Blood, Год журнала: 2023, Номер 141(15), С. 1780 - 1782
Опубликована: Апрель 13, 2023
Язык: Английский
New England Journal of Medicine, Год журнала: 2024, Номер 390(11), С. 994 - 1008
Опубликована: Март 13, 2024
BackgroundPersistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or not complement inhibitors. Iptacopan, first-in-class factor B inhibitor, has been shown to improve hemoglobin levels in these patients.MethodsIn two phase 3 trials, we assessed iptacopan monotherapy over 24-week period less than 10 g per deciliter. In the first, anti-C5–treated were randomly assigned switch continue therapy. second, single-group trial, had inhibitors lactate dehydrogenase (LDH) more 1.5 times upper limit normal range iptacopan. The primary end points first trial an increase level at least 2 deciliter from baseline 12 deciliter, each without red-cell transfusion; point second was transfusion.Download PDF Research Summary.ResultsIn 51 60 baseline, 42 none 35 attained end-point levels. 31 33 transfusion. 59 62 14 did require receive no required Treatment increased levels, reduced fatigue, reticulocyte bilirubin resulted mean LDH that range. Headache most frequent adverse event iptacopan.ConclusionsIptacopan treatment improved hematologic clinical outcomes persistent — whom showed superiority (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH NCT04820530.) Quick Take Iptacopan Paroxysmal Nocturnal Hemoglobinuria 2m 48s
Язык: Английский
Процитировано
49
Blood Advances, Год журнала: 2024, Номер 8(7), С. 1776 - 1786
Опубликована: Фев. 5, 2024
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated intravascular hemolysis leading to anemia, fatigue, and potentially life-threatening thrombotic complications. Breakthrough (BTH) was first described in patients with PNH treated terminal complement C5 inhibitors when reoccurred despite treatment. Pegcetacoplan, the proximal C3 inhibitor, offers broad control PNH. While experience of managing BTH on documented, very limited guidance exists for inhibitors. This interim analysis assessed effect intensive treatment pegcetacoplan following an acute event a subset enrolled ongoing open-label extension study Thirteen included received either single IV dose 1080 mg (n = 4) or subcutaneous (SC) dosing 3 consecutive days 9). A potential, clinically-relevant complement-amplifying condition, such as infection vaccination, reported approximately half experiencing BTH. Lactate dehydrogenase (LDH) levels decreased between day 1 2 8 12 evaluable all 13 at 7 12. Nine (69%) achieved LDH <2× upper limit normal 14 19. All adverse events associated were considered resolved investigators. Overall, safe well tolerated. These novel data support effective management SC dosing. trial registered www.clinicaltrials.gov #NCT03531255.
Язык: Английский
Процитировано
20
American Journal of Hematology, Год журнала: 2023, Номер 98(S4)
Опубликована: Фев. 9, 2023
Abstract Within a short few years, the number of complement inhibitors that are either approved for therapeutic application or evaluated in late‐stage clinical trials has expanded remarkably. The sudden emergence this target area pipelines many biotech start‐ups and even large pharmaceutical companies appears more surprising when considering involvement system various conditions had long been recognized. In aspects, however, is far from being traditional drug target, which may explain delayed breakthrough strategy. While modulation now considered an attractive “platform technology” with applications wide spectrum disorders, broad yet heterogeneous disease restricted its placement discovery programs. Concerns about safety complement‐targeted interventions, high plasma concentrations proteins, complexity system's engagement biological processes among other factors kept off radar decades. Alongside technical advances financial incentives, innovation persistence academic researchers have critical driving force to navigate therapeutics out shadow into spotlight. commentary, we document remarkable development using select examples aim venture some predictions where promising field be headed to.
Язык: Английский
Процитировано
19
iScience, Год журнала: 2024, Номер unknown, С. 109021 - 109021
Опубликована: Янв. 1, 2024
Nano-vesicular carriers are promising tissue-specific drug delivery platforms. Here, biomimetic proteolipid vesicles (BPLVs) were used for of glycosylphosphatidylinositol (GPI)-anchored proteins to GPI deficient paroxysmal nocturnal hemoglobinuria (PNH) cells. BPLVs assembled as single unilamellar monodispersed (polydispersity index, 0.1) negatively charged (ζ-potential, -28.6 ± 5.6 mV) system using microfluidic technique equipped with Y-shaped chip. GPI-anchored and not-GPI on BPLV surface detected by flow cytometry. Peripheral blood mononuclear cells (PBMCs) from healthy PNH subjects treated (final concentration, 0.5 mg/mL), displayed an excellent protein uptake, documented cytometry immunophenotyping confocal microscopy. BPLV-treated stressed complement components showed increased resistance complement-mediated lysis, both PBMCs. In conclusion, could be effective nanocarriers transfer targeted revert deficiency, like in disease. However, further
Язык: Английский
Процитировано
6
Immunological Reviews, Год журнала: 2022, Номер 313(1), С. 262 - 278
Опубликована: Сен. 15, 2022
Summary 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 due to T‐cell mediated auto‐immune disorder resembling acquired aplastic anemia, the first two clinical presentations are largely driven complement pathway. Indeed, PNH broad impairment of regulation on affected cells, which lack regulators CD55 CD59. The deficiency these proteins from blood cells somatic mutation in phosphatidylinositol N‐acetylglucosaminyltransferase subunit A gene causing disease, impairs surface expression all linked via glycosylphosphatidylinositol anchor. CD59 erythrocytes accounts for hallmark PNH, chronic, complement‐mediated hemolysis. This hemolysis results impaired alternative pathway upstream cascade, as well downstream terminal represented indication development anti‐complement agents, therapeutic interception cascade at level C5 led remarkable changes natural history disease. Nevertheless, use an inhibitor highlighted broader derangement shedding light pivotal role Here we review current understanding including emergence C3‐mediated extravascular patients anti‐C5 therapies. These observations provide rationale novel inhibitors treatment PNH. Recent preclinical data proximal intercepting with aim improving discussed, together their implications animating lively debate scientific community.
Язык: Английский
Процитировано
26
Blood Advances, Год журнала: 2024, Номер 8(11), С. 2718 - 2725
Опубликована: Апрель 9, 2024
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 clinical parameters the phase 3 PEGASUS trial patients PNH who remained anemic despite C5 inhibitor therapy. The present post hoc analysis describes 26 adverse events (AEs) experienced 19 during pegcetacoplan therapy baseline patient characteristics associated increased risk. Lactate dehydrogenase (LDH) ≥2× upper limit of normal (ULN) was observed events, including 2 LDH ≥10× ULN. All decreased hemoglobin (mean decrease, 3.0 g/dL). In 16 (62%), potential complement-amplifying condition underlying event could be identified. Hemolysis AEs led study discontinuation 5 patients. However, AEs, 17 (65%) were manageable without discontinuation. A greater proportion (n = 19) had key higher disease activity at compared 61), namely higher-than-label eculizumab dose (53% vs 23%), detectable CH50 (total complement function; 74% 54%), ≥4 transfusions previous 12 months (68% 51%). These may useful predictors future events. This registered www.ClinicalTrials.gov as #NCT03500549.
Язык: Английский
Процитировано
5
ImmunoHorizons, Год журнала: 2025, Номер 9(3)
Опубликована: Янв. 27, 2025
Abstract C3 glomerulopathy (C3G), a rare kidney disease caused by dysregulation of alternative pathway complement activation, is characterized glomerular deposition, proteinuria, crescentic glomerulonephritis, and renal failure. The anti-C5 monoclonal antibody (mAb) drug eculizumab has shown therapeutic effects in some but not all patients with C3G, no approved therapy currently available. Here, we developed used triple transgenic mouse model fast progressing lethal C3G (FHm/mP−/−hFDKI/KI) to compare the efficacy bifunctional mAb fused functional factor H (FH) fragment (short consensus repeat 1–5 [SCR1–5]) itself. new derived humanizing D (hFDKI/KI) previously described FHm/mP−/− that C3G. We tested effectiveness these 2 inhibitors mice established disease. No FHm/mP−/−hFDKI/KI treated vehicle survived 30-d study period. All C5 mAb-FH SCR1–5 fusion protein 50% treatment Moreover, protein, those mAb, showed restored plasma control. reversed greater degree than mAb. These data suggest simultaneously inhibiting terminal proximal pathways, FH SCR1–5, respectively, can reverse more efficacious alone. A similar approach may be effective treating human
Язык: Английский
Процитировано
0
The Journal of Immunology, Год журнала: 2025, Номер unknown
Опубликована: Апрель 21, 2025
Abstract The complement system is an essential part of innate immunity, and dysregulated underlying driver in many inflammatory autoimmune diseases. Currently approved complement-focused therapeutics rely on systemic blockade activation, but a major challenge with this approach that components exist high abundance undergo rapid turnover, creating large pharmacologic sink. To improve the arsenal therapies, tissue-targeting has emerged as strategy to re-regulate diseased tissue, while limiting blockade. This approach, which based directing modulators tissues through recognition tissue-fixed activated fragments, tissue-specific epitopes, or injury-associated neoepitopes, potential for enhanced potency durability reduced infection risk. In review, we discuss rationale tissue-targeted strategies taken achieve local regulation, current state preclinical clinical stage therapeutics, future directions.
Язык: Английский
Процитировано
0
Blood, Год журнала: 2023, Номер unknown
Опубликована: Март 22, 2023
Язык: Английский
Процитировано
6
CNS Neuroscience & Therapeutics, Год журнала: 2023, Номер 29(10), С. 2760 - 2774
Опубликована: Июнь 27, 2023
Abstract Background Cerebral venous thrombosis, a rare stroke, is characterized by neurological dysfunction caused bleeding and/or infarction resulting from sinus the so‐called stroke. Current guidelines recommend anticoagulants as first‐line therapy in treatment of With complicated causes cerebral difficult, especially when combined with autoimmune diseases, blood and even COVID‐19. Aims This review summarizes pathophysiological mechanisms, epidemiology, diagnosis, treatment, clinical prognosis thrombosis or infectious diseases such Conclusion A systematic understanding particular risk factors that should not be neglected unconventional occurs for scientific thus contributing to knowledge on special types
Язык: Английский
Процитировано
4