Ecu Treatment Research Articles

Ravulizumab Effectiveness in the Real World: Evidence from the International PNH Registry

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease of uncontrolled terminal complement activation on blood cells that can cause intravascular hemolysis (IVH), major adverse vascular events (MAVEs), including thromboembolic events (TEs), and organ damage resulting in early mortality. Complement C5 inhibitors eculizumab (Ecu) and ravulizumab (Rav) are standard-of-care treatments that inhibit terminal complement activity and reduce morbidity and mortality by controlling IVH (reduction of lactate dehydrogenase [LDH]) and preventing TEs. Rav provides the same benefits as Ecu but with substantially longer half-life, improved control of terminal complement, and reduction in breakthrough intravascular hemolysis achieved via weight-based dosing, thus reducing the burden of treatment. Long-term efficacy and safety data are available for up to 20 y from trials and real-world evidence (RWE) with Ecu and up to 6 y from trials in patients (pts) treated with Rav who were naïve to C5 inhibitors or who switched from Ecu to Rav; however, RWE is limited with Rav. The objective of this analysis was to describe pt characteristics at treatment initiation, outcomes, and changes from treatment initiation in laboratory markers of pts switching to Rav from Ecu using data from the prospective, observational International PNH Registry (NCT01374360). Methods The PNH Registry is the largest global real-world database of pts with PNH and provides extensive information on the natural history of PNH, irrespective of PNH treatment status. This analysis included data from pts enrolled in the PNH Registry, with complete information for birth date, sex, enrollment date, and Ecu/Rav treatment status. Pts included in the study switched from >6 mos of Ecu treatment to Rav for >6 mos. Pts were required to have discontinued Ecu within <28 days of Rav initiation. Changes from Rav treatment initiation (baseline) in key laboratory values, including LDH ratio, absolute hemoglobin (Hgb) levels, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scores were analyzed descriptively. Poisson regression estimate of incidence density was used for MAVEs, TEs, and red blood cell (RBC) transfusion rates across treatment exposure during registry follow-up. High disease activity (HDA), defined as LDH ≥1.5 X upper limit of normal and ≥1 of the following: history of a MAVE (including TE), anemia (Hgb <10 g/dL), or physician-reported abdominal pain, dyspnea, dysphagia, fatigue, hemoglobinuria and/or erectile dysfunction, was assessed during follow-up visits. Results As of 3 April 2023, 110 pts in the International PNH Registry had switched to Rav for ≥6 mos. The median age at start of Rav treatment was 42.1 y (Q1, Q3: 33.1, 52.2 years), 50% were female, and 70% were non-Asian. Over 24 mos of follow-up time was recorded for >50% of pts from the analysis population. The median time on Ecu was 6.5 y and Rav was 2 y. During Ecu treatment and before Rav initiation, 20/42 (47.6%) pts had ongoing bone marrow disorder (eg, aplastic/hypoplastic anemia, myelodysplastic syndromes). Before Ecu treatment, 24/101 (23.8%) pts had MAVEs (TE, 18/100 [18.0%] pts) and at Rav initiation, 27/109 (24.8%) pts had MAVEs (TE, 21/109 [19.3%] pts). Over time, Rav maintained IVH and disease control, with minimal change across time points for LDH ratios, absolute Hgb levels, and FACIT-Fatigue scores ( Table 1). Rates of clinical events (ie, MAVEs, TEs, and RBC transfusions) decreased over time from untreated time to time on Ecu treatment and were lowest when pts were treated with Rav ( Table 2). There were no reported MAVEs and TEs in pts treated with Rav. At Rav initiation, 6/65 pts still had HDA; only 1/6 had HDA at last follow-up visit while on Rav. No meningococcal infections or deaths were reported during Rav treatment. Four pts had discontinued Rav treatment (physician decision, switched to other anti-complement treatment, lack of efficacy). Conclusions These data from the International PNH Registry, one of the largest global real-world datasets of Rav-treated pts, confirmed that improvements in clinical outcomes observed with Ecu, including control of IVH, Hgb level, RBC transfusion rates, and fatigue, were maintained with Rav. HDA resolved in most pts when switching from Ecu to Rav. Transfusion rates were lowest with Rav treatment. Pts treated with Rav experienced no MAVEs, TE, meningococcal infections, or deaths.

A phase III, randomised, double-blind, multi-national clinical trial comparing SB12 (proposed eculizumab biosimilar) and reference eculizumab in patients with paroxysmal nocturnal haemoglobinuria.

Treatment of paroxysmal nocturnal haemoglobinuria (PNH) includes the monoclonal antibody eculizumab. This randomised, double-blind, multi-national cross-over Phase III study in PNH patients aimed to demonstrate the equivalence of the proposed eculizumab biosimilar SB12 and reference eculizumab (Soliris, ECU). PNH patients with lactate dehydrogenase (LDH) ≥1·5× upper limit of normal were randomised into treatment sequences SB12-ECU or ECU-SB12. Four weekly infusions of 600mg eculizumab were followed by fortnightly infusions of 900mg until week 50 (ECU/SB12 cross-over at week 26). Primary endpoints were LDH at week 26 and the time-adjusted area under the effect curve (AUEC) of LDH over weeks 14‒26 and 40‒52. Among 46 patients (92%) who completed the study, the least squares mean (LSM) difference in LDH at week 26 (34·48; 95% confidence interval [CI] -47·66‒116·62U/l) and geometric LSM ratio of time-adjusted AUEC of LDH (1·08; 90% CI 0·95‒1·23) were within pre-defined equivalence margins. Mean numbers of transfused red blood cell units, other secondary endpoints, pharmacokinetics, and pharmacodynamics were comparable. No patients developed anti-drug antibodies. Treatment-emergent adverse events were reported in 72% and 68% of patients in the SB12 and ECU treatment groups, respectively. The results demonstrate equivalence of SB12 to ECU and support SB12-use in PNH patients.

S303: EFFECT OF PEGCETACOPLAN ON QUALITY OF LIFE IN COMPLEMENT-INHIBITOR NAÏVE PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA: RESULTS FROM THE PHASE 3 PRINCE STUDY

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Historically, PNH was treated with C5 inhibitors (eculizumab [ECU)/ravulizumab). Despite their proven efficacy in the control of intravascular hemolysis (IVH), up to 72% of patients experience persistent hemolysis leading to suboptimal hemoglobin (Hb) levels and 36% require transfusions despite ECU treatment which results in a significant impact on the quality of life (QoL), including persistent fatigue. Pegcetacoplan (PEG) is an FDA/EMA-approved C3 complement-inhibitor that provides broad hemolysis control (including IVH and extravascular hemolysis) in patients with PNH. Aims: This analysis evaluates QoL measures in the Phase 3 PRINCE study (NCT04085601), a multicenter, randomized, open-label, controlled study evaluating the efficacy and safety of PEG compared to control treatment (CTRL; excluding complement-inhibitors) in complement-inhibitor naïve patients with PNH. Methods: PRINCE has been described previously and was superior for the coprimary endpoints of hemoglobin (Hb) stabilization (avoidance of >1 g/dL decrease in Hb from baseline), change from baseline in lactate dehydrogenase at 26 weeks and PEG-treated patients saw clinically meaningful increases in the FACIT-Fatigue scores (Wong SR, et al. Blood 2021; 138 [Supplement 1]: 606). Secondary endpoints specific to QoL measures included the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Scale (EORTC QLQ-C30), Linear Analog Scale Assessment (LASA) and The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue). The EORTC QLQ-C30 contains 30 questions comprising 5 functional, 9 individual symptoms, and one global health status/QoL item(s), where a ≥10-point change in score is considered clinically meaningful. The LASA consists of 3 sections asking to rate the perceived level of functioning (scale 0-100, where a higher score corresponds to a better QoL) and contains specific domains for activity level, ability to carry out daily activities, and overall QoL. The FACIT-Fatigue is a 13-item Likert scaled instrument (scale 0-51), where a ≥3-point increase is considered clinically meaningful. Results: Relevant baseline characteristics for PRINCE are reported in Table A. Mean baseline scores of the EORTC QLQ-C30 functional and symptom scales were generally similar between groups (except for role and cognitive functioning and insomnia; Table B). After 26 weeks of PEG-treatment, patients displayed clinically meaningful improvements in most of the functional scales and the global health status/QoL at Week 26 as indicated by a ≥10-point score increase from baseline (Table B). Improvements in the symptom scales, including fatigue and dyspnea scales, were also observed in the PEG group at Week 26 as indicated by a reduction in the symptom score close to the general population norms (general population norm: fatigue: 24.1, dyspnea: 10.9). Mean total LASA scores increased in the patients receiving PEG treatment for 26 weeks (Table B). FACIT-Fatigue scores increased for PEG-treated patients to near the general population norm [43.6], supporting the gains shown in the EORTC QLQ-C30-Fatigue scale. Image:Summary/Conclusion: Substantial and clinically relevant improvements in QoL were consistently observed with PEG across both EORTC QLQ-C30, total LASA and FACIT-Fatigue scores and clinically significant improvements in fatigue and dyspnea are highly relevant to the symptomology of PNH.

The Use of Eculizumab for the Treatment of Atypical Hemolytic Uremic Syndrome: A Description of Our Experience at an Academic Hematology Center

BackgroundAtypical hemolytic uremic syndrome (aHUS) is a rare disorder with an incidence of 0.23 to 1.9 per million population and presents with hemolytic anemia, thrombocytopenia and kidney failure. Eculizumab, a complement inhibitor and one of the most expensive drugs (about $26,000/dose), is the first specific treatment of aHUS. There is sufficient literature available regarding the use of Ecu in aHUS; however, practice conventions have not been well described.AimsThe purpose of this study was threefold: 1) to describe patient demographics 2) report the clinical characteristics and laboratory outcomes 3) depict the outcomes of our cohort of patients (pts) treated for aHUS with Ecu.MethodsA retrospective chart review was conducted to identify all pts age 18 and over who received 1 dose or more of Ecu for a diagnosis of aHUS/TMA and had an encounter at our tertiary academic center between 1/1/2017 to 7/30/2021. A linear mixed effects model was used with random effects for each pt and fixed effects corresponding to Ecu and a polynomial function of time since admission. Confidence intervals and p-values were calculated for the Ecu treatment effect on hemoglobin (Hg), platelets, lactate dehydrogenase (LDH), and creatinine (Cr).ResultsSo far, 9 pts with aHUS/TMA treated with Ecu met criteria to be included in the study. Median duration of follow up was 12 months (1 - 51 months). The main findings are summarized in Table 1. Average time from admission to Ecu initiation was about 14 days. Most pts had received PLEX prior to Ecu. Only 1 out of 8 pts received meningococcal vaccination 2 weeks prior to initiation of Ecu. Pts were found to have a significant decrease in LDH (p=0.029; figure 1) and Cr (p=0.012; figure 2) while on treatment. No significant increase was found in Hg (p=0.258) nor was there a significant increase in platelets (p=0.569). 6 pts needed dialysis, but all of them were able to stop dialysis except the 2 pts who died. 1 pt did have interruption in treatment due to loss of insurance and 3 patients stopped treatment due to personal preference (n=2) or improvement in symptoms after more than a year on treatment (n=1).Conclusions:Ecu has been proven to be effective in pts with aHUS in clinical studies by resolving and preventing complement-mediated TMA, improving organ dysfunction and hematologic outcomes. Our study supported the available data by demonstrating an improvement in renal function and LDH, which is commonly used as a disease marker in aHUS. Optimal duration of Eculizumab therapy in aHUS has not yet been determined and current recommendations are to continue treatment indefinitely. Limited experience suggested that certain selected pts can be safely monitored off Ecu and prompt reinitiation of treatment on recurrence could be efficient in controlling the disease. Interestingly, our study found that all 3 patients who stopped treatment had stability of disease with sufficient follow-up. Also, the cost associated with Ecu use is a significant issue given the length of treatment currently recommended. Many of our patients did not have private insurance, which may influence the treatment patterns with Ecu. Lastly, just under half of our patients did not undergo genetic testing to determine the underlying cause of their aHUS presentation. Genetic mutations seem to be more clinically relevant to decide risk of relapse and to understand the pathophysiology of the disease. Improvement in these measures may help determine more information in their role in predicting clinical outcomes and treatment regimen duration.Overall, more research is needed to elucidate the optimal treatment duration and investigate the role of various factors (such as insurance availability, genetic mutation testing, and patient preference) play in determining Ecu duration. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Post Hoc Analysis of the Effect of Pegcetacoplan Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria and Baseline Hemoglobin Levels Greater Than 10 Grams per Deciliter

Post Hoc Analysis of the Effect of Pegcetacoplan Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria and Baseline Hemoglobin Levels Greater Than 10 Grams per Deciliter

MDS-134: Efficacy and Safety at 48 Weeks of Pegcetacoplan in Adult Paroxysmal Nocturnal Hemoglobinuria Patients with Suboptimal Response to Prior Eculizumab Treatment

Context: Pegcetacoplan (PEG) is a C3 complement inhibitor recently approved by the FDA for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). PEG was superior to eculizumab (ECU; C5-inhibitor) in improving hemoglobin levels at week 16 during the phase 3 PEGASUS trial (NCT03500549) in patients with suboptimal response to prior ECU treatment. Objective: We report on efficacy and safety of PEG and results from a post hoc time-aligned analysis based on start of PEG dosing. Design: Eighty PNH patients (≥18 years, hemoglobin levels Results: PEG-to-PEG patients achieved sustained improvements in hemoglobin levels at week 16 through the OLP (week 48 mean hemoglobin level: 11.3 g/dL; CFB: 2.5 g/dL). ECU-to-PEG patients displayed improved hemoglobin levels during the OLP (week 48 mean hemoglobin level: 11.6 g/dL; CFB: 2.9 g/dL). Timepoint alignment demonstrated no significant difference (p=0.64) between improvements in hemoglobin levels at 28 and 48 weeks among PEG-to-PEG and ECU-to-PEG groups, respectively. Thirty percent of patients reported a serious AE, 6% possibly PEG-related. Common AEs for PEG-treated patients were injection site reactions (36%), hemolysis (24%), and diarrhea (21%). Twelve patients (15%) discontinued PEG due to AEs: 3 in RCP, 8 in OLP, 1 during follow-up, including one death due to COVID-19, unrelated to PEG. Conclusions: PEG-treated patients experienced sustained improvements in hemoglobin levels at week 48, and the safety profile of PEG was consistent with previously reported data. The treatment effect of PEG on hemoglobin levels over time was similar between PEG-to-PEG and ECU-to-PEG groups. Thus, PEG represents a new effective therapeutic option for PNH patients.

MDS-135: Injection Site Reactions at Week 48 in the Randomized Phase 3 PEGASUS Trial of Pegcetacoplan Compared with Eculizumab for Individuals with Paroxysmal Nocturnal Hemoglobinuria

<h3>Context:</h3> Pegcetacoplan (PEG) is a C3-complement inhibitor recently approved by the FDA for the treatment of paroxysmal nocturnal hemoglobinuria. PEG was superior to eculizumab (ECU; C5-inhibitor) in improving hemoglobin levels at week 16 in patients with suboptimal response to prior ECU treatment (phase 3 PEGASUS trial NCT03500549). PEG is self-administered twice weekly via two 10-mL subcutaneous injections at two distinct sites, which may lead to injection site reactions (ISRs). <h3>Objective:</h3> To compare ISR safety outcomes from PEGASUS to ISR incidences from similarly administered treatments based on published literature. <h3>Design:</h3> PEGASUS patients completed a 4-week run-in period (RIP) with ECU+PEG before 1:1 randomization to PEG (n=41) or ECU monotherapy (n=39). Primary endpoint was change from baseline in hemoglobin to week 16. Patients receiving ECU during the RCP entered another 4-week RIP (ECU+PEG), followed by an open-label period (OLP), in which all patients received PEG monotherapy. Safety was a secondary endpoint, including monitoring treatment-emergent adverse events (TEAEs) and ISR incidences. Therapies comparable to PEG (subcutaneously administered, having ≥10 mL injection volume or PEGylated) were evaluated from the published literature to establish a context for PEG-associated ISRs. <h3>Results:</h3> Total reported TEAEs were: i) RIP (n=80 [86%]); ii) RCP (PEG arm: n=36 [88%]; ECU arm: n=36 [92%]); iii) OLP (PEG arm: n=38 [87%]; ECU arm: n=39 [95%]). Most ISRs were mild and occurred during treatment initiation: RIP: 58%, RCP: PEG arm: 36.6%, ECU arm: 2.6%; OLP: PEG arm: 18%; ECU arm: 28%. Subjects with moderate ISRs: RIP: 2.5%, RCP: PEG arm: 2.4%, ECU arm: 0%; OLP: PEG arm: 2.6%; ECU arm: 2.6%. No ISRs were severe or led to study drug discontinuation. Five therapies were identified as comparable to PEG; these had ISR incidences of 5-67% and were generally mild. ISR management strategies from literature included injection site rotation and empowering patients to gain confidence and experience in self-administration through training by healthcare providers. <h3>Conclusions:</h3> PEGASUS trial ISRs observed with PEG treatment were mostly mild, decreased over time, and had comparable incidences to other drugs delivered similarly to PEG. Management strategies for ISRs with these drugs may potentially be useful for reactions observed with PEG.

Hematological Response to Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: Application of a Novel Classification to Identify Unmet Clinical Needs and Future Clinical Goals

Hematological Response to Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: Application of a Novel Classification to Identify Unmet Clinical Needs and Future Clinical Goals

Progression to end-stage renal disease is reduced with eculizumab in patients with atypical haemolytic uraemic syndrome

Atypical haemolytic uraemic syndrome (aHUS) is associated with severe kidney damage; almost one-half of adults with aHUS progress to end-stage renal disease (ESRD) after the first episode [1]. Two prospective clinical trials have assessed the efficacy of eculizumab (Ecu) in patients with aHUS [2]. We now evaluate data on progression to ESRD before and during Ecu treatment.

Biomarkers Of Complement and Endothelial Activation, Inflammation, Thrombosis and Renal Injury In Patients (pts) With aHUS Treated With Eculizumab (ECU)

▪ IntroductionaHUS is a genetic, life-threatening disease of chronic, uncontrolled complement activation leading to systemic complement-mediated thrombotic microangiopathy (TMA). Ecu (anti-C5 mAb) blocks terminal complement and inhibits TMA, normalizes platelets, and improves renal function in aHUS pts. We describe levels of key biomarkers of complement alternative pathway (CAP) and endothelial activation, as well as inflammation, coagulation, and renal injury that together characterize the disease process in pts with aHUS, prior to and during Ecu treatment. MethodsBiomarkers were evaluated using standard methods in healthy subjects (healthy) and adult aHUS pts (N=29-39) at baseline and during 26 weeks (wks) of Ecu treatment in a Phase 2 aHUS clinical trial. ResultsAll biomarkers were elevated at baseline in the majority of pts (Table), including pts with normal platelet counts (Figure), LDH, and/or haptoglobin levels. Following Ecu treatment in all pts, coagulation markers (F1+2 and D-dimer) were significantly reduced by 2.5 wks and decreased by >50% by wk 26. Renal injury markers (U-cystatin C and U-TIMP-1) also reduced significantly by 2.5wks. Interestingly, mean plasma levels of complement Ba, a key marker of CAP activation, were significantly decreased by 4-6 wks following Ecu but remained elevated. Soluble tumor necrosis factor receptor 1 (sTNFR1) and U-clusterin levels decreased by 4-6 wks, while thrombomodulin, VCAM-1, CXCL10, U-FABP-1, U-β2m and IL-6 levels reduced more slowly (12-26 wks). By 26 wks of Ecu, levels of all renal injury markers had normalized (≈78%-90% reduction) but markers of CAP and endothelial activation, inflammation, and coagulation remained elevated relative to levels in healthy subjects. [Display omitted] ConclusionsAt baseline, alternative pathway complement activation and elevated biomarkers of inflammation, coagulation, endothelial activation, and renal injury were evident in the majority of pts with aHUS, including those exhibiting normal markers of TMA. Ecu reduced but did not normalize plasma Ba, suggesting ongoing complement activation (CAP) upstream of C5 and the need for sustained complement inhibition downstream. Ecu treatment rapidly and markedly reduced biomarkers of thrombin generation, fibrinolysis, and inflammation, and normalized markers of renal injury; this reduction was sustained with ongoing Ecu treatment. Endothelial activation biomarkers reduced more slowly, suggesting ongoing effects of CAP C3 activation upstream of C5. These data point to the chronicity of the disease process and support the continuous administration of Ecu in aHUS pts, including those with normal hematological markers of TMA. Disclosures:Cofiell:Alexion Pharmaceuticals: Employment. Kukreja:Alexion Pharmaceuticals: Employment. Bedard:Alexion Pharmaceuticals: Employment. Yan:Alexion Pharmaceuticals: Employment. Mickle:Alexion Pharmaceuticals: Employment. Ogawa:Alexion Pharmaceuticals: Employment. Bedrosian:Alexion Pharmaceuticals: Employment. Faas:Alexion Pharmaceuticals: Employment.

Time To Hematologic and Renal Improvements In aHUS Patients With Progressing Thrombotic Microangiopathy Treated With Eculizumab Over Two Years

IntroductionAtypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening disease of chronic, uncontrolled complement activation, leading to platelet activation, thrombosis, hemolysis, and thrombotic microangiopathy (TMA). Despite PE/PI, up to 65% of patients (pts) sustain permanent renal damage, progress to end-stage renal disease, or die within 1 year (yr) of diagnosis. Significant hematologic and renal improvements were demonstrated in pts with progressing TMA who were treated with eculizumab (Ecu) in a Phase 2 trial. The current analysis was undertaken to gain further insight into the timing of those hematologic and renal improvements. MethodsPts ≥12 yrs of age with progressing TMA (platelet count<150×109/L despite ≥4 PE/PI sessions in the week [wk] prior to screening) enrolled in a 26-wk single-arm, Phase 2 trial of Ecu with a long-term extension period. Change from baseline in platelet count, LDH, hemoglobin (Hb), haptoglobin (Hp), creatinine (Cr) and eGFR were measured. The timing of platelet normalization (≥150x109/L), hematologic normalization (platelet normalization and LDH ≤ULN), Cr decrease (≥25%) and eGFR increase (≥15 mL/min/1.73 m2) – all for ≥2 consecutive measurements ≥4 wks apart – were assessed over the study period. ResultsSeventeen pts (median, 28 yrs; 71% female; 41% with prior renal transplant) enrolled and 15 continued into the long-term extension. The median time from diagnosis to screening was 10 months, and the median time from the onset of the current clinical manifestation was 0.75 months. The median duration of Ecu exposure at the data cut was 100 wks. Mean baseline values were as follows: platelet – 109.0x109/L; LDH – 323 U/L; Hb – 89 g/L; Hp – 0.5 g/L; Cr – 352 μmol/L; eGFR – 22.9 mL/min/1.73 m2.Significant improvements in mean platelet count from baseline were seen within the first wk of Ecu treatment and were sustained throughout the study period (Figure 1a). Significant and rapid improvements from baseline in Hb and Hp are shown in Figures 1b and 1c. With ongoing Ecu treatment, platelet and hematologic normalization was reached starting at wk 4 (the first assessable time point based on the criteria definition), with the majority of pts achieving normalization by wks 6 and 26, respectively (Figure 2A). With ongoing Ecu treatment, the threshold for both Cr decrease and eGFR increase were met as early as wk 6 in some pts, with the majority meeting these thresholds by wks 10 and 38, respectively. (Figure 2B). Earlier Ecu intervention (shorter duration of aHUS clinical manifestation prior to treatment) was associated with greater increases in eGFR (P<0.01). ConclusionsInitial platelet count and LDH normalization was observed at the first assessable time point, with the majority of pts achieving normalized levels by 6 months. Renal function also improved rapidly, with the majority of pts reaching the threshold for Cr and eGFR improvement by 9 months. These results illustrate that, in this population of pts with progressing TMA, early and ongoing treatment with Ecu led to rapid improvements in hematologic and renal parameters, demonstrating sustained TMA control.Figure 1. Platelet count change (a), mean hemoglobin (b), and haptoglobin (c) from baseline through 2 yearsFigure 2. Cumulative % of pts reaching key hematologic (a) and renal (b) endpoints over time Disclosures:Bedrosian:ALexion Pharmaceuticals: Employment. Furman:Genentech: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Gilead: Consultancy.

Time To Hematologic and Renal Improvements In Atypical Hemolytic Uremic Syndrome Patients With Long Disease Duration and Chronic Kidney Disease (CKD) Treated With Eculizumab

IntroductionAtypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening, chronic, and progressive disease of thrombotic microangiopathy (TMA). Plasma exchange/plasma infusion (PE/PI) has been shown to lack efficacy in patients (pts) with aHUS. Despite PE/PI, up to 65% of pts sustain permanent renal damage, progress to end-stage renal disease, or die within 1 year (yr) of diagnosis. Among aHUS pts with long disease duration and CKD receiving chronic PE/PI, significant improvements in hematologic parameters and renal function were achieved in a clinical trial of eculizumab (Ecu). The current analysis was undertaken to gain better insight into the timing of hematologic and renal improvements in a 26-week (wk), Phase 2 trial with a long-term extension. MethodsaHUS pts ≥12 yrs of age with long disease duration and CKD receiving chronic PE/PI were enrolled. This analysis assessed the percentage of pts achieving each of the following outcomes – all for ≥2 consecutive measurements, ≥4 wks apart – at specific time points: Platelet count normalization (≥150x109/L); LDH ≤ULN; serum creatinine (Cr) decrease ≥25%; eGFR increase ≥15 mL/min/1.73 m2; and CKD improvement ≥1 Stage. Results20 pts aged ≥12 yrs receiving long-term PE/PI were enrolled and treated with Ecu in a 26-wk, single-arm, Phase 2 trial, and 19 continued in the extension study. The median time (range) from aHUS diagnosis to screening was 48.3 months (0.7–285.8), and the median time from the current manifestation of aHUS to screening was 8.6 months (1.2–45). The median duration of Ecu treatment at the time of the data cut was 114 wks. Mean baseline values were as follows: platelet – 228x109/L; Hb – 10.7 g/L; LDH – 223 U/L; Cr – 287 μmol/L; and eGFR – 30.8 mL/min/1.73 m2. 3 pts had platelet counts <150 x109/L at baseline, and 4 had LDH levels >ULN.The timing and duration of the criteria-defined hematologic and renal improvements during continued treatment with Ecu are shown in Figure 1. At wk 4, the percentage of pts achieving platelet and LDH normalization was 75% and 50%, respectively (the first assessable time point based on the criteria definition). 90% of pts had platelet count normalization by wk 8, which was sustained with ongoing Ecu treatment for the remainder of the study period. 85% of pts had LDH ≤ULN by wk 8, which increased to 95% by wk 12 (Figure 1). With ongoing Ecu treatment, 10% of pts achieved Cr decrease (≥25%) at wk 14, and 55% by wk 80. eGFR increase (≥15 mL/min/1.73 m2) was first seen at wk 18 (by 5% of pts). This proportion increased to a maximum of 40% at wk 104 with ongoing Ecu treatment. CKD improvement (≥1 Stage) was seen at wk 4 by 5% of pts. This proportion increased to 60% at wk 76 with ongoing Ecu treatment (Figure 1). Significant mean changes from baseline in eGFR were observed as early as wk 4, and were followed by time-dependent improvements through the end of the study (Figure 2). All patients were able to discontinue PE/PI. [Display omitted] [Display omitted] ConclusionsThe use of Ecu in aHUS pts with long disease duration and CKD on long-term PE/PI led to sustained normalization of hematologic values within the first month of treatment, followed by time-dependent improvements in renal function. These data demonstrate that improvement in renal function may be achieved over time in pts with long-standing aHUS and CKD, and underscore the importance of ongoing and consistent treatment with Ecu. The underlying mechanism of the observed renal function improvement over the study period (e.g., normalization of endothelial cell function) warrants further exploration. Disclosures:No relevant conflicts of interest to declare.

Eculizumab (ECU) in Atypical Hemolytic Uremic Syndrome (aHUS) Patients with Progressing Thrombotic Microangiopathy (TMA): 2-Year Data.

AbstractAbstract 2084 Introduction:aHUS is a rare, life-threatening genetic disease marked by chronic, uncontrolled complement activation leading to TMA and subsequent kidney and vital organ damage. 33%–40% patients (pts) die or progress to end-stage renal disease after the first clinical manifestation. In a phase 2 extension trial (64-week [wk] median ECU duration), pts receiving the terminal complement inhibitor ECU had a highly significant increase in platelet count (98×109/L; P=0.0001)—a measure of TMA improvement—and 4 pts (80%) discontinued prior dialysis by data cutoff. Here we report 2-year (y) results. Methods:Pts ≥12 y with aHUS and progressing TMA enrolled in an open-label, phase 2 trial with long-term extension. Pts had ≥4 plasma exchange/infusion (PE/PI) sessions in the wk before screening. ECU was administered at 900 mg/wk × 4 wk, 1200 mg at wk 5 and 1200 mg q2 wk thereafter. Results:The 26-wk study enrolled 17 pts, and 13 entered the extension phase. Data analysis was on the intention-to-treat population (n=17). Median time from diagnosis to screening was 10 months (range 0.3–236). Four pts (24%) had no identified complement regulatory factor mutation. Seven pts (41%) had prior renal transplant. All pts had estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 prior to ECU. Median ECU duration was 100 wk (range 2–145).Suppression of terminal complement activity was sustained at data cutoff. Significant platelet count improvement from baseline was seen at the 2-y data cutoff (P<0.0001; Table), with 15 pts (88%) achieving and maintaining a platelet count ≥150×109/L. Hematologic normalizationa was achieved by 88% of pts for an average duration of 629 days (d). Fifteen pts (88%) achieved TMA event-free status,b and TMA intervention ratec decreased from a median 0.88 (range 0.04–1.59) prior to ECU to 0 (range 0–0.31) during ECU treatment. Significant improvements in eGFR were observed throughout the study period (P=0.0008; Table). Earlier intervention with ECU was associated with greater eGFR improvement (P<0.01). Results of a 3-piece linear model demonstrated a flat slope for eGFR change from d −42 to 0, followed by a steep positive slope from d 0 to 28 (P<0.0001), then a continuous increase from d 28 to 860 (P=0.03). Improvements in other renal endpoints, including serum creatinine, proteinuria, and chronic kidney disease (CKD) stage, were observed with ongoing ECU. Significant improvements in quality of life (QOL) were observed. Pts received benefit regardless of the presence or absence of an identified complement mutation. Treatment with ECU was generally well tolerated, with 1 report of a serious adverse event (SAE; hypertension) deemed possibly drug related, which resolved with no change in ECU dosing. Two pts discontinued treatment due to worsening renal function unrelated to ECU. Conclusions:Long-term ECU therapy inhibited complement-mediated TMA and resulted in significant and continuous time-dependent improvements in renal function. At a median duration of almost 2 y, all pts entering the extension phase remain alive and report better QOL. The low rate of SAEs is consistent with the known safety profile of ECU. These results highlight the ongoing benefit of earlier intervention and long-term treatment with ECU in aHUS.TableChange from baseline in key outcomes from 26 wk and 100 wk of ECU treatment (N=17)Key OutcomesWk 26Median 100 WkMean platelet count change (primary), ×109/L (95% CI)73 (40–105)88 (63–112)P=0.0001P<0.0001 (wk 96)Hematologic normalization (primary),a n (%)13 (76)15 (88)TMA event-free status,b n (%)15 (88)15 (88)eGFR increase of ≥15 mL/min/1.73 m2, n (%)8 (47)10 (59)CKD improvement ≥1 stage, n (%)10 (59)12 (71)Serum creatinine decrease ≥25%, n (%)11 (65)13 (76)Mean eGFR change, mL/min/1.73 m2 (95% CI)31 (17, 45)32 (15, 49)dP=0.0001P<0.0008 (wk 96)Proteinuria decrease ≥1 grade,e n/N12/157/9 (wk 96)Mean health-related QOL change,f0.32 (0.27, 0.38)0.33 (0.30, 0.36)EuroQOL 5D score (95% CI)P<0.0001P=0.0001 (wk 96)CI=confidence interval.cPE/PI or new dialysis events/pt/d.aNormal platelet and lactate dehydrogenase levels, ≥2 consecutive measurements, ≥4 wk apart.b≥12 wk of stable platelet count, no PE/PI and no new dialysis.dECU eliminated need for dialysis in 4/5 pts receiving dialysis at baseline. An additional pt initiated dialysis at wk 64 (eGFR, 19 mL/min/1.73 m2 at screening).eEvaluable pts.fClinically meaningful threshold ≥0.6. Disclosures:Greenbaum:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Legendre:Alexion Pharmaceuticals: Speakers Bureau. Babu:Alexion Pharmaceuticals: Honoraria, Research Funding. Cohen:Alexion Pharmaceuticals Inc.: Research Funding. Bedrosian:Alexion Pharmaceuticals: Employment. Loirat:Alexion Pharmaceuticals: Coordinator of Alexion trials of eculizumab in atypical HUS for France. Honoraria for conferences. Other.

Eculizumab Is An Effective Long-Term Treatment In Patients with Atypical Hemolytic Uremic Syndrome (aHUS) Previously Receiving Chronic Plasma Exchange/Infusion (PE/PI): Extension Study Results,

Abstract 3303▪▪This icon denotes a clinically relevant abstract INTRODUCTION:Chronic uncontrolled complement activation drives systemic thrombotic microangiopathy (TMA) and life-threatening complications in aHUS. In the initial 26-wk, phase II trial of eculizumab, (ECU) a terminal complement inhibitor, in pts with aHUS requiring chronic PE/PI for an extended period of time, a statistically significant and sustained suppression of TMA was observed. In addition, no pt required PE/PI, no new dialysis was required and all pts either maintained/improved renal function in the absence of PE/PI (Licht ASN 2011). We report longer follow-up data from this trial. METHODS:Pts ≥12 yrs with aHUS, receiving chronic PE/PI on an unchanged regimen were enrolled in a controlled, open-label, single-arm, phase II trial. After an 8-week observation period, pts discontinued PE/PI and started ECU (900mg/week for 4 wks, 1200mg at wk 5, then 1200mg q2 wks). Pts received a meningococcal vaccine. Primary endpoint: TMA event-free status defined as ≥12 consecutive wks of stable platelet count, no PE/PI and no new dialysis. Secondary endpoints included TMA intervention rate (no. of PE/PI and new dialysis events/pt/day), renal function, and safety. Pts continued into an extension trial. RESULTS:Of 20 pts (median age=28 yrs) who received ECU through Wk 26 of the initial trial, 19 pts continued ECU treatment into the extension trial. Mean (SD) duration of ECU treatment was 60 (12) wks at data cut-off. Median time from diagnosis to screening=48 mo (0.66–286). Median time from overt clinical symptoms of aHUS to screening=8.6 mo (1.2–45). Median no. of PE/PI sessions per pt during current clinical presentation=62 (20–230). Median duration of eGFR ≤60 mL/min/1.73m2=180 days (23–485). Six pts had no complement regulatory factor mutation (CRFM) identified. Ongoing treatment with long-term ECU was associated with continued improvements in TMA intervention rate and TMA event-free status and further improvement in renal function (Table). Long-term ECU treatment showed a highly significant time-dependent improvement in eGFR (p<0.0001) with a significant improvement from baseline of 8 mL/min/1.73m2 at 1 yr (p<0.0001). PE/PI or new dialysis was not required with chronic ECU treatment in any pt through Wk 26 or during ongoing long-term ECU therapy (through data cut-off). ECU was similarly effective in pts with/without identified CRFMs. ECU was well tolerated; only 7 pts had adverse events deemed possibly or probably related to drug (mild to moderate in severity). The extension trial continues. CONCLUSIONS:Despite PE/PI, >50% of pts with aHUS are expected to die, require dialysis or have permanent renal damage within the first year of diagnosis. In this trial, all pts treated with ECU for a mean duration of >1 year are still alive and none progressed to ESRD or required new dialysis with sustained ECU treatment. Importantly, compared with historical outcomes with chronic PE/PI, initiation of sustained, long-term ECU therapy, without PE/PI, was associated with a highly significant time-dependent improvement in eGFR. Switching to chronic ECU therapy significantly changed the course of the disease in severe and prolonged renal insufficiency pts, resulting in sustained suppression of TMA. These data further demonstrate ECU to be the new standard of care for aHUS.ParameterWk 26 ECU Treatment (N=20)Data cut-off (mean* duration of ECU=60 wks] (N=20)TMA event-free status, n†1617Median TMA intervention rate0 (p<0.0001)0 (p<0.0001)Improvement in ≥ 1 CKD from BL, n†79≥25% reduction in serum creatinine from BL, n†37Change in eGFR from BL, mL/min/1.73m26 (p=0.0003)8‡ (p<0.0001)Significance was tested with two sided signed rank test or repeated measures analyses.BL=baseline.*Median (range) duration=62 wks (26–74);†n=number of pts;‡At1 yr. Disclosures:Licht:Alexion: Honoraria, Research Funding. Off Label Use: Eculizumab but as part of clinical controlled trials. Muus:Alexion: Membership on an entity's Board of Directors or advisory committees, Research Funding. Legendre:Alexion: Research Funding. Douglas:Alexion: Genzyme, but not relevant to current submission, Research Funding. Hourmant:Alexion: Research Funding. Delmas:Alexion: Research Funding. Herthelius:Alexion: Research Funding. Trivelli:Alexion: Research Funding. Goodship:Alexion: Honoraria, Research Funding. Bedrosian:Alexion: Employment. Loirat:Alexion: Honoraria, Research Funding.

Eculizumab Is An Effective Long-Term Treatment In Patients with Atypical Hemolytic Uremic Syndrome (aHUS) Resistant to Plasma Exchange/Infusion (PE/PI): Results of An Extension Study

Abstract 193▪FN2▪This icon denotes a clinically relevant abstract INTRODUCTION:aHUS is a genetic, systemic disease with a devastating prognosis caused by chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA), progressive organ damage and premature mortality. In a 26-wk phase II trial, pts receiving ECU, a terminal complement inhibitor, had a highly significant increase in platelet count (a measure of TMA improvement) (primary endpoint: 73×109/L increase; p=0.0001). 13/15 pts with low platelet count at baseline (BL) (ITT) had platelet normalization at Wk 26. 15/17 pts (88%) achieved TMA event-free status (≥12 wks of stable platelet count, no PE/PI and no new dialysis). 13/13 pts treated with ECU for 26 wks had platelet normalization at Wk 26 and 15/15 treated with ECU for 26 wks achieved TMA event-free status. Median TMA intervention rate was 0 (no. of PE/PI and new dialysis events/pt/day). Importantly, 4/5 pts on dialysis with PE/PI discontinued dialysis with ECU. ECU was well tolerated (Legendre. ASN 2010). We report longer follow-up data from the extension phase of this ongoing trial. METHODS:Pts ≥12 yrs with aHUS and persistent TMA despite ≥4 PE/PI sessions 1 wk before screening were enrolled in a 26-wk, controlled, open-label, single-arm phase II trial and continued into an extension trial. ECU dosage: 900mg/wk for 4 wks, 1200mg at Wk 5, 1200mg q2 wks. All pts received a meningococcal vaccine and prophylactic antibiotics ≥14 days after vaccination. Efficacy analyses were based on ITT population. RESULTS:17 pts enrolled (2 discontinued at Wks 1 and 6; systemic lupus erythematosus [protocol violation] and an adverse event unrelated to ECU, respectively). Median time from diagnosis to screening=10mo (0.3–236). Median duration from overt clinical manifestations of aHUS to screening=0.75mo (0.2–4). Median number of PE/PI sessions per pt during aHUS current clinical presentation=17 (2–37). 5 patients (29%) required dialysis at baseline. Median age=28 yrs. 4 pts (24%) had no identified complement regulatory factor mutations (CRFM). ECU mean (SD) duration=58 (29) wks at data cut-off. Mean change (SD) in platelet count from BL was maintained (97×109/L [81] at Wk 26 vs 98×109/L [60] at 1 yr). All 13 pts who had platelet normalization at Wk 26 continued to maintain normal levels at data cut-off. The same 15/17 (88%) pts achieved TMA event-free status at data cut-off. All pts receiving sustained ECU treatment throughout the study achieved TMA event-free status at data cut-off. Renal function was maintained and continued to further improve in pts with ongoing ECU: improvement ≥1 CKD stage from BL: from 10 (59%) pts at Wk 26 to 11 (65%) pts at data cut-off and ≥25% decrease in creatinine from BL: from 11 (65%) pts at Wk 26 to 13 (77%) pts at data cut-off. With sustained ECU therapy, only 1 of the 5 pts at baseline continued on to require dialysis and no patient newly required dialysis (as of data cut off). Long-term chronic ECU was similarly effective in pts with/without identified CRFM. ECU was generally well tolerated; adverse events deemed related to ECU were reported in 12 pts (mostly mild to moderate, 1 severe). The extension trial continues. CONCLUSIONS:In aHUS, despite PE/PI, >50% of pts either die, require dialysis, or have permanent renal damage within the first year of diagnosis. In contrast, all pts treated with ECU for a mean duration of >1 yr remain alive, 4 out of 5 pts became dialysis free, and no pt newly required dialysis. This demonstrates that continued ECU treatment significantly transformed the clinical course of aHUS in this pt population. In addition, long-term ECU therapy suppressed TMA and dramatically improved renal function. These long-term follow-up data further strengthen the evidence for ECU as the new standard of care for aHUS. Disclosures:Greenbaum:Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Eculizumab for the treatment of atypical hemolytic syndrome as part of clinical trials. Babu:Alexion: Research Funding. Furman:Alexion: Research Funding. Sheerin:Alexion: Research Funding. Cohen:Alexion: Research Funding. Gaber:Alexion: Research Funding. Delmas:Alexion: Research Funding. Loirat:Alexion: Research Funding. Bedrosian:Alexion: Employment. Legendre:Alexion: Research Funding.

C3-Mediated Extravascular Hemolysis In Paroxysmal Nocturnal Hemoglobinuria: An In Vitro Model to Dissect Complement C3 Activation Comparing the Effects of Complement Inhibitors Eculizumab, 3E7 and TT30 on C3 Fragment Processing and Hemolysis of PNH Erythrocytes

AbstractAbstract 637PNH is characterized by complement (C)-mediated chronic intravascular hemolysis (IVH) due to the absence of CD55 and CD59 on erythrocytes (E) and subsequent impaired C regulation. C alternative pathway (CAP)-derived normal ongoing low level activity (termed the tickover mechanism) is the pivotal initial step, which subsequently leads to C3 fragment (C3frag) deposition on E followed by membrane attack complex (MAC)-mediated IVH. C3frag processing on E proceeds from the initially covalently attached C3b form that is serially converted through proteolysis, mediated on E by factor I and cofactors factor H and complement receptor 1 (CR1), to iC3b and then to C3d as forms that all remain membrane-bound. To develop an improved mechanistic understanding of this process in PNH, which results in C3frag accumulation and extravascular hemolysis (EVH) in vivo during eculizumab (Ecu) treatment, herein we exploited an in vitro model to characterize and dissect C3frag generation after CAP activation on PNH E. We used monoclonal antibodies (mAbs) specific for the different C3 fragments, including C3b/iC3b (mAbs 2C5, 3C11, 3E7, 7C12 and 8E11) and C3b/iC3b/C3d (mAbs A702, 1H8 and 14A10). We also investigated the effect of the C inhibitors (C-Inh) Ecu, 3E7 (a CAP-inhibitory anti-C3b/iC3b mAb) and TT30 (a cell surface-targeted CAP-inhibitory complement receptor 2/factor H fusion protein) on C3frag accumulation and hemolysis of PNH E. E from PNH patients, either naïve or on Ecu treatment, were washed and incubated in ABO-matched acidified normal human serum (aNHS). Assessment of hemolysis and C3 activation and processing was performed by serial flow cytometry analyses of both intact E and E ghosts, as previously described (Risitano et al, Blood 2009; Lindorfer et al, Blood 2010). We first studied E from PNH patients on Ecu, which were known to be C3frag+ using an anti-C3 polyclonal Ab (pAb). Only the anti-C3b/iC3b/C3d mAbs A702, 1H8 and 14A10 demonstrated binding to these PNH E, with a pattern overlapping with that of the anti-C3 pAb, while the anti-C3b/iC3b mAbs 2C5, 3C11, 3E7, 7C12 and 8E11 did not bind. To investigate the kinetics of generation of specific C3frag on PNH E, fresh E from untreated PNH patients that did not show either membrane-bound C3b/iC3b or C3d were exposed in vitro to aNHSs. Analysis at 1h and 24h revealed that intact E, which remained C3frag-negative, progressively decreased and finally disappeared, being transformed into C3b/iC3b+ and C3d+ ghosts. In the presence of Ecu (using serum from patients on Ecu treatment, drawn within 1h of dosing), the same experiments revealed a dramatic reduction of hemolysis, but residual CAP-mediated hemolysis in a process of pharmacodynamic breakthrough was confirmed by the presence of C3b/iC3b+, C3d+, CD59− E ghosts. More interestingly, intact E showed substantial C3frag deposition which progressed over time, initially characterized by the presence of C3b/iC3b and C3d, and subsequently converting after 24h exclusively into C3d+ E, with an identical phenotype as found in C3frag+ PNH E obtained from patients on Ecu. This result demonstrates that PNH E, despite exhibiting only C3d when recovered from patients, pass through an earlier phase where C3b/iC3b frag are present that can interact with their cognate receptors on fixed cells in liver and spleen during EVH in vivo. Both 3E7 and TT30 completely inhibited hemolysis, with an IC50 of 120 μg/mL for 3E7 and 30 μg/mL for TT30; consistent with their mechanism of action, both 3E7 and TT30 bound to PNH RBCs. No C3b/iC3b nor C3d was detected on surviving PNH E at any time, indicating that 3E7 and TT30 effectively inhibit the earliest phases of CAP activation involved in EVH. Similar results were obtained when E from PNH patients on Ecu were challenged in vitro with aNHS in the presence or absence of C-Inh. In conclusion, we demonstrate that CAP-mediated C3b/iC3b fixation to PNH RBCs is the early event leading to IVH or, in presence of Ecu, to C3frag deposition and subsequent EVH in vivo. Unlike Ecu, use of 3E7 or TT30 resulted in complete inhibition of hemolysis as well as CAP-mediated C3 activation, preventing C3b/iC3b and C3d deposition on intact PNH E. Thus, use of this model will allow assessment of the roles of both endogenous and therapeutic C regulators in CAP activation and C3 processing (and subsequent EVH) in PNH. Preclinical data suggest that TT30 is an optimal candidate agent to assess in vivo the effect of CAP inhibition in PNH patients. Disclosures:Risitano:Taligen Therapeutics: Consultancy, Research Funding. Horvath:Taligen Therapeutics: Employment. Fridkis-Hareli:Taligen Therapeutics: Employment. Holers:Taligen Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Chronic Renal Insufficiency in Japanese Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH): Improvement with Eculizumab Treatment in the Long-Term Follow-up of the AEGIS Study.

Abstract 1980Poster Board I-1002PNH is a progressively debilitating and life-threatening disease characterized by chronic complement-mediated hemolysis. The clinical complications associated with chronic hemolysis include life-threatening thrombosis, chronic kidney disease (CKD), pulmonary hypertension, organ damage, ischemic bowel disease, and hepatic failure - all of which contribute to shortened survival of patients with PNH. CKD, a consequence of hemolysis, has significant impact on survival in Japanese patients with PNH, accounting for 18% of deaths. We previously reported results from the Japanese AEGIS study, a 12-week open-label single-arm phase II study, which demonstrated that eculizumab (ecu), a humanized monoclonal antibody against the terminal complement molecule C5, significantly reduced complement-mediated intravascular hemolysis. Ecu treatment subsequently improved anemia, fatigue and renal function in 11 Japanese patients with PNH. Given the important impact on survival of renal disease, the effects of ecu on renal function were further evaluated among 27 Japanese patients with PNH enrolled in a 26-week extension of the AEGIS study. Ecu was dosed as follows: 600mg weekly for 4 weeks; 900mg one week later; and then 900mg every other week for a total of 38 weeks of therapy. Patients received meningococcal vaccine 2 weeks prior to treatment. Consistent with the previous 12 week study report, there was a sustained reduction in intravascular hemolysis, as measured by lactate dehydrogenase (LDH), through the 38 weeks of ecu treatment. LDH decreased 87% from a median of 1,814 U/L at baseline to a median of 232 U/L at 38 weeks of treatment (P<0.001; see table). Control of hemolysis resulted in continued improvement in anemia; hemoglobin continued to increase from 7.5 g/dL at baseline to 9.75 g/dL at 38 weeks (P<0.001) despite the reduction in transfusion requirements (P=0.004). Fatigue levels, as measured by the FACIT-Fatigue instrument, continued to significantly improve with ecu treatment (P<0.001; see table). Renal function was defined by KDOQI CKD stage, recognized as objective evidence of abnormal glomerular function, determined by glomerular filtration rate (GFR), along with persistent proteinuria, from Stage 0 (normal) to Stage 5 (Kidney failure). An improvement in renal function was defined as a categorical reduction (improvement) in CKD stage. Worsening in renal function was defined as a categorical increase (decline) in CKD stage. At study entry, 65% of the Japanese group demonstrated evidence of CKD. During the 38-week treatment period, 33.3% (9/27) of all patients who entered the trial showed improvement while 66.7% (18/27) showed no change or progression from baseline and no patients worsened. Further, 52.9% (9/17) of patients with CKD at baseline demonstrated improvement. Among the 9 patients who showed improvement, 8 had stage 1-2 CKD at baseline and one had stage 3-5, underscoring the importance of early intervention with ecu in patients with mild kidney disease. The CKD results of the Japanese study were compared to the 26-week placebo-controlled TRIUMPH trial and the combined data from the multinational clinical trials (see table). In the overseas multinational trials, 64% (121/189) of patients had evidence of CKD at study entry, similar to the 65% in the Japanese cohort. The results from the 26-week placebo group in the TRIUMPH trial suggest that there is no significant change in CKD over the course of 6 months. In contrast, treatment with ecu significantly improved CKD in patients in the TRIUMPH and overseas multinational studies (P<0.001) and in the Japanese study (0% worsened, 33% improved, P<0.05). The results from both studies also demonstrate that the benefit from ecu treatment was most evident in patients with early CKD stage 1-2. In conclusion, kidney disease is an important cause of premature mortality in Japanese PNH patients. The current study suggests that evidence of CKD is common in Japanese PNH patients. Further, this study demonstrates that ecu is safe and well tolerated in Japanese patients with PNH. We see continued improvement in PNH symptoms from 12 to 38 weeks with ecu treatment. Similar to the beneficial effects of ecu in patients with PNH in overseas multinational phase III trials, reduction of hemolysis with ecu treatment was associated with clinical improvement in kidney function in Japanese patients with PNH. [Display omitted] Disclosures:Kanakura:Alexion Pharmaceuticals: Research Funding. Ohyashiki:Alexion Pharmaceuticals: Research Funding. Shichishima:Alexion Pharmaceuticals: Research Funding. Okamoto:Alexion: Research Funding. Ando:Alexion: Research Funding. Ninomiya:Alexion: Research Funding. Kawaguchi:Alexion: Research Funding. Nakao:Alexion: Research Funding. Nakakuma:Alexion: Research Funding. Nishimura:Alexion: Honoraria, Research Funding. Kinoshita:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Valentine:Alexion: Employment, Equity Ownership. Ozawa:Alexion: Research Funding. Omine:Alexion: Consultancy, Research Funding.

From Renal Siderosis Due to Perpetual Hemosiderinuria to Possible Liver Overload Due to Extravascular Hemolysis: Changes in Iron Metabolism in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients On Eculizumab.

Abstract 4031Poster Board III-967Iron metabolism in PNH patients is dominated by perpetual iron loss consequent to the chronic complement-mediated intravascular hemolysis; thus, they are prone to develop iron deficiency rather than iron overload, even in presence of large transfusional requirement. Eculizumab (Ecu) has proven effective for the treatment of intravascular hemolysis in PNH patients, resulting in reduction and even abolishment of transfusion requirement and improvement of signs and symptoms of intravascular hemolysis; however, Hb gain is heterogeneous among patients, in most cases due to residual C3-mediated extravascular hemolysis hampering Hb normalization. The goal of our study was to identify possible modifications in iron compartmentalization associated with Ecu treatment and possible clinical consequences. We evaluated iron metabolism in 5 untreated PNH patients and 23 who were receiving Ecu (of whom 4 have been also studied before treatment), combining biochemical parameters with a semiquantitative T2* MRI technology. MRI was performed using four gradient-echo sequences and one spin-echo sequence; signal intensity (SI) was measured on images obtained with each sequence by means of three regions of interest placed in the renal cortex, liver, spleen and at the level of the para-spinal muscle, resulting in a semiquantitative SI value (Grandon et al., Radiology 1994). Within the total patient cohort (regardless they were or were not on Ecu), there was a significant correlation between liver SI and serum ferritin (P<0.001), while kidney SI correlated with the presence of hemosiderinuria (HS, P<0.001). All untreated PNH patients showed similar MRI findings, with significant renal cortex siderosis and normal SI in liver and spleen. This was consistent with overt intravascular hemolysis, as confirmed by biochemical routine testing, and consequent perpetual hemosiderinuria; as expected, all these patients had abundant HS. In contrast, the 23 PNH patients on Ecu showed a distinct and heterogeneous pattern. All patients showed a normal renal SI, with the exception of 2 cases who have recently started Ecu and 2 experiencing Ecu breakthrough; these 4 patients had normal hepatic and splenic SI. All of them (but none of those with normal renal SI) had persistent HS, while only the latter 2 had increased LDH; we conclude that these 4 patients have had residual intravascular hemolysis, and that HS was more sensitive than LDH to identify recent history of intravascular hemolysis. In contrast, the majority of patients showed increased hepatic SI: we found 6 cases with moderate and 5 cases with severe iron overload; in some patients, high hepatic SI was associated with increased SI in the spleen. The 4 patients evaluated before and during treatment showed pre-treatment renal siderosis which progressively disappeared after months of Ecu therapy; in 2 of them, who had a longer exposition to Ecu, moderate hepatic iron overload was demonstrated. Hepatic SI significantly correlated with serum ferritin (P<0.05), but not with transferrin saturation nor with LDH. Iron overload was predictable as a result of persistent transfusional need only in two patients with partial response to Ecu; however, within the whole cohort, patients with suboptimal hematological response (i.e., those with persistent Hb<11) were more likely to develop severe hepatic iron overload (P=0.02). Thus, we hypothesized that iron overload in these patients may be pathophysiilogically linked to persistent extravascular hemolysis; we found a direct correlation between liver SI and both % of C3+ PNH RBCs (P=0.02) and absolute reticulocyte count (P=0.02), which were considered markers of extravascular hemolysis (Risitano et al, Blood 2009). In conclusion, we show by T2* RMI that untreated PNH patients have significant renal siderosis, which tends to disappear during Ecu treatment as a result of the blockade of intravascular hemolysis. However, such blockade of urinary iron loss may render PNH patients susceptible to liver iron overload resulting from transfusions, as well as from residual extravascular hemolysis. While is still not clear the proportion of patients developing clinically significant iron overload requiring specific treatment, we provide evidence that iron metabolism substantially changes during eculizumab treatment, and C3-mediated extravascular hemolysis may play a major role in this process. Disclosures:Risitano:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.