Treatment Of Paroxysmal Nocturnal Hemoglobinuria Research Articles

Trial in Progress: An Open-Label, Phase 2 Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of KP104 in Complement Inhibitor-Naïve Subjects with Paroxysmal Nocturnal Hemoglobinuria

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening disease characterized by destruction of red blood cells by the complement system, leading to pathologies such as anemia and thrombosis. Currently approved complement inhibitors target C5 which addresses primarily intravascular hemolysis (IVH). However, many treated patients are still anemic and transfusion dependent since C5 inhibitors cannot treat extravascular hemolysis (EVH), which is driven by the alternative pathway (AP). C3 inhibitors need frequent administration, high dosage, and are associated with breakthrough hemolysis (BTH) (Hillmen, 2021; Rother, 2007; Stern, 2019; Rosario, 2022). Thus, the treatment of PNH still remains a challenge with significant unmet medical needs to develop more efficacious and convenient complement drugs. KP104 is a bi-functional complement inhibitor that can inhibit both C5 and C3 convertase activities and thereby achieve high potency in treating complement mediated pathologies. KP104 is an engineered anti-C5 immunoglobulin G4 monoclonal antibody (mAb) fused with the N-terminal 5 short consensus repeats of human factor H (a potent AP inhibitor) and engineered to extend serum half-life. KP104 was generally well tolerated and safe in the First-in-Human (FIH), healthy volunteer Phase 1 trial (n=66). PD data from this FIH study also support the dual mechanisms of KP104 inhibiting both AP and terminal pathway (TP). In addition, an extended half-life for KP104 has been observed in healthy volunteers, compared to other approved bispecific/fusion proteins on the market. Details of the FIH study will be published at another major conference (Wabinitz, 2022). KP104 is being developed for multiple diseases with complement cascade dysregulation, with PNH being the first indication to be investigated. Study Design and Methods: This is an open-label, 2-part, Phase 2 study to evaluate safety, tolerability, PK, PD, and efficacy of KP104 in complement inhibitor-naïve subjects with PNH (NCT05476887). Approximately 35 subjects with PNH are planned to be enrolled, including up to 18 in the dose-ranging Part 1, and up to 17 in the proof-of-concept (POC) Part 2. The primary objectives of Part 1 are to assess safety and tolerability and estimate optimal biologic dose (OBD) and regimen of KP104 in complement inhibitor-naïve subjects with PNH. Part 1 will include up to 3 cohorts of 3 to 6 subjects/cohort dosed for 12 weeks (Figure 1). When the third subject in the last cohort of Part 1 completes 4 weeks of treatment, a KP104 OBD will be estimated for evaluation in Part 2. Part 2 is to confirm POC by studying the KP104 OBD in 1 cohort of complement inhibitor-naïve subjects with PNH (Figure 1). The primary efficacy endpoint is the proportion of subjects with a ≥2 g/dL increase in hemoglobin from baseline to the end of the treatment period, with the absence of transfusion through the treatment period. The percent of subjects showing an increase from baseline in hemoglobin of ≥2 g/dL at the end of the treatment period will be compared to a 15% reference rate using an exact binomial one-sample test. The sample size was calculated to achieve approximately 90% power with 0.025 type 1 error rate (one-sided). In summary, KP104, through effective inhibition of both AP and TP complement pathways, may achieve high potency and address IVH, EVH, and BTH for treating subjects with PNH. Hillmen P, Szer J, et al. 2021. Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 384:1028-1037. Rosario N, Lucio L. 2022. Breakthrough Hemolysis in PNH with Proximal or Terminal Complement Inhibition. N Engl J Med 387(2):160-166. Rother, R.P., et al. 2007. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 25:1256-1264. Stern, R.M., and Connell, N.T. 2019. Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol 10:2040620719874728. Wabinitz, P., et al. 2022. SYNERGY-1: A Phase 1, first-in-human, randomized, double-blind, placebo-controlled safety, tolerability, immunogenicity, PK and PD study of KP104 in escalating single and multiple doses. ASN abstract. Under review. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Biosimilar Candidate ABP 959 As Compared with Eculizumab Reference Product in Paroxysmal Nocturnal Hemoglobinuria

Introduction: ABP 959 is a biosimilar candidate to eculizumab reference product (RP). Eculizumab is a humanized recombinant immunoglobulin antibody that binds to the human complement component 5 protein to inhibit progression of complement cascades and is approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder. Methods: This multicenter, randomized, double-blind, active-controlled, 2-period crossover study compared the efficacy and safety of ABP 959 and eculizumab RP in adult patients with PNH who were stable on eculizumab 900 mg IV every 14 ± 2 days. The primary objective of this study was to evaluate the efficacy of ABP 959 compared to eculizumab RP based on control of intravascular hemolysis, with a secondary objective to compare their safety, pharmacokinetics (PK), and immunogenicity. Results from Period 1 of the crossover study are presented here. Patients were randomized 1:1 to receive either ABP 959 at 900 mg IV for 52 weeks in Period 1 followed by eculizumab RP 900 mg IV for 26 weeks in Period 2 (ABP 959/RP) or eculizumab RP 900 mg IV for 52 weeks followed by ABP 959 at 900 mg IV for 26 weeks (RP/ABP 959) (Figure). The primary efficacy endpoint for the parallel comparisons was hemolysis, measured by lactate dehydrogenase (LDH) at week 27; clinical similarity between treatments was assessed by comparing the 1-sided 97.5% upper confidence interval (CI) limit for the geometric least squares (LS) mean ratio between ABP 959 and eculizumab RP, with a non-inferiority (NI) margin of 2.873. To assess the robustness of the primary analysis result, a sensitivity analysis was conducted using a subset of randomized patients who did not experience any important protocol deviation affecting their primary efficacy evaluation. Secondary endpoints included total complement (50% total hemolytic complement activity [CH50]), LDH-time profile, number of units of packed red blood cells (pRBCs) transfused, safety, immunogenicity, and PK area under the serum concentration-time curve (PK AUC) of ABP 959 and eculizumab RP. Results: Forty-two patients (20 in the ABP 959/RP group; 22 in the RP/ABP 959 group) were randomized and treated in Period 1 across 25 centers. Forty-one (97.6%) patients (20 [100%] in ABP 959/RP and 21 [95.5%] in RP/ABP 959) completed Period 1 dosing. Baseline demographic and disease characteristics were comparable between the 2 treatment groups - mean (SD) age: 50.2 (16.6) years; time since original PNH diagnosis: 128.3 (116.1) months; duration of pre-study treatment: 68.4 (39.8) months. Results for week 27 LDH geometric LS means are presented below (Table). The ratio of the geometric LS means of LDH (ABP 959/RP) was 1.0628, with a 1-sided 97.5% upper CI of 1.1576 contained within the prespecified NI margin of 2.873, establishing similarity in clinical efficacy between ABP 959 and eculizumab RP in the parallel comparison; 95% CI was 0.9758 to 1.1576. Results from the sensitivity analysis were identical with results from the primary efficacy analysis. Total complement (CH50), total hemoglobin, serum-free hemoglobin, haptoglobin, bilirubin, and type III erythrocytes values were generally stable over time and results were comparable between the 2 treatment groups. The overall LDH profile and the mean number of units of pRBCs transfused during the study period were also comparable. Total PK AUC from week 13 to week 15 were similar between the 2 treatment groups. A comparable safety profile was observed in Period 1 between treatment groups, with only a single patient (4.5%) in the eculizumab RP group discontinuing the study due to any adverse event (grade 2 non-serious asthenia and grade 2 non-serious fatigue). The nominal difference in serious adverse event incidence was determined to be not clinically meaningful. Additionally, immunogenicity results through Period 1 were similar between ABP 959 and eculizumab RP groups. No patients in either treatment group tested positive for binding antidrug antibodies (ADAs), neutralizing ADAs, or treatment-boosted ADAs. Conclusions: Similarity in clinical efficacy was established between ABP 959 and eculizumab RP in the primary endpoint of hemolysis, measured by LDH at week 27. Additionally, comparable safety, PK, and immunogenicity results support the conclusion of clinical similarity between ABP 959 and eculizumab RP. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Population Pharmacokinetic Analyses of Ravulizumab on-Body Delivery System for Subcutaneous Administration in Patients with Paroxysmal Nocturnal Hemoglobinuria

Background: The efficacy of ravulizumab (intravenous [IV] formulation administered every 8 weeks) for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) has been demonstrated in randomized trials (NCT02946463, NCT03056040, NCT03406507, NCT02949128). Studies of IV ravulizumab have established the target therapeutic pharmacokinetic (PK) threshold of 175 μg/mL for complete and sustained terminal complement inhibition (free C5 < 0.5 µg/mL) in patients with PNH and aHUS; maintenance of serum ravulizumab trough concentration (Ctrough) above this threshold ensures clinical efficacy. In study 303 (NCT03748823), the on-body delivery system for subcutaneous (SUBQ) ravulizumab administration (490 mg self-administered weekly) showed PK non-inferiority to IV ravulizumab after 71 days of treatment in adult patients with PNH weighing ≥ 40 to < 100 kg who were clinically stable on prior IV eculizumab treatment (Yenerel et al. HemaSphere 2021;5:e566). In this study, a population PK (popPK) model was developed to characterize ravulizumab PK following IV or SUBQ ravulizumab treatment in patients with PNH, which was then used to generate model-based dosing simulations to support SUBQ and IV ravulizumab posology. Aims: To develop a popPK model and perform simulations to evaluate model-predicted 1) ravulizumab concentrations following IV and SUBQ administration over 1 year of treatment, 2) ravulizumab exposures following SUBQ administration in patients weighing ≥ 100 kg and 3) impact of switching administration route (from IV to SUBQ ravulizumab and vice versa). Methods: A popPK analysis of ravulizumab was performed using data from patients enrolled in three clinical trials (NCT05288829, NCT05396742, NCT03748823). Concentration-time profiles of ravulizumab following IV and SUBQ administration were simultaneously modeled with a 2-compartment model with linear clearance. Ravulizumab absorption following SUBQ administration was modeled using a first-order rate constant of absorption (Ka), bioavailability and lag time. Model-based analyses for repeated measures PK endpoints were conducted using nonlinear mixed effects modeling. The final popPK model accounted for covariates such as body weight, body mass index, disease status and hemoglobin, and was used to simulate steady state concentration profiles following dosing over 1 year, exposure in virtual patients weighing ≥ 100 kg and the impact of a switch in administration route after differing durations of dosing. Results: In total, 2689 blood samples (SUBQ: 1728; IV: 961) were obtained from 178 participants (129 with PNH and 49 without; 115 treated with SUBQ and 63 IV ravulizumab; 46.6% female; aged 18-79 years; body weight 43.5-98.4 kg). The mean (standard deviation) terminal elimination half-life of ravulizumab after SUBQ dosing was 52.4 (9.72) days. The bioavailable fraction of ravulizumab after SUBQ administration was 79.4%. The model-predicted geometric mean ratio (GMR) of SUBQ compared with IV Ctrough on Day 71 and 351 (steady state) were 1.213 and 1.392, respectively (Figure) and comparable to the Day 71 GMR of 1.257 in study 303, indicating the developed popPK model accurately characterized ravulizumab exposure for the ≥ 40 to < 100 kg body weight range in the trial. Simulations predicted that SUBQ ravulizumab Ctrough both remained above the target PK threshold and was non-inferior to ravulizumab IV for body weights ≥ 100 kg. Simulations describing a switch in ravulizumab formulation (IV to SUBQ or SUBQ to IV) show all concentrations remained within our target exposure range regardless of dosing order, after a single dose or after 6 months of dosing. Conclusions: A popPK model was developed and used to support an expanded indication and unrestricted dosing interchangeability between SUBQ and IV ravulizumab. Simulations using the popPK model predicted that switching SUBQ or IV ravulizumab administration route still maintained ravulizumab concentration within the target exposure range supporting treatment flexibility for patients receiving ravulizumab, and that the studied dose regimen maintained ravulizumab concentrations above the PK threshold for patients with body weight ≥ 100 kg. This study illustrates the utility of popPK modeling and simulation to supplement clinical trial results in expanding the target population and dosing options for patients with rare diseases. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Allogenic Hematopoietic Stem Cell Transplant in Paroxysmal Nocturnal Hemoglobinuria: A Single Centre Study from Pakistan

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disorder of clonal hematopoiesis1 .The resulting abnormalities in complement regulatory proteins can manifest as hemolysis, thrombosis, and marrow failure2. The management and clinical outcomes of patients with PNH significantly changed with the development of complement inhibitor therapies3. Allogenic Hematopoietic stem cell transplant (HSCT) despite being the sole curative option for PNH is not recommended as first line therapy owing to its toxicities 4,5. Current indications for HSCT include a suboptimal response to eculizumab, severe AA/PNH, clonal evolution to myelodysplastic syndrome (MDS), or acute myelogenous leukemia2. However, in low and middle income countries (LMIC) where complement inhibitor therapies are not available, allogenic HSCT still remains the only treatment option for classical PNH as well as for PNH in the setting of another specified bone marrow disorder. Objective: To analyze the efficacy and safety of Allogenic HSCT in patients with paroxysmal nocturnal hemoglobinuria (PNH). Study design: Observational, retrospective study. Place and duration of study: Armed Forces Bone Marrow Transplant Centre/ National Institute of Blood and Marrow Transplant (AFBMTC/NIBMT) Rawalpindi, Pakistan, from June 2008 till February 2022. Methodology: From June 2008 till February 2022, a total of 65 patients of PNH were registered at AFBMTC/NIBMT. Out of these16 patients underwent allogenic HSCT and were included in the final retrospective analysis. PNH diagnosis was confirmed by flow cytometry by the demonstration of GPI-negative cells in at least two cell lineages i.e neutrophils, red blood cells (RBCs) in 62.5% (n=10) patients and by fluorescent aerolysin (FLAER)-based assay in 37.5% (n=6) patients. Median time from diagnosis to transplant was 380 days. All patients received HLA identical sibling donor HSCT. Stem cell source was Bone marrow harvest (BMH), BMH plus peripheral blood stem cell (PBSC) and PBSC alone in 81% (n=13), 12.5% (n=2) and 6% (n=1) patients respectively. Graft versus host disease (GVHD) prophylaxis was with Antithymocyte globulin (ATG) + Cyclosporin (CSA) in patients receiving NMA conditioning or ATG + CSA + short term Methotrexate (MTX) in those receiving MAC. Results: Median age of the study cohort was 24 years (range, 18 to 42 years) and all were male. 68.7% (n=11) patients received immunosuppressive therapy before HSCT with partial or no response. History of thrombosis prior to HSCT was present in only one patient (cPNH). Allogenic HSCT done for classical PNH (cPNH) in 75% (n=12) patients and for PNH in the setting of another specified bone marrow disorder (PNH/AA) in 25% (n=4) patients. Patients with classical PNH received Myeloablative conditioning (MAC) i.e Flu150Bu12.8IV (75%, n=9), Bu16Cy120 (8.3%, n=1), or Flu150Cy200 (8.3 %, n=1) except for one patient who received Flu150Cy160. Patients with PNH/AA, received non myeloablative conditioning (NMA) i.e Flu150Cy120, except for one who received Flu150Bu12.8IV. Out of 16 patients, 94% (n=15) patients achieved successful engraftment with full donor chimerism. One patient (cPNH) had Primary graft failure. Median time to neutrophil and platelet engraftment was day +12 and day +22 respectively. Disease relapse was monitored by donor chimerism till Day +180 post BMT and thereafter by peripheral blood counts. PNH clone post BMT was not tested. Incidence of acute GVHD grade I/II involving skin and gut, was 25% (n=4). No incidence of chronic GVHD was noted. One patient (PNH/AA) had secondary graft failure on Day +46. With a median post-transplant follow-up of 15 months (range, 4 to 157) overall survival (OS) was 93.7% and disease-free survival (DFS) was 87.5%. Conclusion: In resource constrained, LMIC, where complement inhibitor therapies are currently unavailable, allogenic HSCT remains the valid option for treatment of PNH, with good overall survival rate and acceptable treatment related toxicites. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pharmacokinetic Characterization and Exposure-Response Relationship of Crovalimab in the COMPOSER and COMMODORE 3 Trials of Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Background Crovalimab is a novel anti-human C5 monoclonal antibody being developed for the treatment of PNH, a rare, life-threatening, acquired hematopoietic stem cell disorder. Crovalimab is a next-generation C5 inhibitor that enables rapid and sustained C5 inhibition with subcutaneous (SC) self-administration every 4 weeks. COMPOSER (NCT03157635) is a 4-part open-label adaptive Phase I/II trial evaluating crovalimab in healthy volunteers and in patients with PNH who were treatment-naive or switched from eculizumab to crovalimab. COMMODORE 3 (NCT04654468) is a multicenter, single-arm, Phase III study evaluating crovalimab in treatment-naive patients with PNH in China. Crovalimab dosing and regimen were optimized in COMPOSER (Sostelly ASH 2019) and are currently being investigated in pivotal studies, including COMMODORE 3. The dose and regimen were: Week 1, Day 1: 1000 mg IV for body weight 40 to <100 kg or 1500 mg IV for weight ≥100 kgWeek 1, Day 2 and Weeks 2, 3, and 4: 340 mg SCWeek 5 onward: 680 mg SC for weight 40 to <100 kg or 1020 mg SC for weight ≥100 kg, Q4W The objectives were to characterize crovalimab's pharmacokinetics (PK) in healthy volunteers and treatment-naive patients with PNH, and to characterize the relationship between crovalimab's exposure parameters and pharmacodynamic (PD) biomarkers, efficacy, and safety, using data from COMPOSER and COMMODORE 3. Methods The legacy population PK model (Sostelly ASH 2019) was updated using data from healthy volunteers and treatment-naive patients from COMPOSER and COMMODORE 3 to characterize the crovalimab PK profile and evaluate impact of potential covariates. Simulations were conducted using the population PK model to evaluate the need for dose adjustment in the population based on the identified significant covariates. The relationships between crovalimab exposure and PD biomarkers, efficacy (normalized lactate dehydrogenase [LDH]), and safety endpoints were graphically explored. PD biomarkers included markers of terminal complement activity (50% hemolytic activity [CH50] as measured by liposome immunoassay [LIA]) and free C5. Safety endpoints included adverse events (AEs) of special interest, related serious AEs, related Grade ≥3 AEs, and any infections. Results Crovalimab PK was best described by a linear two-compartment model with first-order elimination and absorption. After SC administration, bioavailability was estimated to be 73.8% with a typical terminal half-life of 58.7 days (90% CI: 50.7, 74.1). Crovalimab clearances and volumes of distribution were allometrically scaled by body weight; patients with lower weight may experience relatively higher drug exposure vs those with higher weight. Age was found to be negatively correlated with the absorption rate constant without a clinically relevant impact on crovalimab exposure. The PK/PD relationship showed that crovalimab induced a concentration-dependent inhibition of terminal complement activity (Figure 1) and free C5 concentrations. Crovalimab concentrations above approximately 100 μg/mL resulted in inhibition of terminal complement activity as indicated by low CH50 values (LIA close or below the lower limit of quantification [10 U/mL]) and low free C5 (<0.0001 g/L in COMMODORE 3). No relationship was identified between observed steady-state crovalimab concentrations and LDH. For concentrations above approximately 100 μg/mL, no further LDH reduction could be achieved with higher concentrations. The recommended dosing regimen delivered adequate crovalimab concentration to achieve the desired LDH reduction. No relationship between crovalimab exposure and AE occurrence was identified, in line with other C5 inhibitors. Using the recommended dose and regimen, simulations of a representative treatment-naive patient population (based on patient characteristics across studies) showed that the predicted trough concentration at steady state remained above the threshold of 100 µg/mL in >95% of simulated patients (Figure 2). No dose adjustment was required for other intrinsic factors such as ethnicity, anti-drug antibody status, and hepatic or renal impairment. Conclusion PK characterization and exposure-response analyses supported the effectiveness and safety of the weight-based two-tiered crovalimab dosing approach for the treatment of adult and adolescent patients with PNH not currently treated with complement inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Development of an Automated Complement C5 Functional Assay for Personalized Monitoring of Patients on C5 Inhibitors

Abstract Background Humanized anti-C5 monoclonal antibody therapeutics has been heralded as a breakthrough treatment for Paroxysmal Nocturnal Hemoglobinuria and atypical Hemolytic Uremic Syndrome. Therapeutic drug monitoring is currently not widely available but assessing complement blockage maybe useful to monitor and optimize Eculizumab or Ravlizumab treatment efficacy. Recent studies have suggested using C5 functional assays as a specific target to assess complement blockage. The aim of this study was to assess the analytical performance of an automated C5 functional assay we developed by modifying the complement CH50 assay used in our laboratory. Methods Patient sera mixed in different ratios (20-90%) with commercially available C5-deficient (C5d) serum (Quidel corp. SD) were tested for lytic activity using the CH50 liposome assay (Optilite, Binding site, Birmingham, UK). Normal lysis ensures intact C5 functional activity exclusively from the patient serum. A ratio that led to normal lysis in healthy sera and in patient sera defective in complement factors other than C5 was considered optimal. This ratio was adopted for preliminary reference intervals (n=34 normal donors) using bi-weight quantile method estimation at a 90% confidence interval. Accuracy was assessed by recovery studies. Specimens (n=2) were created with varying levels of C5 functional activity using Eculizumab (Biovision, CA). Recovery was calculated (measured/expected) by adding back 100 ug/mL of purified C5 (Quidel corp. SD) and comparing the CH50 values to the original results. To evaluate specificity, patient specimens (n=22) defective in complement components other than C5 (C2, C3, C4) were mixed with C5d and lytic activity measured. Results A ratio of 75% C5d to 25% patient serum was used to establish a reference interval of 32.3 – 46.7 U/mL. The two accuracy samples had initial CH50 values of 37.9 and 41.7 U/mL and 14.2 and 20.6 U/mL after Eculizumab depletion, respectively. Adding C5 back to the Eculizumab-depleted samples yielded values of 36.5 and 39.9 U/mL and recoveries of 96%. The non-C5 complement-deficient specificity samples had low CH50 values ranging from 11.8 to 28.8 U/mL. After mixing with C5d, 21/22 samples demonstrated low-normal or normal lytic activity (range: 28.4 -41.6 U/mL). Conclusion A ratio of 75% C5d to 25% patient serum was optimal for maintaining CH50 activity in normal specimens and recovering activity in specimens with complement deficiencies other than C5. The C5-depleted specimens did not regain normal CH50 activity after mixing with C5d serum. Adding C5 to these specimens regained normal CH50 activity, confirming that C5 was non-functional and the C5 inhibitor was not interfering with the assay. Specimens’ defective in complement components other than C5 recovered lytic activity when mixed with C5d serum in 95.5% of the specimens, confirming the analytical specificity of the assay. These data demonstrate an acceptable analytical performance for the C5 functional assay developed.

Clinical guidelines for the management of patients with paroxysmal nocturnal hemoglobinuria

Introduction. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal disease of the blood system characterized by intravascular hemolysis, bone marrow dysfunction and an increased risk of thrombotic and organ complications.Aim — to provide relevant clinical recommendations for the provision of medical care to adults and children with PNH.Basic information. Experts from the National Hematological Society association which is focused on the promotion of hematology, transfusiology and bone marrow transplantation along with experts from the public organization, National Society of Pediatric Hematologists and Oncologists, have developed current clinical recommendations for providing medical care to adults and children with PNH. The recommendations address in detail the issues of etiology, pathogenesis, epidemiology, and clinical manifestations of the disease. Special attention is paid to the diagnosis, differential diagnosis, and treatment of PNH based on the principles of evidence.

The complement alternative pathway in paroxysmal nocturnal hemoglobinuria: From a pathogenic mechanism to a therapeutic target.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal, not malignant, hematological disease characterized by intravascular hemolysis, thrombophilia and bone marrow failure. While this latter presentation is due to a T-cell mediated auto-immune disorder resembling acquired aplastic anemia, the first two clinical presentations are largely driven by the complement pathway. Indeed, PNH is characterized by a broad impairment of complement regulation on affected cells, which is due to the lack of the complement regulators CD55 and CD59. The deficiency of these two proteins from PNH blood cells is due to the somatic mutation in the phosphatidylinositol N-acetylglucosaminyltransferase subunit A gene causing the disease, which impairs the surface expression of all proteins linked via the glycosylphosphatidylinositol anchor. The lack of the complement regulators CD55 and CD59 on PNH erythrocytes accounts for the hallmark of PNH, which is the chronic, complement-mediated intravascular hemolysis. This hemolysis results from the impaired regulation of the alternative pathway upstream in the complement cascade, as well as of the downstream terminal pathway. PNH represented the first indication for the development of anti-complement agents, and the therapeutic interception of the complement cascade at the level of C5 led to remarkable changes in the natural history of the disease. Nevertheless, the clinical use of an inhibitor of the terminal pathway highlighted the broader derangement of complement regulation in PNH, shedding light on the pivotal role of the complement alternative pathway. Here we review the current understanding of the role of the alternative pathway in PNH, including the emergence of C3-mediated extravascular hemolysis in PNH patients on anti-C5 therapies. These observations provide the rationale for the development of novel complement inhibitors for the treatment of PNH. Recent preclinical and clinical data on proximal complement inhibitors intercepting the alternative pathway with the aim of improving the treatment of PNH are discussed, together with their clinical implications which are animating a lively debate in the scientific community.

Concomitant Immunosuppressive Therapy and Eculizumab Use in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Analysis

Introduction: Complement C5 inhibitor eculizumab is the first approved treatment for paroxysmal nocturnal hemoglobinuria (PNH), a rare hematologic disorder caused by uncontrolled terminal complement activation. Approximately 50% of patients with aplastic anemia (AA) have PNH cells. Limited data are available for patients with AA-PNH taking concomitant immunosuppressive therapy (IST) and eculizumab. Methods: Data from the International PNH Registry (NCT01374360) were used to evaluate the safety and effectiveness of eculizumab and IST in patients taking IST followed by concomitant eculizumab (IST + c-Ecu) or eculizumab followed by concomitant IST (Ecu + c-IST). Results: As of January 1, 2018, 181 Registry-enrolled patients were included in the eculizumab effectiveness analyses (n = 138, IST + c-Ecu; n = 43, Ecu + c-IST); 87 additional patients received IST alone. Reductions from baseline with eculizumab were observed in the least squares mean lactate dehydrogenase ratio (IST + c-Ecu, −3.4; Ecu + c-IST, −3.5); thrombotic event incidence rates were similar between groups (IST + c-Ecu, 1.3; Ecu + c-IST, 0.7). Red blood cell transfusion rate ratios decreased from baseline for IST + c-Ecu (0.7) and increased for Ecu + c-IST (1.2); there were none for IST alone. Hematological parameters generally improved for IST + c-Ecu and IST alone, and changed minimally or worsened for Ecu + c-IST. Safety signals were generally consistent with those previously described for the respective therapies. Discussion/conclusion: Although some intergroup differences were seen, concomitant eculizumab and IST were safe and effective regardless of treatment sequence.

Pregnancy in paroxysmal nocturnal hemoglobinuria: from survival to life

Pregnancy in paroxysmal nocturnal hemoglobinuria (PNH) patients has historically been a high-risk situation. The combination of chronic complement-mediated hemolysis caused by the disease and physiological activation of the complement system during pregnancy, significantly worsened the prognosis for the life. For a long time, there were no effective methods for the PNH treatment, and pregnancy in patients seemed to be extremely risky, as it significantly increased the risk of life-threatening complications. The advent of targeted therapy with eculizumab turned the prognosis of this disease upside down: patients began not only to survive, but also to live comparable to healthy people. A comparative analysis of the course and outcomes of pregnancy in patients with PNH treated with eculizumab and in patients without targeted therapy was carried out. The study was to evaluate the course and outcomes of pregnancy in patients with PNH, depending on the therapeutic approach. We analyzed data from 57 pregnancies in 49 women (31 used eculizumab, 26 with supportive care only) observed at the Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology or with remote consultation (23 clinics from 19 cities of Russia). The high probability of pregnancy complications and its adverse outcomes outside of targeted therapy indicates the vital need for its use: all observations were accompanied by complications of varying severity. The course of pregnancy with the eculizumab is generally more favorable: an apparently higher rate of live births and a lower likelihood of complications are registered. Without increasing the incidence of complications, eculizumab significantly improves pregnancy outcomes for both mother and fetus, and does not adversely affect the health of newborns. Thus, eculizumab allows not only to increase the survival rate of patients with PNH, but also to comprehensively improve their quality of life, including the possibility of safe childbirth.

The cost-effectiveness, of pegcetacoplan compared with ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria, in a UK setting.

Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia, bone marrow failure and thrombosis. We evaluated, the cost-effectiveness of pegcetacoplan, a novel proximal C3 inhibitor, versus ravulizumab in patients with PNH and hemoglobin levels <10.5 g/dl despite eculizumab treatment in the UK healthcare and social services setting. Materials & methods: A Markov cohort framework model, based on the data from the pivotal trial of pegcetacoplan (PEGASUS/NCT03500549), evaluated lifetime costs and outcomes. Patients transitioned through 3 PNH hemoglobin level/red blood cell transfusion health states. Results: Pegcetacoplan provides lower lifetime costs/greater quality-adjustedlifeyears (£6,409,166/14.694QALYs, respectively) versus ravulizumab (£6,660,676/12.942QALYs). Conclusion: Pegcetacoplan is associated with enhanced anemia control, greater QALYs and reduced healthcare costs versus ravulizumab in the UK healthcare and social services setting.

HSD77 Real-World Dosing Patterns of Eculizumab-Naive and Eculizumab-Experienced Patients with Paroxysmal Nocturnal Hemoglobinuria Receiving Ravulizumab in the US

Treatment of paroxysmal nocturnal hemoglobinuria (PNH) includes C5 complement inhibitors ravulizumab and eculizumab. Ravulizumab dosing varies by weight and includes a loading dose, followed by maintenance doses given every 8 weeks via intravenous infusion. This study investigated real-world dosing patterns of eculizumab-naive and eculizumab-experienced patients with PNH receiving ravulizumab.

EE100 Treatment-Related Lost Productivity in Paroxysmal Nocturnal Hemoglobinuria: A Comparison of Investigational Subcutaneous Ravulizumab and Pegcetacoplan in the United States

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare intravascular hematologic disorder characterized by uncontrolled terminal complement activation, thrombosis and organ damage. The terminal complement C5 inhibitor, ravulizumab, was approved by the FDA in 2018 for the intravenous treatment of PNH. A subcutaneous (SC) ravulizumab formulation (ravulizumab SC; 480 mg) is currently in clinical development which aims to provide a once weekly, self-administered treatment dose, compared with recently approved pegcetacoplan (1,080 mg); a proximal complement C3 inhibitor, self-administered SC twice weekly–every 3 days.

P833: CATEGORIZING HEMATOLOGICAL RESPONSE TO PEGCETACOPLAN IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA: A POST HOC ANALYSIS OF THE PHASE 3 PRINCE STUDY DATA

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare complement-mediated hematological disorder characterized by anemia, hemolysis, and bone marrow failure. Pegcetacoplan (PEG), an FDA/EMA-approved targeted C3 therapy for the treatment of PNH, can control intravascular and prevent extravascular hemolysis. A prior post hoc analysis of PEGASUS reported a higher proportion of patients presenting good or better hematologic responses to PEG versus eculizumab (Risitano A, et al., Blood, 2021;138 [Supplement 1]: 1104). The PRINCE study demonstrated efficacy/safety of PEG compared to control treatment (CTRL; supportive treatment of PNH without complement inhibitors) in complement-inhibitor naïve patients with PNH. Aims: This post hoc analysis categorized the hematologic response to PEG and CTRL at baseline and Week 26 in the PRINCE Trial (phase 3, multicenter, randomized, open-label, controlled trial [NCT04085601]). Methods: Adult complement-inhibitor naïve (no complement-inhibitor treatment within 3 months prior to screening) patients with PNH who had low hemoglobin (Hb) levels and high lactate dehydrogenase levels were included. Patients were randomized 2:1 to receive PEG or CTRL through Week 26. Hematologic response to PEG and CTRL was categorized as complete, good, partial, or minor at baseline and at Week 26 using the number of packed red blood cells transfusions needed in the last 6 months and Hb level at the specified timepoints (revised categorization criteria per Debureaux PE, et al. Bone Marrow Transplant. 2021; 56(10):2600-2602). Hematologic response categorization was performed according to the following criteria: Complete response: no transfusions, no anemia (≥12 g/dL); Good response: no transfusions, but with chronic mild anemia (10-12 g/dL); Partial response: no/occasional transfusions (≤2 units/6 months) and chronic moderate anemia (8-10 g/dL); Minor response: regular transfusions (≥3 units/6 months) and chronic moderate/severe anemia (<10 g/dL), or no/occasional transfusions (≤2 units/6 months) and chronic severe anemia (<8 g/dL). Any patients with missing data at Week 26 were evaluated using the most recent value within the 6 weeks prior. Statistical tests assessed significance for responses of ‘Good’ or ‘Complete’, collectively (Fisher’s Exact Test between PEG and CTRL groups at baseline; McNemar’s test within PEG group at baseline vs. Week 26). Results: In this study, 53 patients were randomized to PEG (n=35) or CTRL (n=18). At baseline, most patients had a partial or minor response to supportive therapy prior to randomization, with only 5.7% of patients in the PEG group and 0.0% in the CTRL group presenting a Good or Complete hematologic response (p= 0.5428). Hematologic response categorization for patients in the PEG group are shown for baseline and Week 26 (Figure). At Week 26, 80.0% of patients in the PEG group exhibited a Good or Complete response. The proportion of patients in the PEG group who demonstrated a Good or Complete response was significantly higher at Week 26 as compared to baseline (p<0.0001). One patient treated with PEG had missing data at Week 26 due to being lost to follow-up and was not evaluated. Image:Summary/Conclusion: This post hoc analysis of PRINCE trial data revealed that a substantial proportion of patients achieved good or complete hematologic response to PEG after 26 weeks. These findings further support the positive efficacy of PEG on hematologic parameters and provide evidence for the role of proximal complement inhibition on hematological and clinical improvements for patients with PNH.

P840: A MATCHING-ADJUSTED INDIRECT COMPARISON OF THE EFFICACY OF PEGCETACOPLAN USING PRINCE TRIAL DATA VERSUS RAVULIZUMAB AND ECULIZUMAB IN COMPLEMENT-NAÏVE PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Background: Pegcetacoplan (PEG) is a PEGylated peptide targeting proximal complement protein C3 that has been shown to control both intravascular and extravascular hemolysis and recently approved by the FDA and EMA for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). PRINCE (NCT04085601), was a phase-3, randomized, open-label trial assessing the efficacy and safety of PEG compared to control (CTL) treatment, excluding complement inhibitors among treatment naïve patients with PNH. PEG demonstrated superior efficacy to CTL by improving hemoglobin (Hb) levels and reductions in lactate dehydrogenase (LDH) levels in patients with PNH. To date, no head-to-head clinical trials exist comparing PEG to complement inhibitors in treatment naïve patients. Aims: To assess the comparative effectiveness of PEG for complement-naïve patients with PNH against ravulizumab (RAV) and eculizumab (ECU) using matching-adjusted indirect comparison (MAIC) methodology to conduct cross-trial comparisons. Methods: Individual patient data from PRINCE as well as aggregated published results of RAV and ECU in the ALXN1210-PNH-301 (“301”) study (Lee et al. 2019) were used. To adjust for cross-study differences, propensity score weighting was developed using logistic regression analyses and used to balance demographic and clinical characteristics between the PEG arm and RAV and ECU arms from 301. Outcomes were compared at 26 weeks using unanchored MAIC between PEG versus RAV and PEG versus ECU and included mean and percent change in LDH levels from baseline, LDH normalization (defined as LDH levels dropping <1xULN [246 U/L] in the absence of transfusions during the randomized controlled period), Hb stabilization (defined as the avoidance of a ≥2 g/dL decrease in hemoglobin level in the absence of transfusions during the randomized controlled period), and transfusion avoidance. Weighted Wald tests and 95% confidence intervals were computed for comparisons of categorical and continuous outcomes. Results: A total of 34 patients were included in the PEG arm, 125 patients in the RAV arm, and 121 patients in the ECU arm. Prior to matching, significant differences existed between arms in the proportion of patients with White and American Indian or Alaska Native race, and mean LDH (all p<0.001). After matching the PEG to the RAV and ECU arms, separately, most patient characteristics were well balanced with a mean age of 43.8 years, 44.8 years, 46.2 years, respectively, 43.0-50.0% females, and a mean Hb of 9.4-9.6g/dL across arms; however, there were significant differences in Asian race and baseline LDH (all p<0.01). At week 26, patients in the PEG arm showed a significantly greater improvement in their LDH levels from baseline, with a mean of -523 U/L (-11.2%) compared to RAV and -578 U/L (-12.0%) compared to ECU (all p<0.001; Figure 1). Patients receiving PEG also showed significant improvements in LDH normalization (35.6% compared to RAV, p<0.001; 39.6% compared to ECU, p<0.001), Hb stabilization (28.2% compared to RAV, p<0.001; 31.7% compared to ECU, p<0.001), and transfusion avoidance (22.6% compared to RAV, p<0.001; 30.1% compared to ECU, p<0.001; Figure 1). Image:Summary/Conclusion: In the absence of head-to-head comparisons, this unanchored MAIC study shows that PEG is more efficacious versus RAV and ECU in complement inhibitors treatment naïve PNH patients in terms of significant improvements across all evaluated endpoints, Hb stabilization, LDH improvement, LDH normalization and transfusion avoidance.

P834: REAL-WORLD EVIDENCE OF SAFETY AND EFFECTIVENESS OF ECULIZUMAB AND SWITCH TO RAVULIZUMAB IN A SWISS PATIENT POPULATION WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Background: Eculizumab (ECU) a complement component 5 (C5) inhibitor, is the current standard of care for patients with paroxysmal nocturnal hemoglobinuria (PNH). Ravulizumab (RAV) is engineered from ECU with the main advantage of having an extended 8-week (vs 2-week with ECU) dosing interval, which decreases treatment burden markedly. Hence, RAV is expected to become the new standard of care to treat PNH. In Switzerland, RAV was approved for PNH treatment in 2020. Aims: The objective of this study was to evaluate data from the PNH Swiss Soliris and Ultomiris Reimbursement Registry (SSURR) to assess key parameters for safety and effectiveness of ECU and to assess the adoption of RAV for PNH treatment by physicians under real-world conditions. Methods: The SSURR was designed in 2012 as a prospective, longitudinal, multi-center registry study in Switzerland. Patients were recruited and followed in 9 centers. Health-related data were collected at the first consultation (baseline) and during follow-up visits. In this report, results are based on data collected from 23 February 2012 to 30 September 2021. Data were summarized using descriptive analysis. Ethics approval was obtained. All participants provided written informed consent. Results: In total, 56 patients with a median age of 51 (range 20-84) years were enrolled in the Registry, 52% were female. For 42 patients, the 12-month follow-up (FU) was available: 39 patients on ECU and 3 on RAV (switched from ECU). Median FU was 27 (range 12-108) months. Hemoglobin (Hb) mean was 63 ± 47 g/L at baseline (n=41), and Hb mean was 105 ± 25 g/L (n=26) at the last visit. The lactate dehydrogenase (LDH) decreased from a mean 1457 ± 706 U/L (baseline, n=42) to 403 ± 212 U/L after 12 months FU (n=40; 65% of patients < 1.5 × upper limit of normal [ULN]), and was for 88% of the patients < 1.5 × ULN at their last visit (n=24). Thrombosis events (TE) were reported in 33% of patients prior to treatment start (n=42) and 3 (7%) had thrombosis during FU of which 2 patients had no prior history of TE. Within 12 months prior to treatment start, 21 patients (50%) received one or more red blood cell (RBC) transfusions. At 12 months of FU, 91% (n=42) were RBC transfusion-free. RBC transfusions remained reduced (82%; n=27 at last visit). After 12 months FU, 19% (n=8) of the patients had withdrawn from the registry due to allogenic bone marrow transplantation, low PNH clone size, transformation to hypoplastic MDS, and 5 non-disease related reasons. Eight patients from the 56 enrolled received RAV as initial treatment. They were all C5-inhibitor treatment-naïve with a mean LDH level of 1481 ± 1432 U/L at inclusion, which decreased to 230 ± 62 U/L at the 6-month visit (n=4; all below 1.5 × ULN). Of the 56 enrolled patients with PNH, 43% were switched from ECU to RAV. These patients (58% female) had a median age of 55 (range 26-85) years and 75% of them had LDH < 1.5 × ULN at their last LDH measurement on ECU before RAV administration. There were 7 patients with a 6-month FU after switching at which 6 of them had a LDH below 1.5 × ULN. Summary/Conclusion: The current analysis provides real world evidence for the safety and effectiveness of ECU in the Swiss PNH patient population, demonstrated by pronounced reduction in LDH, low need for RBC transfusion and stable hemoglobin as well as reduced occurrence of thrombosis. The fast adoption of RAV demonstrates RAV may likely become the new standard of care for patients with PNH. In time, more data will become available for safety and effectiveness of RAV under real-world conditions.

P1747: A REAL-WORLD ANALYSIS OF HEALTHCARE RESOURCE UTILIZATION AMONG PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA WHO RECEIVED TREATMENT WITH RAVULIZUMAB

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening disease involving complement-mediated hemolysis and thrombosis. C5 inhibition (C5i) therapy for PNH with ravulizumab (RAV) has led to hemoglobin (Hb) stabilization (avoiding a ≥2 g/dL decrease in Hb levels from baseline) and some decreases in transfusion dependence. However, international guidance recommends assessing PNH treatment response with Hb normalization (e.g., Hb levels ≥12 g/dL; Debureaux et al., Bone Marrow Transplant. 2021 Oct;56(10):2600-2602), and evidence showing Hb normalization with RAV is scarce. Anemia-related complications, including transfusions, contribute significantly to PNH-associated costs of care, thus highlighting the need to understand Hb level changes and healthcare resource utilization (HCRU) in patients with PNH. Aims: To evaluate Hb level changes in patients with PNH and corresponding HCRU after 6 months of RAV treatment. Methods: Data were extracted from patients with PNH aged ≥12 years between 2010-2021 from the TriNetX Dataworks USA Network, a federated electronic medical record (EMR) data network of >68 million de-identified patients. Patients were required to have a PNH diagnosis based on the International Classification of Diseases 9th or 10th Revision code, a medical visit recorded ≥6 months before index/first RAV treatment, and no record of myasthenia gravis, atypical hemolytic uremic syndrome, or neuromyelitis optica spectrum disorder. RAV-treated patients were analyzed as a whole and stratified by C5i treatment history (C5i naïve or prior C5i/eculizumab). Patients were categorized by Hb levels using changes in Hb levels from baseline (within 365 days pre-index) to the final Hb value recorded between 91-180 days post-index. Patients were excluded if they were missing baseline Hb levels, Hb values at 91-180 days or received a transfusion between 0-180 days post-index. HCRU values were evaluated through 180 days post-index for inpatient visits (total number of events post-index) and length of stay ([LOS] total days in the inpatient setting post-index, calculated among all patients regardless of hospitalization history). Results: Data from 36 RAV-treated patients were extracted from the EMR network (Table). Before starting RAV treatment, 24 (66.7%) patients were naïve to C5i, and 12 (33.3%) patients had prior C5i treatment. Following 6 months of RAV, many patients displayed decreased or no change in Hb levels (77.8%, n=28). Patients with decreased or no change in Hb levels after 6 months of RAV experienced more inpatient visits (mean visits [SD]: 1.3 [2.0]) compared to patients with increased Hb levels (mean visits [SD]: 0.9 [1.5]). RAV-treated patients with decreased or no change in Hb levels also demonstrated a longer mean LOS (mean days [SD]: 2.2 [6.7]) compared to patients with increased Hb levels (mean days [SD]: 0.2 [0.4]). Findings were similar among all three analysis groups (All RAV; RAV, C5i naïve; RAV, prior C5i), but slightly more C5i naïve patients with decreased or no change in Hb levels following RAV treatment (79.2%, n=19) had higher HCRU values for inpatient visits and LOS (Table). Image:Summary/Conclusion: The majority of RAV-treated patients did not display Hb improvement after 6 months of treatment, and patients lacking Hb improvement also demonstrated increased HCRU. This suggests improvements in Hb may be an important driver of morbidity and costs among patients with PNH. These findings also highlight the utility of improved Hb levels as a metric for assessing the PNH treatment response.

Pharmacokinetics and pharmacodynamics of pozelimab alone or in combination with cemdisiran in non-human primates.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease caused by uncontrolled complement activation; effective and approved treatments include terminal complement inhibition. This study assessed whether combination cemdisiran (an investigational N-acetylgalactosamine-conjugated RNAi therapeutic that suppresses liver production of complement component C5) and pozelimab (an investigational fully human monoclonal antibody against C5) results in more effective and durable complement activity inhibition than the individual agents alone in non-human primates. Cynomolgus monkeys received a single subcutaneous injection of cemdisiran (5 or 25 mg/kg), pozelimab (5 or 10 mg/kg), or combination cemdisiran and pozelimab (5+5 mg/kg, 5+10 mg/kg, or 25+10 mg/kg, respectively). When given in combination, pozelimab was administered 2 weeks after cemdisiran dosing. Pharmacokinetics and ex vivo pharmacodynamic properties were assessed. The half-life of pozelimab alone was 12.9–13.3 days; this increased to 19.6–21.1 days for pozelimab administered in combination with cemdisiran. In ex vivo classical pathway hemolysis assays (CH50), pozelimab + cemdisiran combinations achieved durable and more complete suppression of complement activity (8–13 weeks) vs monotherapy of either agent. Cemdisiran monotherapy demonstrated dose-dependent suppression of total C5 concentrations, with the higher dose (25 mg/kg) achieving >90% maximum suppression. Total C5 concentrations after administration of pozelimab + cemdisiran combinations were similar compared with administration of cemdisiran alone. The combination of pozelimab + cemdisiran mediates complement activity inhibition more efficiently than either pozelimab or cemdisiran administered alone. The pharmacokinetic/pharmacodynamic profile of combination pozelimab + cemdisiran in non-human primates appears suitable for further clinical investigation as a potential long-acting treatment for PNH and other complement-mediated diseases.

Pegcetacoplan for paroxysmal nocturnal hemoglobinuria

AbstractApproximately a third of patients with paroxysmal nocturnal hemoglobinuria (PNH) remain transfusion dependent or have symptomatic anemia despite treatment with a C5 inhibitor. Pegcetacoplan inhibits complement proximally at the level of C3 and is highly effective in treating persistent anemia resulting from C3-mediated extravascular hemolysis. We describe the rationale for C3 inhibition in the treatment of PNH and discuss preclinical and clinical studies using pegcetacoplan and other compstatin derivatives. We propose an approach for sequencing complement inhibitors in PNH.

Ravulizumab (Ultomiris)

&#x0D; CADTH recommends that Ultomiris should be reimbursed by public drug plans for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) if certain conditions are met.&#x0D; Ultomiris should only be covered to treat patients who meet existing reimbursement criteria for a similar drug, eculizumab, for the treatment of PNH. Patients already receiving eculizumab for treatment of PNH are eligible to switch to Ultomiris as long as they still have a good response to treatment with eculizumab.&#x0D; Ultomiris should be reimbursed in a similar way to eculizumab for PNH. Also, the cost of treatment with Ultomiris should not be more than the cost of treatment with eculizumab.&#x0D;