontinueda (n = 42) | All Patients (N = 93) | |
---|---|---|---|
Patients available for eGFR analysisb, n | 39 | 24 | 63 |
eGFR prior to first dose of eculizumab in parent study, mL/min/1.73 m2 | |||
Mean (SD) | 30.9 (26.9) | 29.6 (29.1) | 30.4 (27.5) |
Median (range) | 24.0 (8.4, 128.3) | 12.0 (10.0, 105.5) | 22.1 (8.4, 128.3) |
eGFR at time of discontinuationc, mL/min/1.73 m2 | |||
Mean (SD) | – | 92.4 (38.6) | – |
Median (range) | – | 92.3 (34.2, 181.5) | – |
eGFR at last follow-up, mL/min/1.73 m2 | |||
Mean (SD) | 65.2 (33.1) | 85.9 (31.8) | 73.1 (33.9) |
Median (range) | 59.5 (14.8, 152.2) | 75.6 (40.0, 153.5) | 65.7 (14.8, 153.5) |
Patients on dialysis prior to first dose of eculizumab in parent study, n/N (%) | 18/51 (35.3) | 17/35 (48.6) | 35/86 (40.7) |
Patients on dialysis at last follow-up, n/N (%) | 2/51 (3.9) | 5/35 (14.3) | 7/86 (8.1) |
Patients, n (%) | Never Discontinued (n = 48) | Discontinued, Did Not Reinitiate (n = 19) | Discontinued and Reinitiated (n = 16) | All Discontinued (n = 35) |
---|---|---|---|---|
Improved | 17 (35) | 2 (11) | 0 (0) | 2 (6) |
Stable | 20 (42) | 15 (79) | 4 (25) | 19 (54) |
Declined | 11 (23) | 2 (11) | 12 (75) | 14 (40) |
Safety
Outcome | Sex | Age Category | Description |
---|---|---|---|
Experienced meningococcal infection while on eculizumab treatment | Female | 20–29 | • CFH mutation • Vaccinated with Mencevax® (ACYW135), not on prophylactic antibiotics • Meningococcal infection serogroup B identified • Received antibiotics for treatment of infection, which resolved after 9 days, and continued on eculizumab |
Female | 20–29 | • CFH mutation, renal transplant • Vaccinated with Mencevax® (ACYW135), not on prophylactic antibiotics • Meningococcal infection serogroup W135 identified • Received antibiotics for treatment of infection, which resolved after 17 days, and continued on eculizumab | |
Male | 20–29 | • No identified complement abnormality at diagnosis; renal transplant • Vaccinated with Menveo® (ACYW135), prophylactic antibiotics • Meningococcal infection serogroup B identified • Received antibiotics for treatment of infection, which resolved after 10 days, and continued on eculizumab | |
Male | 13–19 | • C3 mutation, renal transplant • Vaccinated with Menactra®, prophylactic antibiotics • Clinical presentation was consistent with possible meningococcal infection (sore throat, knee pain and swelling, skin lesions), but all blood cultures were negative • Received antibiotics for treatment of infection, which resolved after 6 days, and continued on eculizumab | |
Deatha | Male | 30–39 | • C3 mutation, renal transplant, hemorrhagic gastric ulcer s/p gastrotomy • Had discontinued eculizumab approximately 6 months prior to death • Cause of death: Severe intensive care complications and multiorgan dysfunction secondary to gastrointestinal hemorrhage, lithiasic cholecystitis, and sepsis |
Male | < 5 | • No complement abnormality identified at diagnosis; renal failure, respiratory distress, hepatitis, and seizure disorder • Patientb experienced abdominal pain, series of infections and bacterial infection after 10 months on eculizumab at a reduced dose; had seizures attributed to metabolic encephalopathy • Cause of death: Hypoxia due to diffuse alveolar hemorrhage | |
Female | < 5 | • No complement abnormality identified at diagnosis; renal and cardiac failure, pulmonary hypertension, cardiomyopathy • Was on dialysis at diagnosis and was treated with eculizumab for 2 months but discontinued due to “lack of efficacy” • Patient experienced a TMA manifestation with multiorgan failure • Cause of death: Respiratory failure led to cardiac arrest and anoxic brain injury after being off treatment for 7 months |