Table 2.

Clinical trials and studies on eculizumab

Study	Number of patients	Inclusion criteria (IC) and primary end-points for patients (EP)	Number of patients with genetic mutations	Patients who received dialysis before eculizumab initiation	Patients who received PE/PI before Eculizumab initiation	Patients with history of renal transplant	Duration of study	Outcome
Legendre et al (2013) Prospective study23	37 17 in trial 1 20 in trial 2 ≥12 years old	IC – trial 1: low platelet counts and renal damage Trial 2: renal damage, but no decrease in platelet count of more than 25% for at least 8 weeks during PE/PI EP – trial 1: change in platelet count Trial 2: TMA event-free status (no decrease in platelet count of >25%, no PE/PI, and no dialysis)	13 in trial 1 and 14 in trial 2	5 in trial 1 and 2 in trial 2	16 in trial 1 and 20 in trial 2	7 in trial 1 and 8 in trial 2	26 weeks Optional extension phase: 1 year	-Trial 1: 50% of patients had a normal platelet count after 1 week and by the end of the study, platelets and LDH levels were normal in 90% of patients. -80% were able to discontinue dialysis throughout the 26 weeks -Trial 2: 80% of the patients had TMA event-free status. -Patients discontinued PE/PI and dialysis, and had improved kidney function -Patients in both trials where eculizumab was started earlier had better improvement in renal function (P=0.007 in trial 1 and P<0.001 in trial 2)
Licht et al (2015)40 Two-year analysis for Legendre et al's study	Same as noted above	Same as noted above	Same as noted above	Same as noted above	Same as noted above	Same as noted above	2 years	-Data were evaluated at three time points, i.e., 26 weeks, 1 year, and 2 years. -In trial 1, statistically significant increase in platelet counts was noted at all three time points. -14/17 patients attained normal platelet count at 26 weeks, and 15/17 attained the same at 1- and 2-year time points -In trial 2, 16/20 patients achieved TMA free event status at week 26 and nearly all patients (19/20) had TMA event-free event status by 2 years.
Cofiell et al (2015)41 Open-label, nonrandomized, single-group, multi-center trial	41 patients ≥18 years old	IC – platelet counts <150×103/L, hemoglobin levels ≤ LLN, LDH levels 1.5× ULN, SCr ≥ULN at screening, ADAMTS13 activity ≥5% or higher and no positive Shiga toxin-producing E. coli test EP – serum, plasma and urine biomarker levels at baseline, 26 and 52 weeks.	20	24	35	9	26 weeks Optional extension phase 1 year	-After 1 year, patients had reduced U-C5a, U-sC5b-9 levels, renal injury markers (clustering cystatin-c, b2-M, L-FABP-1), markers of inflammation (sTNFR1), markers of coagulation (prothrombin F112 and D-dimer), and endothelial damage (thrombomodulin). -TCA and renal markers were reduced to levels seen in healthy volunteers, but other biomarkers were only reduced to levels compared to pre-treatment.
Cavero et al (2017)42 Retrospective analysis	29 patients	IC – patients with secondary aHUS, worsening renal function and persistent TMA despite plasmapheresis. EP – normalization of platelet count and hemoglobin, disappearance of all MAHA markers, improved renal function with a ≥25% reduction of SCr baseline	8 patients were detected with genetic mutations but only 3 were considered pathogenic. 2 patients had Anti FH auto antibodies	14	24	1	2–30 weeks Discontinued at 8 weeks on average	−68% of patients experienced a rapid resolution of the TMA -Only four patients needed dialysis at last follow-up -12/15 patients with drug-induced aHUS, and all patients with postpartum, cancer-related, acute humoral rejection and intestinal lymphangiectasis, responded to eculizumab. -Patients with aHUS secondary to systemic diseases formed a larger part of the cohort that did not respond to treatment with only 2 of 8 patients responding. -Six patients had hematological resolution but no improvement in renal function -Three patients had persistent hematological and renal abnormalities despite eculizumab treatment
Walle et al (2017)43 Post-hoc analysis of four Phase II prospective studies	97 Age 1 month-80 years	IC – documented set of TMA onset symptoms, baseline eGFR of <90 mL/min/1.73 m2 EP – proportion of patients achieving sustained eGFR increase (defined: C15 mL/min/1.73 m2 for C28 days) and platelet count normalization evaluated 1-year post-treatment.	57	43	71	26	1 year	-Patients who received eculizumab ≤7 days after initial presentation of the aHUS showed a significantly (P<0.05) greater improvement in mean eGFR after 1 month -17/21 patients in the group that received eculizumab in ≤7days after presentation had a sustained increase in eGFR after 3 months which remained stable throughout 1 year. -In the group that received eculizumab after >7days, 36/76 had sustained increase in eGFR at1 year.
Greenbaum et al (2016)44 First prospective trial conducted exclusively in aHUS patients <18 years	22 19 completed 26 weeks Ages 5 months–17 years	IC – LDH ≥1.5× ULN, hemoglobin ≤ LLN, fragmented RBCs with a negative Coombs test EP – complete TMA response by 26 weeks	11	11	10	2	26 weeks	−14 patients had achieved a complete TMA response by 26 weeks. -18 patients achieved hematological normalization, and 16 had 25% or better serum creatinine after a median of 55 and 21 days, respectively. -9/11 patients discontinued dialysis -PE/PI was discontinued in all patients.
Kato et al (2019)31 Interim analysis of the post-marketing surveillance	33 patients with aHUS 27 patients with secondary TMA	IC – patients with aHUS diagnosis based on the Japanese diagnostic guide and received at least 1 dose of eculizumab EP – TMA event-free status, complete TMA response, hematologic outcomes, and renal outcomes	11 of the 18 aHUS patients tested for genetic mutations	17	18	None	24 weeks	-Among 29 aHUS patients with available baseline data, platelet count, LDH, and SCr improved in 1 month after beginning eculizumab. -19 patients were TMA event-free, 5 patients had a complete TMA response, 13 patients had platelet normalization, and 16 patients had a decrease in serum creatinine.
Kumar et al45 Retrospective cohort study	14 Median age 64 months	IC –platelet count ≥150×109/L LDH levels <ULN ≥25% decrease in SCr level from baseline on two consecutive measurements obtained ≥4 weeks apart	NA	6	6	NA	Patients were followed from January 2012 to January 2018	−9 days after patients had received eculizumab treatment, 14 had improved hematological response and 13 had improved TMA response. -6 patients, who had required PE/PI, none continued to require further transfusions after eculizumab treatment. - 6 patients who had previously required dialysis, only 1 remained on dialysis after treatment.
Fakhouri et al46 (2016) Open-label single-arm phase 2 trial	41 patients Age 18 years or older	IC – platelet count <150×10(3)/μL, hemoglobin ≤ LLNLDH≥1.5×ULN, and SCr≥ULN EP – complete TMA response	21	24	35	9	26 weeks	-Platelet counts and eGFR increased from baseline in 40 and 22 patients, respectively (P<0.001). -35 patients receiving PE/PI at the beginning, discontinued by week 26. -OF 24 dialysis- dependent patients, five recovered kidney function before starting therapy with eculizumab and 15 of the remaining 19 discontinued dialysis during eculizumab treatment.
Merill et al47 (2017) Single center, retrospective review	17 Median patient age at presentation was 46 years, with 76% females	IC – patients fulfilling aHUS criteria, testing negative for Shiga toxin, with ADAMTS13 levels above 10%, and receiving eculizumab EP – dialysis independence at last follow-up, TMA-event-free status	11	9	12	None	Median duration of eculizumab therapy was 90.5 days Follow-up after cessation of eculizumab was a median 308.5 days	−94% of all patients had TMA event-free status -82% patients were dialysis-free after last follow-up -Two patients died during eculizumab treatment
Huerta et al48 (2018) Retrospective study	22	IC – women with pregnancy-associated aHUS	9	9	NA	NA	Median duration of eculizumab treatment – 10 months	−17 patients received PE/PI, but only 3 showed improvement in renal function. -Ten patients received eculizumab and all of them had resolution of TMA - Amongst the remaining 12 patients, six patients needed RRT during follow- up and later-on received renal transplants.

Note: Data from references.23,31,40–48

Abbreviations: TMA, thrombotic microangiopathy; TCA, total complement activity; LDH, lactate dehydrogenase; PE/PI, plasma exchange/plasma infusion; eGFR, estimated glomerular filtration rate; SCr, serum creatinine; ULN, upper limit of normal; LLN, lower limit of normal; NA, data unavailable; sTNFR1, soluble tumor necrosis factor receptor-1; MAHA, microangiopathic hemolytic anemia; aHUS, atypical hemolytic uremic syndrome; FH, factor H.