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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.

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.

Eculizumab, the monoclonal antibody targeting C5, is the only licensed treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH) in the UK. Inherent to the mechanism of action, C5 inhibitors increase patient susceptibility to encapsulated microorganisms, particularly Neisseria meningitidis. The PNH National service (UK), has 18 years of experience treating patients with PNH using complement inhibition. The risk of N. meningitidis is mitigated by vaccination, ciprofloxacin (500 mg bd) on days 1-13 since we moved to vaccination on day one of complement inhibitor therapy, followed by daily prophylaxis with penicillin (or erythromycin). Since a case of sepsis with penicillin-resistant meningococci was observed, patients also have a rescue course ciprofloxacin. Patient education, safety cards, prompt action in case of fever and a 24 hour on-call service for patients are equally important. Until 2010 patients were revaccinated with MenACWY every 3 years. Bexsero (MenB vaccine) vaccination (2 vaccines within first 6 months) with boosters every 5 years was added in 2015. In collaboration with the Public Health England Meningococcal Reference Unit in 2010 a program was developed to monitor antibody titers after vaccination and to revaccinate against MenACWY if titers declined to below protective levels. It is technically not possible to assay for meningoccal serogroup B antibody titers when on Eculizumab therapy. We present the outcome of this project. Methods: Antibody titers to serogroups ACWY were assayed following vaccination and then once per annum. Patients with unprotective antibody titers were revaccinated. We evaluate our practice and review the 9 meningococcal infections in 8 patients. We present disease characteristics, serogroup and outcome, vaccination history and antibody status. Results: Between May 2002 and July 2020, 324 patients commenced complement inhibitor treatment for PNH. 801 vaccinations with MenACWY were administered; median 2 vaccinations per patient (range 1 - 10). A total of 1,671 antibody titer assessments were conducted in 294 patients, median of 4 tests per patient (range 1 - 15). Every test assessed antibodies against all four serogroups. Titers were not assessed in 9% of patients (30), due to vaccination prior to change in practice or recent commencement on treatment. A protective antibody response to all serogroups after first vaccination was observed in 170 / 294 patients (57.8%) and a partial response (antibodies to 3 serotypes) in 51 /294 (17.3%). Revaccination of 51 partial responders resulted in an additional 21 patients with a full response. Revaccination of 73 non-responders (antibodies to 0-2 serotypes) resulted in 32 more partial or full responses. 287 of 324 patients received MenB vaccinations; median 2 vaccinations per patient (range 1 - 4). Eight of 324 (2%) patients with median age 22.5 years developed meningococcal sepsis (see table); patient 5 had 2 episodes. 3 of 5 cases with serogroup B infection were before serogroup B vaccination was introduced. The other 4 episodes in 3 patients were due to Y, C, W meningococci, in one the serogroup is unknown. All except patient 1 were compliant with antibiotic prophylaxis. Patient 7 died from meningococcemia, a delay in seeking medical attention may have contributed, however this was also a penicillin resistant strain. Discussion: We report the largest experience of managing meningococcal risk in patients on complement inhibitor therapy for PNH. Despite our proactive management we had 9 cases of meningococcal sepsis, with one fatal infection. Our most recently introduced practice of prompt treatment with ciprofloxacin if pyrexic on antibiotic prophylaxis will prevent cases like patient 7 with a penicillin resistant strain. Three patients had a meningococci sepsis with serogroups C, W and Y; whilst 1 patient had no check of titers due to recent commencement on treatment, the titres of the other 2 had suggested protective immunity. We demonstrated that a full antibody response can be obtained on a second vaccination in most patients if the first one failed. If no response is achieved upfront or revaccination then further MenACWY vaccination is not likely to be successful. Current practice significantly mitigates the risk of meningococcal disease, however it is essential patients remain vigilant for fever, seeking immediate medical attention stating their diagnosis of PNH on complement inhibitor therapy. Disclosures Arnold: Alexion Pharmaceuticals: Honoraria. Borrow:Pfizer: Research Funding; GlaxoSmithKline: Research Funding; Alexion pharmacueticals: Research Funding; Sanofi: Research Funding. Riley:Alexion: Honoraria. 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. Kelly:Alexion: Honoraria. Pike:Apellis: Research Funding. Hillmen: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; AstraZeneca: Consultancy, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hemolytic and thrombotic condition. Patients can experience severe anemia due to intravascular hemolysis, thrombotic events, renal impairment and pulmonary hypertension. Symptomatic patients are treated with complement inhibitors either in clinical trials or with eculizumab the only licensed treatment in the UK. Due to the mechanism of action of eculizumab, it increases susceptibility to Neisseria infection, including Neisseria meningitidis. To reduce this risk of infection, worldwide practice is for patients to be vaccinated at least 2 weeks prior to receiving eculizumab (serogroups A, C, Y, W 135 and B). It was noted within the PNH National Service at Leeds (UK) that a small number of patients deteriorated with enhanced intravascular hemolysis and thrombosis during the period between vaccination and eculizumab, leading to a review of practice. We report five of 121 patients with events in the intervening 2 weeks between vaccination and commencement of eculizumab from 2002-2012:A 44 year female presented with hemolysis and hemoglobinuria, with a granulocyte PNH clone of 99.4%. She was transfusion dependent and on anticoagulation. She consented to the PNH pilot eculizumab study, undergoing meningococcal vaccination as per protocol. Twenty two days later, she suffered an ischemic stroke with left hemiplegia and permanent weakness, resulting in exclusion from the study. Two years later she received eculizumab in the TRIUMPH study.A 37 year male presented with hemoglobinuria and fatigue with a granulocyte PNH clone of 99.58%. He had significant hemolysis, managed initially with warfarin and blood transfusions. He consented to start eculizumab and received meningococcal vaccination. 4 days later he presented with a symptomatic right hepatic vein thrombosis, promptly commenced eculizumab.A 29 year male, with abdominal pain and hemoglobinuria for 3 years developed a stroke and portal vein thrombosis leading to a diagnosis of PNH, with a granulocyte PNH clone of 84.99%. He commenced anticoagulation. Four months after the stroke he received meningococcal vaccination in preparation for scheduled commencement with eculizumab. He experienced a left central retinal vein thrombosis 15 days after its administration prior to starting eculizumab.A 47 year old male, was diagnosed with haemolytic PNH but only had mild symptoms and anaemia. Twenty four years later, he developed increasing hemolysis and symptoms; granulocyte PNH clone of 96.45%. Eculizumab was planned and he received meningococcal vaccination, but presented ten days later with acute renal failure secondary to massive intravascular haemolysis, necessitating emergency eculizumab therapy.A 35 year female, with a granulocyte PNH clone of 99.87%. Although she had active intravascular hemolysis, eculizumab was declined, and anticoagulation commenced. Four years later she consented to start eculizumab, receiving meningococcal vaccination. She was admitted 24 hours later with a stroke and commenced eculizumab the same day, but has persistent neurological impairment to date. See Table 1 Discussion: The close time proximity of these serious events to the patients' vaccinations raised concern that the complement system was being activated by administration of the vaccine, precipitating complications of PNH. It is also concerning that 4 of the 5 patients experienced thrombotic events despite therapeutic anticoagulation, confirming that anticoagulation only partially mitigates the risk of thrombosis in patients with PNH. The decision was taken to administer the vaccination immediately after the first dose of eculizumab, with therapeutic doses of antibiotic (ciprofloxacin 500mg bd) for the first 14 days post vaccination, followed by long term meningococcal prophylaxis (penicillin V or erythromycin 500mg bd) whilst receiving a complement inhibitor. Since this change in practice in 2012 we have commenced eculizumab therapy in 211 patients with no similar complications as described. Thus the change in practice appears to reduce the occurrence of these severe complications associated with vaccinations prior to initiating anti-complement therapy. Whilst it is possible these events could have been caused by the underlying condition of PNH, we would advise colleagues to also adopt a change in practice to reduce potentially significant complications. Disclosures Arnold: Alexion Pharmaceuticals: Honoraria. Kelly:Alexion: Honoraria. 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. Pike:Apellis: Research Funding. Riley:Alexion: Honoraria. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference Support; Biocryst: Membership on an entity's Board of Directors or advisory committees. Hillmen: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; AstraZeneca: Consultancy, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding.

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.

BACKGROUND In paroxysmal nocturnal hemoglobinuria (PNH), intravascular hemolysis (IVH) is mediated by the membrane attack complex, while extravascular hemolysis (EVH) is facilitated by C3 opsonization. Although eculizumab (ECU), a C5 inhibitor, inhibits IVH, ~70% of patients remain anemic and 36% require ≥1 transfusion per year due to C3-mediated EVH. Pegcetacoplan (APL-2), a C3 inhibitor, has the potential to control both IVH and EVH in PNH. AIMS PEGASUS, a phase 3, randomized, open-label, controlled trial (NCT03500549), assessed the efficacy and safety of pegcetacoplan compared to ECU in patients with PNH. METHODS Eighty patients aged ≥18 years with a confirmed diagnosis of PNH, hemoglobin levels 1.0 × ULN, platelets >50 × 109/L and neutrophils >0.5 × 109/L were included. All patients provided written informed consent and completed a run-in period of 4 weeks with pegcetacoplan plus ECU before 1:1 randomization to monotherapy with pegcetacoplan (41 patients, 1080 mg subcutaneously twice a week) or ECU (39 patients, continuing current dosing regimen). The primary endpoint was change in hemoglobin level from baseline (start of run-in period) to week 16. Key secondary and secondary endpoints were hemoglobin normalization (defined as hemoglobin level greater than or equal to lower limit of normal range) in the absence of transfusions, transfusion avoidance, absolute reticulocyte counts, lactate dehydrogenase (LDH), Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, and adverse events (AEs). Hierarchical significance testing for secondary efficacy endpoints was gated on the success of the primary efficacy endpoint. Post hoc analyses included hemoglobin stabilization (defined as avoidance of a >1 g/dL decrease from baseline) in the absence of transfusions. RESULTS Pegcetacoplan demonstrated superiority to ECU in change in hemoglobin level at week 16, with an adjusted treatment difference of 3.84 g/dL (p CONCLUSIONS In this phase 3 trial in patients with PNH, pegcetacoplan demonstrated superiority to ECU in hemoglobin level, and improved clinical outcomes at week 16 with transfusion avoidance in most patients. The safety profile of pegcetacoplan was comparable to that of ECU. The efficacy of pegcetacoplan validates the prevention of extravascular as well as intravascular hemolysis in PNH, leading to a potential new therapeutic option. Disclosures Hillmen: Acerta: Other: Financial or material support; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; Alexion: Consultancy, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau. Szer:Prevail Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy; Takeda: Honoraria, Speakers Bureau; 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. Weitz:Apellis: Consultancy, Honoraria; Alexion: Consultancy, Honoraria, Speakers Bureau. Röth:Biocryst: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding. Hoechsmann:Alexion: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Panse:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Grunenthal: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees. Usuki:Apellis: Research Funding; Chugai: Research Funding; Novartis: Research Funding, Speakers Bureau; Alexion: Research Funding, Speakers Bureau. Griffin:Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals: Honoraria, Other: Conference Support. Kiladjian:Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. de Castro:Biocryst: Honoraria, Other: Data monitoring committee; Novartis: Honoraria, Other: Steering committee; Alexion: Honoraria, Research Funding; Apellis: Consultancy, Honoraria, Research Funding. Tan:Apellis: Consultancy, Patents & Royalties. Hamdani:Apellis: Current Employment, Current equity holder in publicly-traded 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. Risitano: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; 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. Peffault De Latour:Apellis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; 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. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria.

A retrospective analysis of presentation clinical, laboratory and immunophenotypic features of 1 081 patients with paroxysmal nocturnal haemoglobinuria (PNH) clones [glycosylphosphatidylinositol (GPI)‐deficient blood cells] identified at our hospital by flow cytometry over the past 25 years was undertaken. Three distinct clusters of patients were identified and significant correlations between presentation disease type and PNH clone sizes were evident. Smaller PNH clones predominate in cytopenic and myelodysplastic subtypes; large PNH clones were associated with haemolytic, thrombotic and haemolytic/thrombotic subtypes. Rare cases with an associated chronic myeloproliferative disorder had either large or small PNH clones. Cytopenia was a frequent finding, highlighting bone marrow failure as the major underlying feature associated with the detection of PNH clones in the peripheral blood. Red cell PNH clones showed significant correlations between the presence of type II (partial GPI deficiency) red cells and thrombotic disease. Haemolytic PNH was associated with type III (complete GPI deficiency) red cell populations of >20%. Those with both haemolytic and thrombotic features had major type II and type III red cell populations. Distinct patterns of presentation age decade were evident for clinical subtypes with a peak incidence of haemolytic PNH in the 30–49 year age group and a biphasic age distribution for the cytopenia group.

Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-orphan disease, which until 15 years ago had limited treatment options. Eculizumab, a monoclonal antibody that inhibits C5 in the terminal complement cascade, has revolutionised treatment for this disease, near normalising life expectancy and improving quality of life for patients. The treatment landscape of PNH is now evolving, with ravulizumab a second longer acting intravenous C5 inhibitor now licenced by the FDA and EMA. With different therapeutic targets in the complement cascade and difference modalities of treatment, including subcutaneous, oral and intravenous therapies being developed, increasing independence for patients and reducing healthcare requirements. This review discusses the current and future therapies for PNH. Lay summary Review of current and future treatments for patients with Paroxysmal Nocturnal Haemoglobinuria What is Paroxysmal Nocturnal Haemoglobinuria? Paroxysmal nocturnal haemoglobinuria (PNH) is a very rare disease. It arises from PNH stem cells in the bone marrow. In a normal bone marrow these are inactive; however, if there has been a problem in the bone marrow, the PNH stem cells can expand and make PNH red blood cells, white blood cells and platelets. The problem with these cells is that they lack the cell surface markers that usually protect them. Red blood cells are broken down in the circulation rather than the spleen, which gives rise to PNH symptoms such as abdominal pain, difficulty swallowing, erectile dysfunction and red or black urine (known as haemoglobinuria). The white blood cells and platelets are ‘stickier’ increasing the risk of blood clots. Previously life expectancy was reduced as there were limited treatment options available. What was the aim of this review? To provide an overview of current and future treatment options for PNH Which treatments are available? • Eculizumab is an treatment given through a vein (intravenous) every week for 5 weeks then every 2 weeks after this, and has been available for 13 years, improving life expectancy to near normal. • Ravulizumab is a newer intravenous treatment similar to eculizumab but is given every 8 weeks instead of every 2 weeks. In clinical studies it was comparable with eculizumab. • Future Treatments - There is new research looking at different methods of treatment delivery, including injections under the skin (subcutaneous) that patients can give themselves, treatments taken by mouth (oral) or a combination of an intravenous and oral treatment for those patients who are not optimally controlled on eculizumab or ravulizumab. What does this mean? PNH is now treatable. For years, the only drug available was eculizumab, but now different targets and drug trials are available. Ravulizumab is currently the only second licenced product available, in USA and Europe, there are other medications active in clinical trials. Why is this important? The benefit for patients, from treatment every 2 weeks to every 8 weeks is likely to be improved further with the development of these new treatments, providing patients with improved disease control and independence. As we move into an era of more patient-friendly treatment options, the PNH community both physicians and patients look forward to new developments as discussed in this article.

Introduction: Hematopoiesis is severely reduced in severe aplastic anemia (SAA) probably due to immunological destruction of hematopoietic stem and progenitor cells. Bone marrow transplantation is preferred as first-line therapy in patients younger than 40 years with a matched related sibling donor. For those who are not candidate for transplant, immunosuppressive therapy with horse antithymocyte globulin (hATG) plus cyclosporine (CsA) remains the standard of care. However, hATG was discontinued in most Asian, South American, and European countries with only rabbit ATG (rATG) available. rATG is a more potent immunosuppressant which has associated with a worst hematological response and survival at 6 months in prospective studies. Using rATG in first-line therapy appears to add little to what has been observed with CSA alone. Alemtuzumab (ALZ), a humanized anti-CD52 monoclonal antibody is also active in AA due to its lymphocytotoxic properties. The use of ALZ in monotherapy has shown an overall response rate (ORR) comparable to that of r-ATG (37% and 33%, respectively) when applied as salvage (following hATG failure) in a randomized study. Other experiences which combined ALZ and CsA led to a 58% ORR in SAA patients after a cumulative dose of 103 mg of subcutaneous (SC) ALZ. Here we describe a multicenter retrospective analysis of SC ALZ in association with CsA for patients with AA. Methods: We retrospectively analyzed all patients who received outpatient SC ALZ for the treatment of aplastic anemia in 2 centers: Universidade Federal de Sao Paulo (Sao Paulo-BRAZIL) and Leeds Teaching Hospitals, UK from March 2009 until March 2019. In Sao Paulo, alemtuzumab total dose was 103 mg in an escalating dose of 3-10-30-30-30 mg, except for three elderly patients who received a total dose of 73. In Leeds-UK, total dose varied from 120 mg to 150 mg. The primary outcome was overall response rate (ORR) at six months. Median follow up was 31 months (range 4-110 months). Results: We identified 35 treatments with SC ALZ in 32 AA patients of which 78% had SAA or very severe aplastic anemia. Calcineurin inhibitors were used in association with ALZ in 80% of cases (cyclosporine in 26 cases, tacrolimus in 2 cases). Median age was 44 years (range: 18-79), and nineteen patients (59%) were male. Seventeen patients (53%) were treatment-naïve, and six patients (19%) had one prior line of therapy. Nine patients (28%) were relapsed/refractory, and received ALZ after at least two lines of prior therapy. Seventeen patients (53%) presented a PNH clone at diagnosis. Median time between diagnosis and ALZ treatment was 6 months (range 1-293). No treatment-related serious adverse events were observed. Infectious complications were infrequent: there was only one case of successfully treated CMV reactivation and one case of fatal EBV-related infection. ORR at 6 months was 57% (complete response: 11%, partial response: 46%), with corresponding cumulative incidence of response of 47% at 6 months and 62% at 1 year (figure 1). ORR was 69% in treatment-naïve patients younger than 60 years. Overall survival was 72% at 2 years. Adverse events were of low grade and infectious events were infrequent. Conclusion: Subcutaneous alemtuzumab appears to be a feasible, effective and safe alternative to hATG in patients with AA requiring immunosuppressive treatment, especially in centers with limited access to hATG. Disclosures Hill: Apellis: Honoraria; Roche: Honoraria; Akari: Honoraria; Alexion: Honoraria; Bioverativ: Honoraria; Novartis: Honoraria; Regeneron: Honoraria; Ra Pharma: Honoraria. Munir:AbbVie: Honoraria; Alexion: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Roche: Honoraria; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis: Consultancy; Pharmacyclics: Other: TBC; Acerta: Membership on an entity's Board of Directors or advisory committees. Hillmen:Roche: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses, Research Funding; Apellis: Research Funding; Gilead: Research Funding. Risitano:Achillion: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Biocryst: 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; Alnylam: Research Funding; Achillion: Research Funding; Alexion: Honoraria, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; Ra Pharma: Research Funding; Apellis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Research Funding, Speakers Bureau. Scheinberg:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer,: Speakers Bureau; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau.

In the developed world, the incidence of human immunodeficiency virus (HIV)-related non-Hodgkin lymphoma (NHL) has significantly declined since the introduction of effective anti-retroviral therapy...

Background:Uncontrolled complement activation plays a pivotal role in a variety of disorders such as paroxysmal nocturnal hemoglobinuria (PNH). Challenges to be addressed with eculizumab therapy include inter-individual variation in clearance of eculizumab, economic burden, and improvements in the current biweekly intravenous infusion maintenance schedule. ALN-CC5 is a subcutaneous (SC) investigational RNA interference (RNAi) therapeutic targeting hepatic complement C5 (C5) synthesis. Previously presented data from our ongoing Phase 1/2 study showed that ALN-CC5 was generally well tolerated and exhibited a clamped C5 knockdown and complement activity inhibition in healthy volunteers (Hill et al. Haematologica 2016; 101, Suppl 1). The aim of this abstract is to report updated tolerability and clinical activity of ALN-CC5 in patients with PNH. Methods: A phase 1/2 single-ascending dose (Part A) and multiple-ascending dose study (Part B) of ALN-CC5 was conducted in healthy adult volunteers and in patients with PNH (Part C). In Part C, patients with PNH received weekly doses of 200 mg or 400 mg of ALN-CC5 for 2 to 16 weeks; ALN-CC5 is administered subcutaneously at a concentration of 200 mg/mL. The primary endpoints are safety and tolerability and secondary endpoints include: pharmacokinetics (PK), reduction of circulating C5 and complement activity, as measured by CAP/CCP Wieslab ELISA assays and sheep erythrocyte hemolysis assay, as well as reduction in LDH. Results: Part C included 6 patients with PNH (treatment naïve n=3; patients receiving eculizumab n=3), including 1 patient who was experiencing breakthrough hemolysis despite receiving 1200mg eculizumab q2wk. ALN-CC5 was generally well tolerated in patients with PNH after multiple doses with the majority of adverse events (AEs) being mild or moderate in severity. There were no serious AEs or discontinuations due to AEs. One patient, who was also taking eculizumab, cyclosporine and anabolic steroids as concomitant medications, experienced a transient asymptomatic grade 3 elevation of liver transaminases that was deemed possibly related to study drug. In eculizumab naïve patients (n=3), ALN-CC5 monotherapy achieved a mean maximum C5 knockdown of 98.2% ± 0.3%, residual C5 levels of 0.9 mcg/mL and a mean maximum CCP inhibition of 94.2 ± 1.7%. During treatment with ALN-CC5, maximum reduction in LDH was 37% and 50% in 2 patients who received 17 doses of ALN-CC5 but remained above the goal of less than 1.5 times the ULN. In the remaining eculizumab naïve patient, LDH lowering was not observed following 8 doses of ALN-CC5. After completion of ALN-CC5 dosing and in the setting of ongoing >95% ALN-CC5-mediated KD of serum C5, treatment naïve patients received a single 600 mg dose of eculizumab (labeled induction dose is 600 mg weekly x 4) for the treatment of residual hemolysis followed by close clinical monitoring. An exploratory analysis was conducted to understand the potential for ALN-CC5 to reduce eculizumab dose and frequency. All 3 patients achieved sustained lowering of LDH Conclusion: ALN-CC5 was shown to be generally well tolerated in patients with PNH. The PD effects of ALN-CC5 were found to be durable, with clamped C5 knockdown and complement activity inhibition. Collectively, the data suggest that clamped inhibition of hepatic C5 synthesis may provide the foundation to potentially reduce the dose and frequency of eculizumab administration for patients with PNH, and to improve disease control in patients with inadequate response to eculizumab. Disclosures Hill: Alnylam Pharmaceuticals: Consultancy, Honoraria. Griffin:Alexion Pharmaceuticals: Honoraria, Other: Conference support. Munir:Alexion pharmaceuticals: Honoraria. Borodovsky:Alnylam Pharmaceuticals: Employment, Equity Ownership. Kawahata:Alnylam Pharmaceuticals: Employment, Equity Ownership. Mclean:Alnylam Pharmaceuticals: Employment, Equity Ownership. Shi:Alnylam Pharmaceuticals: Employment, Equity Ownership. Partisano:Alnylam: Employment, Equity Ownership. Kim:Alnylam Pharmaceuticals: Employment, Equity Ownership. Najafian:Alnylam Pharmaceuticals: Employment, Equity Ownership.

Introduction Aplastic anaemia (AA) affects 1-2 per million of the UK population. At least 50% of patients have a Paroxysmal Nocturnal Hemoglobinuria (PNH) clone, which may either require monitoring or concomitant management with the aplasia if clinical indications for eculizumab are fulfilled. There is a paucity of data available to guide concurrent treatment for AA and PNH. Method The UK PNH National Service (Leeds and London) database was reviewed retrospectively. Patients commencing eculizumab within a year of AA treatment, or those treated for aplasia who were already established on eculizumab were selected. Response to AA therapy was assessed according to aplastic anaemia guidelines. Results Twenty six patients were identified who were treated with eculizumab and immunosuppressive therapy (IST) concurrently. Median age 39.5 years (range 7-75). Median granulocyte clone immediately prior to eculizumab was 82%. Ten patients had severe AA, 15 non severe and one had hypoplastic MDS. Treatment varied as per national guidelines dependant on patient's age, patient choice, prior treatment and co-morbidities. Eight patients received ATG and ciclosporin (median follow-up 21 months post ATG treatment), 14 patients received ciclosporin monotherapy (median follow-up from commencement of ciclosporin 29 months). One patient received androgens as a single agent achieving a partial response (PR),3 patients underwent haematopoietic stem cell transplant (HSCT) as initial treatment at the time of eculizumab and IST overlap (5 other patients received HSCT as discussed below). Six of the 8 (75%) patients receiving ATG+Ciclosporin responded, one patient achieved complete remission (CR) and five PR, one of whom subsequently achieved a CR with androgen therapy. Two patients did not respond and both achieved a CR after HSCT. In five patients who had data available six months post ATG there was no change in the median granulocyte or monocyte PNH clone size. Of 14 patients treated with single agent ciclosporin, 1 patient achieved CR; 7 PR, 2 of whom achieved a subsequent CR with further therapy ( androgens N=1, HSCT N=1); 6 had no response, 3 of whom received subsequent treatment, two HSCT (one achieved a CR and one died), and one eltrombopag (response awaited; follow-up 12 weeks) . Three patients underwent HSCT during the defined entry criteria above. 2 had frontline HSCT, and 1 had a transplant due to late relapse following ATG and ciclosporin 6 years prior. Five other patients underwent HSCT as discussed above for second or third line treatment (ATG and ciclosporin N=2, ciclosporin single agent N=3). All transplant patients achieved a CR except 1 who died during the procedure. All 7 patients who survived transplant stopped eculizumab due to resolution of PNH. Six of 26 (9.8%) patients died,1 who achieved a CR with HSCT and died 2 years later of GVHD , two patients who had achieved a partial response to treatment one of whom died of infection, two had not responded to treatment, and one HSCT recipient died during the procedure. Fourteen age matched controls not on eculizumab received similar therapies, 9 of whom received ATG and ciclosporin, median follow-up from ATG commencement 37 months. Four of the 9 had a CR, 1 had a CR then a relapse with no response to the re-introduction of ciclosporin, 3 had a partial response one of whom achieved a CR with androgens and 1 patient had no response achieving a CR with HSCT. 5 matched controls were treated with ciclosporin single agent, median follow-up from ciclosporin commencement 115 months. Two patients had a CR, 1 had a PR then relapsed, 2 had no response. Conclusion This is the largest reported cohort of patients receiving concurrent treatment for both AA and PNH. The presence of symptomatic PNH requiring complement inhibition should not influence AA treatment decisions. The response rates for IST in patients on eculizumab compared with age matched controls were similar, with similar numbers of patients achieving CR or PR with immunosuppressive therapy, suggesting no detriment to response to IST with concurrent eculizumab therapy. Therefore, patients with concurrent AA and PNH should be treated as per AA guidelines and PNH can be managed concurrently if required. This strategy will increasingly be required in the future, especially with improved life expectancy for PNH patients receiving complement inhibition therapy. Eculizumab therapy does not appear to affect response to IST for AA patients Disclosures Griffin: Alexion Pharmaceuticals: Honoraria, Other: Conference support. Kulasekararaj:Alexion pharmaceuticals: Honoraria, Other: conference support. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Munir:Alexion pharmaceuticals: Honoraria. Richards:Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding. Arnold:Alexion Pharmaceuticals: Honoraria. Riley:Alexion pharmaceuticals: Other: Travel for conference. Marsh:Alexion pharmaceuticals: Honoraria. Hill:Alnylam Pharmaceuticals: Consultancy, Honoraria.