Thrombosis and meningococcal infection rates in pegcetacoplan-treated patients with paroxysmal nocturnal hemoglobinuria in the clinical trial and postmarketing settings.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disease characterized by complement-mediated hemolysis and thrombosis. Complement component 5 (C5) inhibitors have decreased PNH-related thrombosis rates and reduced mortality compared with those of age-matched controls. A small but significantly increased risk of life-threatening Neisseria infections, especially N meningitidis, represents a long-term safety risk of complement inhibition. Objectives: To evaluate the rates of thrombosis and meningococcal infections in patients with PNH treated with the complement component 3-targeted therapy pegcetacoplan. Methods: Cumulative patient-year exposure to pegcetacoplan was calculated, and thrombotic events and meningococcal infections were reviewed in 7 clinical trials and in the postmarketing setting. The clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae, N meningitidis, and Haemophilus influenzae before pegcetacoplan use; the label allowed for prophylactic antibiotic use if pegcetacoplan must be administered before vaccination. Results: As of November 13, 2022, 464 patients with PNH had 619.4 patient-years of pegcetacoplan exposure in completed/ongoing clinical trials and the postmarketing setting. Seven thrombotic events were reported: 5 in clinical trials (2 in the same patient) and 2 in the postmarketing setting. The overall thrombosis rate was 1.13 events per 100 patient-years (clinical trials: 1.22 events/100 patient-years in 409.4 years; postmarketing: 0.95 events/100 patient-years in 210.0 years). No infections with meningococcal bacteria were reported. Conclusion: Event rates for thrombosis were comparable between pegcetacoplan and previously reported rates of C5 inhibitors in patients with PNH, and no cases of meningococcal infection were reported with pegcetacoplan. Continued follow-up is required.

Safety and Efficacy of Pegcetacoplan in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria over 48 Weeks: 307 Open-Label Extension Study.

INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first targeted complement component 3 (C3) PNH therapy, was safe and efficacious in treatment-naive and pre-treated patients with PNH in five clinical trials. METHODS: The 307 open-label extension (OLE) study (NCT03531255) is a non-randomized, multicenter extension study of long-term safety and efficacy of pegcetacoplan in adult patients with PNH who completed a pegcetacoplan parent study. All patients received pegcetacoplan. Outcomes at the 48-week data cutoff (week 48 of 307-OLE or August 27, 2021, whichever was earlier) are reported. Hemoglobin concentrations, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and transfusion avoidance were measured. Hemoglobin > 12 g/dL and sex-specific hemoglobin normalization (i.e., male, ≥ 13.6 g/dL; female, ≥ 12 g/dL) were assessed as percentage of patients with data available and no transfusions 60 days before data cutoff. Treatment-emergent adverse events, including hemolysis, were reported. RESULTS: Data from 137 patients with at least one pegcetacoplan dose at data cutoff were analyzed. Mean (standard deviation [SD]) hemoglobin increased from 8.9 (1.22) g/dL at parent study baseline to 11.6 (2.17) g/dL at 307-OLE entry and 11.6 (1.94) g/dL at data cutoff. At parent study baseline, mean (SD) FACIT-Fatigue score of 34.1 (11.08) was below the general population norm of 43.6; scores improved to 42.8 (8.79) at 307-OLE entry and 42.4 (9.84) at data cutoff. In evaluable patients, hemoglobin > 12 g/dL occurred in 40.2% (43 of 107) and sex-specific hemoglobin normalization occurred in 31.8% (34 of 107) at data cutoff. Transfusion was not required for 114 of 137 patients (83.2%). Hemolysis was reported in 23 patients (16.8%). No thrombotic events or meningococcal infections occurred. CONCLUSION: Pegcetacoplan sustained long-term improvements in hemoglobin concentrations, fatigue reduction, and transfusion burden. Long-term safety findings corroborate the favorable profile established for pegcetacoplan. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03531255.

Hemolysis events in the phase 3 PEGASUS study of pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria.

ABSTRACT: Patients with paroxysmal nocturnal hemoglobinuria (PNH) experience complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Pegcetacoplan, a C3 inhibitor, demonstrated sustained improvements in hematologic and clinical parameters in the phase 3 PEGASUS trial in patients with PNH who remained anemic despite C5 inhibitor therapy. The present post hoc analysis describes 26 hemolysis adverse events (AEs) experienced in 19 patients during pegcetacoplan therapy in PEGASUS and baseline patient characteristics potentially associated with increased hemolysis risk. Lactate dehydrogenase (LDH) ≥2× the upper limit of normal (ULN) was observed in 19 events, including 2 with LDH ≥10× ULN. All patients experienced decreased hemoglobin during hemolysis (mean decrease, 3.0 g/dL). In 16 events (62%), a potential complement-amplifying condition underlying the event could be identified. Hemolysis AEs led to study discontinuation in 5 patients. However, of 26 hemolysis AEs, 17 (65%) were manageable without pegcetacoplan discontinuation. A greater proportion of patients with hemolysis AEs (n = 19) had key characteristics of higher disease activity at baseline compared to patients without hemolysis AEs (n = 61), namely higher-than-label eculizumab dose (53% vs 23%), detectable CH50 (total complement function; 74% vs 54%), and ≥4 transfusions in the previous 12 months (68% vs 51%). These characteristics may be useful predictors of potential future hemolysis events. This trial was registered at www.ClinicalTrials.gov as #NCT03500549.

Management of acute breakthrough hemolysis with intensive pegcetacoplan dosing in patients with PNH.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Breakthrough hemolysis (BTH) was first described in patients with PNH treated with terminal complement C5 inhibitors when intravascular hemolysis reoccurred despite treatment. Pegcetacoplan, the first proximal complement C3 inhibitor, offers broad hemolysis control in patients with PNH. While experience of managing BTH on C5 inhibitors is documented, very limited guidance exists for proximal complement inhibitors. This interim analysis assessed the effect of intensive treatment with pegcetacoplan following an acute BTH event in a subset of patients enrolled in the ongoing open-label extension study of pegcetacoplan in PNH. Thirteen patients with acute BTH included in the analysis received either a single IV dose of 1080 mg (n = 4) or 1080 mg subcutaneous (SC) dosing on 3 consecutive days (n = 9). A potential, clinically-relevant complement-amplifying condition, such as infection or vaccination, was reported in approximately half of the patients experiencing an acute BTH. Lactate dehydrogenase (LDH) levels decreased between day 1 and day 2 in 8 of 12 evaluable patients and in all 13 patients at day 7 to 12. Nine of 13 patients (69%) achieved LDH <2× the upper limit of normal by day 14 to 19. All adverse events associated with the acute BTH event were considered resolved by the investigators. Overall, intensive treatment with pegcetacoplan was safe and well tolerated. These novel data support effective management of acute BTH events in patients on pegcetacoplan with intensive IV or SC pegcetacoplan dosing. This trial was registered at www.clinicaltrials.gov as #NCT03531255.

Pegcetacoplan in paroxysmal nocturnal haemoglobinuria: Its use, its clinical effectiveness, and its influence on health-related quality of life and productivity.

OBJECTIVES: To describe real-world use/effectiveness of pegcetacoplan (PEG) in paroxysmal nocturnal haemoglobinuria (PNH). METHODS: Data were drawn from the Adelphi PNH Disease Specific Programme™, a cross-sectional survey conducted in France, Italy, Germany, Spain and the United States from January to November 2022. Patients had a confirmed PNH diagnosis and received PEG for ≥1 month. Physicians reported patient characteristics, treatment use/satisfaction and their perception of patients' fatigue and health-related quality of life (HRQoL). Patients reported treatment satisfaction and completed questionnaires assessing fatigue, HRQoL and productivity. Descriptive statistics were reported. RESULTS: Overall, 14 physicians provided data for 61 patients who had received 1080 mg/dose PEG for 1.3-14.8 months. At data collection compared to PEG initiation: haemoglobin was 2.5 g/dL higher on average; proportion of patients with lactate dehydrogenase (LDH) ≥1.5 × upper limit of normal was reduced by 27.4%; physician-perceived fatigue was lower and HRQoL better. Physician- and patient-reported treatment satisfaction was high for >90% of patients. Physicians and patients were more satisfied with PEG than previously prescribed C5 complement inhibitors. Mean work impairment and activity impairment in the 7 days prior to data collection were 32.9% and 22.4%, respectively. CONCLUSIONS: These real-world data support the effectiveness of PEG through positive effects on haemoglobin, LDH, fatigue and HRQoL.

Fatigue and health-related quality of life in paroxysmal nocturnal haemoglobinuria: A post hoc analysis of the pegcetacoplan PEGASUS trial data.

OBJECTIVES: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, non-malignant haematological disorder associated with disabling fatigue and reduced health-related quality of life. Post hoc analysis of PEGASUS phase 3 trial (NCT03500549) characterised improvements in patient-reported fatigue measured by functional assessment of chronic illness therapy-fatigue (FACIT-fatigue) instrument item-level ratings for pegcetacoplan and eculizumab for the treatment of PNH. METHODS: Item-level responder analysis was conducted on a ≥2-level change from baseline (CFB) clinically important response (CIR) for the FACIT-fatigue 13 individual items rated on a 5-level Likert scale. We evaluated ≥2-level change against the minimal clinically important difference (MCID) of the FACIT-fatigue total score (≥5 points) and clinical parameters, haemoglobin (Hb; ≥1 g/dL) and normalised absolute reticulocyte count (ARC; 30-100 pg/cells). Logistic regressions estimated baseline-to-Week-16 FACIT-fatigue item-level transitional probabilities; Kaplan-Meier analysis estimated time to FACIT-fatigue item CIR. RESULTS: Pegcetacoplan versus eculizumab was associated with significantly greater odds of Week 16 CIR across 8/13 items and on total score MCID (OR [CI] = 11.19 [3.73, 33.57]) and faster times to responses. The item-level CIR threshold also showed clinical relevance on Hb level and ARC normalization. CONCLUSIONS: Compared with eculizumab, pegcetacoplan was associated with clinically meaningful greater improvements on a majority of FACIT-fatigue items.

Phosphorylation of the outer membrane mitochondrial protein OM64 influences protein import into mitochondria.

Mitochondrial localized proteins are mostly synthesized in the cytosol and translocated across the outer mitochondrial membrane via the translocase of the outer membrane (TOM) complex. Although the channel protein is conserved among eukaryotes, the receptor proteins are more divergent and show features specific to the plant lineage. OM64, which is a paralogue of the chloroplast docking protein Toc64, is unique to plants. However, due to the presence of a cytosolic exposed TPR domain it might functionally replace yeast/mammalian Tom70, which is not found in plant mitochondria, by interacting with the C-terminal (M)EEVD motif of the heat shock proteins Hsp90 and Hsp70. In this study, we show that OM64 is phosphorylated within its TPR domain. Using isothermal titration calorimetry it could be demonstrated that phosphorylation reduces the binding affinity of OM64 to Hsp90. Moreover, in vivo expression of genes encoding different OM64 variants in planta revealed that phosphorylation of OM64 impairs the import efficiency of the mitochondrial preprotein pFAD, a subunits of the mitochondrial ATP synthase. In summary, our data provide significant insight into the fine-tuning mechanisms of mitochondrial protein import mediated by phosphorylation of the cytosolic exposed receptor protein OM64.