Eculizumab In Patients Research Articles

US Clinical Practice Experience with Eculizumab in Myasthenia Gravis: Acute Clinical Events and Healthcare Resource Utilization.

The terminal complement inhibitor eculizumab is approved in the USA for the treatment of patients with acetylcholine receptor antibody-positive generalized myasthenia gravis (MG). The ELEVATE study aimed to examine clinical-practice outcome data on eculizumab effectiveness in US adults with MG (generalized or ocular). This paper reports the findings on MG exacerbations and crises and associated healthcare resource utilization, and the use of rescue therapy. A retrospective chart review was conducted of US adults with MG who initiated eculizumab. Outcomes assessed for up to 2 years before and after eculizumab initiation included percentages and rates per patient per year (PPPY) of exacerbations and crises (the latter defined as intubation/impending intubation), healthcare resource utilization, and rescue therapy administration. A total of 119 patients diagnosed with MG were enrolled in the study; 92 patients had ≥3 months of data both before and during eculizumab therapy and were included in the analyses. The mean rate of MG exacerbations decreased from 0.385 PPPY before eculizumab initiation to 0.152 PPPY during eculizumab treatment (p = 0.0034); the mean rate of MG crises decreased from 0.411 to 0.056 PPPY (p = 0.0018). Rates of healthcare resource utilization and rescue therapy use also decreased significantly during eculizumab treatment. This retrospective chart review analysis provides evidence for a beneficial impact of eculizumab treatment on the incidence of MG exacerbations and crises and associated healthcare resource utilization in clinical practice, and on rescue therapy use. These data further support the therapeutic benefits of eculizumab in patients with MG.

United States clinical practice experience with eculizumab in myasthenia gravis: symptoms, function, and immunosuppressant therapy use

Background/objectivesThe phase 3 REGAIN study and its open-label extension demonstrated the efficacy of the complement C5 inhibitor eculizumab in patients with treatment-refractory, acetylcholine receptor antibody–positive generalized myasthenia gravis (gMG). The aim of the ELEVATE study was to assess the effectiveness of eculizumab in clinical practice in adults with MG in the United States.MethodsA retrospective chart review was conducted in adults with MG who initiated eculizumab treatment between October 23, 2017 and December 31, 2019. Outcomes assessed before and during eculizumab treatment using a pre- versus post-treatment study design included Myasthenia Gravis–Activities of Daily Living (MG-ADL) total scores; minimal symptom expression (MSE); physician impression of clinical change; minimal manifestation status (MMS); and concomitant medication use.ResultsIn total, 119 patients were included in the study. A significant reduction was observed in mean MG-ADL total score, from 8.0 before eculizumab initiation to 5.4 at 3 months and to 4.7 at 24 months after eculizumab initiation (both p < 0.001). At 24 months after eculizumab initiation, MSE was achieved by 19% of patients. MMS or better was achieved by 30% of patients at 24 months. Additionally, 64% of patients receiving prednisone at eculizumab initiation had their prednisone dosage reduced during eculizumab treatment and 13% discontinued prednisone; 32% were able to discontinue nonsteroidal immunosuppressant therapy.DiscussionEculizumab treatment was associated with sustained improvements in MG-ADL total scores through 24 months in adults with MG. Prednisone dosage was reduced in approximately two-thirds of patients, suggesting a steroid-sparing effect for eculizumab.

Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition.

Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low-volume self-administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter, phase 3 trial evaluating the non-inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor-naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co-primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT-Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non-inferior to eculizumab in the co-primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, -2.8 [-15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, -3.9 [-14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [-11.4, 16.3]). A clinically meaningful improvement in FACIT-Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit-risk profile of crovalimab.

Effectiveness and Safety of Transitioning to Ravulizumab from Eculizumab in Patients with Generalized Myasthenia Gravis: Evidence from a Global Registry (P10-11.002)

Effectiveness and Safety of Transitioning to Ravulizumab from Eculizumab in Patients with Generalized Myasthenia Gravis: Evidence from a Global Registry (P10-11.002)

Danicopan: First Approval.

Danicopan (Voydeya®) is an oral complement factor D inhibitor that is being developed by Alexion AstraZeneca Rare Disease as add-on treatment to ravulizumab or eculizumab for patients with clinically significant extravascular haemolysis. Danicopan recently received approval in Japan for the treatment of adults with paroxysmal nocturnal haemoglobinuria (PNH) when used in addition to a complement component 5 (C5) inhibitor. Subsequently, the European Medicines Agency adopted a positive opinion recommending the granting of marketing authorisation for danicopan for the treatment of patients with PNH who continue to have residual haemolytic anaemia despite treatment with a complement C5 inhibitor. This article summarizes the milestones in the development of danicopan leading to this first approval for PNH.

Eculizumab in patients with paroxysmal nocturnal hemoglobinuria: a real-world study in China

Objective: To evaluate the efficacy and safety of eculizumab in the treatment of paroxysmal nocturnal hemoglobinuria (PNH) in China. Methods: Data from PNH patients who received at least 3 months of full-dose eculizumab and were followed for at least 3 months between December 2022 and July 2023 were retrospectively collected. We evaluated changes in clinical and laboratory parameters after 1, 2, 3, and 6 months of eculizumab treatment. The rates of breakthrough hemolysis (BTH), extravascular hemolysis (EVH), and the occurrence of adverse reactions were also monitored. Results: The study included nine patients, six males and three females, with a median age of 54 (28-69) years. 5 of the patients had classic PNH, while 4 had PNH/AA. The number of episodes of hemoglobinuria was 5 (1-25) per month before eculizumab. 4 patients required blood transfusion, 5 had thrombosis and one had renal impairment before eculizumab. The median time to eculizumab was 6 (3-7) months and the followup period was 3 (3-6) months after treatment. The number of episodes of hemoglobinuria following eculizumab was 0 (0-1). During the followup period, no additional thrombotic events occurred. LDH at any time after eculizumab was lower than at baseline, and some patients' HGB increased. All transfused patients became transfusion-independent after receiving eculizumab. The FACIT-Fatigue score improved by an average of 17.3 points following treatment. 2 patients developed BTH and improved with symptomatic treatment. There were three adverse events that caused mild symptoms. There are no serious adverse events or deaths. Conclusion: Eculizumab can effectively control the hemolytic-related symptoms of PNH in China, reducing the need for blood transfusions to some extent, while also demonstrating a higher safety profile.

Real-life study to assess effectiveness and safety of eculizumab in patients with neuromyelitis optica spectrum disorders in France: protocol for ECUP4, an observational study.

Eculizumab, a humanized monoclonal antibody targeting the C5 complement protein, has been approved for the treatment of neuromyelitis optica spectrum disorders (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive (Ab+). The aim of this study is to evaluate the long-term effectiveness and safety of eculizumab in French adults with NMOSD and to describe patients' characteristics, disability, and quality of life using data collected in a real-world setting. This is the protocol for ECUP4, an ongoing prospective, observational, non-comparative, multicenter study conducted in 32 reference centers in France. Eligible patients must also be enrolled in NOMADMUS, a nested cohort of the French national multiple sclerosis registry (OFSEP). The primary endpoint is the annualized relapse rate. Secondary endpoints include the long-term safety of eculizumab, as well as patients' characteristics, treatment outcomes, disability, pain, visual acuity, and quality of life. Visits and treatments follow routine clinical practice. The case report forms (CRF) comprise data recorded in the context of the NOMADMUS cohort, collected during routine visits. The inclusion period is planned for 3 years, with no limitation on the number of patients enrolled. The maximum follow-up duration will be 5.5 years. The efficacy and safety of eculizumab in patients with AQP4+ NMOSD have been demonstrated in randomized clinical trials that showed a significant reduction in the risk of relapse, with a safety profile consistent with other indications. This study will provide clinical and patient-reported evidence of the benefits of eculizumab, using data from a real-world setting in France. This study is registered at the French public repertory Health data Hub, N° F20211228123801. All information can be accessed at: https://www.health-data-hub.fr/.

Translated article] Pharmacokinetics of eculizumab in adult and pediatric patients with atypical hemolytic uremic syndrome and C3 glomerulopathy

ObjectiveThe objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. MethodsObservational, ambispective, and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in 5 hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre- and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal–Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. ResultsTwenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (interquartile range (IQR) 35.7–48.8) and 10.1 (IQR 9.6–11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre- and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) μg/mL and 747.4 (standard deviation (SD) 444.3) μg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (P = .002) and decreased serum creatinine at both higher pre- and post-dose concentrations (P = .001 and P = .017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 μg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78–0.95). Finally, high inter-individual (48.9% variation coefficient (CV)) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. ConclusionsThe present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

Addition of danicopan to ravulizumab or eculizumab in patients with paroxysmal nocturnal haemoglobinuria and clinically significant extravascular haemolysis (ALPHA): a double-blind, randomised, phase 3 trial

Symptoms of anaemia due to clinically significant extravascular haemolysis can affect patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with C5 inhibitors (ravulizumab or eculizumab). The aim of this study was to assess the efficacy and safety of danicopan (ALXN2040), an investigational, first-in-class, oral complement factor D inhibitor, as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant extravascular haemolysis. ALPHA is an ongoing, international, phase 3, randomised, double-blind, placebo-controlled trial evaluating danicopan as add-on therapy to ravulizumab or eculizumab. Eligible patients were adults (age ≥18 years) with PNH and clinically significant extravascular haemolysis (haemoglobin ≤9·5 g/dL; absolute reticulocyte count ≥120 × 109/L) on ravulizumab or eculizumab for at least 6 months. Patients were randomly assigned (2:1) to danicopan or placebo added to ravulizumab or eculizumab for 12 weeks using an interactive response technology system. Randomisation was stratified based on transfusion history, haemoglobin, and patients enrolled from Japan. The initial oral danicopan dose was 150 mg three times a day; escalation to 200 mg three times a day was permitted based on clinical response. The infusion dose level of eculizumab (every 2 weeks) ranged from 900 mg to 1500 mg, and for ravulizumab (monthly or every 8 weeks) ranged from 3000 mg to 3600 mg. The primary endpoint was change in haemoglobin concentration from baseline to week 12. Here we present the protocol-prespecified interim analysis, planned when approximately 75% of participants were randomly assigned to treatment and completed or discontinued at 12 weeks. This trial is registered with ClinicalTrials.gov (NCT04469465). Individuals were randomly assigned between Dec 16, 2020, and Aug 29, 2022. At data cutoff (June 28, 2022), 73 individuals were randomly assigned, received treatment, and were analysed for safety (danicopan, n=49; placebo, n=24). The protocol-prespecified interim efficacy analysis set included the first 63 participants (danicopan, n=42; placebo, n=21). At week 12, danicopan plus ravulizumab or eculizumab increased haemoglobin versus placebo plus ravulizumab or eculizumab (least squares mean [LSM] change from baseline: danicopan, 2·94 g/dL [95% CI 2·52 to 3·36]; placebo, 0·50 g/dL [-0·13 to 1·12]; LSM difference, 2·44 g/dL [1·69 to 3·20]; p<0·0001). Grade 3 adverse events in the danicopan group were increased alanine aminotransferase (two [4%] of 49 patients), leukopenia (one [2%]), neutropenia (two [4%]), cholecystitis (one [2%]), COVID-19 (one [2%]), increased aspartate aminotransferase (one [2%]), and increased blood pressure (one [2%]), and in the placebo group were anaemia (one [4%] of 24 patients), thrombocytopenia (one [4%]), and asthenia (one [4%]). The serious adverse events reported in the danicopan group were cholecystitis (one [2%] patient) and COVID-19 (one [2%]) and in the placebo group were anaemia and abdominal pain, both in one (4%) patient. There were no serious adverse events related to study drug or deaths reported in the study. These primary efficacy and safety results show that danicopan as add-on treatment to ravulizumab or eculizumab significantly improved haemoglobin concentrations at week 12 with no new safety concerns, suggesting an improved benefit-risk profile in patients with PNH and clinically significant extravascular haemolysis. Alexion, AstraZeneca Rare Disease.

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

Background SB12 is a humanized monoclonal antibody biosimilar to reference eculizumab (ECU) which received marketing authorization in Europe in May 2023 after a comprehensive biosimilarity demonstration including non-clinical and clinical assessments. The pivotal SB12 Phase III study demonstrated equivalent clinical efficacy by evaluating lactate dehydrogenase (LDH) and comparable safety, pharmacokinetics, pharmacodynamics, and immunogenicity between SB12 and ECU in patients with paroxysmal nocturnal hemoglobinuria (PNH) (Jun Ho Jang et al., eJHaem 2022). Objective To analyze the efficacy of SB12 in Asian and non-Asian patients with PNH from the pivotal phase III study. Methods A total of 50 adult patients with a confirmed diagnosis of PNH and ≥ 1.5 upper limit of normal range (ULN) of LDH without previous exposure to a complement inhibitor (naïve) were randomized. 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), to receive 600 mg of SB12 or ECU 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). Patients were switched to ECU or SB12 at Week 26, and switched treatment was provided until Week 50. The primary endpoints included 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. In addition, 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 included the LDH profile over time. Overall, post-hoc analysis in Asian and Non-Asian (based on race) patients who received either ECU or SB12 during the study period was conducted for the aforementioned efficacy endpoints. Results Asian patients were 27 (54.0%) of total 50. Overall, 15 (60%) Asian patients and 10 (40%) Non-Asian patients were randomized to TS1 and 12 (48%) Asian patients and 13 (52%) Non-Asian patients were randomized to TS2. Baseline demographic and disease characteristic were comparable between the two treatment sequences, with no significant differences between the treatment sequences by race between Asian and Non-Asian patients. The 95% CI of mean difference in LDH level at Week 26 between SB12 and ECU in Asian (SB12 − ECU: -12.02, 95% CI [−126.87, 102.83]) and Non-Asian patients (SB12 − ECU: 76.12, 95% CI [−56.75, 208.99]) lied within the pre-defined equivalence margins (Table). The 90% CI of ratio of time-adjusted AUEC of LDH between SB12 and ECU in Asian patients (SB12/ECU: 1.01, 90% CI [0.92, 1.10]) lied within the pre-defined equivalence margin and was also comparable in Non-Asian patients (SB12/ECU: 1.15, 90% CI [0.90, 1.46]). The overall LDH profile during the study period was also comparable between Asian and Non-Asian patients. No patient developed anti-drug antibodies during the study period and no patient discontinued due to lack of efficacy. While the limited sample size suggests for caution, the comparable efficacy results by Asian and Non-Asian subgroups are also comparable to previously published results in the overall population (Jun Ho Jang et al., eJHaem 2022), with no significant differences identified. Conclusion SB12 showed comparable efficacy to ECU in complement-inhibitor naïve PNH patients in both Asian and Non-Asian subgroups. No patient developed anti-drug antibodies nor discontinued due to lack of efficacy during the study period.

Экулизумаб в лечении атипичного гемолитико-уремического синдрома, связанного с беременностью: ретроспективное исследование у 85 пациенток

To evaluate the efficacy of prompt and delayed complement inhibition therapy with eculizumab in patients with pregnancy associated atypical hemolytic uremic syndrome (aHUS).

Farmacocinética de eculizumab en pacientes adultos y pediátricos con síndrome hemolítico urémico atípico y glomerulopatía C3

ObjectiveThe objective of the study was to analyze and describe the concentrations of eculizumab and the complement blockade in patients with atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy, and to define a therapeutic margin where there is a high probability of achieving therapeutic efficacy. MethodsObservational, ambispective and multicenter study that included adult and pediatric patients diagnosed with aHUS and C3 glomerulopathy from September 2020 to October 2022 in five hospitals in Spain. Eculizumab was administered at the doses recommended by the data sheet according to the European Medicines Agency (EMA). Pre-dose and post-dose concentrations of eculizumab were determined, as well as blockade of the classical complement pathway (CH50). Sociodemographic and clinical data were collected, and pharmacokinetic parameters were calculated. To establish the cut-off point for eculizumab concentrations that predicted complement blockade, Receiver Operating Characteristic (ROC) curve analysis was performed. Lastly, the Kruskal-Wallis test was used to contrast the differences in different parameters according to eculizumab concentrations. ResultsTwenty-five patients were included, 19 adults (76.0%) and 6 pediatrics (24.0%), with median ages of 43.4 (IQR 35.7-48.8) and 10.1 (IQR 9.6-11.3) years, respectively. Of these, 22 (88.0%) patients were diagnosed with aHUS and 3 (12.0%) with C3 glomerulopathy. A total of 111 eculizumab concentrations were determined. Mean pre-dose and post-dose concentration values detected during the maintenance phase were 243.8 (SD 240.6) μg/mL and 747.4 (SD 444.3) μg/mL, respectively. Increased complement blockade was observed at higher pre-dose concentrations (p=0.002) and decreased serum creatinine at both higher pre- and post-dose concentrations (p=0.001 and p=0.017, respectively). Using ROC curves, it was determined that a pre-dose concentration >149.0 μg/mL was optimal to achieve complement blockade, with an AUC of 0.87 (0.78-0.95). Finally, high inter-individual (48.9% CV) with low intra-individual variabilities (11.9% CV) in eculizumab clearance were observed. ConclusionsThe present study reports supratherapeutic concentrations of eculizumab in patients with aHUS, and defines higher concentrations than those described in the data sheet to achieve blockade, thus encouraging the personalization of treatment with eculizumab.

Real-world safety profile of eculizumab in patients with paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, or generalized myasthenia gravis: an integrated analysis of post-marketing surveillance in Japan.

Eculizumab is a C5 inhibitor approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor antibody-positive generalized myasthenia gravis (AChR + gMG) in Japan. We report integrated safety data from post-marketing surveillance in these three indications, focusing on commonly occurring adverse events (AEs) and infection-related AEs. Of 1219 patients registered, 1055 (PNH: 780; aHUS: 192; AChR + gMG: 83) had available safety data. Total eculizumab exposure was 3977.361 patient-years. AEs were reported in 74.03% of patients. AEs with an incidence of ≥ 1.0 per 100 patient-years included hemolysis, headache, nasopharyngitis, renal impairment, anemia, pneumonia, upper respiratory tract inflammation, influenza, condition aggravated, and infection. The incidence of infection-related AEs was 21.30 per 100 patient-years, the most frequent types (≥ 1.0 per 100 patient-years) being nasopharyngitis, pneumonia, influenza, and infection. Meningococcal infections were reported in four patients (0.10 per 100 patient-years). Two patients died from meningococcal sepsis, with a mortality rate of 0.05 per 100 patient-years. This is the largest safety dataset on eculizumab in Japan derived from more than 10years of clinical experience. No new safety signals were observed and the safety profile of eculizumab was consistent with that in previous clinical trials and international real-world safety analyses.

#5163 RATIONAL USE OF ECULIZUMAB IN SECONDARY ATYPICAL HAEMOLYTIC UREMIC SYNDROME

Abstract Background and Aims Secondary atypical hemolytic uremic syndrome (secondary aHUS) is a heterogeneous group of thrombotic microangiopathies (TMA) associated with various underlying conditions. Unlike primary aHUS, there is still no hard evidence on the efficacy of complement blockade in treating secondary aHUS since the two main series in the literature that investigate this subject show discrepant results. Our work aims to reassess Eculizumab's efficacy in treating secondary aHUS. Method Observational, retrospective, single-center study, in which we analyzed the hematological and renal evolution of 24 patients diagnosed with secondary aHUS who received treatment with Eculizumab compared with a control cohort of 14 patients who did not receive Eculizumab. Complete renal response was defined as the recovery of renal function before the event, partial renal response as a recovery of 50% of lost glomerular filtration rate, and hematological response as normalization of hemoglobin and platelets. Results We found no statistically significant differences in baseline characteristics or disease severity between both groups. After a median of 5 doses of Eculizumab, the group of patients who received complement blockade presented a significant difference in renal response (complete in 47.8% of patients and partial in 17.4%) compared to the control cohort (complete response 14.3% and partial of 14.3%). Rates of hematological remission were similar in both groups (87% in the eculizumab cohort and 85.7% in the control cohort). Conclusion Rational and early use of Eculizumab in patients with secondary aHUS could be an effective and safe therapeutic option, guaranteeing better renal recovery compared to patients who do not receive complement blockade.

Myasthenia Gravis Activities of Daily Living (MG-ADL) Response to Eculizumab Treatment in Patients from the Generalized Myasthenia Gravis Registry (P1-5.020)

Myasthenia Gravis Activities of Daily Living (MG-ADL) Response to Eculizumab Treatment in Patients from the Generalized Myasthenia Gravis Registry (P1-5.020)

Long-term safety and effectiveness of eculizumab in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: a 2-year interim analysis of post-marketing surveillance in Japan.

The terminal complement C5 inhibitor eculizumab is approved in Japan for relapse prevention in aquaporin-4 antibody-positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and is undergoing mandatory post-marketing surveillance (PMS) of clinical use. The objective of the study is to assess the real-world, long-term safety and effectiveness of eculizumab in Japanese patients with AQP4+ NMOSD. Regulatory-mandated PMS analysis implemented as an all-case surveillance of all patients with AQP4+ NMOSD who have been treated with eculizumab in Japan since its approval in November 2019. This PMS interim analysis assessed the safety and effectiveness of eculizumab in Japanese patients with AQP4+ NMOSD from November 2019 to April 2022. Of 147 patients treated with eculizumab who consented to publication, 71 had at least one case report form collected and locked at the interim analysis data cut-off, constituting the safety analysis set; three patients from PREVENT (NCT01892345) were excluded from the effectiveness analysis set. Twelve and 10 patients in the safety and effectiveness analysis sets discontinued, respectively. In the safety analysis set, 67/71 patients (94.4%) were female, mean illness duration was 6.8 [standard deviation (SD): 6.2] years, mean age at eculizumab initiation was 50.7 (SD: 13.3) years, and mean eculizumab treatment duration was 44.6 (SD: 23.7) weeks. At diagnosis of NMOSD, 34/71 patients (47.9%) and 35/71 patients (49.3%) in the safety analysis set had symptoms of optic neuritis and transverse myelitis, respectively. In the safety analysis set, 19/71 patients (26.8%) reported adverse events, 10/71 (14.1%) reported adverse drug reactions (ADRs), and 7/71 (9.9%) reported serious ADRs; no meningococcal infections were observed. In the effectiveness analysis set, 64/68 patients (94.1%) were female, mean disease duration was 6.9 (SD: 6.3) years, mean age at eculizumab initiation was 50.6 (SD: 13.2) years, and 27/68 (39.7%) were tested for C5 genetic polymorphism (all negative). In the 2 years before eculizumab, 51/68 patients (75.0%) experienced relapse. Relapse rate was 0.02/patient-year after eculizumab initiation versus 0.74/patient-year in the 2 years before eculizumab. Overall, 37/68 patients (54.4%) were prescribed immunosuppressants in the 6 months before and 19/40 (47.5%) in the 6-12 months after starting eculizumab treatment. The proportion of patients taking >10 mg/day of prednisolone decreased from 45.6% at 24-20 weeks before to 23.1% and 0% at 48-52 and 100-104 weeks after eculizumab, respectively. This article reports interim PMS data for Japanese patients and provides updated real-world evidence for the safety of eculizumab and its effectiveness at preventing relapses in patients with AQP4+ NMOSD. Safety and effectiveness results are consistent with those from PREVENT.

Long-Term Efficacy and Safety of Eculizumab in Patients With Paroxysmal Nocturnal Hemoglobinuria and High Disease Burden: Real-World Data From Korea.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by uncontrolled terminal complement activation. Eculizumab, a monoclonal antibody C5 inhibitor was introduced in Korea in 2009 and has been the standard treatment option for PNH. This study assessed the long-term efficacy/safety of eculizumab in PNH using real-world data from the Korean Health Insurance Review and Assessment Service. Eighty patients who initiated eculizumab from 2009-2020 were enrolled. At eculizumab initiation, the median age was 51.5 years, lactate dehydrogenase (LDH) 6.8 × upper limit of normal, and granulocyte clone size 93.0%. All patients had at least one PNH-related complication before eculizumab initiation, including renal failure (n = 36), smooth muscle spasm (n = 24), thromboembolism (n = 20), and pulmonary hypertension (n = 15). The median (range) duration of eculizumab treatment was 52.7 (1.0, 127.3) months (338.6 total treated patient-years). Despite high disease activity in the study population before treatment initiation, overall survival was 96.2% and LDH levels were stabilized in most patients during treatment. PNH-related complications at treatment initiation were resolved in 44.4% of patients with renal failure, 95.8% with smooth muscle spasm, 70.0% with thromboembolism, and 26.7% with pulmonary hypertension. Extravascular hemolysis occurred in 28.8% of patients (n = 23; 0.09 per patient-year) and breakthrough hemolysis in 18.8% (n = 15; 0.06 per patient-year). No treatment discontinuation cases related to eculizumab were observed. These data provided evidence for the long-term efficacy and safety of eculizumab in Korean PNH patients with high disease burdens.

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

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

EE52 Cost-Minimisation Analysis of Ravulizumab Compared With Eculizumab in Patients With Atypical Hemolytic Uremic Syndrome (AHUS) in the Netherlands

aHUS is a rare disease characterized by a dysregulated and overactive complement system. Prior to the introduction of eculizumab, a complement C5-inhibitor, outcomes for patients with aHUS were generally poor. Eculizumab has substantially improved patient prognosis, but requires biweekly infusions that can impose a large treatment burden for patients and caregivers. Ravulizumab was designed via targeted modification of eculizumab to reduce dosing frequency to every 4 to 8 weeks, with an immediate, complete and sustained inhibition of complement C5.

Terminal Complement Inhibition and Control of Hemolysis in Paroxysmal Nocturnal Hemoglobinuria Following Switching from High-Dose Eculizumab to Ravulizumab: An Interim Analysis

Background: Intravenous (IV) complement component 5 (C5) inhibitors, eculizumab and ravulizumab, are the current standards of care in patients with paroxysmal nocturnal hemoglobinuria (PNH), a rare chronic blood disorder characterized by terminal complement activation, intravascular hemolysis (IVH), thrombotic events and organ damage. Ravulizumab is a second-generation analog of eculizumab with substitutions of four amino acids in the chemical backbone. This design enables ravulizumab to provide the same clinical benefit as eculizumab in patients with PNH at a longer dosing interval (every 8 weeks [q8w] vs every 2 weeks [q2w]). Approximately 10-15% of patients with PNH who receive the approved, fixed eculizumab dose (900 mg q2w) experience insufficient inhibition of IVH, as characterized by breakthrough hemolysis (BTH) towards the end of the dosing interval. In such patients, increasing the eculizumab dose (to > 900 mg q2w) can be effective. However, currently there are no recommendations or clinical trial data regarding the impact of switching these patients to ravulizumab. Aim: To assess the safety of switching from high-dose eculizumab to approved, weight-based ravulizumab dosing in patients with PNH. Methods: Study 401 (NCT04320602) is an ongoing, phase 4, single-arm, multicenter trial designed to investigate the impact of switching treatment from fixed, high-dose IV eculizumab (1200 mg q2w) to weight-based IV ravulizumab q8w in adult (≥ 18 years of age; N = 18) patients with PNH. Prior to (≥ 3 months) screening, patients receive high-dose IV eculizumab (1200 mg q2w); patients continue to receive this throughout the 3-month screening period before switching to weight-based IV ravulizumab. Patients receive loading and maintenance ravulizumab doses, as per the approved prescribing information (Alexion, AstraZeneca Rare Disease. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761108s000lbl.pdf). The primary endpoint is the proportion of patients who experience serum free C5-associated BTH (defined as ≥ 1 new or worsening symptom or sign of IVH [fatigue, hemoglobinuria, abdominal pain, dyspnea, anemia, major adverse vascular events, dysphagia or erectile dysfunction] with lactate dehydrogenase [LDH] levels ≥ 2 × upper limit of normal [ULN] and free C5 concentrations ≥ 0.5 μg/mL). Other endpoints include change in free C5 concentrations and LDH levels over time, and the proportion of patients with treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs). This interim analysis describes data up to day 183 of follow-up. Results: Data for 10/18 enrolled patients (55.6%) were available. Baseline demographics and clinical characteristics are described in Table 1. From baseline to day 183, no instances of free C5-associated BTH were reported and free C5 concentrations remained below 0.5 μg/mL for all patients at all study timepoints (Figure 1). Similarly, from baseline to day 183, LDH levels remained ≤ 1.5 × ULN in all patients. Up to day 183, 7/10 patients (70.0%) reported TEAEs that were mild (n = 3, 30.0%) or moderate (n = 4, 40.0%) in severity. There were no instances of meningococcal infection, TESAEs and none of the documented TEAEs led to death or study withdrawal. BTH was reported in one patient (local laboratory-reported LDH level = 492.0 U/L; local normal range: 120.0-246.0 U/L), this was deemed to be vaccine-related as both coronavirus disease 2019 and influenza vaccinations were administered the day prior to the event. However, no elevated free C5 level was detected in the earliest available sample (0.11 μg/mL, collected four days after the event) and the patient continued ravulizumab treatment. Conclusions: Results of this interim analysis showed that, based on a small sample of patients with PNH (N = 10), switching treatment from high-dose IV eculizumab (1200 mg q2w) to standard, weight-based IV ravulizumab q8w was well tolerated, with minimal changes in laboratory measures associated with PNH symptoms. Up to day 183, no free C5-associated BTH was reported and the safety profile of ravulizumab was considered comparable to previously published studies, with no instances of meningococcal infection or TESAEs reported. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal