Search

Blocking the terminal complement pathway with the C5 inhibitor eculizumab has revolutionized the clinical management of several complement-mediated diseases and has boosted the clinical development of new inhibitors. Data on the C3 inhibitor Compstatin and the C5 inhibitors eculizumab and Coversin reported here demonstrate that C3/C5 convertases function differently from prevailing concepts. Stoichiometric C3 inhibition failed to inhibit C5 activation and lytic activity during strong classical pathway activation, demonstrating a “C3 bypass” activation of C5. We show that, instead of C3b, surface-deposited C4b alone can also recruit and prime C5 for consecutive proteolytic activation. Surface-bound C3b and C4b possess similar affinities for C5. By demonstrating that the fluid phase convertase C3bBb is sufficient to cleave C5 as long as C5 is bound on C3b/C4b-decorated surfaces, we show that surface fixation is necessary only for the C3b/C4b opsonins that prime C5 but not for the catalytic convertase unit C3bBb. Of note, at very high C3b densities, we observed membrane attack complex formation in absence of C5-activating enzymes. This is explained by a conformational activation in which C5 adopts a C5b-like conformation when bound to densely C3b-opsonized surfaces. Stoichiometric C5 inhibitors failed to prevent conformational C5 activation, which explains the clinical phenomenon of residual C5 activity documented for different inhibitors of C5. The new insights into the mechanism of C3/C5 convertases provided here have important implications for the development and therapeutic use of complement inhibitors as well as the interpretation of former clinical and preclinical data.

Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade–naive (part 2) and C5 inhibitor–treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor–pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay

We report 5 cases of prothrombotic immune thrombocytopenia after exposure to the ChAdOx1 vaccine (AZD1222, Vaxzevria) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients presented 5 to 11 days after first vaccination. The spectrum of clinical manifestations included cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, and thrombotic microangiopathy. All patients had thrombocytopenia and markedly elevated D-dimer. Autoantibodies against platelet factor 4 (PF4) were detected in all patients, although they had never been exposed to heparin. Immunoglobulin from patient sera bound to healthy donor platelets in an AZD1222-dependent manner, suppressed by heparin. Aggregation of healthy donor platelets by patient sera was demonstrated in the presence of buffer or AZD1222 and was also suppressed by heparin. Anticoagulation alone or in combination with eculizumab or intravenous immunoglobulin (IVIG) resolved the pathology in 3 patients. Two patients had thromboembolic events despite anticoagulation at a time when platelets were increasing after IVIG. In summary, an unexpected autoimmune prothrombotic disorder is described after vaccination with AZD1222. It is characterized by thrombocytopenia and anti-PF4 antibodies binding to platelets in AZD1222-dependent manner. Initial clinical experience suggests a risk of unusual and severe thromboembolic events.

Some patients with paroxysmal nocturnal hemoglobinuria (PNH) remain persistently anemic despite treatment with eculizumab and may have significant extravascular hemolysis. Kulasekararaj and colleagues report a phase 2 trial of danicopan, a first-inclass oral complement factor D inhibitor, added to ongoing eculizumab therapy in PNH patients who still needed transfusions. This small study of 12 patients reveals that the combination has acceptable safety while substantially increasing the hemoglobin concentration, reducing extravascular hemolysis, and improving the fatigue score., Key Points Danicopan, a first-in-class oral factor D inhibitor showed clinical benefit when given in addition to eculizumab in patients with PNH.Addition of danicopan reduced extravascular hemolysis and improved anemia in patients with PNH with suboptimal eculizumab response., Visual Abstract, Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation and subsequent intravascular hemolysis (IVH). C5 inhibitors prevent membrane attack complex formation, but patients may experience extravascular hemolysis (EVH) and continue to require blood transfusions. Danicopan, an oral proximal complement inhibitor of alternative pathway factor D (FD), is designed to control IVH and EVH. In a phase 2 dose-finding trial, eculizumab-treated transfusion-dependent patients with PNH (n = 12) received danicopan, 100 to 200 mg thrice daily, in addition to their eculizumab regimen for 24 weeks. End points included hemoglobin (Hgb) change vs baseline at week 24 (primary), reduction in blood transfusions, and patient-reported outcomes. Safety, tolerability, and pharmacokinetics/pharmacodynamics were measured. Twelve patients received ≥1 danicopan dose; 1 patients discontinued from a serious adverse event deemed unlikely related to danicopan. Eleven patients completed the 24-week treatment period. Addition of danicopan resulted in a mean Hgb increase of 2.4 g/dL at week 24. In the 24 weeks prior to danicopan, 10 patients received 31 transfusions (50 units) compared with 1 transfusion (2 units) in 1 patient during the 24-week treatment period. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score increased by 11 points from baseline to week 24. The most common adverse events were headache, cough, and nasopharyngitis. Addition of danicopan, a first-in-class FD inhibitor, led to a meaningful improvement in Hgb and reduced transfusion requirements in patients with PNH who were transfusion-dependent on eculizumab. These benefits were associated with improvement of FACIT-Fatigue. This trial was registered at www.clinicaltrials.gov as #NCT03472885.

In 2007 and 2009, the regulatory approval of the first-in-class complement inhibitor eculizumab revolutionized the clinical management of 2 rare, life-threatening clinical conditions: paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Although being completely distinct diseases affecting blood cells and the glomerulus, PNH and aHUS remarkably share several features in their etiology and clinical presentation. An imbalance between complement activation and regulation at host surfaces underlies both diseases precipitating in severe thrombotic events that are largely resistant to anticoagulant and/or antiplatelet therapies. Inhibition of the common terminal complement pathway by eculizumab prevents the frequently occurring thrombotic events responsible for the high mortality and morbidity observed in patients not treated with anticomplement therapy. Although many in vitro and ex vivo studies elaborate numerous different molecular interactions between complement activation products and hemostasis, this review focuses on the clinical evidence that links these 2 fields in humans. Several noninfectious conditions with known complement involvement are scrutinized for common patterns concerning a prothrombotic statues and the occurrence of certain complement activation levels. Next to PNH and aHUS, germline-encoded CD59 or CD55 deficiency (the latter causing the disease complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy), autoimmune hemolytic anemia, (catastrophic) antiphospholipid syndrome, and C3 glomerulopathy are considered. Parallels and distinct features among these conditions are discussed against the background of thrombosis, complement activation, and potential complement diagnostic and therapeutic avenues.

Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor–naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)–Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), −4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (−76.8% vs −76.0%; difference [95% CI], −0.83% [−5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [−1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], −6.7% [−14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [−8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired blood disease characterized by hemolytic anemia, bone marrow failure, and thrombosis. Prior to the FDA approval of the C3 inhibitor pegcetacoplan, PNH treatment only included the C5 inhibitors (C5i) ravulizumab (RAV) and eculizumab (ECU) to decrease intravascular hemolysis and improve anemia. A Phase III trial of RAV in a treatment-naïve PNH population reported hemoglobin (Hb) stabilization (avoidance a >2 g/dL decrease in baseline Hb) occurred in 68% of RAV and 64% of ECU patients after 6 months. (Lee et al, 2019). However, real world (RW) evidence of the efficacy of these agents on Hb measures in clinical practice are lacking. The objectives of this study were to describe the demographic, healthcare resource utilization (HCRU), and clinical characteristics of PNH patients prior to C5i therapy, and to examine changes in Hb levels from baseline to 6 months after treatment initiation in a PNH patient population using a RW electronic medical record (EMR) network. Methods: This was a retrospective study of PNH patients aged ≥ 12 years seen between 2010-2021 within the TriNetX Dataworks USA Network, a federated EMR network of 68+ million de-identified patients. Included patients had a diagnosis of PNH on or before the index event of C5i therapy initiation. Patients were excluded if there was no visit recorded ≥6 months before the index event or if they had a diagnosis of atypical hemolytic uremic syndrome, myasthenia gravis, or neuromyelitis optica spectrum disorder. Demographic, HCRU, and clinical characteristics were captured for the year prior to therapy initiation. Hb results closest to the first treatment date and to the 6-month follow-up dates were used for Hb values. Mean and median Hb and distribution of Hb were calculated, as well as Hb stabilization (avoidance of a >2 g/dL decrease in baseline Hb) and response (Hb≥1 g/dL improvement) rates. Results: Fifty-eight PNH patients treated with RAV and 124 patients treated with ECU met inclusion criteria. Among the RAV and ECU cohorts respectively, patients were on average 50 and 43 years old and 59% and 56% female. Both cohorts experienced an average of ~3 inpatient visits in the year prior to C5i initiation. Aplastic anemia (36% vs 43%) and myelodysplastic syndromes (3% vs 6%) were less common among the RAV vs ECU cohort. Previous ECU treatment occurred in 34 of 58 (59%) RAV patients. All ECU patients were treatment-naïve at baseline. Hb results were available at baseline and 6 mo. in 50 and 32 RAV patients and in 110 and 81 ECU patients. The mean (SD) baseline and 6 mo. Hb values were 10.6 (2.0) and 10.7 (2.2) g/dL for the RAV cohort and 9.8 (2.2) and 10.4 (2.2) g/dL for the ECU cohort. Analysis of baseline and 6 mo. Hb values showed trends toward Hb increase for both cohorts driven by the larger proportion of patients achieving Hb≥12 g/dL (Figure). While the proportion of patients with Hb Conclusions: This analysis shows that patients treated with ECU had modest improvements in Hb measures after 6 mo., likely reflecting the effects of C5i in a treatment-naïve population. However, RAV treatment did not markedly alter Hb measures, perhaps due to this being mainly a cohort switching between two therapies with identical mechanisms of action. These RW Hb results suggest that despite C5i treatment, anemia was still largely persistent in this PNH cohort, possibly due to incomplete control of ongoing hemolysis, including extravascular hemolysis, which is not treated by these therapies. Our current analysis has limitations that we plan to address: Subgroup analysis by prior treatment is planned to further characterize RAV efficacy. Transfusion requirements have not yet been incorporated into this analysis; however, their inclusion is likely to attenuate the observed Hb efficacy. Other labs, such as absolute reticulocyte count and LDH, will be incorporated to gain a more holistic picture of therapeutic response. Finally, HCRU encounters reflecting adverse events, such as breakthrough hemolysis, need to be analyzed to understand the real-world safety profile of these therapies. Figure 1 Figure 1. Disclosures Yeh: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Kuranz: TriNetX: Current Employment; Apellis Pharmaceuticals, Inc.: Other: Payments from Apellis Pharmaceuticals to my institution TriNetX. Brzozowski: Apellis Pharmaceuticals, Inc.: Other: Payments from Apellis Pharmaceuticals to my institution TriNetX; TriNetX: Current Employment. Hoffman: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Fishman: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Chen: TriNetX: Current Employment; Apellis Pharmaceuticals, Inc.: Other: Payments from Apellis Pharmaceuticals to my institution TriNetX.

Background: In the absence of clinical guidelines for paroxysmal nocturnal hemoglobinuria (PNH), the European Society for Blood and Marrow Transplantation (EBMT) developed categories for classifying hematological response to complement inhibitor treatment (per Risitano AM, et al. Front Immunol. 2019;10:1157). These categories are: complete (no transfusions, normal stable Hb, and no evidence of hemolysis); major (no transfusions, normal Hb, but evidence of residual intravascular/extravascular hemolysis); good (no transfusions, but persistent chronic mild anemia); partial (persistent chronic moderate anemia and/or occasional red blood cell transfusions); minor (3-6 transfusions every 6 months); no response (>6 transfusions every 6 months). In the phase 3 PEGASUS trial (NCT03500549), 41 and 39 patients previously treated with C5 inhibitors with Hb Objectives: The objective of this study was to evaluate the number needed to treat (NNT) and treatment costs of pegcetacoplan and eculizumab using EBMT response criteria. Methods: The analysis used a United States payer perspective and included drug acquisition costs and associated intravenous or subcutaneous administration costs. Drug costs were calculated using dosages for each treatment as given in the PEGASUS trial, including dosage and frequency escalations. Weekly dosages were multiplied by each drug's wholesale acquisition costs from RedBook (2020 United States dollars). We calculated the following outcomes over 16 weeks and by treatment: NNT to achieve each level of response, mean cost per treated patient, total costs, mean cost per treated patient per week, cost per complete responder, cost per good responder, and cost spent on patients with partial/minor/no response. Additional analyses were conducted to calculate outcomes for treatment-naïve patients treated with pegcetacoplan using similar post hoc analyses of combined 16-week data from the phase 1b-2a PADDOCK/PALOMINO (NCT02588833 and NCT03593200) trials. Results: Results are summarized in Table 1. Based on response rates, patients with PNH treated with pegcetacoplan had a lower NNT (1.4) to achieve good-to-complete response compared with eculizumab (19.5). NNT to achieve complete response was 2.6 for pegcetacoplan; no patients treated with eculizumab achieved complete response at 16 weeks. For the PEGASUS trial, mean cost per treated patient was $182,762 (with C5 inhibitor loading dose) and $176,504 over 16 weeks for pegcetacoplan and eculizumab, respectively. Among the 41 pegcetacoplan-treated patients, the total costs were $7,493,256 over 16 weeks. Of 41 pegcetacoplan patients, 16 achieved a complete response, and their total costs were $2.9 million over the 16-week period ($468,328 per complete responder). The total 16-week costs were $2.6 million for 14 patients with good response ($535,233 per good responder). For the 39 eculizumab-treated patients, total 16-week costs were $6,883,637. Two of 39 patients achieved a good response, and their total costs were $353,007 ($3,441,818 per good responder). Of the 39 patients, 37 achieved partial, minor, or no response or discontinued treatment, for a total cost of $6.5 million. This resulted in 95% of total treatment costs being spent on inadequate or no response in the eculizumab arm compared with 27% in the pegcetacoplan arm. For treatment-naïve patients treated with pegcetacoplan, the mean cost per complete responder ($347,339) and per good responder ($496,198) over 16 weeks were both lower than the cost per responder for patients treated with either pegcetacoplan or eculizumab after previous C5 inhibitor treatment. Conclusion: Based on the treatment response observed in PEGASUS, the NNT and cost to achieve good or good-to-complete response was lower for pegcetacoplan-treated patients than eculizumab-treated patients, according to EBMT consensus-based hematological response categories. PNH treatment with pegcetacoplan allowed more patients to achieve EBMT defined good-to-complete response and better overall response and is a more efficient use of spending with lower cost per responder in all response categories. Figure 1 Figure 1. Disclosures Anderson: Apellis: Consultancy, Research Funding. Talbird: Apellis: Consultancy, Research Funding. Fishman: Apellis: Current Employment, Current equity holder in publicly-traded company.

Background: SB12 has been developed as a biosimilar of the reference product (RP) eculizumab. Eculizumab is a humanized monoclonal antibody (IgG2/4 kappa immunoglobulin) that binds to the human C5 complement protein with high affinity. Binding to this protein blocks its cleavage into C5a and C5b, thereby inhibiting terminal complement-mediated intravascular haemolysis. It is currently indicated for the treatment of patients with paroxysmal nocturnal haemoglobinuria, atypical haemolytic uremic syndrome (aHUS), refractory generalized Myasthenia Gravis (gMG) and Neuromyelitis Optica Spectrum Disorder (NMOSD). Objectives: To demonstrate pharmacokinetic (PK) equivalence and evaluate pharmacodynamic (PD), safety, tolerability, and immunogenicity profiles between SB12 and the RP eculizumab. Methods: This was a double-blind, three-arm, parallel group, and single-dose study in healthy subjects, between 18-55 years of age, randomized in a ratio of 1:1:1 to receive a single 300 mg dose of either SB12, European Union (EU) sourced eculizumab, or United States of America (US) sourced eculizumab via intravenous (IV) infusion for 35 minutes. Blood samples for PK and PD analysis were collected over 64 days. The primary objective of this study was to demonstrate PK similarity between the investigational products (IPs), as assessed by area under the concentration-time curve from time zero to infinity (AUC inf). Secondary PK endpoints included area under the concentration-time curve from time zero to the last quantifiable concentration (AUC last) and maximum observed concentration (C max). Equivalence for the primary endpoint (AUC inf) was determined if 90% confidence intervals (CIs) for the ratio of geometric least squared means (LSMeans) of SB12 to EU sourced eculizumab, SB12 to US sourced eculizumab, and EU sourced eculizumab to US sourced eculizumab was within the equivalence margin of 80.00% to 125.00%, respectively. Other objectives for the study were to evaluate safety, tolerability, immunogenicity, and PD profiles for the IPs. Results: A total of 240 subjects (80 in each treatment group) were enrolled. Back transformation provided the geometric LSMean ratio for the comparison of SB12/EU sourced eculizumab, SB12/US sourced eculizumab and EU sourced eculizumab/US sourced eculizumab for AUC inf were 99.1 % (95.41,102.85), 95.1 % (91.40, 99.04), and 96.0 % (92.16, 100.10), respectively. The corresponding 90% CI was within the pre-defined equivalence margin of 80.00-125.00%, indicating that the each of two treatments are bioequivalent. The profiles of mean terminal complement activity and mean change from baseline of complement activity were superimposable following administration of SB12, EU sourced eculizumab, and US sourced eculizumab. There was a rapid decrease in the complement activity at the end of infusion and then a slow restoration. There was no non-responder in the aspect of the measured complement activity after treatment. There were no deaths or discontinuation of IP due to treatment-emergent adverse events (TEAEs) during the study. Two serious adverse events (SAEs) (renal colic in the SB12 treatment group and back pain in the US eculizumab treatment group) were reported, in 2 subjects. Both events were considered not related to the IP. The proportion of subjects who experienced TEAEs were similar between the SB12, EU sourced eculizumab, and US sourced eculizumab treatment groups (70.0%, 65.0%, and 71.3% of subjects, respectively). The overall incidence of subjects with post-dose anti-drug antibodies (ADA) to eculizumab was 2 (2.5%), 1 (1.3%), and 0 (0.0%) subjects in the SB12, EU sourced eculizumab, and US sourced eculizumab treatment groups, respectively. There was no significant difference between treatment groups. None of the subjects with post-dose ADA to eculizumab had a positive result for neutralizing antibodies. Conclusion: The Phase I study demonstrated PK bioequivalence and showed comparable PD, safety, immunogenicity between SB12 and the RP eculizumab. Disclosures Lee: Samsung Bioepis, Co., Ltd.: Current Employment. Jang: Samsung Bioepis, Co., Ltd.: Current Employment. Kim: Samsung Bioepis, Co., Ltd.: Current Employment. Jeong: Samsung Bioepis, Co., Ltd.: Current Employment. Lee: Samsung Bioepis, Co., Ltd.: Current Employment. Jung: Samsung Bioepis, Co., Ltd.: Current Employment. Demichelis: Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol/Celgene: Consultancy, Speakers Bureau; AMGEN: Consultancy, Speakers Bureau; ASH: Research Funding; Jazz: Consultancy; Gilead: Consultancy; Astellas: Consultancy; Abbvie: Consultancy, Speakers Bureau.

Background Atypical HUS (aHUS) is a rare thrombotic microangiopathy (TMA) caused by complement dysregulation. Eculizumab is a humanized monoclonal antibody targeting against complement factor C5. Ravulizumab, a longer acting C5 inhibitor developed through minimal, targeted modifications to eculizumab was recently approved for treatment of aHUS in 2019. Here we describe the clinical presentation, laboratory, genetic profile, treatment along with long-term sequelae of patients diagnosed with aHUS. The outcomes of restrictive use of eculizumab and the use of ravulizumab were also studied. Materials and Methods We conducted a single center retrospective cohort study, searching electronic medical records of patients diagnosed and treated for aHUS at University of Arkansas for Medical Sciences, from January 1, 2013 to January 31, 2021, after IRB approval. Inclusion criteria :1) Presence of microangiopathic hemolytic anemia (MAHA) with thrombocytopenia 2) ADAMTS13 activity > 10 % 3) Age > 18. Exclusion criteria: 1) Age < 18 years 2) TMA associated with hemolytic uremic syndrome, scleroderma renal crises, anti-phospholipid syndrome. Results Seventeen patients meeting the inclusion criteria were enrolled in the study. The mean age at diagnosis was 47.4 ± 17.9 years. Most of the patients were Caucasians (n=10, 58%) and females (n= 14, 82%). All the patients except one had acute kidney injury (AKI) at presentation (n=16, 94.1%), the most frequent extra-renal presentation was CNS involvement -seizures, confusion and altered mental status (n= 7, 41.2 %) followed by Gastrointestinal- non-bloody diarrhea, nausea and vomiting (n=5, 29.4 %) [Figure 1]. Lab investigations are described in [Table 1]. Complement genetic testing was done in 100% of study population. Factor H related genes 1/3 (CFHR1/3) and complement factor H (CFH) were the most commonly found pathogenic mutations [Table 2]. In this study, pregnancy and infection (n= 4, 23.5% each) were identified as the most common triggers [Figure 2]. For two of the patients, it was the first pregnancy and for the other two, it was their second and third pregnancies. They presented at the second, sixth, and sixteenth week postpartum respectively. Eleven (64.70%) patients developed chronic kidney disease (CKD) with six (35.29%) patients progressing to end stage renal disease (ESRD). Two (11.76 %) pregnant patients developed cardiomyopathy, two (11.76%) patients developed pulmonary complications (pneumonia and pulmonary hypertension) and three (17.64%) patients developed epilepsy. All the postpartum females in our study were able to breastfeed while on eculizumab with no long-term complications in the neonates. One patient had two subsequent deliveries with no ante, intra, or post-partum consequences or repeated triggers of aHUS. Fourteen patients (82.3%) received therapeutic plasma exchange, four (23.5%) patients received iv methyl prednisone (1mg/kg) and two (11.7%) patients received IVIg prior to initiating eculizumab. Over time, five (29.41%) patients opted to completely stop drug therapy and four patients (23.52%) chose to shift to ravulizumab because of the ease of treatment duration (every 8 weeks rather than every 2 weeks for eculizumab). All these nine patients remained in remission with stable hematologic and renal parameters on subsequent follow-ups [Table 3]. Three patients (17.6 % mortality) died in our study due to causes unrelated to aHUS. Conclusions: The clinical diagnosis of atypical HUS can be challenging especially with extra-renal manifestations. Females were four times more affected than males. PCMs were present in 11 patients. Early diagnosis and treatment with C5 inhibitors improves morbidity and mortality. The decision to discontinue or switch eculizumab to ravulizumab will likely decrease healthcare costs and improve patient compliance but should be based on disease severity. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Eculizumab, the first C5 inhibitor approved for paroxysmal nocturnal hemoglobinuria (PNH), transformed PNH treatment by improving survival to that of an age- and sex- matched general population. Previous analyses demonstrating the survival benefit of eculizumab in patients with PNH leveraged historical data and were limited by small patient numbers and short follow-up durations; few evaluated survival of patients receiving eculizumab compared with untreated patients. The objective of the current analysis was to describe the baseline characteristics and overall survival of a large international cohort of eculizumab-treated patients compared with a contemporaneous untreated cohort using data from the prospective, observational International PNH Registry (NCT01374360). Methods Data from patients enrolled in the Registry after March 16, 2007 with complete information for birth date, sex, enrollment date, and treatment status were included (database cut-off, April 12, 2021). Ever-treated patients were those who received eculizumab for a minimum treatment period of 35 days while enrolled in the Registry; never-treated patients did not receive eculizumab at any time before or during Registry participation. Univariate and multivariate analyses were performed using a Cox proportional hazards that incorporated the following parameters at baseline as covariates: treatment status, presence of high disease activity (HDA), age, sex, history of bone marrow failure (BMF), history of thrombotic events (TE), transfusion dependence, and estimated glomerular filtration rate ≤60 mL/min/1.73 m 2. HDA was defined as lactate dehydrogenase (LDH) ratio ≥1.5 × upper limit of normal (ULN) and ≥1 of the following: history of major adverse vascular events (including TE); anemia (hemoglobin Results Baseline characteristics of the 4627 patients included in the analysis (mean [SD] age at disease start, 40.2 [18.71] years; 53% female; 75% white) were comparable between the ever-treated and never-treated groups (n=1892 and n=2735, respectively). Compared with never-treated patients, more ever-treated patients had LDH ≥1.5 × ULN (90% vs 35%), and fewer had Conclusion In this analysis of Registry data, treatment with the C5 inhibitor eculizumab improved patient survival compared with a never-treated cohort at a comparable time point in their disease course. Covariates were assessed at baseline only and competing risks and time on treatment were not controlled for, which are potential limitations. Survival benefits conferred by eculizumab treatment were observed regardless of HDA status at baseline, were more pronounced in treated patients with HDA vs those without HDA, and were maintained through 2 decades of real-world follow-up. Figure 1 Figure 1. Disclosures Terriou: Alexion, AstraZeneca Rare Disease: Consultancy, Membership on an entity's Board of Directors or advisory committees. Patriquin: Alexion, AstraZeneca Rare Disease: Consultancy, Honoraria, Speakers Bureau; Biocryst: Honoraria; Apellis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Griffin: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioCryst Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Educational grant support. Lee: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gustovic: Alexion, AstraZeneca Rare Disease: Current Employment. Patel: Alexion, AstraZeneca Rare Disease: Current Employment. Szer: Alexion, AstraZeneca Rare Disease: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background Atypical 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. Aims The 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. Methods A 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). Results So 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. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Introduction Atypical hemolytic uremic syndrome (aHUS) is a rare disease that can cause irreversible organ damage or death. Ravulizumab is a long-acting complement C5 inhibitor approved in the USA, Europe, and Japan for the treatment of aHUS. Ravulizumab was engineered from eculizumab to leverage its clinical benefits and safety profile while reducing dosing frequency. This study assessed real-world patient characteristics, treatment patterns, and clinical outcomes for adult and pediatric patients with aHUS in the USA who switched from eculizumab to ravulizumab. Methods This retrospective, non-interventional study evaluated the period from January 1, 2012 to March 22, 2021, using US claims data from the Decision Resources Group Real World Data repository. Eligible patients had ≥ 1 medical claim with an aHUS-related International Classification of Diseases 9/10 diagnosis code and ≥ 1 medical or pharmacy claim for treatment with eculizumab or ravulizumab. Patients with evidence of paroxysmal nocturnal hemoglobinuria, myasthenia gravis, neuromyelitis optical spectrum disorder or Shiga toxin Escherichia coli-related hemolytic uremic syndrome in the 3 months prior to their first aHUS-related treatment were excluded. A patient was classified as 'switched' if they had ≥ 1 claim for eculizumab followed by an initial claim for ravulizumab from 14 to 30 days after the last eculizumab claim. Patients were required to have ≥ 3 months of continuous enrollment in the database prior to their first ravulizumab claim. Ravulizumab treatment was considered to be continuous if all treatment intervals were ≤ 63 days. Data extracted included: demographics and clinical characteristics at the time of switching to ravulizumab; treatment patterns (including service setting, treatment history before switching to ravulizumab, and subsequent adherence); and clinical outcomes (dialysis, plasma exchange [PE], kidney transplant, and utilization of other end-stage renal disease [ESRD] services) in the 6 months before and after switching to ravulizumab. Data were summarized using descriptive statistics. Results Overall, 2101 patients had ≥ 1 eculizumab or ravulizumab claim and an aHUS-related diagnosis. Of these patients, 227 had claims for both eculizumab and ravulizumab with ≥ 3 months of continuous enrollment data before the first ravulizumab claim. The median (lower quartile, upper quartile) treatment interval between the last eculizumab claim and the first ravulizumab claim was 15 (14, 41) days. In total, 131 patients met the 'switched' criteria. Table 1 presents patient characteristics at the time of switching from eculizumab to ravulizumab. Outpatient facilities were the most common places of service for initiation of switch to ravulizumab (n = 41/89 patients [46%]); private practice facilities were the most common sites for administration of ravulizumab maintenance treatment (n = 84/213 claims [39%]). Prior to switching to ravulizumab, the median (lower quartile, upper quartile) duration between the first and last eculizumab claim was 788 (252, 1719) days. Among the 95 patients with ≥ 6 months of continuous enrollment after switching to ravulizumab, 73 (77%) patients were treated with ravulizumab continuously for ≥ 6 months. Selected clinical outcomes in the 6 months before and after switching to ravulizumab treatment are presented in Table 2. Although no inferential statistical comparisons were made, data show that fewer switched patients underwent dialysis or utilized other ESRD services in the 6-month post-switch period (with no recorded cases of PE or kidney transplant) compared with the 6-month pre-switch period. Discussion and conclusions This study provides real-world data on clinical characteristics and treatment patterns for patients with aHUS who have switched from eculizumab to ravulizumab. The majority of patients switching to ravulizumab were treated continuously for ≥ 6 months according to the treatment schedule in the prescribing information. Ongoing analyses with longer follow-up time will provide inferential assessment of the clinical and economic impacts of switching to ravulizumab. Figure 1 Figure 1. Disclosures Wang: Alexion: Current Employment; AstraZeneca: Current Employment. Al-Dakkak: Alexion: Current Employment; AstraZeneca: Current Employment. Garlo: Alexion: Current Employment; AstraZeneca: Current Employment. Ong: Alexion: Current Employment; AstraZeneca: Current Employment. Tomazos: Alexion, AstraZeneca Rare Disease: Current Employment. Mahajerin: Alexion: Consultancy; AstraZeneca: Current Employment.

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, clonal, nonmalignant hematologic disease characterized by complement-mediated red blood cell hemolysis. The current standard of care for patients with PNH is C5 inhibition. Anemia persists in up to ~70% of patients receiving eculizumab and is attributed to persistent intravascular hemolysis (IVH) and mostly to C3-mediated extravascular hemolysis (EVH). Pegcetacoplan is a pegylated pentadecapeptide C3 inhibitor targeting proximal complement to control both IVH and EVH. PEGASUS is a phase 3, open-label, active-comparator controlled study of efficacy and safety of pegcetacoplan versus eculizumab. This post hoc analysis of data from PEGASUS categorized the clinical response to pegcetacoplan or ECU in patients with PNH and hemoglobin METHODS Hematologic response to treatment was categorized (per Risitano AM, et al. Front Immunol. 2019;10:1157) as complete, major, good, partial, minor, or no response, using number of packed red blood cell transfusions required, hemoglobin level, lactate dehydrogenase (LDH) level, and absolute reticulocyte count (ARC). Complete response: no transfusions required, stable hemoglobin in the normal range, and no evidence of hemolysis (ie, LDH ≤1.5× upper limit of normal, ARC ≤150,000/µL). Major response: no transfusion, normal hemoglobin, but with evidence of hemolysis (LDH >1.5× upper limit of normal and/or ARC >150,000/µL). Good response: no transfusion, but with chronic mild anemia or evidence of hemolysis. Partial response: chronic moderate anemia and/or occasional transfusions (6 units/6 months). Nine patients (6 from the pegcetacoplan arm and 3 from the eculizumab arm) did not readily fit within the existing criteria due to the availability of data at week 16. Although these 9 patients were manually categorized identically by the lead and senior author in a blinded, independent manner, they were not included among these data. RESULTS The intention-to-treat population was comprised of 41 patients randomized to pegcetacoplan and 39 patients randomized to eculizumab. Four patients in the pegcetacoplan arm and 1 patient in the eculizumab arm were not evaluable for analysis due to incomplete data at week 16. Altogether, 61.0% of patients (25/41) in the pegcetacoplan arm have achieved at least a good hematological response, in contrast to 5.1% (2/39) of the eculizumab arm. At week 16, the distribution of response categories was as follows (Figure): in the pegcetacoplan arm and eculizumab arm, respectively, complete responses were 36.6% and 0%, good responses were 24.4% and 5.1%, partial responses were 12.2% and 33.3%, minor responses were 2.4% and 23.1%, and no responses were 0% and 28.2%. The addition of the 9 manually categorized patients did not significantly alter the proportions reported here. Among the factors that may contribute to heterogeneity of hematologic response to treatment are impaired bone marrow function, residual IVH, and residual C3-mediated EVH. Bone marrow failure was ruled out, and no difference in LDH was observed, suggesting that the major factor accounting for the difference between the 2 arms was the prevention of C3-mediated EVH (as confirmed by reduction of C3-opsonization of PNH red blood cells). CONCLUSION In PEGASUS, treatment with pegcetacoplan resulted in a greater proportion of patients with better hematological responses compared to eculizumab. These results further support the concept that proximal complement inhibition, by preventing EVH in addition to controlling IVH, leads to clinical and hematological improvement in the treatment of PNH. Disclosures Risitano: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Achillion: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. de Castro:Novartis: Honoraria, Other: Steering committee; Alexion: Honoraria, Research Funding; Biocryst: Honoraria, Other: Data monitoring committee; Apellis: Consultancy, Honoraria, Research Funding. Kiladjian:AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees. Griffin:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Other: Conference Support. Hamdani:Apellis: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by chronic complement-mediated intravascular and extravascular hemolysis. In the phase 3 PEGASUS study (NCT03500549), pegcetacoplan, a C3 inhibitor targeting the proximal complement pathway, was superior to eculizumab (ECU) on the primary endpoint of hemoglobin (Hb) change from baseline at week 16, and improved clinical and hematologic parameters. Additional analyses assessed if any groups of patients might experience further benefit from pegcetacoplan. METHODS Patients ≥18 years old with a diagnosis of PNH and persistent anemia (Hb RESULTS Pegcetacoplan treatment was associated with significantly greater increases in Hb levels than ECU at week 16, regardless of baseline age group, sex, race, prior transfusions, or platelet count (Tables 1-2). At week 16, regardless of baseline platelet count strata, mean Hb significantly increased from baseline in the pegcetacoplan group and decreased in the ECU group. The proportion of transfusion-free patients was similar in the pegcetacoplan group, regardless of age (≤65 years, 87.1%; >65 years, 80%), sex (female, 81.5%; male, 92.9%), race (Asian, 100%; black, 100%; white, 75.0%), transfusion strata (65 years, 0%), sex (female, 18.2%; male, 11.8%), race (Asian, 28.6%; black, 0%; white, 16.0%), transfusion strata ( CONCLUSIONS In this prespecified stratified analysis of the phase 3 PEGASUS study of patients with PNH and persistent anemia, mean Hb levels increased significantly more, the proportion of transfusion-free patients was significantly higher, ARC change from baseline at week 16 was significantly lower, and LDH decreases were larger with pegcetacoplan versus ECU, regardless of baseline age group, sex, race, prior transfusion numbers, and platelet count. Disclosures Peffault De Latour: Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees. de Castro:Alexion: Honoraria, Research Funding; Apellis: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Other: Steering committee; Biocryst: Honoraria, Other: Data monitoring committee. Szer:Apellis: Consultancy; Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Usuki:Alexion: Research Funding, Speakers Bureau; Apellis: Research Funding; Chugai: Research Funding; Novartis: Research Funding, Speakers Bureau. Hillmen:Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Acerta: Other: Financial or material support. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees. Hamdani:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Ajayi:Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Weitz:Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis: Consultancy, Honoraria. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

Background: PNH is a rare, life-threatening disease caused by uncontrolled terminal pathway activation leading to intravascular hemolysis (IVH). The C5 inhibitors eculizumab (ECU) and ravulizumab (RAV) prevent IVH by inhibiting terminal complement; however, some C5 inhibitor-treated patients may experience persistent anemia due to extravascular hemolysis (EVH) caused by C3 fragment deposition and opsonization driven by constitutive activation of the alternative pathway (AP). Inhibition of factor D (FD), the rate limiting enzyme of the AP, acts on the complement cascade upstream of C3. Danicopan (ALXN2040, ACH-4471) is a first-in-class oral small molecule FD inhibitor. In vitro studies with RBCs collected from PNH patients have shown that danicopan not only inhibited hemolysis but also prevented deposition of C3 fragments on PNH RBCs. In a 24-week Phase 2 study of ECU-treated PNH patients with transfusion-dependent anemia (hemoglobin [Hgb] The purpose of this randomized, double-blind, pivotal Phase 3 trial (NCT04469465; EudraCT 2019-003829-18) is to evaluate the efficacy of oral danicopan add-on therapy in PNH patients with clinically evident EVH (CE-EVH) on an approved C5 inhibitor. Study Design and Methods: This study consists of a 12-week double-blind placebo-controlled treatment period 1 followed by a 12-week danicopan+C5 inhibitor treatment period 2 and a long-term extension up to 1-year. Patients (target enrollment, N=84) will be randomized to danicopan or matched placebo TID in a 2:1 ratio for the 12-week treatment period 1. Patients randomized to placebo for treatment period 1 will switch to danicopan at week 12 (Figure). Eligible adult patients must be receiving a stable regimen of ECU or RAV (no change in drug/dose/interval for ≥24 weeks), and have CE-EVH, defined by anemia (Hgb ≤9.5 g/dL), absolute reticulocyte count ≥120 x 109/L, and ≥1 transfusion within 6 months before study entry. The starting dose of danicopan is 150 mg TID. Patients with alanine aminotransferase (ALT) or direct bilirubin values >1.5 × upper limit of normal (ULN) will start at 100 mg TID. Doses may be escalated in 50-mg increments, with ≥4 weeks between escalations, to a maximum of 200 mg TID based on safety and clinical effect at protocol-specified time points. Exclusion criteria include major organ transplant or hematopoietic stem cell transplantation (HSCT), aplastic anemia requiring HSCT, complement deficiency, or ALT >2 × ULN. The primary efficacy endpoint is change in Hgb at week 12. Secondary endpoints are proportion of patients not requiring a transfusion through week 12, change from baseline in FACIT-Fatigue scores, and change from baseline in absolute reticulocyte count at week 12. Other secondary endpoints (at weeks 12 and 24) include RBC units transfused, Hgb stabilization, laboratory markers (including bilirubin, LDH, and PNH clone size), and patient-reported outcomes (EQ-5D-3L, EORTC-QLQ-C30, WPAI, and health resource utilization). Primary and secondary efficacy analyses will be performed on the intent-to-treat population; safety analyses will include all patients who received ≥1 dose of study drug. Danicopan has the potential to be the first oral PNH therapy, and offers an opportunity to enhance the well-characterized efficacy of C5 inhibitors without compromising safety. This Phase 3, pivotal trial will be the largest clinical evaluation of danicopan to date. More importantly, the trial has the potential to generate robust data to demonstrate the efficacy and safety of add-on, oral danicopan to C5 inhibitor therapy in PNH patients with clinically evident hemolysis. Figure Disclosures Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Huang:Alexion: Current Employment, Current equity holder in publicly-traded company. Nishimura:Alexion: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; Chugai: Consultancy. Ramirez-Santiago:Alexion: Current Employment, Current equity holder in publicly-traded company.

INTRODUCTION: Complement factor D is the rate-limiting enzyme for activation of the complement alternative pathway (AP). Targeting factor D is therefore an attractive therapeutic strategy for treatment of AP-mediated diseases including paroxysmal nocturnal hemoglobinuria (PNH), C3 glomerulopathy, and atypical hemolytic uremic syndrome. BCX9930 is a potent and selective orally bioavailable inhibitor of factor D in development for the treatment of PNH and other complement-mediated diseases. PNH is an acquired, chronic, non-malignant disorder of hematopoietic stem cells that is characterized by clonal deficiency of AP regulatory proteins CD55 and CD59, resulting in dysregulated AP amplification, opsonization, membrane attack complex (MAC) formation, and hemolysis. The approved intravenously (IV) administered C5 inhibitors eculizumab and ravulizumab inhibit MAC formation and intravascular hemolysis, but do not inhibit opsonization, leading to extravascular hemolysis and potentially incomplete treatment response. Inhibition of factor D is expected to prevent both intravascular and extravascular hemolysis in PNH, a distinct advantage over currently available parenteral therapies. METHODS: This abstract describes preliminary data in healthy subjects enrolled in the single ascending dose (SAD) and multiple ascending dose (MAD) evaluations of Study BCX9930-101 (NCT04330534), an ongoing first in human (FIH) study that includes randomized, double-blind, placebo-controlled evaluations of the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of BCX9930 in healthy subjects. Safety and tolerability are evaluated via clinical and laboratory monitoring. Plasma concentrations of BCX9930 are measured using a validated liquid chromatography-dual mass spectrometry (LC/MS/MS) assay; PD effects are assessed using multiple assays, including inhibition of AP activity in the AP-specific Wieslab (AP-W) and AP Hemolysis ([AP-H], lysis of rabbit red blood cells [RBCs] by human serum) assays. RESULTS: To date, 48 subjects have been enrolled into 6 SAD cohorts (n = 6 BCX9930, n = 2 placebo per cohort), with doses ranging from 10 to 1200 mg. Sixty subjects have been enrolled into 5 MAD cohorts (n = 10 BCX9930, n = 2 placebo per cohort), with doses ranging from 50 mg every 12 hours (Q12h) to 400 mg Q12h. The mean age of all enrolled subjects was 34.3 years and 50.9% were male. BCX9930 was safe and generally well-tolerated at all doses evaluated. There were no serious adverse events or dose-related safety signals. Mild headache was the most frequent treatment-emergent adverse event and showed no correlation with dose. A benign maculopapular exanthem attributed to study drug was observed following MAD administration. These events were mild or moderate in severity and resolved in a median of 5 days. BCX9930 exposure was approximately linear and dose-proportional across all evaluated SAD and MAD doses. Mean BCX9930 concentrations at 12 hours post dose were ≥ 8 to 10 times the factor D half-maximal effective concentration (EC50) for SAD doses ≥ 300 mg and for MAD doses ≥ 100 mg Q12h at steady-state. Rapid, dose-dependent AP suppression was observed following SAD and MAD, as measured by the AP-W and AP-H assays (Figure 1). AP suppression > 98% was observed in both assays at steady state for MAD doses ≥ 200 mg Q12h. Duration of complete suppression increased with dose and was ≥ 12 hours for MAD doses ≥ 200 mg Q12h. Doses ≥ 200 mg Q12h showed greater, more durable, and more consistent inhibition across subjects compared with doses ≤ 100 mg Q12h. PK/PD modeling of AP-H and AP-W demonstrates a clear concentration-response, with estimated EC50 values between 21.7 and 40.7 nM. These estimates are consistent with the in vitro IC50 for inhibition of proteolytic activity against the natural substrate C3bB of 28.1 nM. CONCLUSIONS: BCX9930 is a potent and selective orally bioavailable inhibitor of human complement factor D. In this preliminary analysis of an ongoing FIH study, BCX9930 displayed a promising safety and tolerability profile. Exposure was approximately linear and dose-proportional across a wide dose range, and complete and durable suppression of the AP was achieved. Together, these findings support further evaluation of BCX9930 in patients with PNH and other AP-mediated diseases. Disclosures Davidson: BioCryst Pharmaceuticals, Inc.:Current Employment.Mathis:BioCryst Pharmaceuticals, Inc.:Current Employment.Mair:Quotient Sciences:Current Employment.Gesty-Palmer:BioCryst Pharmaceuticals, Inc.:Current equity holder in publicly-traded company, Ended employment in the past 24 months.Cornpropst:BioCryst Pharmaceuticals, Inc.:Current Employment.Sheridan:BioCryst Pharmaceuticals, Inc.:Current Employment.Chen:BioCryst Pharmaceuticals, Inc.:Current Employment.Reynolds:BioCryst Pharmaceuticals, Inc.:Current Employment.Parker:BioCryst Pharmaceuticals, Inc.:Current Employment.Babu:BioCryst Pharmaceuticals, Inc.:Current Employment.

Introduction Atypical hemolytic uremic syndrome (aHUS) is a rare systemic thrombotic microangiopathy (TMA) characterized by hemolytic anemia, thrombocytopenia and end organ damage, predominately in the kidneys. Disease emergence is often unpredictable, occurring with or without an identified trigger or in the presence of a concomitant clinical condition. The persistence of TMA and long-term disease manifestations are also not well described. The aims of this study were to characterize the frequency and distribution of potential triggering conditions preceding a diagnosis of aHUS, and to describe the persistence of TMA and long-term disease manifestations in those not treated with eculizumab. Methods This retrospective study included two cohorts of patients with aHUS identified in the Optum® Clinformatics® Data Mart commercial and the Medicare Advantage claims databases, encompassing approximately 62 million patients, from January 2007 to March 2019. As aHUS does not have a dedicated diagnosis code, patients with aHUS were defined as having ≥ 2 HUS or TMA diagnostic codes, and ≥ 1 claim for each of the following aHUS-associated clinical manifestations: hemolytic anemia, thrombocytopenia, and renal/neurological/gastrointestinal organ involvement. Patients with paroxysmal nocturnal hemoglobinuria, myasthenia gravis or Shiga toxin-producing E. coli diagnoses were excluded. Additionally, patients were required to have ≥ 1 lactate dehydrogenase, reticulocyte, schistocyte, haptoglobin or blood smear test within 3 months of any HUS or TMA diagnosis, or ≥ 1 ADAMTS13 test with results demonstrating activity of ≥ 5%. Eculizumab, a C5 inhibitor, was the only approved therapy during this time period. Two cohorts were analyzed. Cohort 1: eligible patients with aHUS were required to have ≥ 12 months continuous database enrollment prior to and ≥ 18 months after the date of first HUS or TMA diagnostic code, and may or may not have been receiving eculizumab. Clinical disease manifestations were evaluated up to 15 months after the date of first aHUS diagnosis. Cohort 2: patients with aHUS and persistent TMA (≥ 1 International Classification of Diseases code for TMA and one diagnosis of thrombocytopenia within 12 months following the first TMA diagnosis) were identified. Eligible patients were required to have 3 months enrollment prior to and 12 months after the date of first TMA diagnosis. Those receiving eculizumab were excluded. Claims data relating to prespecified potential triggers of aHUS were identified during the 0-3-month period prior to the first diagnosis of HUS or TMA. Data were summarized using descriptive statistics. Results Cohort 1: a total of 431 patients with aHUS were identified (mean age of 58 years, 55% female). Prespecified triggers for the development of aHUS were identified in 147 patients (34%), with infections representing the most common trigger (reported by 92 patients [63%]), followed by chemotherapy (28 patients [19%]) and systemic lupus erythematosus (26 patients [18%]), as shown in the Table. Among patients not receiving eculizumab (n = 415), disease manifestations persisted for > 1 year following the first diagnosis date of aHUS, with 298 patients (72%) reporting clinical disease manifestations 13-15 months after diagnosis. Kidney disease represented the most common manifestation (90 patients [30%] with chronic kidney disease and 26 patients [9%] with end-stage renal disease), followed by thrombocytopenia (87 patients [29%]) and hemolytic anemia (82 patients [28%]). Cohort 2: among those with aHUS and persistent TMA (n = 218; 69.3% of patients aged 35-74 years, 67% female), a total of 191 patients had data available for analysis. Of these, 95 patients (50%) reported prespecified triggers, with a similar trigger pattern observed as in the patients with aHUS in Cohort 1. Conclusions Triggers of aHUS were identified in 34% of patients with aHUS and 50% of those with aHUS and persistent TMA. In those with aHUS alone not receiving eculizumab, long-term clinical disease manifestations persisted in the majority of patients. Further evidence on treating trigger-associated aHUS with complement inhibition is required. Disclosures Tomazos: Alexion Pharmaceuticals Inc.: Current Employment. Garlo:Alexion Pharmaceuticals Inc.: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Chen:Alexion Pharmaceuticals Inc.: Current Employment. Laurence:Alexion Pharmaceuticals: Honoraria, Research Funding.

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal hematopoietic stem cell disorder characterized by chronic complement-mediated intravascular and extravascular hemolysis (IVH and EVH), and thrombosis. C5 inhibitors reduce IVH by inhibiting membrane attack complex formation and are the current standard of treatment for PNH. EVH persists in the presence of C5 inhibition. Pegcetacoplan is a C3 inhibitor targeted to control both IVH and EVH. The PADDOCK and PALOMINO studies assessed the safety and preliminary efficacy of pegcetacoplan in complement inhibitor-naïve patients. METHODS PADDOCK was a phase 1b, open-label, pilot study (NCT02588833) with 2 cohorts. Subjects in cohort 1 received pegcetacoplan at a suboptimal dose of 180 mg/day for 28 days; subjects in cohort 2 received pegcetacoplan 270 mg/day for up to 1 year. Subjects could participate in both cohorts. PALOMINO was a phase 2a, open-label, single-cohort study (NCT03593200) in which subjects received pegcetacoplan 270 mg/day for up to 1 year. Both studies enrolled subjects ≥18 years old diagnosed with PNH and no prior treatment with eculizumab. Primary efficacy endpoints in both studies were change from baseline in lactate dehydrogenase (LDH), haptoglobin, and hemoglobin. Secondary efficacy endpoints included change from baseline in reticulocyte count, total bilirubin, and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. The number of packed red blood cell transfusions was also recorded. Primary safety endpoints were the incidence and severity of treatment emergent adverse events (TEAEs). RESULTS Three subjects were enrolled in PADDOCK cohort 1 and 20 in cohort 2; 1 subject was enrolled in both cohorts. PALOMINO enrolled 4 subjects. PADDOCK cohort 2 and PALOMINO efficacy data are shown in the Table. At baseline, mean LDH levels were >8× upper limit of normal in both studies. At day 365, mean LDH had decreased to CONCLUSIONS In PADDOCK and PALOMINO, pegcetacoplan improved hematological parameters by controlling both IVH and EVH in patients with PNH. Improvements in clinical parameters were also observed. Pegcetacoplan was shown to have an acceptable safety profile and was generally well tolerated in both studies. PADDOCK and PALOMINO demonstrate the therapeutic potential of pegcetacoplan in the treatment of PNH and support further evaluation in the ongoing phase 3 PRINCE trial (NCT04085601) in complement inhibitor-naïve patients. Disclosures Wong: Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis: Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Sathar:Novo Nordisk: Honoraria; Bayer: Honoraria; Roche: Honoraria. Tse:MSD: Research Funding; Janssen: Research Funding. Roman:Alexion: Speakers Bureau; Novartis: Speakers Bureau. Amine:Acibadem City Clinic Tokuda Hospital: Current Employment. Tan:Apellis: Consultancy, Patents & Royalties. Di Casoli:Apellis: Current Employment, Current equity holder in private company. Deschatelets:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Francois:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Grossi:Apellis: Current Employment, Current equity holder in private company, Patents & Royalties. Bogdanovic:Takeda (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer (regional office in Serbia, only local activities in Serbia): Membership on an entity's Board of Directors or advisory committees; Apellis: Other: Investigator fee in clinical trial; Novartis Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

Background Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the loss of endogenous complement regulators CD59 and CD55 on hematopoietic cells. Peripheral blood elements are susceptible to destruction by complement, resulting in intravascular hemolysis and thrombosis. Standard therapy is terminal complement inhibition with eculizumab, an anti-C5 monoclonal antibody. However, up to 3.5% of individuals of Asian descent carry polymorphisms in C5 that affect Arg885, which corresponds to the eculizumab and ravulizumab binding site (Nishimura et al. N Engl J Med. 2014). Patients with PNH who have these polymorphisms experience poor control of intravascular hemolysis with eculizumab, thus constituting a group with a high unmet medical need. Crovalimab is a novel anti-C5 monoclonal antibody that binds a distinct epitope on the beta subunit of C5. In vitro studies have demonstrated that crovalimab equally binds and inhibits the activity of wild-type and Arg885-mutant C5 (Fukuzawa et al. Sci Rep. 2017). Objectives The aim of the current report is to describe the response to crovalimab of PNH in patients with C5 polymorphism. Study Design and Methods Crovalimab is being evaluated in the ongoing Phase I/II COMPOSER study (NCT03157635) to establish its optimal dose, safety, and efficacy (Röth A, et al. Blood 2020). C5 inhibitor-naive or -experienced patients received an initial intravenous loading dose followed by an average subcutaneous maintenance dose of 680 mg every 4 weeks. Plasma concentration of crovalimab, lactate dehydrogenase (LDH), free and total C5, and complement activity were determined at every visit. Patients were followed up for occurrence of blood transfusions, breakthrough hemolytic events, and safety. Results Of the 59 patients enrolled in COMPOSER, 4 had the c.2654G->A nucleotide polymorphism predicting Arg885His substitution. The data cutoff was January 29, 2020. Follow-up ranged from 12.4 to 98.3 weeks. All 4 patients were male and had been diagnosed 44 to 734 weeks before enrollment with PNH granulocyte clone size ranging from 89% to 95%. At enrollment, 1 patient switched from ongoing therapy with eculizumab, while 3 had previously discontinued eculizumab. At enrollment, all patients had LDH > 3-fold the upper limit of normal (ULN), which declined rapidly and was maintained at < 1.5 × ULN throughout the follow-up period (Figure). One patient required transfusions after enrollment (12 red blood cell units over 6 months); this patient had an underlying diagnosis of aplastic anemia and required 198 units of red blood cells in the 12 months prior to enrollment. None of the 4 patients experienced a breakthrough hemolysis event. All 4 patients achieved complete terminal complement inhibition as measured by liposome immunoassay (LIA). LIA levels ranged from 32 to 42 U/mL at study entry, declined to < 10 U/mL (lower level of quantification) by day 2, and were maintained thereafter. Similarly, free C5 levels were maintained at < 0.5 µg/mL after week 6 (day 43). The safety profile in these patients was similar to that in the remainder of the participants. Three serious adverse events (SAEs) were reported, none of which were related to study treatment. One patient had 2 SAEs: bile duct stone and cholelithiasis. A second patient had an SAE of upper respiratory tract infection with admission to the hospital, which occurred after 20 months and resolved during treatment. Conclusions Crovalimab achieved complete and sustained terminal complement inhibition in patients with Arg885 polymorphism, consistent with previously reported outcomes for patients in the COMPOSER study. Crovalimab is a promising treatment for these individuals with high unmet medical need. Disclosures Nishimura: Chugai: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; Alexion: Honoraria, Research Funding. Usuki:Alexion: Consultancy, Research Funding, Speakers Bureau; Chugai: Research Funding; Aperis: Research Funding; F. Hoffmann-La Roche. Ltd.: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. , Research Funding. Ramos:F. Hoffmann-La Roche Ltd: Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.; Genentech, Inc: Current Employment, Other: Received fellowship support from Genentech, Inc.. Ichikawa:F. Hoffmann-La Roche Ltd: Other: All authors received editorial support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. , Research Funding. Hernández-Sánchez:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Kiialainen:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.. Sostelly:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Peffault De Latour:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paz-Priel:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company, Other: All authors received editorial support for this abstract, provided by Scott Battle, PhD, of Health Interactions and funded by F. Hoffmann-La Roche.; Genentech, Inc: Current Employment. Röth:Sanofi: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Yes, Crovalimab is an anti-C5 monoclonal antibody being evaluated as a therapy for paroxysmal nocturnal hemoglobinuria

BACKGROUND Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening hematologic disease characterized by complement-mediated hemolysis resulting in anemia, thrombosis, and bone marrow failure. The PEGASUS phase 3 randomized study demonstrated superiority of pegcetacoplan vs. eculizumab on improvements in hemoglobin, and pegcetacoplan improved clinical and hematological outcomes such as fatigue in patients with partial response to eculizumab after treatment for at least 3 months (Hb METHODS Patients ≥18 years of age with PNH and hemoglobin concentration 12 g/dL), and by degree of hemoglobin improvement: RESULTS At Week 16, in the overall sample (n = 80; intent-to-treat), the FACIT-Fatigue total score was significantly correlated with hemoglobin (r = 0.47, p < 0.0001; Figure 1), reticulocyte count (r = -0.37, p < 0.01), indirect bilirubin (r = -0.25, p < 0.05), and with multiple EORTC domains including fatigue and physical function (r = -0.88, p < 0.0001 and r = 0.82, p < 0.0001 respectively). In a responsiveness analysis, groups with greater improvement in hemoglobin over 16 weeks showed the most improvement in fatigue (F = 9.03, p < 0.0001), with the largest reduction in fatigue in the group with an increase in hemoglobin of ≥2 g/dL (11.3-point improvement in FACIT-F total score). In contrast, individuals with little to no hemoglobin improvement (12 g/dL) at Week 16 (F = 4.78, p = 0.0019). An analysis of the correlation of change scores indicates a clear separation between pegcetacoplan and eculizumab, showing a greater effect of pegcetacoplan on change in hemoglobin and improvement in fatigue (Figure 2). CONCLUSION In PNH, hemoglobin level and positive change in hemoglobin were significantly related to reduced fatigue. Pegcetacoplan resulted in significantly lower fatigue and hemoglobin scores at Week 16 compared to eculizumab. Disclosures Cella: Novartis:Consultancy;Kiniksa:Consultancy;IDDI:Consultancy;BMS:Consultancy, Research Funding;Oncoquest:Consultancy;ASAHI KASEI PHARMA CORP.:Consultancy;Mei Pharma:Consultancy;Ipsen:Consultancy, Research Funding;Evidera:Consultancy;DSI:Consultancy, Research Funding;BlueNote:Consultancy;Abbvie:Consultancy, Research Funding;Astellas:Consultancy, Honoraria;FACIT.org:Membership on an entity's Board of Directors or advisory committees, Other: President;PROMIS Health Org:Membership on an entity's Board of Directors or advisory committees, Other;Pled Pharma:Research Funding;Janssen:Research Funding;Clovis:Research Funding;Alexion:Research Funding;Apellis:Consultancy;Pfizer:Consultancy, Research Funding.Lenderking:Evidera:Current Employment.Sarda:Apellis:Current Employment, Current equity holder in publicly-traded company.Baver:Apellis:Current Employment, Current equity holder in publicly-traded company.Hamdani:Apellis Pharmaceuticals:Current Employment, Current equity holder in publicly-traded company.Hsieh:Evidera/PPD:Current Employment.Shaffer:Evidera:Current Employment.Röth:Sanofi:Consultancy, Honoraria;Roche:Consultancy, Honoraria, Research Funding;Novartis:Consultancy, Honoraria;Biocryst:Consultancy, Honoraria;Apellis:Consultancy, Honoraria;Alexion Pharmaceuticals Inc.:Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

Background Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired disorder characterised by intravascular hemolysis and thrombosis. Patients with symptomatic PNH are commenced on the complement inhibitor eculizumab (600mg weekly for 5 weeks then 900mg 2 weekly). This monoclonal antibody targets C5 in the complement cascade, halting terminal complement activation thus inhibiting intravascular hemolysis. In some patients intravascular hemolysis is not adequately controlled on the standard regimen. Patient symptoms, transfusion requirements and raised Lactate dehydrogenase (LDH) levels are indicators for suboptimal control of PNH and review of eculizumab dosing. The 50% hemolytic complement (CH50) test is a functional assay assessing capability of serum complement components of the classical pathway to lyse sheep red blood cells pre-coated with rabbit anti-sheep red blood cell antibody. Patients with complement inhibited PNH should demonstrate absent lysis. As the test is expensive and difficult to organise, we tested if incomplete complete blockade as determined by CH50 activity would be better to confirm under-dosing than LDH value. Methods The Leeds (UK) PNH National Service reviewed patients who underwent CH50 assay between January 2015 and March 2020. All patients were on eculizumab with clinical concerns regarding suboptimal control of PNH. Patients receive eculizumab infusions intravenously every 14 days and routine follow up from the PNH Service. Serum samples were obtained 24 hours prior to infusions for CH50 assay; LDH values were routinely collected. Complete complement blockade was defined by 1.5x upper limit of normal (ULN). Confidence intervals were set at 95% and significance set at p Results In the study period, 327 tests (median 2, range 1 - 8) were carried out in 146 patients (median age 54 years, range 16 - 89; 74 female). 81% (265) were successful; 19% (62) were unsuccessful due to processing errors. Of the successful tests, 74% (197 in 127 patients) indicated complete complement blockade and 26% (68 in 38 patients) indicated incomplete blockade. Of the patients with incomplete blockade, 68% (26) demonstrated complete blockade on repeat testing and 32% (12) had their eculizumab dose increased. Clinical symptoms of under-dosing in the 12 patients requiring a dose increase included increased transfusion requirements and/or breakthrough hemolysis (7), pregnancy (2; both returned to 900mg post pregnancy) and significant lethargy (3). Of the patients requiring a dose increase, 3 were on 1200mg before 2015; their dose was increased to 1500mg. Repeat testing was carried out in 10/12 patients after dose increase; 8 indicated complete blockade; 2 patients were incompletely blocked at 1200mg and received a further dose increase to 1500mg. Further testing indicated complete blockade in 1 patient; 1 required a 3rd dose increase to 1800mg due to incomplete blockade and ongoing transfusion requirement. Corresponding LDH values were analysed; median LDH for the complete blockade group was 1.16xULN (range 0.54 - 2.16) and 1.28xULN (range 0.76 - 2.38) for the incomplete blockade group. LDH values were not significantly higher in the incomplete blockade group compared to the complete blockade group, p=0.08. There was no significant difference in LDH values pre- and post-dose increase, p=0.38 (Figure 1); median pre-dose increase LDH 1.14xULN; median post-dose increase LDH 1.13xULN. Correlation coefficient shows that CH50 activity was positively correlated with LDH value, r(123)=0.18, p=0.04. Conclusion We report the effective utilisation of CH50 analysis where there is clinical concern of suboptimal control of PNH. All patients demonstrating hemolytic activity on CH50 assays indicated subsequent complement blockade following increase of eculizumab dose. Increasing eculizumab is costly requiring robust evidence of suboptimal complement inhibition; a positive correlation between CH50 activity and LDH values was shown however this is not sufficient to guide clinical decisions. LDH values of the incomplete blockade group were not significantly higher than those with complete blockade, suggesting the use of LDH values as an assessment of complement inhibition in patients with ongoing symptoms or transfusion requirements is not sufficient to guide eculizumab dose increases. Disclosures Munir: Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Pike:Apellis: Research Funding. Arnold:Alexion Pharmaceuticals: Honoraria. Hillmen:AstraZeneca: Consultancy, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees.

INTRODUCTION The C5 inhibitor eculizumab is the current standard of care for the treatment of PNH. However, some pts receiving eculizumab to treat PNH continue to experience ongoing hemolysis and anemia, resulting in red blood cell transfusion dependence, substantial unmet clinical needs, and considerable health economic burden. This study evaluated the treatment patterns of pts with PNH receiving eculizumab and compared HRU among blood transfusion-dependent (TD) pts versus blood transfusion-free (TF) pts in real-world clinical practice in the United States. METHODS Pts aged ≥12 years with ≥2 claims for eculizumab infusion between April 1, 2014, and September 30, 2019, were identified from the IBM® MarketScan® Research Databases. The index date was the first observed claim for eculizumab infusion with ≥3 months of continuous eligibility prior (baseline period). Pts with ≥1 diagnosis of indications other than PNH for eculizumab (ie, atypical hemolytic uremic syndrome, generalized myasthenia gravis, neuromyelitis optica spectrum disorder) during the baseline period or on the index date were excluded to identify pts with PNH. The full cohort of PNH pts treated with eculizumab were then stratified into the TD cohort (≥1 claim for blood transfusion within 6 months following any eculizumab infusion) or TF cohort. Patient demographic and clinical characteristics in the baseline period were compared between TD and TF cohorts using standardized differences (std diff), with >20% indicating substantial differences. Treatment patterns and HRU (all-cause and PNH-related) were evaluated during the observation period (ie, from index date to earliest date between end of continuous healthcare plan enrollment and end of data availability). Time from index date to treatment discontinuation among pts in the full cohort was assessed using Kaplan-Meier analysis. HRU was compared between TD and TF cohorts using incidence rate ratios (IRRs) adjusted for baseline covariates. RESULTS A total of 151 eculizumab users with PNH were identified as the full cohort; 55 (36%) were TD and 96 (64%) were TF. Mean (range) age was 36.7 (12-74) years among all pts (TD: 35.1 years; TF: 37.6 years). Overall, 56% of pts were female, with a higher proportion in the TD vs TF cohort (67% vs 49%; std diff = 38%). More pts in the TD vs TF cohort had blood transfusions (71% vs 18%; std diff = 127%) and use of corticosteroid therapy (46% vs 32%; std diff = 27%) during baseline. Baseline coagulopathy and aplastic anemia were more common in the TD vs TF cohort (coagulopathy: 49% vs 30%; std diff = 39%; aplastic anemia: 64% vs 43%; std diff = 43%). Myelodysplastic syndrome was present in 10% of the full cohort (TD: 13%; TF: 8%; std diff = 14%). During a mean observation period of 19 months for the overall sample (TD: 20 months; TF: 19 months), pts had a median (interquartile range) of 8 (3-30) eculizumab infusions (TD: 5 infusions; TF: 8 infusions) during maintenance phase; 29% of pts (TD: 21%; TF: 33%) had on average 14 days between maintenance eculizumab infusions; 61% of pts (TD: 66%; TF: 58%) discontinued eculizumab treatment (ie, gap of >42 days between 2 infusions) and the median time to treatment discontinuation was 254 days (TD: 180 days; TF: 337 days). Mean (range) number of blood transfusions among TD pts was 8.5 (1-54). During the observation period, pts in the TD cohort had 2.95 times more all-cause hospitalizations and 4.58 times more hospitalization days compared to pts in the TF cohort (all P < 0.05). Similar trends were observed for PNH-related hospitalizations. Results for all-cause and PNH-related HRU are presented in the Table. CONCLUSIONS This study demonstrated a considerable economic burden among pts with PNH treated with eculizumab, particularly among pts dependent on blood transfusions. TD eculizumab users comprised >36% of the overall sample, indicating that disease activity may not be well controlled. These pts had >4 times the number of hospitalization days compared to TF pts, emphasizing the substantial unmet clinical need despite treatment with eculizumab. These findings suggest that the current PNH standard of care may be insufficient for TD pts. Based on time between dosing intervals, >70% of PNH pts in this study were not dosed per label, and two-thirds of pts discontinued eculizumab within an average of a 1.5-year timeframe. New therapies are needed to reduce the considerable burden of pts with PNH. Disclosures Cheng: Apellis: Research Funding. Sarda:Apellis: Current Employment, Current equity holder in publicly-traded company. Mody-Patel:Apellis: Current Employment, Current equity holder in publicly-traded company. Krishnan:Apellis: Current Employment, Current equity holder in publicly-traded company. Yenikomshian:Apellis: Research Funding. Scoble:Apellis: Current Employment, Current equity holder in publicly-traded company. Mahendran:Apellis: Research Funding. Lejeune:Apellis: Research Funding. Yu:Apellis: Research Funding. Duh:Apellis: Research Funding; Takeda Oncology: Research Funding; GlaxoSmithKline: Research Funding; AstraZeneca: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Shire: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding.

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening disease of dysregulated complement activation characterized by hemolysis and thrombosis and is associated with bone marrow failure. PNH can also impair patient quality of life and negatively impact the ability to work. PNH is a rare disease with an estimated incidence of 1 to 1.5 cases per million people globally. Inhibition of complement component 5 (C5) has been shown to reduce intravascular hemolysis, stabilize hemoglobin, reduce the need for blood transfusion, and improve quality of life for patients with PNH. C5 inhibitors eculizumab and ravulizumab are approved in the United States and other countries for treatment of PNH, yet there are limited data on the real-world use of these agents, especially in populations not eligible to participate in registrational clinical trials. Here we describe the COMMODORE Cohort study, which will use a novel patient-centered study design to collect both retrospective and prospective patient data on the real-world use, safety, and effectiveness of eculizumab and ravulizumab, as well as disease burden and outcomes, in patients with PNH in the United States. Study Design and Methods This noninterventional cohort study will collect data using the PicnicHealth digital personal health record platform. This platform uses a novel human-in-the-loop machine learning system to integrate, harmonize, and structure patient data, including clinical notes, medications, laboratory results, and diagnostic reports contained in medical records collected from any healthcare facility in the United States. This study was designed in collaboration with patient advocacy groups to ensure that data generated will answer questions important to the patient community. In contrast to many studies, patients will be directly recruited to participate through multiple avenues, including working with patient advocacy groups and societies as well as outreach through social media and other communication tools. All patients must complete an informed consent form to participate. Patient data is anonymized, and the study complies with the Health Insurance Portability and Accountability Act data security standards. The study will be submitted to IntegReview for institutional review board approval. Patients who report a diagnosis of PNH within the past 5 years and have subsequently been treated with eculizumab or ravulizumab can be included in this study (Figure). Data extracted by the platform will confirm that the patient meets study criteria. The study has 3 arms: arm A is comprised of patients who initiated therapy with eculizumab, arm B is patients who initiated therapy with ravulizumab, and arm C is patients who initiated therapy with eculizumab and later switched to ravulizumab. Exclusion criteria for patients in arms A and B includes treatment with a complement inhibitor prior to PNH diagnosis and treatment with eculizumab or ravulizumab for > 25 weeks. Exclusion criteria for all patients include platelet count < 30,000/μL, absolute neutrophil count < 500/μL, and history of bone marrow transplant. The primary objective is to describe the proportion of patients who do not receive packed red blood cell transfusion. Secondary objectives are to determine the proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and a thromboembolic event and the change in normalized lactate dehydrogenase. Safety objectives are to determine the rates and proportions of selected adverse events. Primary, secondary, and safety objectives will be evaluated from week 5 to 25 of treatment. The effectiveness and safety analyses will be conducted in all patients who fulfill entry criteria and have a minimum of 25 weeks of accrued person-time from treatment initiation. Exploratory analyses assessing long-term experiences and outcomes and will be conducted in all patients who fulfill entry criteria with no minimum treatment duration requirement. Descriptive statistics will be provided. Summary The COMMODORE Cohort study will use a novel, patient-centered approach to data generation including collaborating with patient groups to ensure that the study answers questions important to the PNH community. This approach may serve as a model for future studies evaluating other rare diseases with limited real-world data. Disclosures Shang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Faghmous:Kite Pharma: Current Employment; F. Hoffmann-La Roche Ltd: Ended employment in the past 24 months, Other: All authors received medical writing support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. . Drozd:PicnicHealth: Current Employment, Current equity holder in private company; F. Hoffmann-La Roche Ltd: Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Katz:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland..

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening disease of dysregulated complement activation. It is a rare disease with an estimated incidence of 1 to 1.5 cases per million people globally. Eculizumab is a humanized monoclonal anti-complement component 5 antibody that was approved for the treatment of patients with PNH in the United States and European Union in 2007, yet unmet medical needs remain. Up to half of patients continue to require blood transfusions despite treatment with eculizumab, and hemolytic activity remains detectable in many patients (Brodsky et al. Blood. 2008). Eculizumab is not available in many countries. In places where treatment is approved, there are further impediments to access, such as cost of treatment, reimbursement issues, infrastructure limitations, and patient restrictions (Risitano et al. Am J Hematol. 2018; Risitano et al. Front Immunol. 2019). Data published on real-world outcomes of eculizumab are limited. Here we describe a study that will retroactively analyze data from patients with PNH treated with eculizumab at the Essen University Hospital in Germany. Study Design and Methods This retrospective, secondary data use, cohort study will include all patients at the Essen University Hospital who were diagnosed with PNH and treated with eculizumab prior to April 2018. Clinical data from medical records were entered into an electronic case report form (eCRF). Source data verification has been performed for all clinical data. Laboratory data were extracted directly from the hospital computer system. The Essen University hospital also checked and verified missing laboratory data. Patient-level data in the eCRF and laboratory data were fully anonymized. The primary objective of the study is to understand the remaining unmet medical need by describing the eculizumab dose and frequency of dose adjustment and describing the proportions of patients who experience intravascular and extravascular hemolysis while on treatment. The secondary objectives include explorations of the association between lactate dehydrogenase (LDH) and hemoglobin stabilization with clinical outcomes (eg, breakthrough hemolysis and the need for red blood cell transfusion), the association between PNH clone size and clinical outcomes and the risk of thrombosis, the changes in LDH and hemoglobin levels over time, the need for red blood cell transfusion during eculizumab treatment, and the proportion of eculizumab-treated patients with positive monospecific Coombs test results. In addition, opportunities to apply machine-learning methodologies to predict patients who may not respond to eculizumab will be explored. Many of the analyses will be descriptive. The associations between LDH and hemoglobin with clinical outcomes will be evaluated using rank correlation coefficients or logistic regression. Multivariable regression will be used to explore the prognostic value of clone size on clinical outcomes and thrombosis events. This retrospective study includes 85 patients with PNH with complete clinical and laboratory data (Table). The median age of the cohort was 38 years old, and the cohort was split evenly between men and women. Many patients received a diagnosis of PNH prior to the availability of eculizumab, as the year of diagnosis was 2010 or earlier for 53 patients (62%). The median years of follow-up from initiation of eculizumab was 4.7 years. Overall, 34% had aplastic anemia at diagnosis, and symptoms of fatigue, abdominal pain, and kidney failure were reported in 60%, 34%, and 15%, respectively. At data cutoff, 92% of patients were still alive. Summary The patient demographics in this study are comparable to other studies in PNH, suggesting a representative population. With median follow-up time of nearly 5 years, this study will allow for a long-term assessment of the patient experience with eculizumab. High-quality study data is ensured via full source data verification of clinical data and verification of missing laboratory data. These study results will help to address many research questions in PNH, identify the remaining unmet medical need, and also inform new drug development. Disclosures Versmold: F. Hoffmann-La Roche Ltd: Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Raiser:F. Hoffmann-La Roche Ltd: Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Faghmous:F. Hoffmann-La Roche Ltd: Ended employment in the past 24 months, Other: All authors received medical writing support for this abstract, furnished by Scott Battle, funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. ; Kite Pharma: Current Employment. Katz:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Shang:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Röth:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding.

Background Eculizumab, a monoclonal antibody targeting C5, is an effective treatment for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy has been suggested, the optimal treatment schedule is unknown, while eculizumab discontinuation does not universally lead to relapse. Data evaluating risk factors associated with an increased risk of CM-TMA recurrence following eculizumab withdrawal are scarce. Prior to the eculizumab era, complement genetic studies have been used to assess morbidity and mortality in patients with CM-TMA. Our aim was to assess the impact of complement gene variants on CM-TMA relapse rate (RR) after eculizumab discontinuation. Methods Search protocols were developed for the Ovid and PubMed databases to identify existing reports on CM-TMA and eculizumab withdrawal published before February 1st 2020. Cases were cross-referenced to eliminate duplicates. Inclusion criteria included patients diagnosed with CM-TMA who had undergone eculizumab discontinuation. Reasons for exclusion were patients with no follow-up after eculizumab withdrawal and patients lacking complement gene testing. Patients undergoing eculizumab dose extension, but not discontinuation, were not included. Results Fifteen studies including 557 individuals were retrieved. Of these, 363 (65.2%) were excluded as outlined in Figure 1 and 194 cases were included in the final analysis with a global RR of 28.9% (n=56). Distribution based on gene impacted and variant type are presented in Table 1. RR was highest among patients with CFH variants (52.5% to 60%) -particularly if involving exon 22 or nonsense mutations-, MCP/CD46 variants (38.9% to 45%) -particularly if affecting splice regions-, and cases with multiple concomitant variants (57.1%) -particularly those including CFH or a CFH-CFHR1 Hybrid (Table 2). Patients with relapse were more likely to have the presence of a complement variant (p On univariate analysis, complement gene variants (OR 4.217 95%CI 1.97-9.026; p Conclusion Relapse after eculizumab discontinuation is rare in cases with no genetic variants identified but can increase to more than 80% in high-risk subgroups. Complement genetic testing is not required for CM-TMA diagnosis or for initiation of complement inhibiting therapy; however, our results demonstrate the value of complement genetic testing when stratifying risk of patients for consideration of eculizumab discontinuation. Disclosures Sridharan: Alexion: Honoraria.

Introduction: Dysregulation of complement system is the driver of many immune disorder diseases, including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and etc. All pathways of complement activation converge at the cleavage of C5, which leads to the generation of membrane attack complex (MAC). The approval of Eculizumab, anti-C5 monoclonal antibody, opened the complement-inhibitor era and proved C5 to be a feasible therapeutic target with manageable risk. Eculizumab and Crovalimab are currently approved for treatment of patients with PNH, yet treatment limitations include hemolysis breakthrough for non-sufficient C5 inhibition, lack of efficacy in patients with C5 mutational variants, and the burden of regular intravenous infusions. The next-generation C5 inhibitor emerges as a new/existing C5 monoclonal antibody engineered to have pH dependence (to reduce dosing frequency), and other new approached to target C5 in complement system. Here we report the results of a novel pH dependent C5 monoclonal antibody-LP-005, to prevent the hemolysis of red blood cells (RBCs) from PNH patients in vitro experiment. Methods: The sequence of Ravulizumab and Crovalimab were obtained from INN. LP-005 was generated using hybridoma method and multidimentionally optimized in variable and content regions. All antibodies were expressed by NHK293 cells. For antibody affinity test, Fortebio Octet K2 was used, different C5 antibodies were first loaded on the AHC sensors and serial diluted recombinant human C5 have been run for global-fit analysis. For antibody biological function test, antibody-sensitized sheep RBCs hemolysis (classic pathway/CP activity) inhibition assay have been run in 1% normal human serum (NHS) with antibodies serial diluted by GVB++ buffer. Antibody-sensitized chicken RBC hemolysis (CP activity) inhibition assay have been run in 6.25% NHS with antibodies serial diluted by GVB++ buffer. Ex vivo inhibition of PNH patients (with more than 70% CD59 deficiency) RBCs hemolysis by anti-C5 antibodies was performed using ABO blood group-compatible serum (20%) under conditions of robust alternative pathway (AP) specific activation (GVB0 + MgEGTA, pH7.3). CD59 deficiency on RBCs of PNH patients has been analyzed by flow cytometry using APC-conjugated anti-human CD59 (negative) and PE-conjugated anti-human CD47 antibodies (positive). Antibody stability test was conducted, antibodies were treated at 66℃ and 67.5℃ for 1hr, and C5 binding activity was then tested using by ELISA. Results: In the present study, we report a novel humanized anti-C5 monoclonal antibody, named LP-005. LP-005, Ravulizumab and Crovalimab exhibits different binding kinetics to C5 (Table 1), however, there is no clear correlation between their binding affinity and complement inhibition activity (NHS-induced CP and AP hemolysis). In antibody-sensitized sheep RBCs hemolysis inhibition assay (CP), LP-005 shows an IC50 of 0.41 nM, whereas Ravulizumab and Crovalimab has IC50 of 0.99 nM and 0.4 nM respectively (Figure 1). For AP induced helmolysis assay, PNH patient's RBCs with more than 70% CD59 absence was used, however, little difference was found between LP-005 and Ravulizumab hemolysis inhibition activity. Moreover, Crovalimab showed incomplete and less efficient inhibition compared with Ravulizumab and LP-005 (Figure 2). The thermal stability study showed that LP-005 is comparable to Crovalimab and is more stable than Ravulizumab (Figure 3). Conclusion: In summary, LP-005 is a novel anti-C5 monoclonal antibody with higher bioactivity in CP induced hemolysis compared to Ravulizumab, and comparable activity in AP induced hemolysis using PNH patient's RBCs. LP-005 is also engineered to increase FcRn binding property as well as thermal stability, which has the potential to be a good drug candidate with improved pharmacokinetic properties of decreasing doses frequency during clinical practice as well as a more robust manufacture process during drug development. Disclosures He: Celgene: Research Funding; furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland: Other: Medical writing support; Celgene, Novartis, Amgen, Ra Pharma, Alexion, Achilleon, Biocryst, Akari, F. Hoffmann-La Roche: Speakers Bureau; Celgene, Novartis, Amgen, Ra Pharma, Alexion, Achilleon, Biocryst, Akari, F. Hoffmann-La Roche: Honoraria; Celgene, Novartis, Amgen, Ra Pharma, Alexion, Achilleon, Biocryst, Akari, Apellis, F. Hoffmann-La Roche: Consultancy.

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologic disease characterized by chronic complement-mediated hemolysis. Treatment with the C5 inhibitor eculizumab has resulted in a reduction in intravascular hemolysis (IVH) and improvements in morbidity and mortality. However, in a single-center cohort of patients with PNH receiving treatment with eculizumab, 72% remained anemic and 36% continued to require transfusions due to ongoing IVH and extravascular hemolysis (McKinley CE, et al.Blood. 2017;130(Suppl 1):3471; Risitano AM, et al.Front Immunol. 2019;10:1157). This study aims to describe the burden of illness in patients with PNH currently being treated with C5 inhibitors (eculizumab and ravulizumab). Overall, the study aims to understand the clinical and hematological outcomes associated with burden of illness in about 150 patients with PNH globally. In these preliminary analyses, the impact of PNH on hematologic and clinical measures is assessed from patients in the United States. METHODS A cross-sectional survey was administered to adult patients ≥18 years of age in the United States with a self-reported diagnosis of PNH, recruited through a patient advocacy group. Inclusion criteria to complete the secure online survey included current treatment with either eculizumab or ravulizumab, informed consent, and agreement to adverse event reporting. This study was initiated in July 2020 and is ongoing. Results presented herein are preliminary. Impact of PNH on hematologic and clinical measures will be assessed using the following variables: diagnosis levels; and any patient history of blood transfusions, thrombotic events, renal impairment, fatigue, and other PNH-associated symptoms as well as dosing frequency and treatment patterns. For these preliminary analyses, descriptive statistics will be reported for patients who have completed the survey. RESULTS As of August 6, 2020, 58 adult patients with a median age of 52 years (range, 21-88) completed the survey, among which 78% were female. Current medications included eculizumab (n = 20 [34.5%]) or ravulizumab (n = 38 [65.5%]), as well as concurrent anticoagulants (n = 9 [15.5%]) and/or anti-thrombotics (n = 2 [3%]). Most patients initiated treatment with eculizumab (n = 20 [100%]) or with ravulizumab (n = 34 [90%]) ≥3 months before. Median (interquartile range) last known hemoglobin level for patients on eculizumab and ravulizumab was 9.3 g/dL (8.0-11.1) and 10.1 g/dL (8.9-11.5), respectively. Overall, 45 (82%) patients reported hemoglobin values 4 transfusions in the previous 12 months for eculizumab and ravulizumab, respectively. Seventeen patients (29%) reported ≥1 thrombotic event at any point during their disease. Seven patients reported thrombotic events over the previous 12 months; six were receiving ravulizumab. The majority (77%) of patients reported fatigue. Fatigue was reported by nearly 95% of eculizumab-treated patients and 68% of ravulizumab-treated patients. CONCLUSIONS Preliminary results from this burden of illness survey demonstrate that a majority of patients with PNH report remaining anemic, despite treatment with C5 inhibitors eculizumab and ravulizumab for a period of ≥3 months. Disclosures Dingli: Sanofi-Genzyme:Consultancy;Karyopharm Therapeutics:Research Funding;Bristol Myers Squibb:Research Funding;Millenium:Consultancy;Alexion:Consultancy;Apellis:Consultancy;Rigel:Consultancy;Janssen:Consultancy.Matos:Kantar:Current Employment.Lehrhaupt:Kantar:Current Employment.Krishnan:Apellis:Current Employment, Current equity holder in publicly-traded company.Sarda:Apellis:Current Employment, Current equity holder in publicly-traded company.Baver:Apellis:Current Employment, Current equity holder in publicly-traded company.

Background Crovalimab is a novel anti-human complement component 5 (C5) antibody currently under investigation as a therapy for paroxysmal nocturnal hemoglobinuria (PNH), a life-threatening disorder characterized by hemolytic anemia and thrombosis. In the Phase I/II COMPOSER trial (NCT03157635; Roth et al. Blood. 2020), crovalimab showed promise as a therapy for PNH in patients with or without prior treatment with C5 inhibitors. Eculizumab and ravulizumab are C5 inhibitors currently approved for the treatment of patients with PNH, yet treatment limitations remain. Some patients experience breakthrough hemolysis due to unsustained C5 inhibition, there may be a lack of efficacy in patients with C5 mutational variants, and the requirement for regular intravenous (IV) infusions contributes to the treatment burden. Crovalimab is engineered to have a significantly extended half-life, enabling subcutaneous (SC) administration once every 4 weeks (Q4W), which could significantly reduce the treatment burden on patients with PNH. Study Design and Methods The Phase III, randomized, open-label, active-controlled, multicenter COMMODORE 1 study (NCT04432584) is evaluating the efficacy and safety of crovalimab compared with eculizumab in adult and adolescent patients with PNH currently treated with complement inhibitors. The study design is divided into 2 parts: randomized arms (Arms A and B) for primary and secondary efficacy analyses and a descriptive arm (Arm C) for exploratory analysis in patients of clinical relevance and importance (Figure). Adult patients with PNH (aged ≥ 18 years) are randomized 1:1 to receive either crovalimab (Arm A) or eculizumab (Arm B). The crovalimab regimen includes a loading series of an IV dose on Day 1 followed by weekly SC doses for 4 weeks starting on Day 2. This is followed by SC Q4W maintenance dosing starting at Week 5. Arm B patients receive IV maintenance dosing starting on Day 1 and then once every 2 weeks (Q2W) for 24 weeks. The descriptive analysis arm (Arm C) patients will receive crovalimab (same dosing regimen as Arm A patients). It will include: 1. Adolescent patients (aged 12-17 years) currently treated with eculizumab 2. Patients (aged ≥ 12 years) currently treated with ravulizumab 3. Patients (aged ≥ 12 years) currently treated with eculizumab at a dose > 900 mg and/or more frequent than Q2W 4. Patients (aged ≥ 12 years) with a known C5 polymorphism whose hemolysis was poorly controlled After 24 weeks of treatment, patients from each treatment arm can continue crovalimab or switch from eculizumab to crovalimab if their physician determines this is in their best interest. The primary efficacy objective for the randomized arms is to determine the noninferiority of crovalimab compared with eculizumab based on mean percent change in lactate dehydrogenase (LDH) levels from baseline to after 24 weeks of treatment. Secondary efficacy objectives are to determine the noninferiority of crovalimab compared with eculizumab based on (1) proportion of patients who achieve transfusion avoidance, (2) proportion of patients who experience breakthrough hemolysis, (3) proportion of patients who achieve stabilization of hemoglobin, and (4) mean change in fatigue as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue questionnaire. The safety objective is to evaluate the safety and tolerability of crovalimab compared with eculizumab based on the incidence and severity of adverse events, including infections (meningococcal meningitis and other infections), injection-site reactions, infusion-related reactions, hypersensitivity, adverse events leading to study drug discontinuation, and type 3 hypersensitivity reactions in patients who switch to crovalimab from eculizumab or ravulizumab. Pharmacokinetic, immunogenicity, biomarker, and health status utility objectives will also be assessed. Download : Download high-res image (223KB) Download : Download full-size image Disclosures Risitano: Amyndas: Consultancy; Samsung: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Membership on an entity’s Board of Directors or advisory committees; Jazz: Speakers Bureau; RA pharma: Research Funding; Biocryst: Membership on an entity’s Board of Directors or advisory committees; Apellis: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; Achillion: Membership on an entity’s Board of Directors or advisory committees. Roth: Biocryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding; Apellis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding. Kulasekararaj: Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Pu: F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Pennsylvania State University: Patents & Royalties; SUNY Upstate Medical University: Current Employment. Nishimura: Chugai: Membership on an entity’s Board of Directors or advisory committees; Alexion: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Membership on an entity’s Board of Directors or advisory committees, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Wright: Genentech, Inc: Current Employment; F. Hoffmann-La Roche Ltd: Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Appius: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Sostelly: F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Sreckovic: F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third-party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Vignal: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Munir: F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland; Alexion: Honoraria.

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, hematologic disease characterized by chronic complement-mediated hemolysis. Treatment with the C5 inhibitor eculizumab has resulted in a reduction in intravascular hemolysis and improvements in morbidity and mortality. Even with the clinical benefit in PNH, eculizumab entails twice-monthly intravenous infusions in a hospital setting in most countries, adversely impacting patients' work productivity (Mastellos DC, et al.Semin Hematol. 2018;55(3):167-175). Lost productivity associated with eculizumab ranged from $344,000 in Russia to $4.3 million in the United States, without caregivers (Levy AR, et al.Blood. 2019;134(Supplement_1):4803). Furthermore, patients in a real-world study treated with eculizumab for 1 year experienced continued impairment in overall quality-of-life relative-to-normative reference scores for the general adult population (Ueda Y, et al.Int J Hematol. 2018;107(6):656-665). This study aims to understand the clinical, humanistic, and economic outcomes associated with burden of illness in about 150 patients with PNH globally. In these preliminary analyses, productivity loss and quality of life (QoL) in patients with PNH currently being treated with C5 inhibitors (eculizumab and ravulizumab) are assessed in patients in the United States. METHODS This cross-sectional survey administered to adult patients in the United States, ≥18 years of age, with self-reported diagnosis of PNH, was initiated in July 2020 and is ongoing. Patients were recruited through a patient advocacy group. Inclusion criteria to complete the secure online survey include current treatment with either eculizumab or ravulizumab, and agreement to provide informed consent and adverse event reporting. To investigate the impact of PNH on employment and activity, the Work Productivity and Activity Impairment-General Health (WPAI-GH) questionnaire was used. QoL was assessed using Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). For the preliminary WPAI-GH analysis presented here, descriptive statistics are reported for patients who have completed the survey thus far. Analyses examining the impact of PNH on FACIT-Fatigue, EORTC QLQ-C30, and other clinical outcomes assessments among patients on anti-C5 therapy are ongoing. RESULTS A total of 58 adult patients completed the survey as of August 6, 2020. Patients' median age was 52 years (range, 21-88) and 78% of patients were female. Twenty patients (34%) were on eculizumab and 38 (66%) were on ravulizumab. Most patients (93%) had initiated treatment ≥3 months prior to enrollment. In total, 23 (40%) patients reported that they were gainfully employed. Overall, 52% of employed patients reported missing hours of work in the prior 7 days due to their health problems (67% eculizumab and 43% ravulizumab). About 77% of working patients reported that their illness affected their productivity at work (89% eculizumab and 69% ravulizumab) due to the same reason. Employed patients reported an average of 13% (standard deviation, 21%) absenteeism (ie, work time lost due to being absent for illness in the previous week; eculizumab, 22% ± 29%, ravulizumab, 7% ± 12%). Patients reported 26 ± 27% impairment while working over the past 7 days (ie, presenteeism; eculizumab, 39 ± 31%, ravulizumab, 18 ± 22%). Total work productivity impairment was on average 32 ± 31% (eculizumab, 46 ± 35%; ravulizumab, 23 ± 24%). Nearly all patients (n = 54 [93%]) reported at least some impairment in their usual activities regardless of employment (eculizumab, 100%; ravulizumab, 90%). On average, patients reported 38 ± 23% of impaired activity in the previous week (eculizumab, 43 ± 20%; ravulizumab, 36 ± 25%). CONCLUSIONS Preliminary results from this burden of illness survey evaluating humanistic and economic outcomes in patients with PNH demonstrated substantial loss of work-related productivity, greatly diminished ability to work, and limitations in patients' usual activities while being treated with the C5 inhibitors eculizumab and ravulizumab. Disclosures Dingli: Karyopharm Therapeutics:Research Funding;Alexion:Consultancy;Bristol Myers Squibb:Research Funding;Janssen:Consultancy;Rigel:Consultancy;Apellis:Consultancy;Sanofi-Genzyme:Consultancy;Millenium:Consultancy.Matos:Kantar:Current Employment.Lehrhaupt:Kantar:Current Employment.Krishnan:Apellis:Current Employment, Current equity holder in publicly-traded company.Baver:Apellis:Current Employment, Current equity holder in publicly-traded company.Sarda:Apellis:Current Employment, Current equity holder in publicly-traded company.

INTRODUCTION Current pharmacologic management of patients who are diagnosed with paroxysmal nocturnal hemoglobinuria (PNH) includes C5 complement inhibitors, such as eculizumab. The standard dosage of eculizumab, administered via intravenous infusion, is 600 mg/week for the first 4 weeks (induction phase), 900 mg for the fifth dose 1 week later, and 900 mg biweekly thereafter (maintenance phase). There is limited information describing dosing patterns of eculizumab in clinical practice. The purpose of this study was to conduct a comprehensive assessment of the real-world dosing patterns of patients with PNH treated with eculizumab in a large US population. METHODS A retrospective longitudinal cohort study using provider-based claims data from the Symphony Health Integrated Dataverse® was conducted. Patients were ≥12 years of age and received ≥2 infusions of eculizumab between October 1, 2014, and September 30, 2019. The index date was defined as the first medical claim for eculizumab infusion with ≥3 months of prior continuous clinical activity, defined as ≥1 claim of any type per quarter (ie, the baseline period). Patients with ≥1 diagnosis of another indication for eculizumab, including atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder, during the baseline period or on the index date were excluded to identify patients with PNH. Patient baseline demographic and clinical characteristics, including PNH-related comorbidities and PNH-symptoms, were described. Mean starting dose and the proportion with high (>600 mg), label-recommended (600 mg), and low ( RESULTS A total of 707 patients with PNH who had ≥2 infusions of eculizumab during the study period were included in this analysis; mean observation period was 23.9 months. Mean age was 45.4 years, 55.7% were female, and 35.9% were from the South. The majority of patients (77.1%) were insured through a commercial insurance plan. Respectively, 32.5% and 6.8% of patients had a diagnosis for aplastic anemia and myelodysplastic syndrome during baseline. The most frequent comorbidities in this sample included hypertension (26.6%), coagulopathy (26.6%), and renal failure (20.5%). In addition, 85.1% of patients experienced anemia (other than aplastic anemia) at baseline. The mean (standard deviation) starting dose during the induction phase was 862 (412) mg; the proportion of patients with high, label-recommended, and low starting dose was 64.1%, 30.6%, and 5.4%, respectively. The mean (standard deviation) and mode dose was 859 (391) mg and 900 mg during the induction phase, and 1011 (333) mg and 900 mg during the maintenance phase. Respectively, 67.9%, 25.9%, and 6.2% of patients had a high, label-recommended, and low mean dose during the induction phase, and 45.9%, 41.6%, and 12.5% had a high, label-recommended, and low mean dose during the maintenance phase. CONCLUSIONS This study demonstrates that the majority of patients with PNH treated with eculizumab were started on a dose in the induction phase that was higher than the label-recommended dose of 600 mg, and the mean dose received during the maintenance phase was higher than the label-recommended dose of 900 mg in approximately half of all patients. Future analyses that investigate budget impact of eculizumab in patients with PNH should account for real-world dosing patterns in order to comprehensively assess costs and benefits. Disclosures Cheng: Apellis: Research Funding. Sarda:Apellis: Current Employment, Current equity holder in publicly-traded company. Mody-Patel:Apellis: Current Employment, Current equity holder in publicly-traded company. Krishnan:Apellis: Current Employment, Current equity holder in publicly-traded company. Yenikomshian:Apellis: Research Funding. Scoble:Apellis: Current Employment, Current equity holder in publicly-traded company. Kunzweiler:Apellis: Research Funding. Vu:Apellis: Research Funding. Cheung:Apellis: Research Funding. Duh:Merck: Research Funding; Pharmacyclics: Research Funding; Takeda Oncology: Research Funding; GlaxoSmithKline: Research Funding; AstraZeneca: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Shire: Research Funding; Apellis: Research Funding.

Complement C5 inhibition is the standard of care (SoC) for patients with paroxysmal nocturnal hemoglobinuria (PNH) with significant clinical symptoms. Constant and complete suppression of the terminal complement pathway and the high serum concentration of C5 pose challenges to drug development that result in IV-only treatment options. Crovalimab, a sequential monoclonal antibody recycling technology antibody was engineered for extended self-administered subcutaneous dosing of small volumes in diseases amenable for C5 inhibition. A 3-part open-label adaptive phase 1/2 trial was conducted to assess safety, pharmacokinetics, pharmacodynamics, and exploratory efficacy in healthy volunteers (part 1), as well as in complement blockade-naive (part 2) and C5 inhibitor-treated (part 3) PNH patients. Twenty-nine patients were included in part 2 (n = 10) and part 3 (n = 19). Crovalimab concentrations exceeded the prespecified 100-µg/mL level and resulted in complete and sustained terminal complement pathway inhibition in treatment-naive and C5 inhibitor-pretreated PNH patients. Hemolytic activity and free C5 levels were suppressed below clinically relevant thresholds (liposome assay10 U/mL and50 ng/mL, respectively). Safety was consistent with the known profile of C5 inhibition. As expected, formation of drug-target-drug complexes was observed in all 19 patients switching to crovalimab, manifesting as transient mild or moderate vasculitic skin reactions in 2 of 19 participants. Both events resolved under continued treatment with crovalimab. Subcutaneous crovalimab (680 mg; 4 mL), administered once every 4 weeks, provides complete and sustained terminal complement pathway inhibition in patients with PNH, warranting further clinical development (ClinicalTrials.gov identifier, NCT03157635).

Contains fulltext : 202845.pdf (Publisher’s version ) (Open Access) Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (P inf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.

Eculizumab, a humanized anti-complement C5 monoclonal antibody for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome, blocks the terminal complement pathway required for serum bactericidal activity (SBA). Because treated patients are at >1000-fold increased risk of meningococcal disease, vaccination is recommended, but whether vaccination can protect by opsonophagocytic activity in the absence of SBA is not known. Meningococci were added to anticoagulated blood from 12 healthy adults vaccinated with meningococcal serogroup B and serogroup A,C,W,Y vaccines. Bacterial survival was measured after 3 hours incubation in the presence of eculizumab or, a control complement factor D inhibitor, ACH-4471, that blocks the alternative complement pathway (AP) and is in phase 2 development for treatment of PNH. In the absence of inhibitors, CFU/ml in blood from all 12 immunized subjects decreased from ~4000 at time 0 to sterile cultures at 3 hours. In the presence of eculizumab, there was a >22-fold increase in geometric mean CFU/ml (90,596 and 114,683, for serogroup B and C strains, respectively; P 12-fold decrease (23 and 331 CFU/ml, respectively; P

Introduction: Catastrophic antiphospholipid syndrome (CAPS) is characterized by multiple intravascular thrombotic events occurring over a short time period in the presence of persistently detectable antiphospholipid antibodies (APLA). Despite its clinical significance with mortality rate of 40-50%, the underlying pathophysiology remains somewhat enigmatic. More recent focus on the complement system as it interacts with the coagulation cascade has led to off-label use of eculizumab, a humanized monoclonal antibody against C5, in the treatment of CAPS. Consequently, monitoring of disease status with complement levels is an area of interest. We report complement levels in four patients with CAPS who had various clinical outcomes. Methods: Four patients admitted to SUNY Upstate Medical University with CAPS between February and May 2019 were included in this case series. All patients had APS with prior history of refractory CAPS (persistent disease despite standard therapy with steroids, rituximab, and therapeutic plasma exchange [TPEX]). Antiphospholipid antibodies (APLA) and complement (C3 and C4) levels were monitored during admission until discharge or death. Results: Patient characteristics are summarized in Table 1. Patient 1 was a 42-year-old female with antiphospholipid syndrome (APS) on warfarin, ischemic stroke, and aortic valve replacement admitted on March 2019 with shortness of breath, hemoptysis and menorrhagia. She was found to have elevated APLA, thrombocytopenia, and acute renal failure with renal biopsy confirming APS nephropathy. Despite therapy with ongoing anticoagulation, steroids, rituximab, IVIG, and TPEX her clinical course continued to deteriorate. Hypocomplementemia was present (both low C3 and C4), with lowest C3 level on admission at 31 (Graph 1A). Decision was made to pursue eculizumab on 4/16/19 with continued clinical decline and no improvement in complement levels. She ultimately died on 4/24/19. Patient 2 was a 35-year-old male with systemic lupus erythematosus (SLE), APS, end-stage renal disease, and Libman-Sacks endocarditis status post bioprosthetic aortic valve replacement admitted in February 2019 for worsening digital ischemia. Workup showed presence of lupus anticoagulant, thrombocytopenia, low C3 levels (Graph 1B), normal C4 levels, and arterial thrombi in the upper and lower extremities. Prior to initiation of treatment, respiratory status declined due to massive pulmonary embolus. He died after PEA arrest shortly thereafter. Patient 3 is a 63-year-old male with chronic ITP and APS on warfarin, maintenance rituximab and intermittent apheresis admitted with worsening renal dysfunction in April 2019. Workup demonstrated acute on chronic thrombocytopenia, elevated APLA, and normal C3 and C4 levels (Graph 1C). Renal replacement therapy was commenced and he was discharged to receive ongoing outpatient therapy. Patient 4 is a 35-year-old male with history of SLE and APS admitted in April 2019 with renal failure, anemia and thrombocytopenia. Workup showed presence of APLA. Despite therapy with steroids, IVIG, rituximab and TPEX he became anuric with renal biopsy showing thrombotic microangiopathy. He was also bacteremic with a mitral valve vegetation for which he underwent valve replacement. Hospital course was complicated by need respiratory failure necessitating intubation and ECMO. C3 levels were consistently low, but varied throughout his long admission (Graph 1D) and were not necessarily related to his clinical course (sepsis, ECMO, etc.). C4 levels were normal. Conclusions: Complement levels were variable among the patients in this case series. Three out of four patient had low C3, while only one patient had low C4. Further, complement levels did not improve in one patient after administration of eculizumab. Routine laboratory testing for C3 and C4 may not be optimal assays for monitoring disease status in CAPS. More specialized complement testing, such a C5 a/b, may be more appropriate especially in the setting of eculizumab use. While eculizumab is typically used in refractory disease, it may be pertinent to move this therapy into early line treatment to achieve better outcomes in certain clinical scenarios. Identification of a more specific biomarker to recognize cases in need of early therapy is warranted. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Eculizumab, a humanized monoclonal IgG antibody that binds to complement protein C5, is discussed for its off-label use in the treatment of catastrophic antiphospholipid antibody syndrome.

Introduction: Aplastic Anemia (AA) is diagnosis made after the exclusion of other acquired or inherited disease that can present with pancytopenia. In pediatric AA, there is often overlap with many other diseases including Paroxysmal Nocturnal Hemoglobinuria (PNH) and hypocellular myelodysplastic syndrome (MDS). The diagnosis is often difficult and can evolve. There are new tests and methodologies to guide diagnosis and treatment decision making. Case report: The patient is a previously healthy, 18-year-old Caucasian female referred for pancytopenia. Patient reported progressive fatigue and easy bruising for a month prior to evaluation. Initial white blood count was 2.4 x109/L, hemoglobin 9.7g/dl, platelets 39 x109/L, absolute neutrophil count (ANC) of 590, and absolute retic count 68 x 109/L. A bone marrow exam revealed a hypocellular marrow with 30% cellularity with no dysplasia or blasts on flow cytometry. Viral studies, folate and vitamin B12 levels were normal. Chromosomal analysis, Fluorescent In situ Hybridization (FISH) study for MDS, and telomere length assay were normal. A bone marrow failure (BMF) panel for sixty targeted genes showed no mutations associated with BMF. PNH studies by flow cytometry showed 2.6% erythroid, 2% granulocytes, 2.7% monocytes failed to express GPI associated anchoring proteins (GPI-APs) representing a small PNH clone, not unusual in patients with aplastic anemia (AA). Studies were c/w with moderate AA (mAA). Standard management of mAA is careful observation and treatment if the patient requires transfusions or ANC falls below 500. However, since our patient was soon starting college out of state, we decided to treat with Immunosuppressive Therapy (IST), consisting of equine Anti-thymocyte globulin (eATG) and Cyclosporine. At 24 weeks post IST, no response was observed and the patient was requiring more frequent platelet and red blood cell transfusions. Repeat PNH testing showed 2% erythroid, 5% monocytes and 4% granulocytes that were deficient in GPI-Aps (Table1). BM exam showed 60% cellularity that was consistent with a recovering marrow but there was relative erythroid hyperplasia, without evidence of dysplasia or blasts. At this time, with increasing marrow cellularity but persistent pancytopenia we began to strongly suspect MDS. However, repeat chromosomal analysis and FISH studies were normal and a Foundation One myeloid panel was negative for mutations associated with MDS. At 28 weeks post-IST, repeat BM exam revealed 70% cellularity, again with relative erythroid hyperplasia. At the same time PNH testing, showed that 1.3% erythrocytes, 5.6% granulocytes and 5.4% monocytes were negative for GPI-APs. We concluded that our patient evolved had from mAA to subclinical PNH/AA which accounted for the normocellular marrow. High Disease Activity (HDA) is defined as lactate dehydrogenase (LDH) ≥ 1.5 times upper limit of normal and is associated with large PNH clones. HDA can guide the use of eculizumab as pre-transplant therapy. (DeZern et al, 2012) Throughout the course of the disease, her LDH was normal. She did not have HDA and therefore, was not treated with eculizumab. Because of the normocellular marrow she was not eligible for CTN 1502-CHAMP study. However, the patient underwent reduced intensity conditioning (RIC) and a haplo paternal BMT, followed by post-transplant cyclophosphamide, as per CTN 1502- CHAMP. She tolerated her BMT well without major complications. She is now five months post-transplant, alive and well, fully engrafted with 100% donor chimerism and no signs of GVHD. Post-transplant PNH testing revealed all PNH clones were eliminated. Conclusion: This case illustrates the diagnostic challenges of patients presenting with pancytopenia and the overlap and possible evolution of disease classifications; new diagnostic testing including gene mutation screens to aid in diagnosis; new concepts such as HDA in PNH to help guide treatment decision making; and the successful use of RIC and haplo BMT in a patient with PNH/AA and a normocellular BM Disclosures No relevant conflicts of interest to declare.

Monoclonal gammopathy is a clonal plasma cell disorder associated with an increased risk of progression to lymphoproliferative malignancy. In children, monoclonal and oligoclonal gammopathies are rare, and their clinical relevance unrecognized. Atypical hemolytic uremic syndrome (aHUS) is a rare endotheliopathy associated with dysregulated activation of complement, microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. We present a case of aHUS that we hypothesize was triggered by monoclonal gammopathy in a child several years after cardiac transplantation. An 11 year old African-American girl with sickle trait was transferred to our cardiac center with a two week history of epigastic pain, emesis, microcytic anemia, hypergammaglobulinemia, and development of renal failure requiring dialysis. She had undergone cardiac transplantation at 7 months of age for dilated cardiomyopathy of unknown etiology and had recovered from acute cardiac rejection requiring ECMO at age 5 years. She had previously experienced at least two episodes of acute kidney injury requiring dialysis with full recovery of function reported. Renal biopsy revealed a severe collapsing glomerulopathy and a thrombotic microangiopathy. Upon transfer to our institution, her labs were notable for microcytic anemia, normal platelet count, haptoglobin, and LDH. A week later, she developed aHUS diagnosed by hemoglobin 9.5 gm/dL, haptoglobin < 30 mg/dL, LDH 314 U/L, platelets 100,000, and a predominance of schistocytes on peripheral blood smear in the setting of acute renal failure. Serum protein electrophoresis (SPEP) revealed a monoclonal spike (1g/dL), identified as IgG kappa by immunoabsorption. A second, smaller monoclonal spike was identified as IgA lambda. aHUS evaluation revealed low C3, normal C4, and 50% CD46 expression by flow cytometry. Bone marrow biopsy with flow cytometry excluded lymphoproliferative disorders. EBV did not amplify with quantitative PCR of peripheral blood, and computed tomography imaging of the body did not detect abnormal mass or lymph nodes. A trial of plasmapheresis did not improve biochemical and hematologic features of aHUS. A trial of eculizumab resulted led to normalization of platelet count and C3, increased haptoglobin, reduced need for red cell transfusion, and less frequent dialysis. Monoclonal gammopathy of unknown significance (MGUS) is rare in children, but may be more common in transplant recipients, especially after cardiac transplants in infants when thymectomy is performed. MGUS associated with secondary aHUS has been rarely reported in adults. The mechanism for aHUS was demonstrated in one case to result from affinity of the paraprotein to a binding site on complement factor H, with subsequent loss of factor H cofactor activity to inhibit alternative complement activation. We hypothesize that immune dysregulation from fluctuating levels of paraproteins during inflammation in our patient with monoclonal gammopathy resulted in recurrent, intermittent episodes of aHUS. We speculate that this was responsible for the patient's collapsing glomerulopathy and dialysis-dependent chronic renal failure. This case highlights the importance of considering monoclonal gammopathy in pediatric patients who develop recurrent kidney failure or atypical hemolytic uremic syndrome in the setting of immune dysregulation. The merit of treating the monoclonal gammopathy with Bortezumib and Rituximab is currently under consideration. Disclosures No relevant conflicts of interest to declare.

Background: The 50% hemolytic complement (CH50) assay is a non-specific qualitative assay of complement function. CH50 is sometimes used in patients with complement-mediated thrombotic microangiopathy such as atypical hemolytic uremic syndrome (aHUS) to monitor response to complement inhibition. There are multiple commercial assays as well as research-based CH50 assays that are not directly comparable in outcomes or methods. Ravulizumab is a long-acting anti-C5 monoclonal antibody engineered from eculizumab, currently being investigated for the treatment of aHUS. A fully validated free C5 assay, supporting the primary pharmacodynamic endpoint, was utilized in clinical trials of ravulizumab. We have compared local CH50 results from participating sites with the free C5 assay, performed centrally, in patients with aHUS participating in the clinical trial. Methods: Adults and children with aHUS enrolled in phase 3 trials of ravulizumab (NCT02949128 and NCT03131219) were included in this analysis. A validated Gyros-based immunoassay with a fluorescence readout was used to quantify free C5 during the trial. The regulatory-accepted threshold for complete terminal complement inhibition is a free C5 value Results: CH50 data from 10 patients with aHUS (5 adults and 5 children) from four countries (US, Spain, France and UK) were available. A scatter plot of serum CH50 and free C5 versus time is shown in the figure. Complete terminal complement inhibition throughout the evaluation period was demonstrated by the free C5 assay. Results of CH50 did not consistently confirm full complement inhibition, demonstrating discordance with the free C5 assay. Relative to the adults, there was qualitatively more variability in the CH50 results in the pediatric patients. Conclusions: Results from the CH50 assays inconsistently demonstrated full complement inhibition, with discordance with free C5 levels. This discordance requires further investigation. In clinical practice, this has potential to cause different interpretations of complement blockade and highlights the important limitations of CH50 as a technique for assessing complete terminal complement blockade in patients receiving ravulizumab. This study also underscores the need for a commercially available validated measure for determining complement inhibition. Disclosures Cataland: Alexion: Consultancy, Research Funding; Ablynx/Sanofi: Consultancy, Research Funding. Ariceta:Alexion: Consultancy, Honoraria. Chen:Alexion: Employment. Dixon:Alexion: Consultancy; Apellis Pharmaceuticals: Consultancy; Horizon Pharmaceuticals: Consultancy. Garlo:Alexion: Employment. Greenbaum:Alexion: Consultancy, Honoraria, Research Funding. Rondeau:Alexion: Consultancy, Honoraria. Scully:Novartis: Consultancy; Shire: Research Funding; Shire/Takeda: Consultancy; Alexion: Consultancy; Ablynx/Sanofi: Consultancy. Ortiz:Alexion: Employment.