Bekemv

Pharmacotherapeutic group: Complement Inhibitors, ATC code: L04AJ01 BEKEMV is a biosimilar medicinal product.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ Detailed information is available on the MHRA website https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency. BEKEMV is a recombinant humanised monoclonal IgG 2/4k antibody that binds to the human C5 complement protein and inhibits the activation of terminal complement. The BEKEMV antibody contains human constant regions and murine complementarity-determining regions grafted onto the human framework light- and heavy-chain variable regions. BEKEMV is composed of two 448 amino acid heavy chains and two 214 amino acid light chains and has a molecular weight of approximately 148 kDa. BEKEMV is produced in a CHO cell line and purified by affinity and ion exchange chromatography. The bulk drug substance manufacturing process also includes specific viral inactivation and removal steps. Mechanism of action Eculizumab, the active ingredient in BEKEMV, is a terminal complement inhibitor that specifically binds to the complement protein C5 with high affinity, thereby inhibiting its cleavage to C5a and C5b and preventing the generation of the terminal complement complex C5b-9. Eculizumab preserves the early components of complement activation that are essential for opsonisation of microorganisms and clearance of immune complexes. In PNH patients, uncontrolled terminal complement activation and the resulting complement-mediated intravascular haemolysis are blocked with eculizumab treatment. In most PNH patients, eculizumab serum concentrations of approximately 35 micrograms/mL are sufficient for essentially complete inhibition of terminal complement-mediated intravascular haemolysis. In PNH, chronic administration of eculizumab resulted in a rapid and sustained reduction in complement-mediated haemolytic activity. In aHUS patients, uncontrolled terminal complement activation and the resulting complement-mediated thrombotic microangiopathy are blocked with eculizumab treatment. All patients treated with eculizumab when administered as recommended demonstrated rapid and sustained reduction in terminal complement activity. In all aHUS patients, eculizumab serum concentrations of approximately 50 – 100 microgram/mL are sufficient for essentially complete inhibition of terminal complement activity. In aHUS, chronic administration of eculizumab resulted in a rapid and sustained reduction in complement-mediated thrombotic microangiopathy. Clinical efficacy and safety Paroxysmal nocturnal haemoglobinuria The safety and efficacy of eculizumab in PNH patients with haemolysis were assessed in a randomised, double-blind, placebo-controlled 26 week study (C04-001). PNH patients were also treated with eculizumab in a single arm 52 week study (C04-002), and in a long-term extension study (E05-001). Patients received meningococcal vaccination prior to receipt of eculizumab. In all studies, the dose of eculizumab was 600 mg every 7 ± 2 days for 4 weeks, followed by 900 mg 7 ± 2 days later, then 900 mg every 14 ± 2 days for the study duration. Eculizumab was administered as an intravenous infusion over 25 – 45 minutes (35 minutes ± 10 minutes). An observational non-interventional registry in patients with PNH (M07-001) was also initiated to characterise the natural history of PNH in untreated patients and the clinical outcomes during eculizumab treatment. In study C04-001 (TRIUMPH) PNH patients with at least 4 transfusions in the prior 12 months, flow cytometric confirmation of at least 10% PNH cells and platelet counts of at least 100,000/microlitre were randomised to either eculizumab (n = 43) or placebo (n = 44). Prior to randomisation, all patients underwent an initial observation period to confirm the need for RBC transfusion and to identify the haemoglobin concentration (the "set-point") which would define each patient's haemoglobin stabilisation and transfusion outcomes. The haemoglobin set-point was less than or equal to 9 g/dL in patients with symptoms and was less than or equal to 7 g/dL in patients without symptoms. Primary efficacy endpoints were haemoglobin stabilisation (patients who maintained a haemoglobin concentration above the haemoglobin set-point and avoid any RBC transfusion for the entire 26 week period) and blood transfusion requirement. Fatigue and health-related quality of life were relevant secondary endpoints. Haemolysis was monitored mainly by the measurement of serum LDH levels, and the proportion of PNH RBCs was monitored by flow cytometry. Patients receiving anticoagulants and systemic corticosteroids at baseline continued these medications. Major baseline characteristics were balanced (see table 2). In the non-controlled study C04-002 (SHEPHERD), PNH patients with at least one transfusion in the prior 24 months and at least 30,000 platelets/microlitre received eculizumab over a 52-week period. Concomitant medications included anti-thrombotic agents in 63% of the patients and systemic corticosteroids in 40% of the patients. Baseline characteristics are shown in table 2. Table 2. Patient demographics and characteristics in C04-001 and C04-002 C04-001 C04-002 Parameter Placebo N = 44 Eculizumab N = 43 Eculizumab N = 97 Mean age (SD) 38.4 (13.4) 42.1 (15.5) 41.1 (14.4) Gender - female (%) 29 (65.9) 23 (53.5) 49 (50.5) History of aplastic anaemia or MDS (%) 12 (27.3) 8 (18.7) 29 (29.9) Concomitant anticoagulants (%) 20 (45.5) 24 (55.8) 59 (61) Concomitant steroids/immunosuppressant treatments (%) 16 (36.4) 14 (32.6) 46 (47.4) Discontinued treatment 10 2 1 PRBC in previous 12 months (median (Q1, Q3)) 17.0 (13.5, 25.0) 18.0 (12.0, 24.0) 8.0 (4.0, 24.0) Mean Hgb level (g/dL) at setpoint (SD) 7.7 (0.75) 7.8 (0.79) N/A Pre-treatment LDH levels (median, U/L) 2,234.5 2,032.0 2,051.0 Free haemoglobin at baseline (median, mg/dL) 46.2 40.5 34.9 In TRIUMPH, study patients treated with eculizumab had significantly reduced (p < 0.001) haemolysis resulting in improvements in anaemia as indicated by increased haemoglobin stabilisation and reduced need for RBC transfusions compared to placebo treated patients (see table 3). These effects were seen among patients within each of the three pre-study RBC transfusion strata (4 ‑ 14 units; 15 - 25 units; > 25 units). After 3 weeks of eculizumab treatment, patients reported less fatigue and improved health-related quality of life. Because of the study sample size and duration, the effects of eculizumab on thrombotic events could not be determined. In SHEPHERD study, 96 of the 97 enrolled patients completed the study (one patient died following a thrombotic event). A reduction in intravascular haemolysis as measured by serum LDH levels was sustained for the treatment period and resulted in increased transfusion avoidance, a reduced need for RBC transfusion and less fatigue (see table 3). Table 3. Efficacy outcomes in C04-001 and C04-002 C04-001 C04-002* Placebo N = 44 Eculizumab N = 43 P – value Eculizumab N = 97 P – value Percentage of patients with stabilised haemoglobin levels at end of study 0 49 < 0.001 N/A PRBC transfused during treatment (median) 10 0 < 0.001 0 < 0.001 Transfusion avoidance during treatment (%) 0 51 < 0.001 51 < 0.001 LDH levels at end of study (median, U/L) 2,167 239 < 0.001 269 < 0.001 LDH AUC at end of study (median, U/L × Day) 411, 822 58, 587 < 0.001 -632, 264 < 0.001 Free haemoglobin at end of study (median, mg/dL) 62 5 < 0.001 5 < 0.001 FACIT-fatigue (effect size) 1.12 < 0.001 1.14 < 0.001 * Results from study C04-002 refer to pre- versus post-treatment comparisons. From the 195 patients that originated in C04-001, C04-002 and other initial studies, eculizumab -treated PNH patients were enrolled in a long-term extension study (E05-001). All patients sustained a reduction in intravascular haemolysis over a total eculizumab exposure time ranging from 10 to 54 months. There were fewer thrombotic events with eculizumab treatment than during the same period of time prior to treatment. However, this finding was shown in non-controlled clinical trials. The PNH registry (M07-001) was used to evaluate the efficacy of eculizumab in PNH patients with no history of RBC transfusion. These patients had high disease activity as defined by elevated haemolysis (LDH ≥ 1.5 × ULN) and the presence of related clinical symptom(s): fatigue, haemoglobinuria, abdominal pain, shortness of breath (dyspnoea), anaemia (haemoglobin < 100 g/L), major adverse vascular event (including thrombosis), dysphagia, or erectile dysfunction. In the PNH registry, patients treated with eculizumab were observed to have a reduction in haemolysis and associated symptoms. At 6 months, patients treated with eculizumab with no history of RBC transfusion had significantly (p < 0.001) reduced LDH levels (median LDH of 305 U/L; see table 4). Furthermore, 74% of the patients without a history of transfusion and treated with eculizumab experienced clinically meaningful improvements in FACIT-fatigue score (i.e., increase by 4 points or more) and 84% in EORTC fatigue score (i.e., decrease by 10 points or more). Table 4. Efficacy outcomes (LDH level and FACIT-fatigue) in patients with PNH with no history of transfusion in M07-001 M07-001 Parameter Eculizumab No transfusion LDH level at baseline (median, U/L) N = 43 1447 LDH level at 6 months (median, U/L) N = 36 305 FACIT-fatigue score at baseline (median) N = 25 32 FACIT-fatigue score at last available assessment (median) N = 31 44 FACIT-fatigue is measured on a scale of 0 - 52, with higher values indicating less fatigue Atypical haemolytic uraemic syndrome Data from 100 patients in four prospective controlled studies, three in adult and adolescent patients (C08-002A/B, C08-003A/B, C10-004), one in paediatric and adolescent patients (C10-003) and 30 patients in one retrospective study (C09-001r) were used to evaluate the efficacy of eculizumab in the treatment of aHUS. Study C08-002A/B was a prospective, controlled, open-label study which accrued patients in the early phase of aHUS with evidence of clinical thrombotic microangiopathy manifestations with platelet count ≤ 150 x 10 9 /L despite PE/PI, and LDH and serum creatinine above upper limits of normal. Study C08-003A/B was a prospective, controlled, open-label study which accrued patients with longer term aHUS without apparent evidence of clinical thrombotic microangiopathy manifestations and receiving chronic PE/PI (≥1 PE/PI treatment every two weeks and no more than 3 PE/PI treatments/week for at least 8 weeks before the first dose). Patients in both prospective studies were treated with eculizumab for 26 weeks and most patients enrolled into a long-term, open-label extension study. All patients enrolled in both prospective studies had an ADAMTS-13 level above 5%. Patients received meningococcal vaccination prior to receipt of eculizumab or received prophylactic treatment with appropriate antibiotics until 2 weeks after vaccination. In all studies, the dose of eculizumab in adult and adolescent aHUS patients was 900 mg every 7 ± 2 days for 4 weeks, followed by 1,200 mg 7 ± 2 days later, then 1,200 mg every 14 ± 2 days for the study duration. Eculizumab was administered as an intravenous infusion over 35 minutes. The dosing regimen in paediatric patients and adolescents weighing less than 40 kg was defined based on a pharmacokinetic (PK) simulation that identified the recommended dose and schedule based on body weight (see section 4.2). Primary endpoints included platelet count change from baseline in study C08-002A/B and thrombotic microangiopathy (TMA) event-free status in study C08-003A/B. Additional endpoints included TMA intervention rate, haematologic normalisation, complete TMA response, changes in LDH, renal function and quality of life. TMA-event free status was defined as the absence for at least 12 weeks of the following: decrease in platelet count of > 25% from baseline, PE/PI, and new dialysis. TMA interventions were defined as PE/PI or new dialysis. Haematologic normalisation was defined as normalisation of platelet counts and LDH levels sustained for ≥ 2 consecutive measurements for ≥ 4 weeks. Complete TMA response was defined as haematologic normalisation and a ≥ 25% reduction in serum creatinine sustained in ≥ 2 consecutive measurements for ≥ 4 weeks. Baseline characteristics are shown in table 5. Table 5. Patient demographics and characteristics in C08-002A/B and C08-003A/B Parameter C08-002A/B C08-003A/B Eculizumab N = 17 Eculizumab N = 20 Time from first diagnosis until screening in months, median (min, max) 10 (0.26, 236) 48 (0.66, 286) Time from current clinical TMA manifestation until screening in months, median (min, max) < 1 (<1, 4) 9 (1, 45) Number of PE/PI sessions for current clinical TMA manifestation, median (min, max) 17 (2, 37) 62 (20, 230) Number of PE/PI sessions in 7 days prior to first dose of eculizumab, median (min, max) 6 (0, 7) 2 (1, 3) Baseline platelet count (× 10 9 /L), mean (SD) 109 (32) 228 (78) Baseline LDH (U/L), mean (SD) 323 (138) 223 (70) Patients without identified mutation, n (%) 4 (24) 6 (30) Patients in aHUS study C08-002 A/B received eculizumab for a minimum of 26 weeks. After completion of the initial 26 - week treatment period, most patients continued to receive eculizumab by enrolling into an extension study. In aHUS study C08-002A/B, the median duration of eculizumab therapy was approximately 100 weeks (range: 2 weeks to 145 weeks). A reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. Table 6 summarizes the efficacy results for aHUS study C08-002A/B. All rates of efficacy endpoints improved or were maintained through 2 years of treatment. Complete TMA response was maintained by all responders. When treatment was continued for more than 26 weeks, two additional patients achieved and maintained Complete TMA response due to normalisation of LDH (1 patient) and a decrease in serum creatinine (2 patients). Renal function, as measured by eGFR, was improved and maintained during eculizumab therapy. Four of the five patients who required dialysis at study entry were able to discontinue dialysis for the duration of eculizumab treatment, and one patient developed a new dialysis requirement. Patients reported improved health-related quality of life (QoL). In aHUS study C08-002A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Patients in aHUS study C08-003A/B received eculizumab for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients continued to receive eculizumab by enrolling into an extension study. In aHUS study C08-003A/B, the median duration of eculizumab therapy was approximately 114 weeks (range: 26 to 129 weeks). Table 6 summarizes the efficacy results for aHUS study C08-003A/B. In aHUS study C08-003A/B, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins. Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. All rates of efficacy endpoints improved or were maintained through 2 years of treatment. Complete TMA response was maintained by all responders. When treatment was continued for more than 26 weeks, six additional patients achieved and maintained Complete TMA response due to a decrease in serum creatinine. No patient required new dialysis with eculizumab. Renal function, as measured by median eGFR, increased during eculizumab therapy. Table 6. Efficacy outcomes in prospective aHUS studies C08-002A/B and C08-003A/B C08-002A/B N=17 C08-003A/B N=20 At 26 weeks At 2 years 1 At 26 weeks At 2 years 1 Normalisation of platelet count All patients, n (%) (95% CI) Patients with abnormal baseline, n/n (%) 14 (82) (57-96) 13/15 (87) 15 (88) (64-99) 13/15 (87) 18 (90) (68-99) 1/3 (33) 18 (90) (68-99) 1/3 (33) TMA event-free status, n (%) (95% CI) 15 (88) (64-99) 15 (88) (64-99) 16 (80) (56-94) 19 (95) (75-99) TMA intervention rate Daily pre-eculizumab rate, median (min, max) Daily during-eculizumab rate, median (min, max) P -value 0.88 (0.04, 1.59) 0 (0, 0.31) P<0.0001 0.88 (0.04, 1.59) 0 (0, 0.31) P<0.0001 0.23 (0.05, 1.09) 0 P <0.0001 0.23 (0.05, 1.09) 0 P<0.0001 CKD improvement by ≥1 stage, n (%) (95% CI) 10 (59) (33-82) 12 (71) (44-90) 7 (35) (15-59) 12 (60) (36-81) eGFR change mL/min/1.73m 2 : median (range) 20 (-1, 98) 28 (3, 82) 5 (-1, 20) 11 (-42, 30) eGFR improvement ≥15 mL/min/1.73m 2 , n (%) (95% CI) 8 (47) (23-72) 10 (59) (33-82) 1 (5) (0-25) 8 (40) (19-64) Change in Hgb > 20g/L, n (%) (95% CI) 11 (65) (38-86) 2 13 (76) (50-93) 9 (45) (23-68) 3 13 (65) (41-85) Haematologic normalisation, n (%) (95% CI) 13 (76) (50-93) 15 (88) (64-99) 18 (90) (68-99) 18 (90) (68-99) Complete TMA response, n (%) (95% CI) 11(65) (38-86) 13(76) (50-93) 5 (25) (9-49) 11(55) (32-77) 1 At data cut off (20 April 2012) 2 Study C08-002: 3 patients received ESA which was discontinued after eculizumab initiation 3 Study C08-003: 8 patients received ESA which was discontinued in 3 of them during eculizumab therapy aHUS study C10-004 enrolled 41 patients who displayed signs of thrombotic microangiopathy (TMA). In order to qualify for enrolment, patients were required to have a platelet count < lower limit of normal range (LLN), evidence of haemolysis such as an elevation in serum LDH, and serum creatinine above the upper limits of normal, without the need for chronic dialysis. The median patient age was 35 (range: 18 to 80 years). All patients enrolled in aHUS study C10-004 had an ADAMTS-13 level above 5%. Fifty-one percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 35 patients received PE/PI prior to eculizumab. Table 7 summarizes the key baseline clinical and disease-related characteristics of patients enrolled in aHUS C10-004. Table 7. Baseline characteristics of patients enrolled in aHUS study C10-004 Parameter aHUS study C10-004 N = 41 Time from aHUS diagnosis to first study dose (months), median (min, max) 0.79 (0.03, 311) Time from current clinical TMA manifestation until first study dose (months), median (min, max) 0.52 (0.03, 19) Baseline platelet count (× 10 9 /L), median (min, max) 125 (16, 332) Baseline LDH (U/L), median (min, max) 375 (131, 3318) Baseline eGFR (mL/min/1.73m 2 ), median (min, max) 10 (6, 53) Patients in aHUS study C10-004 received eculizumab for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients elected to continue on chronic dosing. Reduction in terminal complement activity and an increase in platelet count relative to baseline were observed after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. In aHUS C10-004, mean (±SD) platelet count increased from 119 ± 66 x 10 9 /L at baseline to 200 ± 84 x 10 9 /L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 252 ± 70 x 10 9 /L). Renal function, as measured by eGFR, was improved during eculizumab therapy. Twenty of the 24 patients who required dialysis at baseline were able to discontinue dialysis during eculizumab treatment. Table 8 summarizes the efficacy results for aHUS study C10-004. Table 8. Efficacy outcomes in prospective aHUS study C10-004 Efficacy parameter aHUS study C10-004 (N = 41) at 26-weeks Change in platelet count through week 26 (10 9 /L) 111 (-122, 362) Haematologic normalisation, n (%) Median duration of haematologic normalisation, weeks (range) 1 36 (88) 46 (10, 74) Complete TMA response, n (%) Median duration of complete TMA response, weeks (range) 1 23 (56) 42 (6, 74) TMA Event-free status, n (%) 95% CI 37 (90) 77; 97 Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 0.63 (0, 1.38) 0 (0, 0.58) 1 Through data cut-off (September 4, 2012), with median duration of eculizumab therapy of 50 weeks (range: 13 weeks to 86 weeks). Longer term treatment with eculizumab (median 52 weeks ranging from 15 to 126 weeks) was associated with an increased rate of clinically meaningful improvements in adult patients with aHUS. When eculizumab treatment was continued for more than 26 weeks, three additional patients (63% of patients in total) achieved Complete TMA response and four additional patients (98% of patients in total) achieved haematologic normalisation. At the last evaluation, 25 of 41 patients (61%) achieved eGFR improvement of ≥ 15 mL/min/1.73m 2 from baseline. Immunogenicity Infrequent antibody responses have been detected in eculizumab-treated patients across all clinical studies. Paediatric population Paroxysmal nocturnal haemoglobinuria A total of 7 PNH paediatric patients, with a median weight of 57.2 kg (range of 48.6 to 69.8 kg) and aged from 11 to 17 years (median age: 15.6 years), received eculizumab in study M07-005. Treatment with eculizumab at the proposed dosing regimen in the paediatric population was associated with a reduction of intravascular haemolysis as measured by serum LDH level. It also resulted in a marked decrease or elimination of blood transfusions, and a trend towards an overall improvement in general function. The efficacy of eculizumab treatment in paediatric PNH patients appears to be consistent with that observed in adult PNH patients enrolled in PNH pivotal studies (C04-001 and C04-002) (see tables 3 and 9). Table 9. Efficacy outcomes in paediatric PNH study M07-005 P – Value Mean (SD) Wilcoxon signed rank Paired t-test Change from baseline at 12 weeks of LDH value (U/L) -771 (914) 0.0156 0.0336 LDH AUC (U/L × day) -60,634 (72,916) 0.0156 0.0350 Change from baseline at 12 weeks in plasma free haemoglobin (mg/dL) -10.3 (21.13) 0.2188 0.1232 Change from baseline type III RBC clone size (percent of aberrant cells) 1.80 (358.1) Change from baseline at 12 weeks of PedsQL™ 4.0 generic core scale (patients) 10.5 (6.66) 0.1250 0.0256 Change from baseline at 12 weeks of PedsQL™ 4.0 generic core scale (parents) 11.3 (8.5) 0.2500 0.0737 Change from baseline at 12 weeks of PedsQL™ multidimensional fatigue (patients) 0.8 (21.39) 0.6250 0.4687 Change from baseline at 12 weeks of PedsQL™ multidimensional fatigue (parents) 5.5 (0.71) 0.5000 0.0289 Atypical haemolytic uraemic syndrome A total of 15 paediatric patients (aged 2 months to 12 years) received eculizumab in aHUS Study C09-001r. Forty seven percent of patients had an identified complement regulatory factor mutation or auto-antibody. The median time from aHUS diagnosis to first dose of eculizumab was 14 months (range <1,110 months). The median time from current thrombotic microangiopathy manifestation to first dose of eculizumab was 1 month (range <1 to 16 months). The median duration of eculizumab therapy was 16 weeks (range 4 to 70 weeks) for children < 2 years of age (n=5) and 31 weeks (range 19 to 63 weeks) for children 2 to <12 years of age (n=10). Overall, the efficacy results for these paediatric patients appeared consistent with what was observed in patients enrolled in aHUS pivotal studies C08-002 and C08-003 (table 6). No paediatric patient required new dialysis during treatment with eculizumab. Table 10: Efficacy results in paediatric patients enrolled in aHUS C09-001r Efficacy Parameter <2 years (n=5) 2 to <12 years (n=10) <12 years (n=15) Patients with platelet count normalisation, n (%) 4 (80) 10 (100) 14 (93) Complete TMA response, n (%) 2 (40) 5 (50) 7 (50) Daily TMA intervention rate, median (range) Before eculizumab On eculizumab treatment 1 (0, 2) <1 (0, <1) <1 (0.07, 1.46) 0 (0, <1) <1 (0, 2) 0 (0, <1) Patients with eGFR improvement ≥15 mL/min/1.73m 2 , n (%) 2 (40) 6 (60) 8 (53) In paediatric patients with shorter duration of current severe clinical thrombotic microangiopathy (TMA) manifestation prior to eculizumab, there was TMA control and improvement of renal function with eculizumab treatment (table 10). In paediatric patients with longer duration of current severe clinical TMA manifestation prior to eculizumab, there was TMA control with eculizumab treatment. However, renal function was not changed due to prior irreversible kidney damage (table 11). Table 11. Efficacy outcomes in paediatric patients in study C09-001r according to duration of current severe clinical thrombotic microangiopathy (TMA) manifestation Duration of current severe clinical TMA manifestation < 2 months N=10 (%) >2 months N=5 (%) Platelet count normalisation 9 (90) 5 (100) TMA event-free status 8 (80) 3 (60) Complete TMA response 7 (70) 0 eGFR improvement ≥ 15 mL/min/1.73m 2 7 (70) 0* *One patient achieved eGFR improvement after renal transplant A total of 22 paediatric and adolescents patients (aged 5 months to 17 years) received eculizumab in aHUS study C10-003. In study C10-003, patients who enrolled in the study were required to have a platelet count < lower limit of normal range (LLN), evidence of haemolysis such as an elevation in serum LDH above the upper limits of normal and serum creatinine level ≥97 percentile for age without the need for chronic dialysis. The median patient age was 6.5 years (range: 5 months to 17 years). Patients enrolled in aHUS C10-003 had an ADAMTS-13 level above 5%. Fifty percent of patients had an identified complement regulatory factor mutation or auto-antibody. A total of 10 patients received PE/PI prior to eculizumab. Table 12 summarises the key baseline clinical and disease-related characteristics of patients enrolled in aHUS study C10-003. Table 12. Baseline characteristics of paediatric and adolescents patients enrolled in aHUS study C10-003 Parameter 1 month to <12 years (N = 18) All patients (N = 22) Time from aHUS diagnosis until first study dose (months) median (min, max) 0.51 (0.03, 58) 0.56 (0.03,191) Time from current clinical TMA manifestation until first study dose (months), median (min, max) 0.23 (0.03, 4) 0.20 (0.03, 4) Baseline platelet count (x 10 9 /L), median (min, max) 110 (19, 146) 91 (19,146) Baseline LDH (U/L) median (min, max) 1510 (282, 7164) 1244 (282, 7164) Baseline eGFR (mL/min/1.73m 2 ), median (min, max) 22 (10, 105) 22 (10, 105) Patients in aHUS C10-003 received eculizumab for a minimum of 26 weeks. After completion of the initial 26-week treatment period, most patients elected to continue on chronic dosing. Reduction in terminal complement activity was observed in all patients after commencement of eculizumab. Eculizumab reduced signs of complement-mediated TMA activity, as shown by an increase in mean platelet counts from baseline to 26 weeks. The mean (±SD) platelet count increased from 88 ± 42 x10 9 /L at baseline to 281 ± 123 x10 9 /L by one week; this effect was maintained through 26 weeks (mean platelet count (±SD) at week 26: 293 ± 106 x10 9 /L). Renal function, as measured by eGFR, was improved during eculizumab therapy. Nine of the 11 patients who required dialysis at baseline no longer required dialysis after study day 15 of eculizumab treatment. Responses were similar across all ages from 5 months to 17 years of age. In aHUS C10-003, responses to eculizumab were similar in patients with and without identified mutations in genes encoding complement regulatory factor proteins or auto-antibodies to factor H. Table 13 summarises the efficacy results for aHUS C10-003. Table 13. Efficacy outcomes in prospective aHUS study C10-003 Efficacy Parameter 1 month to <12 years (N = 18) At 26-weeks All patients (N = 22) At 26-weeks Complete haematologic normalisation, n (%) Median duration of complete haematologic normalisation, weeks (range) 1 14 (78) 35 (13, 78) 18 (82) 35 (13, 78) Complete TMA response, n (%) Median duration of complete TMA response, weeks (range) 1 11 (61) 40 (13, 78) 14 (64) 37 (13, 78) TMA event-free status, n (%) 95% CI 17 (94) NA 21 (96) 77; 99 Daily TMA intervention rate, median (range) Before eculizumab treatment, median On eculizumab treatment, median NA NA 0.4 (0, 1.7) 0 (0, 1.01) eGFR improvement ≥15 mL/min/1.73m 2 , n (%) 16 (89) 19 (86) Change in eGFR (≥15 mL/min/1.73m 2 ) at 26 weeks, median (range) 64 (0,146) 58 (0, 146) CKD improvement by ≥1 stage, n (%) 14/16 (88) 17/20 (85) PE/PI event-free status, n (%) New dialysis event-free status, n (%) 95% CI 16 (89) 18 (100) NA 20 (91) 22 (100) 85;100 1 Through data cut-off (October 12, 2012), with median duration of eculizumab therapy of 44 weeks (range: 1 dose to 88 weeks). Longer term treatment with eculizumab (median 55 weeks ranging from 1 day to 107 weeks) was associated with an increased rate of clinically meaningful improvements in paediatric and adolescent patients with aHUS. When eculizumab treatment was continued for more than 26 weeks, one additional patient (68% of patients in total) achieved Complete TMA response and two additional patients (91% of patients in total) achieved haematologic normalisation. At the last evaluation, 19 of 22 patients (86%) achieved eGFR improvement of ≥ 15 mL/min/1.73m 2 from baseline. No patient required new dialysis with eculizumab.