Eculizumab Research Articles (Page 1)

Abstract Background and Aims Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) caused by an uncontrolled complement activation, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. Before the availability of treatment with C5 complement inhibitor drugs, the prognosis of aHUS in both pediatric and adult patients was unfavorable despite the use of plasmapheresis or plasma infusion, with a mortality rate during the acute phase of 25%. In fact, the advent of Eculizumab (ECZ), humanized monoclonal antibody directed against the C5 complement factor, has drastically altered the natural history of aHUS, improving prognosis and ensuring rapid recovery of renal function. Although highly effective for the treatment of patients with aHUS since its approval in 2011, ECZ requires intravenous infusions every two weeks, increasing infusion burden, in-hospital visits, patient journey and limiting patients’ and caregivers’ quality of life. Therefore, through targeted modifications of ECZ to enhance antibody recycling, a new anti-C5 monoclonal antibody called Ravulizumab (RVZ) was developed. RVZ presents a optimized halflife in comparison with ECZ, allowing intravenous infusions every 8 weeks. The clinical efficacy and safety of RVZ in adults and pediatric patients with aHUS has been demonstrated in several clinical trials. Although RVZ has been approved for the treatment of aHUS in the United States, Europe, and Japan there is currently no large real-life evidence of the mid- and long-term effects of therapy switch from ECZ to RVZ. Method From June 2023 to January 2025, 15 patients followed at our center for aHUS on ECZ therapy made the switch to RVZ. RVZ was administered via intravenous infusion based on bodyweight. Patients received a first loading infusion of RVZ on day 1, which was 14 days from the last dose of ECZ, followed by maintenance doses administered on day 15 and every 8 weeks thereafter. Patients were followed regularly during follow-up with baseline hematochemical examinations performed on day 1 and then approximately every 8 weeks (preinfusion). t-test for paired data was used to analyze data. Results Patients have a median age of 50.5 (SD 9.4) years and are predominantly female (9 patients). Four patients are on hemodialytic replacement treatment for ESKD, seven patients are on conservative therapy for chronic kidney disease (CKD), and four patients are normal renal function. All patients underwent genetic testing, showing mutations in complement genes in 9 patients. The test was negative in three patients and was still ongoing in three patients. The mean follow-up was 390 (SD 168) days. Baseline and post switch lab values are summarized and compared in Table 1. No patient required hemodialytic treatment at any time during RVZ therapy, and renal function, as measured by eGFR values, remained constant throughout follow-up. No signs of disease recurrence. All patients preserved the same stage of CKD observed at baseline. Throughout the observation period, hematological parameters and indices of hemolysis (platelets, hemoglobin, haptoglobin, LDH) remained stable. Spaghetti Plot image shows the trend of laboratory values for each individual patient. Two adverse events of post-infusion asthenia (unrelated to CPK increase or otherwise) were recorded during follow-up. No other unexpected adverse events were recorded. Conclusion RVZ represents an important therapeutic option for aHUS patients. Long-term treatment with RVZ was well tolerated and associated with stable renal function and hematological parameters. In addition, the reduced infusion frequency of RVZ reduces the therapeutic burden and, as a result, may improve the quality of life for patients and their caregivers.

ABSTRACTIntroductionSB12 demonstrated equivalence to reference eculizumab (ECU) in complement inhibitor‐naïve patients with paroxysmal nocturnal hemoglobinuria (PNH) in the previous randomized, double‐blind, multi‐national, crossover, Phase III study.MethodsThe scope of this post‐hoc study was subgroup analysis by race to compare the efficacy and safety of SB12 and ECU in PNH patients in the Asian and Non‐Asian subgroups of the Phase III study.ResultsResults including lactate dehydrogenase (LDH), number of units of packed red blood cells and safety as primary and secondary endpoints demonstrated comparable efficacy and safety of SB12 and ECU in Asian and Non‐Asian PNH patients, in line with the study results in the overall population. In addition, transfusion avoidance (68.1% for SB12 vs. 72.9% for ECU, p‐value of 0.4492) and hemoglobin stabilization (SB12–ECU: 6.3%, 95% confidence interval [CI] [‐21.5, 34.1] and SB12–ECU: 2.5%, 95% CI [‐24.8, 29.8] using stringent criteria) as post‐hoc endpoints were not substantially different between SB12 and ECU treatment groups in the overall population as well as in Asians and Non‐Asians.ConclusionIn conclusion, this subgroup analysis by race (Asians and Non‐Asians) supports comparable efficacy and safety between SB12 and reference eculizumab in global PNH patients including no difference in transfusion avoidance effect.

Attack prevention is crucial in managing neuromyelitis optica spectrum disorders (NMOSDs). Eculizumab (ECU), an inhibitor of the terminal complement cascade, was highly effective in preventing attacks in a phase III trial of aquaporin-4 (AQP4)-IgG seropositive(+) NMOSDs. In this article, we evaluated effectiveness and safety of ECU in routine clinical care. We retrospectively evaluated patients with AQP4-IgG+ NMOSD treated with ECU between December 2014 and April 2022 at 20 German and 1 Austrian university center(s) of the Neuromyelitis Optica Study Group (NEMOS) by chart review. Primary outcomes were effectiveness (assessed using annualized attack rate [AAR], MRI activity, and disability changes [Expanded Disability Status Scale {EDSS}]) and safety (including adverse events, mortality, and attacks after meningococcal vaccinations), analyzed by descriptive statistics. Fifty-two patients (87% female, age 55.0 ± 16.3 years) received ECU for 16.2 (interquartile range [IQR] 9.6 - 21.7) months. Forty-five patients (87%) received meningococcal vaccination before starting ECU, 9 with concomitant oral prednisone and 36 without. Seven of the latter (19%) experienced attacks shortly after vaccination (median: 9 days, IQR 6-10 days). No postvaccinal attack occurred in the 9 patients vaccinated while on oral prednisone before starting ECU and in 25 (re-)vaccinated while on ECU. During ECU therapy, 88% of patients were attack-free. The median AAR decreased from 1.0 (range 0-4) in the 2 years preceding ECU to 0 (range 0-0.8; p < 0.001). The EDSS score from start to the last follow-up was stable (median 6.0), and the proportion of patients with new T2-enhancing or gadolinium-enhancing MRI lesions in the brain and spinal cord decreased. Seven patients (13%) experienced serious infections. Five patients (10%; median age 53.7 years) died on ECU treatment (1 from myocardial infarction, 1 from ileus with secondary sepsis, and 3 from systemic infection, including 1 meningococcal sepsis), 4 were older than 60 years and severely disabled at ECU treatment start (EDSS score ≥ 7). The overall discontinuation rate was 19%. Eculizumab proved to be effective in preventing NMOSD attacks. An increased risk of attacks after meningococcal vaccination before ECU start and potentially fatal systemic infections during ECU-particularly in patients with comorbidities-must be considered. Further research is necessary to explore optimal timing for meningococcal vaccinations. This study provides Class IV evidence that eculizumab reduces annualized attack rates and new MRI lesions in AQP4-IgG+ patients with NMOSD.

Ravulizumab Treatment during Pregnancy: A Case Report

Neurological complications pose a significant threat in pediatric hemolytic and uremic syndrome (HUS) resulting from infections with Shiga toxin-producing Escherichia coli (STEC), with no established treatment. The involvement of complement activation in the pathogenesis of STEC-HUS is acknowledged, and eculizumab (ECZ), a terminal complement blocker, has been documented in several pediatric series with inconsistent results. Antibody-mediated mechanisms have also been suggested, with IgG-immunoadsorption (IgIA) showing promise in adults with neurological complications. We aimed to assess the benefit of combining IgIA with ECZ in pediatric patients with neurological STEC-HUS compared to patients treated with ECZ alone or supportive care. Multicenter retrospective study conducted on pediatric patients (< 18years) with neurological STEC-HUS treated with IgIA + ECZ or ECZ alone from 2010 to 2020 in France. A historical cohort treated with supportive care served as controls. Primary outcome included survival and neurological evaluation at 1-year follow-up (dichotomized as normal vs. abnormal). A total of 42 children were included: 18 treated with IgIA + ECZ, 24 with ECZ alone, and 27 with supportive care. Although there was no significant difference in survival between groups, three deaths occurred in the control group in the acute phase, while none was reported in both the IgIA + ECZ and ECZ alone groups, despite presenting with more severe neurological symptoms for IgIA + ECZ patients. No significant association was found between treatment group and 1-year neurological evaluation after adjustment for age, sex, and initial neurological presentation. Systematic association of IgIA + ECZ is not supported for all neurological STEC-HUS pediatric patients; potential rescue therapy for severe cases warrants consideration.

PurposeTo describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships.MethodsThe PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA).ResultsThe two-compartment model adequately described the PK of SB12 and ECU, and the subject’s weight was chosen as a clinically significant covariate affecting drugs’ clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid Emax and sigmoid Emax relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients.ConclusionThe population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12.

We determined normalization rates for hemoglobin, lactate dehydrogenase (LDH), and fatigue in patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with pegcetacoplan (PEG) in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) phase III trials. Enrolled patients had PNH and hemoglobin <10.5 g/dL despite ≥3 months of eculizumab (ECU) [PEGASUS], or were complement component 5 (C5) inhibitor-naive, receiving supportive care only, with hemoglobin less than the lower limits of normal (LLN) [PRINCE]. Hematologic and fatigue normalization endpoints were hemoglobin greater than or equal to the LLN (females: 12 g/dL; males: 13.6 g/dL) in the absence of transfusion; LDH ≤226U/L in the absence of transfusion; and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue ≥43.6, the general population norm. Safety was assessed by investigators using standardized terms and definitions for seriousness and severity. Hemoglobin normalization occurred in 34.1% (14/41) of PEG-treated patients at Week 16 (randomized controlled period) in PEGASUS (vs. 0% [0/39] of ECU-treated patients) and in 45.7% (16/35) of PEG-treated patients at Week 26 in PRINCE (vs. 0% [0/18] of supportive care-treated patients). At Week 48 (open-label period) in PEGASUS, 24.4% of PEG-treated patients (PEG-to-PEG) and 30.8% of patients treated with ECU through Week 16 who switched to PEG through Week 48 (ECU-to-PEG) had hemoglobin normalization. Rates of LDH normalization in PEGASUS were 70.7% (PEG-treated patients) and 15.4% (ECU-treated patients) at Week 16, and 56.1% (PEG-to-PEG) and 51.3% (ECU-to-PEG) at Week 48. In PRINCE, 67.5% of PEG-treated patients at Week 26 had normalized LDH concentrations. Rates of FACIT-Fatigue score normalization in PEGASUS were 48.8% and 10.3% in PEG- and ECU-treated patients, respectively, at Week 16, and 34.1% and 51.3% in PEG-to-PEG- and ECU-to-PEG-treated patients, respectively, at Week 48. In PRINCE, 68.6% of PEG-treated patients and 11.1% of supportive care patients had FACIT-Fatigue score normalization at Week 26. PEG was safe and well tolerated. Injection site reactions, mostly mild, were the most common adverse event of special interest in PEG-treated patients in the PEGASUS randomized controlled period (36.6%) and in PRINCE (30.4%). PEG is superior to ECU and supportive care in hemoglobin, LDH, and FACIT-Fatigue score normalization for patients with PNH and persistent anemia despite ≥3 months of treatment with ECU, and in C5 inhibitor-naive patients. The PEGASUS trial (NCT03500549) was registered on 18 August 2018, and the PRINCE trial (NCT04085601) was registered on 11 September 2019.

Abstract Background Liver transplantation is limited by the number of optimal organs for transplantation. Ischaemia reperfusion injury (IRI) plays a key role in the utilisation of organs for transplantation - many organs are still not used due to concerns over viability. We evaluated the C5 inhibitor Eculizumab (EZB) in a cell model of IRI. Methods HepG2 cells, an immortalised hepatocyte cell-line, were utilised to model IRI. Cells were incubated in an anoxic chamber to model 'ischaemia' and then 'reperfused' in a normoxic incubator for 4 and 1 hours, respectively. The incubation media was supplemented with perfusate from donation after circulatory death (DCD) livers that had undergone standard normothermic machine perfusion (n=2) and EZB treated perfusate (n=2). Results The IRI model reduced cell viability and proliferation (p≤0.05). However, the model created no significant changes in the production of biomarkers VEGF, IL-10, IL-8, GDF-15 and ROS (p&amp;gt;0.05). Notably, EZB therapy significantly increased anti-inflammatory IL-10 production (p≤0.0001) and expression (p≤0.001), whilst enhancing cell viability and proliferation (p≤0.0001). Conclusion The complement system may play an important role within IRI and complement inhibition is a promising treatment for DCD livers, as demonstrated by treatment of cells with EZB therapy. Further work is required to optimise the models and treatment strategy before clinical testing.

Background: Rituximab (RTX) and eculizumab (ECU) are treatment options for refractory myasthenia gravis (MG), but comparative clinical data derived from real‐world experience are limited. Here, we describe the baseline characteristics, treatment, and safety outcomes of patients with antiacetylcholine receptor antibody‐positive (AChR+) generalized myasthenia gravis (gMG) treated with ECU and/or RTX in our clinic.Methods: Patients with refractory AChR+ gMG who received ECU or/and RTX treatment for more than 1 year at the Department of Neurology, Istanbul Faculty of Medicine were included in this observational study. After obtaining written patient consent, data were collected retrospectively from medical records.Results: Twelve patients treated with ECU and 25 patients treated with RTX were included in the analysis. Groups were comparable with regard to demographic and clinical characteristics, including age at onset of MG, disease duration, and history of thymoma. ECU was associated with significantly better outcomes compared with RTX, as measured by decreases in the mean MG activities of daily living score at 1 (p = 0.024), 3 (p &lt; 0.001), 6 (p &lt; 0.001), and 12 (p &lt; 0.001) months of treatment; steroid‐sparing effect after 1 year of treatment (decrease in mean [standard deviation] daily prednisolone dose of −21.8 mg [13.5] vs. −6.6 mg [9.4] with RTX; p &lt; 0.001); and need for rescue treatment and number of myasthenic crisis episodes during treatment (p &lt; 0.001). No new safety signals were observed with either treatment.Conclusion: Our data provide real‐world evidence supporting ECU over RTX to treat patients with refractory AChR+ gMG.

Incremental Burden Associated with Dose Escalation in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Complement Inhibitors

Efficacy of SB12 (Eculizumab Biosimilar) in Asian and Non-Asian Patients with Paroxysmal Nocturnal Hemoglobinuria: Subgroup Analysis of a Global Phase III Randomized Controlled Trial

Abstract Background and Aims Clinical differentiation of pregnancy-associated thrombotic microangiopathies is challenging and can occur in conjunction with or mimic conditions including hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome, pre-eclampsia (PET), thrombotic thrombocytopenia purpura (TTP) and atypical HUS (aHUS). aHUS that occurs during pregnancy classically presents in the third trimester. When kidney transplantation is performed in aHUS patients, disease recurrence is high and can be associated with transplant failure. Here, we report a unique case of aHUS that presented early during pregnancy where the patient subsequently underwent kidney transplantation. Method We present a case report. Ethics approval was obtained by the Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board. Results A 30 year old G2P0A1 diabetic African American woman presents at 9 weeks gestation with new hypertension. At 18 weeks, she developed acute kidney injury and proteinuria. Further investigations revealed hemoglobin 68 g/L, platelets 120 x 109/L, increased LDH 588 U/L, undetectable haptoglobin and schistocytes on blood smear. Creatinine was 88 umol/L, increased from a baseline of 50 umol/L, and proteinuria greater than 1 g/day. Pre-eclampsia was ruled out as her presentation began at 9 weeks gestation, prior to placental implantation. Placental growth factor levels at 24 and 28 weeks remained &amp;gt;100 pg/mL. HELLP syndrome was excluded given the timing in pregnancy and normal liver enzymes. TTP was excluded with a normal ADAMTS13. Complement Factor H autoantibody was negative. Complement studies revealed grossly elevated soluble C5b-9 level (sC5b-9) of 1.05 (normal &amp;lt;0.3 mg/L). aHUS was diagnosed and she began treatment with eculizumab (ECU). Ex-vivo serum C5b-9 deposition on human microvascular endothelial cells was assessed and was severely abnormal pre-treatment with ECU (activated 223%, normal &amp;lt;150%), and normalized with ECU therapy (activated 123%, normal &amp;lt;150%). Genetic testing eventually revealed a Complement Factor I mutation, NM_000204.3:c.550G/A, p. Vall84Met reported as likely pathogenic and confirming primary aHUS. Due to worsening renal function, she delivered a healthy boy at 30 weeks gestation by Caesarean section. A renal biopsy performed 3 weeks post-partum demonstrated features of TMA, mainly chronic (i.e. treated) and severe diabetic nephropathy with advanced glomerular sclerosis. Six months post-partum, she required dialysis. She remained on ECU and had an unrelated living kidney transplantation 1.5 years later. Her kidney transplantation included basiliximab and methylprednisolone induction. Calcineurin inhibitors were prescribed in standard fashion. Given severity of original multiorgan aHUS and CFI mutation, she was treated with eculizumab 1200 mg the day prior to surgery and another 1200 mg on post operative day 1. Subsequently she was given eculizumab 900 mg weekly for 4 weeks then 1200 mg every 2 weeks. Eculizumab drug level for adequacy of complement blockade was measured on day 4 post transplant and was 279 (therapeutic &amp;gt;100 mcg/mL) and sC5b-9 was 1504 (normal &amp;lt; 244). Repeated ECU level pre 900 mg dose was 189 and sC5b-9 was 392. 6 months post transplant she has excellent graft function without proteinuria (urine ACR 2.2 mg/mmol) or evidence of aHUS recurrence. Conclusion aHUS, although described to occur late in pregnancy or post-partum, presented here during the first trimester. Thus, TMA in pregnancy is not always PET or HELLP. aHUS is a treatable condition in pregnancy, and should be considered as a possibility particularly for presentations occurring prior to 20 weeks gestation. Complement function studies may aid in aHUS diagnosis. Despite extra ECU dosing and therapeutic ECU levels for this patient post kidney transplantation, she had evidence of massive C5 release (grossly elevated sC5b-9 level). sC5b-9 measurement post transplantation may be useful to guide ECU dosing.

Real-world data on eculizumab treatment in NMOSD: high efficacy and potential challenges (P13-5.017)

Objective Assess number needed to treat (NNT) and costs required to achieve improvements in symptoms and functional activities with targeted therapies for myasthenia gravis (MG). Background NNT and cost per improved efficacy can help inform comparative clinical efficacy and cost-effectiveness across MG treatments. Design/Methods Relative to conventional therapy (CT), NNTs and annual costs for achieving one point improvement in Quantitative Myasthenia Gravis score (QMG), one additional patient with minimal clinically important difference (MCID) in QMG (i.e., = 3 points improvement), and one additional patient achieving minimal symptom expression (MSE; Myasthenia Gravis-Activities of Daily Living score of 0 or 1) were estimated for efgartigimod (EFG), intravenous immunoglobulin (IVIg), and eculizumab (ECU). All treatments were used in conjunction with CT. Costs per improved outcome (CPR) were compared between EFG, IVIg, and ECU. Efficacy evaluated at week 4 of respective phase 3 randomized trials (ADAPT [NCT03669588], NCT02473952, REGAIN [NCT01997229]. Annual drug acquisition and administration costs (2021 USD) were considered. Results Compared with CT, mean NNTs to achieve one point improvement and MCID in QMG were 0.19 and 2.03 for EFG, 0.52 and 7.14 for IVIg, and 0.56 and 6.25 for ECU. NNTs to achieve an additional patient with MSE was 3.46 for EFG and 8.13 for ECU. Compared to EFG, the mean annual CPR to achieve one point improvement and MCID in QMG were higher for IVIg (Difference [95% confidence interval] = $36,130 [$14,024, $58,237] per point improvement in QMG; $661,561 [$0, $1,546,275] per one patient with MCID in QMG) and ECU ($340,659 [$158,038, $523,280]; $3,838,718 [$1,470,740, $6,206,695]). Cost to achieve one additional patient with MSE was $4,761,649 [$2,859,671, $6,663,626] higher for ECU compared with EFG. Conclusions Evidence indicates more favorable treatment benefit and economic value for EFG with fewer NNT and lower cost required to achieve improved outcomes compared to other treatments.

A Matching-Adjusted Indirect Comparison of the Efficacy of Pegcetacoplan Using Prince Trial Data Versus Ravulizumab and Eculizumab in Complement Inhibitor-Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria

Sensitivity Analysis on the Primary Efficacy Results of SB12 (Eculizumab Biosimilar) Phase III Study in Paroxysmal Nocturnal Hemoglobinuria Patients

Pegcetacoplan Corrects Hyperbilirubinemia in Both Untreated Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) and in Patients with PNH Who Previously Received Eculizumab

Intensive Pegcetacoplan Dosing in the Management of Acute Hemolysis As Part of the 307 Open-Label Extension Study

Background: SB12, a proposed eculizumab biosimilar, is a humanized monoclonal antibody that blocks complement C5 cleavage, thereby inhibits terminal complement-mediated intravascular hemolysis. Aims: The randomized, double-blind, multicenter, cross-over study was aimed to demonstrate comparable clinical efficacy by evaluating the lactate dehydrogenase (LDH), safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of SB12 and reference eculizumab (ECU) in paroxysmal nocturnal hemoglobinuria (PNH) patients (NCT04058158). Methods: A total of 50 patients aged ≥ 18 years with a confirmed diagnosis of PNH and ≥ 1.5 upper limit of normal range (ULN) of LDH without previous exposure to a complement inhibitor were included. All patients provided written informed consents and were randomized (1:1) to treatment sequence I (TS1: SB12 to ECU, n=25) or II (TS2: ECU to SB12, n=25). Patient received 600 mg of SB12 (TS1) or ECU (TS2) intravenously every week for first 4 weeks (initial phase) and 900 mg for the fifth week, followed by 900 mg every 2 weeks thereafter (maintenance phase). The treatment was switched to ECU (TS1) or SB12 (TS2) at Week 26, and switched treatment was provided until Week 50. Primary endpoints were LDH level at Week 26 and time-adjusted area of under the effect curve (AUEC) of LDH from Week 14 to Week 26 and Week 40 to Week 52. Equivalence was declared for LDH level at Week 26 if the two-sided 95% confidence interval (CI) of the mean difference in between SB12 and ECU lied within the pre-defined equivalence margin of [−1.2 × ULN, 1.2 × ULN] = [−337.2, 337.2], where ULN = 281 U/L. Equivalence was declared for time-adjusted AUEC of LDH if the two-sided 90% CI of the ratio of geometric means between SB12 and ECU lied within the pre-defined equivalence margin of [0.77, 1.29]. Secondary endpoints were LDH profile over time and number of units of packed red blood cells (pRBCs) transfused throughout the study period, safety, PK, PD, and immunogenicity. Results: Of the 50 randomized patients, 49 patients received the study treatment and 46 patients completed the study. Baseline demographic and disease characteristic were comparable between the two treatment sequences. The 95% CI of mean difference in LDH level at Week 26 between SB12 and ECU (SB12 − ECU: 34.48, 95% CI [−47.66, 116.62]) lied within the pre-defined equivalence margin. The 90% CI of ratio of time-adjusted AUEC of LDH between SB12 and ECU (SB12/ECU: 1.08, 90% CI [0.95, 1.23]) lied within the pre-defined equivalence margin. The overall LDH profile during the study period was also comparable. The mean number of units of pRBCs transfused during Period 1 (TS1: 1.1 U; TS2: 0.9 U, respectively) and Period 2 (TS1: 1.1 U; TS2: 1.0 U, respectively) was comparable. Treatment-emergent adverse events (TEAEs) was reported in 72.3% for SB12 and 68.1% in ECU. Three patients in SB12 and 2 patients in ECU had serious TEAEs. None of three serious TEAEs reported in SB12 were related to the treatment. Two of three TEAEs (cellulitis; infusion site hypersensitivity) reported in ECU were treatment-related, and 1 death due to major adverse vascular event (portal vein thrombosis) not related to the treatment was reported in ECU. The mean eculizumab serum trough concentrations and the mean terminal complement activities in both treatment sequences were comparable. No patient developed anti-drug antibodies during the study period. Image:Summary/Conclusion: SB12 showed clinical equivalence to ECU measured by LDH. SB12 and ECU were comparable in terms of safety, PK, PD, and immunogenicity.

Background: Thrombosis is the main life-threatening complication of paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired hematologic disease. Pegcetacoplan (PEG) is a C3 complement-inhibitor approved by the FDA/EMA for treatment of adults with PNH. Aims: This post hoc analysis examined incidence of thrombosis, anti-thrombotic therapy (ATT), and D-dimer normalization in adult patients with PNH treated with PEG in the Phase 3 PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. Methods: PEGASUS enrolled adult patients with PNH with prior suboptimal response to eculizumab (ECU) despite stable ECU treatment (≥3 months) and hemoglobin (Hb) levels <10.5 g/dL at screening. For the randomized controlled period (RCP), patients were randomized 1:1 to ECU (n=39) or PEG (n=41; 1080 mg subcutaneously [sc] 2x weekly) for 16 weeks. Thereafter, ECU patients were switched to PEG monotherapy and PEG RCP patients remained on PEG during the open-label period (OLP, n=77) through Week 48. PRINCE compared PEG treatment (n=35; 1080 mg sc 2x weekly) in complement-inhibitor-naïve patients to patients receiving control treatment (CTRL; excluding complement-inhibitors i.e., ECU/ravulizumab; n=18). CTRL patients had the option to escape to the PEG group if Hb levels decreased ≥2 g/dL from baseline (n=11). Safety analyses in all trials included monitoring of thrombotic events. D-dimer normalization, defined as D-dimer level less than the upper limit of normal (0.5 µg/mL) was examined at baseline, Week 8, and the end of the study period (PEGASUS: 16 weeks [RCP] and 48 weeks [OLP], PRINCE: 26 weeks). Results: Prior to study entry, 31% (n=25) of PEGASUS patients (6 of these while on ECU therapy) and 9% (n=5) of PRINCE patients experienced at least one type of thrombosis. During the PEGASUS OLP, 2 of 77 patients experienced a thrombotic event, one in the setting of non-Hodgkin’s lymphoma and one during sepsis; neither event was deemed related to PEG. No patients in the PEGASUS RCP or PRINCE trial experienced a thrombotic event. Pooled analysis of completed clinical trials of PEG including PEGASUS and PRINCE indicated there were 2 cases of thrombosis in 164 patients comprising 130 patient-years (1.54 events per 100 patient-years), compared to 1.77 events per 100 patient-years for patients on ECU treatment before entry into PEGASUS. In PEGASUS, 34% (n=27) of patients were on ATT prior to study entry. During the PEGASUS RCP, concomitant ATT was observed in 37% (PEG, n=15) and 33% (ECU, n=13) of patients, and during the PEGASUS-OLP in 23% (n=18) of patients (PEG monotherapy). In PRINCE, concomitant ATT decreased from 21% (n=11) prior to the study to 7% (PEG, n=3) and 0% (CTRL, n=0) during the study. In PEGASUS, D-dimer normalization in the PEG arm increased from 73% (baseline, n=30) to 89% (Week 8, n=33) and was largely sustained at Week 16 and Week 48 (Table 1). D-dimer normalization in the ECU arm increased once ECU patients switched to PEG monotherapy, from 76% (Week 16, n=29) to 89% (Week 48, n=17) (Table 1). In PRINCE, D-dimer normalization in the PEG arm increased from 51% (baseline, n=18) to 67% (Week 8, n=18) and increased further to 68% (n=19) at Week 26 (Table 1). Image:Summary/Conclusion: Overall, these results demonstrate that PEG treatment can increase D-dimer normalization and reduces incidence of thrombotic events in patients with PNH who are complement-inhibitor naïve or remained anemic after ECU treatment, suggesting that PEG treatment is as effective as ECU in these outcomes.