Al-Akash, Samhar I

Ardissimo, Gianluigi

Bedrosian, Camille L

Evans, Jonathan

Fila, Marc

Greenbaum, Larry

Henning, Paul

Licht, Christoph

Lieberman, Kenneth V

Maringhini, Silvio

Ogawa, Masayo

Pape, Lars

Rees, Lesley

Tsimaratos, Michel

Van De Kar, Nicole

Vande Walle, Johan

English

Ghent University Academic Bibliography

Eculizumab Inhibits Thrombotic Microangiopathy and Improves  Renal Function in Pediatric Patients With Atypical Hemolytic Uremic SyndromeLarry A. Greenbaum,1 Marc Fila,2 Michel Tsimaratos,3 Gianluigi Ardissino,4 Samhar I. Al-Akash,5 Jonathan Evans,6 Paul Henning,7 Kenneth V. Lieberman,8 Silvio Maringhini,9  Lars Pape,10 Lesley Rees,11 Nicole Van De Kar,12 Johan Vande Walle,13 Masayo Ogawa,14 Camille L. Bedrosian,14 Christoph Licht151Emory University, Atlanta, GA, USA; 2Hôpital Robert-Debré, Paris, France; 3Hôpital La Timone, Marseille, France; 4Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milano, Italy; 5Driscoll Children’s Hospital, Corpus Christi, TX, USA; 6Nottingham University Hospitals, Nottingham, UK; 7Women’s and Children’s Hospital, North Adelaide, South Australia, Australia; 8Hackensack University Medical Center, Hackensack, NJ, USA; 9G. Di Cristina Children’s Hospital, Palermo, Italy; 10Hannover Medical School, Hannover, Germany; 11Great Ormond Street Hospital for Children, NHS Trust, London, UK; 12Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 13University Hospital Ghent, Ghent, Belgium; 14Alexion Pharmaceuticals, Inc., Cheshire, CT, USA; 15The Hospital for Sick Children, Toronto, CanadaINTRODUCTION • Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening, progressive disease resulting from chronic, uncontrolled complement activation. It is characterized by systemic thrombotic microangiopathy (TMA) leading to renal damage and, frequently, damage to other end organs. • The efficacy and safety of eculizumab has been proven in 2 prospective Phase 2 trials in patients with evidence of progressing TMA and those with long disease duration and chronic kidney disease.1 • Plasma exchange and infusion (PE/PI) has been used historically to manage aHUS2; however, evidence shows that PE/PI affords limited clinical benefit.2  – Within 1 year of aHUS diagnosis, up to 65% of patients managed with PE/PI sustain permanent renal damage, progress to end-stage renal disease (ESRD), or die.3STUDY RATIONALE • Eculizumab (Soliris®; Alexion Pharmaceuticals, Inc., Cheshire, CT), a terminal complement inhibitor, is a humanized monoclonal antibody that binds with high affinity to the human C5 complement protein, blocking the generation of  pro-inflammatory C5a and C5b-9.1 It is the first and only approved treatment for aHUS in pediatric and adult patients.4 • Multiple published cases have reported the efficacy of eculizumab in treating pediatric patients with aHUS,5-9 yet, to date, no prospective trial of alternate treatment options has ever been conducted in children with aHUS. • In addition, a previous retrospective study demonstrated the efficacy of eculizumab in a pediatric population with aHUS in a clinical practice setting.7 • Eculizumab has, therefore, been recommended as first-line therapy in children with aHUS.9 • Herein, we report safety and efficacy results at 26 weeks from the first prospective trial of pediatric patients with aHUS. METHODSStudy Design  • Open-label, single-arm, multicenter, multinational, interventional clinical trial. • Primary outcome – Proportion of patients who achieved complete TMA response during 26 weeks, defined as: • Platelet count normalization (≥150 x 109/L). • Normalization of lactate dehydrogenase (LDH; < upper limit of the normal range [ULN]). • ≥25% improvement in serum creatinine (SCr) from baseline. – All 3 parameters had to be met on 2 consecutive measurements obtained ≥4 weeks apart. • Secondary outcomes included: – Hematologic normalization (platelet count normalization [≥150 x 109/L] and LDH normalization [LDH < ULN]) sustained for ≥2 consecutive measurements obtained ≥4 weeks apart. – TMA event-free status: • No decrease in platelet count >25% from baseline, no PE/PI, and no new dialysis. – Hemoglobin increase of ≥20 g/L from baseline sustained for ≥2 consecutive measurements obtained ≥4 weeks apart. – ≥25% decrease in SCr from baseline (sustained for ≥2 consecutive measurements obtained ≥4 weeks apart). – Change from baseline in estimated glomerular filtration rate (eGFR). – eGFR improvement ≥15 mL/min/1.73 m2 from baseline sustained for ≥2 consecutive measurements obtained  ≥4 weeks apart. – Change in health-related quality of life (as measured by Pediatric FACIT-F). – Pharmacokinetic/pharmacodynamic (PK/PD) measures.Inclusion Criteria  • Pediatric patients with aHUS aged 1 month to <18 years with a body weight ≥5 kg. • Platelet count at screening and baseline visit <150 x 109/L. • Exhibited signs or symptoms of hemolysis at start of current aHUS episode: – LDH ≥1.5 x ULN. – Hemoglobin ≤ lower limit of normal range (LLN). – Fragmented RBC with a negative Coombs test. • SCr ≥97th percentile for age at screening. • No requirement for identified complement mutation or antibody. • Patients must have been vaccinated against Neisseria meningitidis, pneumococcus, and haemophilus (as per the vaccine label) ≥14 days prior to study drug initiation or otherwise be protected by prophylactic antibiotics for 14 days after meningococcus vaccination. Due to unavailability of a vaccine for under 2 years, patients in this age group were  to receive antibiotic prophylaxis throughout the treatment period.Exclusion Criteria  • Chronic dialysis (defined as dialysis on a regular basis as renal replacement therapy for ESRD). • Shiga toxin–producing Escherichia coli (STEC-HUS) infection. • Genetic or acquired severe ADAMTS-13 deficiency (ADAMTS-13 activity <5% [as measured during the screening  period of the trial]). • PE/PI for >5 weeks prior to enrollment. • Prior eculizumab use or hypersensitivity to eculizumab, to murine proteins, or to 1 of the excipients.Dosing • Fixed doses of eculizumab were administered intravenously based on pre-specified body weight cohorts. • Eculizumab induction and maintenance dosing regimens are described in Table 1.Table 1. Schedule of Eculizumab Dose Administration Based on WeightWeight Cohort Induction Maintenance≥40 kg 900 mg weekly x 4 1200 mg week 5; 1200 mg q2 weeks30 to <40 kg 600 mg weekly x 2 900 mg week 3; 900 mg q2 weeks20 to <30 kg 600 mg weekly x 2 600 mg week 3; 600 mg q2 weeks10 to <20 kg 600 mg weekly x 1 300 mg week 2; 300 mg q2 weeks5 to <10 kg 300 mg weekly x 1 300 mg week 2; 300 mg q3 weeksStatistical Analysis • The primary efficacy endpoint was the proportion of patients with a complete TMA response during the first 26 weeks of the study period in the intent-to-treat (ITT) population.  – The ITT population was defined as all patients who signed an informed consent and received ≥1 dose of eculizumab. • Proportion of patients with eGFR change from baseline ≥15 mL/min/1.73 m2 was calculated similarly to primary endpoint (as per the statistical analysis plan). While the patient was on dialysis, the eGFR value was set at 10 mL/min/1.73 m2. • All statistical tests were assessed at the 2-sided α = 5% level without adjusting for multiplicity. The primary analysis was assessed at the 1-sided α = 5% level. • For the composite endpoints, if the post-baseline or baseline data for any component were missing, then the patient was treated as censored at the last follow-up day. Patients who did not have valid baseline values or any valid post-baseline values were also treated as a failure for endpoints. • The eGFR was calculated using the Schwartz formula: eGFR (mL/min/1.73 m2) = [0.413 x height (cm)] / SCr (mg/dL)].RESULTSPatient Disposition  • Twenty-two pediatric patients were treated with eculizumab and 19 patients (86%) completed the 26-week study period (Table 2).Table 2. Trial C10-003: Patient DispositionCategoryIntent-to-Treat Population(N=22)Enrolled 27Not treated, n (%)     Positive test for Shiga toxin     Platelet count normalized     Final diagnosis not aHUS     Unspecified reasons5 (19) 1121Treated 22Discontinued eculizumab treatment before completing  26-week study period, n (%)3 (14)Completed 26-week study period, n (%) 19 (86)Reason for withdrawal, n (%)     Confirmed diagnosis of STEC-HUS     Serious adverse event (agitation)      Family request to withdraw patient 1 (5)1 (5)1 (5)aHUS, atypical hemolytic uremic syndrome; STEC-HUS, Shiga toxin–producing E. coli infection.Patient Demographics and Baseline Laboratory Values (Table 3) • The median duration from the onset of the clinical manifestation to screening was 6 days.  • A total of 12 patients (55%) had no PE/PI prior to eculizumab initiation. • Eleven patients (50%) were on dialysis at baseline. • Twenty patients (91%) had eGFR <90 mL/min/1.73 m2.Table 3. Trial C10-003: Demographics and Baseline Laboratory ValuesCategoryIntent-to-Treat Population(N=22)Age at first infusion (years) – median (range)  6.5 (0.0–17.0) Age, n (%)      1 month to <23 months      ≥23 months to <5 years     ≥5 to <12 years      ≥12 to <18 years 5 (22.7)5 (22.7)8 (36.4)4 (18.2)Female gender, n (%) 10 (45)Race, n (%)     Asian     Black or African American     Caucasian     Other2 (9)0 (0)18 (82)2 (9)Patient-reported family history of aHUS, n (%) 6 (27)Identified genetic mutations, n (%)     Anti-Complement Factor Antibody: Factor H autoantibody positive     Anti-Complement Factor Antibody: Factor H autoantibody positive, CFHR1, CFHR3     Complement Protein 3 (C3) Gain-of-Function Mutation     Factor H     Factor I     Membrane Cofactor Protein (MCP)10 (45)1 (5)1 (5)1 (5)2 (9)2 (9) 3 (14)Patients with CFHR1/3 polymorphism, n (%) 1 (5)No identified mutation, n (%) 11 (50)Median duration (range) from aHUS diagnosis until screening (months) 0.6 (0.03–191)Median duration (range) from current manifestation to first dose (months) 0.20 (0.03–4.3)First clinical TMA manifestation, n (%) 16 (72.7)No PE/PI during current manifestation, n (%) 12 (55)Dialysis at baseline, n (%)* 11 (50)Prior renal transplant, n (%) 2 (9)Platelet count (x 109/L) – mean (SD) 87.5 (42.3)Patients with platelet count <150 x 109/L, n (%) 22 (100)LDH (U/L) – mean (SD) 1943.7 (1824.4)LDH > ULN 19 (86.4)Hemoglobin concentration (g/L) – mean (SD) 80.2 (15.3)Serum creatinine (umol/L) – mean (SD) 154.5 (116.43)eGFR (mL/min/1.73 m2) – mean (SD) 32.7 (30.37)eGFR (mL/min/1.73 m2), n (%)     <15     15–29     30–44     45–59     60–89     ≥9010 (45.5)4 (18.2)2 (9.1)2 (9.1)2 (9.1)2 (9.1)aHUS, atypical hemolytic uremic syndrome; eGFR, estimated glomerular filtration rate; LDH, lactate dehydrogenase; PE/PI, plasma exchange/plasma infusion;  SD, standard deviation; TMA, thrombotic microangiopathy; ULN, upper limit of normal.*One patient who was on dialysis at baseline discontinued dialysis during the baseline window prior to the first dose of eculizumab.Efficacy Outcomes Primary Outcome: Complete TMA Response Through 26 Weeks  • Complete TMA response was achieved in 14 of 22 patients (64%; 95% CI: 41–83) from baseline to 26 weeks (Figure 1).  – Median (range) time to complete TMA response was 60.0 (7.0–153.0) days.Hematologic Outcomes Over 26 Weeks • Twenty-one of 22 patients (95%; 95% CI: 77–99.9) achieved TMA event-free status during 26 weeks. • Hematologic normalization was observed in 18 of 22 patients (82%; 95% CI: 60–95) (Figure 1) after 26 weeks. • Twenty-one of 22 patients (95%; 95% CI: 77–99.9) achieved platelet count normalization from baseline (Figure 1).  – Median (range) time to platelet count normalization was 7.0 (1.0–80.0) days. – Mean (SD) improvement in platelet count from baseline was 164 (76.4) x 109/L (Figure 2). • Eighteen of 22 patients (82%; 95% CI: 60–95) achieved LDH normalization from baseline to 26 weeks of eculizumab treatment (Figure 1). • Fifteen of 22 patients (68%; 95% CI: 45–86) had improvement in hemoglobin concentration of ≥20 g/L from baseline through 26 weeks. • Of 10 patients on PE/PI at baseline, all (100%) discontinued by the end of the 26-week study.Figure 1. Proportion of Patients Achieving Complete TMA Response and Hematologic, Platelet Count, and LDH Normalization During 26 Weeks9010080706050403020100Proportion of Patients (%)Primary Outcome Secondary OutcomesComplete TMAResponse6414/22Platelet CountNormalization9521/22LDH Normalization8218/22HematologicNormalization8218/22LDH, lactate dehydrogenase; TMA, thrombotic microangiopathy.Figure 2. Mean Platelet Count Improvement02550751002750Platelet Count Mean Change From Baseline (x109 /L)1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27Weeks125150175200225250  ****** * * ***P<0.0001.Bars represent standard error of the mean.Renal Outcomes Over 26 Weeks • Nineteen patients (86%) had eGFR improvement ≥15 mL/min/1.73 m2 from baseline through 26 weeks (Table 4). • Mean improvement from baseline in eGFR was 64 mL/min/1.73 m2. Decrease in SCr (≥25%) was observed in 16 patients (73%) (Table 4, Figure 3). • Of the 11 patients on dialysis at baseline, 9 discontinued during the 26-week study period (Table 4). – Of the 11 patients not on dialysis at baseline, 11 (100%) remained dialysis-free during 26 weeks.Table 4. Summary of Renal OutcomesParameterIntent-to-Treat Population(N=22)eGFR improvement from baseline ≥15 mL/min/1.73 m2, n (%) 19 (86)Serum creatinine decrease ≥25%, n (%) 16 (73)CKD improvement ≥1 stage from baseline, n (%) 17 (77)Patients on dialysis at baseline (n=11) who discontinued during study, n (%) 9/11 (82)CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate. Figure 3. Mean Improvement in eGFR Over 26 Weeks0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27Weeks015304590eGFR Mean Change From Baseline (mL/min/1.73 m2 )6075  ††††††  ****  eGFR, estimated glomerular filtration rate. *P<0.001.†P≤0.0001.Bars represent standard error of the mean.Improvement in Health-Related Quality of Life  • The Pediatric FACIT-F LS mean change from baseline to data cutoff was 19.7 (range, 15.6–23.7), which was statistically significant (P<0.0001).Pharmacokinetics and Pharmacodynamics • The population PK analysis suggests that the approved eculizumab pediatric dosing regimen in Study C10-003 resulted in concentrations within the target concentration range (50–700 μg/mL) during the induction and maintenance phases for all age cohorts.  • Results from the population PK/PD analysis demonstrate that the dosing strategy of eculizumab resulted in complete terminal complement inhibition (as measured by hemolytic activity) in all but 1 patient.Eculizumab Was Safe and Well Tolerated Over the 26-Week Study Period • There were no deaths or meningococcal infections reported during the 26-week study period. • Twenty of 22 patients enrolled (91%) reported at least 1 treatment-emergent adverse event (TEAE), the majority  of which were mild to moderate in severity (Table 5). – None of the infection-related TEAEs were considered severe. • Thirteen of 22 patients (59%) reported at least 1 serious TEAE (Table 5). – One patient discontinued due to agitation, a serious TEAE. – One patient had a human anti-human antibody response, and continued eculizumab treatment without apparent adverse effect. Table 5. Safety of Eculizumab Treatment and Summary of TEAEsIntent-to-Treat Population(N=22)TEAEs (frequency ≥20%), n (%)Fever 11 (50)Cough 8 (36)Abdominal pain 7 (32)Diarrhea 7 (32)Upper respiratory tract infection 7 (32)Vomiting 6 (27)Nasopharyngitis 6 (27)Patients with any serious TEAE, n (%) 13 (59)Severity, n (%)MildModerateSevere3 (14) 7 (32) 3 (14) Relationship to eculizumab treatment, n (%)Unrelated Possible10 (45)3 (14)SAEs occurring in 2 or more patients, n (%)Fever 2 (9)Gastroenteritis viral 2 (9)Upper respiratory tract infection 2 (9)Hypertension 2 (9)SAEs, serious adverse events; TEAEs, treatment-emergent adverse events.CONCLUSIONS • In this, the first-ever prospective trial of pediatric patients with aHUS, the use of eculizumab led to rapid and sustained improvement in platelet counts and significant and continuous improvement over time in eGFR. • Most patients (73%) were newly diagnosed. • The median time from current manifestation to first dose of eculizumab was 6 days. • Twelve of the 22 patients (55%) received no PE/PI prior to treatment with eculizumab. • Complete TMA response – the primary endpoint – was achieved in 14 of 22 patients (64%) after 26 weeks. • A total of 21 patients (95%) achieved platelet count normalization from baseline to 26 weeks. • Nineteen patients (86%) had eGFR improvement ≥15 mL/min/1.73 m2 after 26 weeks; 64 mL/min/1.73 m2 mean improvement in eGFR from baseline. • Eculizumab treatment facilitated discontinuation of dialysis and PE/PI. – Of the 10 patients receiving PE/PI at baseline, all discontinued. – Nine of 11 patients on dialysis at baseline were able to discontinue by 26 weeks. – Of the 11 patients not on dialysis at baseline, 11 (100%) remained dialysis-free through 26 weeks. • There were no meningococcal infections reported, and no new safety concerns arose during the 26-week study period. • The safety and efficacy demonstrated in the trial confirm the results observed in the C09-001 pediatric retrospective study,10 as well as the published Phase 2 prospective trials.1,7  • These results also support the recommendation that eculizumab be used as first-line treatment in pediatric patients with aHUS.9 • The trial is ongoing.REFERENCES1. Legendre C, et al. N Engl J Med 2013;368:2169–2181.2. Loirat C, et al. Semin Thromb Hemost 2010;36:673–681.3. Campistol JM, et al. Nefrologia 2013;33:27–45.4. Soliris® (eculizumab) [prescribing information]. Cheshire, CT: Alexion Pharmaceuticals, Inc.; 2011.5. Schmidtko J, et al. Am J Kidney Dis 2013;61:289–299.6. Rother RP, et al. Nature Biotech 2007;25:1256–1264. 7. Vilalta R, et al. Haematologica 2012;97(suppl 1):479. Abstract 1155.8. Povey H, et al. Clin Nephrol 2013 Apr 5. [Epub ahead of print].9. Zuber J, et al. Nat Rev Nephrol 2012;8:643–657.10. Rodig N, et al. Presented at: the 48th ERA-EDTA Congress; 2011.ACKNOWLEDGMENTSThe authors would like to acknowledge Kenyon Ogburn of Alexion Pharmaceuticals, Inc., and Peloton Advantage, LLC,  for providing editorial support with funding from Alexion Pharmaceuticals, Inc.Presented at the American Society of Nephrology Kidney Week 2013 Annual Meeting, November 5–10, 2013, Atlanta, Georgia.SA-PO849

Eculizumab inhibits thrombotic microangiopathy and improves renal function in pediatric patients with atypical hemolytic uremic syndrome

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Eculizumab inhibits thrombotic microangiopathy and improves renal function in pediatric patients with atypical hemolytic uremic syndrome

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