Normalization of Hemoglobin, Lactate Dehydrogenase, and Fatigue in Patients with Paroxysmal Nocturnal Hemoglobinuria Treated with Pegcetacoplan

Drugs in R&D, Год журнала: 2024, Номер 24(2), С. 169 - 177

Опубликована: Май 10, 2024

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

Язык: Английский

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Understanding Rare Anemias: Emerging Frontiers for Diagnosis and Treatment

Journal of Clinical Medicine, Год журнала: 2024, Номер 13(11), С. 3180 - 3180

Опубликована: Май 29, 2024

Background—This review provides a comprehensive overview of rare anemias, emphasizing their hereditary and acquired causes, diagnostic advancements, evolving treatment strategies. It outlines the significance anemias within public health, historical challenges in recognition treatment, role European initiatives like ENERCA EuroBloodNet advancing care. Content—This document discusses technologies next-generation sequencing impact artificial intelligence, alongside promising avenues gene therapy, targeted drug treatments, stem cell transplantation. underscores importance patient-tailored approach, advances tools, necessity for continued research, patient advocacy, international collaboration to improve outcomes individuals with anemias.

Язык: Английский

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CD59 Protects Primary Human Cerebrovascular Smooth Muscle Cells from Cytolytic Membrane Attack Complex

Brain Sciences, Год журнала: 2024, Номер 14(6), С. 601 - 601

Опубликована: Июнь 14, 2024

Cerebral amyloid angiopathy is characterized by a weakening of the small- and medium-sized cerebral arteries, as their smooth muscle cells are progressively replaced with acellular β, increasing vessel fragility vulnerability to microhemorrhage. In this context, an aberrant overactivation complement system would further aggravate process. The surface protein CD59 protects most from complement-induced cytotoxicity, but expression levels can fluctuate due disease varying cell types. degree which human vascular (HCSM) cytotoxicity has not yet been determined. To address shortcoming, we selectively blocked activity HCSM-expressed antibody, challenged complement, then measured cellular viability. Unblocked HCSM proved resistant all tested concentrations resistance decreased anti-CD59 antibody. Complete blockage, however, did result in total loss viability, suggesting that additional factors may have some protective functions. Taken together, implies plays predominant role protection against cytotoxicity. overexpression could be effective means protecting these excessive activity, consequent reductions incidence precise extent repair mechanisms other proteins contribute fully elucidated.

Язык: Английский

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Iptacopan for the treatment of paroxysmal nocturnal hemoglobinuria

Expert Opinion on Pharmacotherapy, Год журнала: 2024, Номер unknown, С. 1 - 9

Опубликована: Окт. 15, 2024

Introduction Standard-of-care first-line treatments for paroxysmal nocturnal hemoglobinuria (PNH) include the anti-C5 therapies eculizumab and ravulizumab. However, persistent anemia, likely due to extravascular hemolysis, reduced quality of life (QoL) frequent infusions remain concerns. Iptacopan is a first-in-class oral proximal complement inhibitor that targets factor B in alternative pathway (upstream C5), limiting intravascular hemolysis.

Язык: Английский

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The complement alternative pathway in health and disease—activation or amplification?

Immunological Reviews, Год журнала: 2022, Номер 313(1), С. 6 - 14

Опубликована: Ноя. 24, 2022

In late 2020, one of us (RAH) was approached by the Professor Sir Peter Lachmann and invited to join him in co-editing a collection articles focused on alternative pathway (AP), or amplification loop (AL), C3 activation. He had recognized that much changed since his first proposal "C3 tickover." New controversies arisen, significant advances our understanding complement involvement disease been made, and, with this, there considerable stimulation interest complement-directed pharmaceutical intervention. Re-evaluation required for effective exploitation new therapeutic opportunities. Sadly, passed away while still content planning stage,1 but, joined CLH JMT, together Immunological Reviews, we have driven project forward. Issue 313 is culmination this effort. We made conscious decision not make comprehensive covering every aspect AP/AL, but instead focus aspects either remain controversial, which re-ignited controversy, whose its infancy. Thus, components only Factor D (FD), Properdin (P), H (FH) related proteins H-like 1 (FHL-1) H-related (FHRs) are discussed detail. That said, B (FB) more than adequately covered other contributions. Component-specific contributions lead fundamental questions regarding basic mechanisms AP/AL complement. The then moves diseases high probability being key driver pathogenesis, starting discussion how animal studies helped these. Finally, concludes consideration therapeutics, those directly address dysregulation. While (Figure 1) many complement, he best recognised proposal, 1973, tickover" hypothesis.2 tickover hypothesis elegant simplicity—it merely stated C3b continually generated blood, without addressing mechanism occurred. making hypothesis, leaned very heavily marriage between particular, properdin as it known, analysis rare diseases. gave insight into functioned vivo, providing essential surveillance an immediate innate immune response invading pathogens absence any adaptive immunity. It immediately accepted, effort laboratories spent subsequent years attempts provide conventional AP activation "firing" AL 2). However, quote from Pangburn's contribution later issue: "50 after proposed nothing has replaced attesting Lachmann's unique scientific boldness",3 particular complementologists will remember him. At simplest, requires just three proteins, C3, FB, FD 3). Proteolytic C3b, generation C3(H2O) hydrolysis internal thioester bond,3 leads assembly C3bB C3(H2O)B proenzyme complexes. FB bound substrate FD, generates C3bBb C3(H2O)Bb complexes, both can cleave further creating positive generation. Unchecked, would rapidly exhaustion hence system tightly regulated protease FI, inactivates generating iC3b, no longer bind participate FI-dependent inactivation cofactor fluid phase, primarily provided FH. addition activity, FH also accelerates decay C3bBb, C3(H2O)Bb, their precursor limiting potential amplified fluid-phase, healthy individuals, down-regulation, amplification, predominates. property, shared C4 (and α2-macroglobulin family), thioester.4 exposes thioester, transient ability react hydroxyl- amino-functions carbohydrates, long-lived "C3-tag".5 This initial C3b-binding adjacent surface non-discriminatory, provides "fixed" location be amplified. stability surface-bound convertases enhanced recruitment properdin, until recently regarded regulator AP/AL. Clearly, such non-discriminatory deposition host cells protected against damaging attack. membrane-bound regulators, CD46 (Membrane Cofactor Protein, MCP), CD55 (Decay Accelerating Factor, DAF), CD35 (Complement Receptor 1, CR1), recruited polyanionic surfaces. interaction and/or surfaces complicated discovered proteins.6 FHRs compete binding termed FH-deregulators. As they too act regulators Their discovery means some earlier work regulation might need re-interpreted take account possible interference assays. Nevertheless, despite these complexities, under normal circumstances exposed blood plasma fully competent effects deposition. contrast, lack regulatory mechanisms, subjected AP/AL-dependent response, ensuing C3- C5-dependent effector functions importance "first-line" defense infection evidenced increased risk complement-deficient particularly early when repertoire responses limited, spectrum evasion evolved.7 review Sekine et al8 challenge given rise nature circulating FD. For function "oven-ready" envisaged sufficient must circulate active form activity rate limiting. Recent discoveries mannan-activated serine 3 (MASP-3) cast doubt this; addressed detail, reference consequences deficiency evolutionary One conclusion manuscript circulates man predominantly form, enable surveillance, removing doubts raised over Related recent data suggest rate-limiting enzyme long assumed be.9 most "additions" family. article, de Jorge al give overview family discussing relationship each functional interactions, timely update current action. draw biochemical molecular biological analysis, associations different members family.6 They discuss intriguing possibility evolution divergence could counter adopted pathogens, recruiting bacteria demonstrated specific cell membrane, diminishing bacterium's mimic cells. differences mice humans species), evolving species-specific pathogens. Despite component purified (at time C3' comprised lytic components), proven difficult analyze. part, because propensity self-aggregate during isolation, aggregated having properties found native protein.10 Pedersen co-workers present description function, largely drawn structural insights, novel data.11 bring interactions complement-evasion strategies. role unusual C-mannosyl glycosylation tryptophan residues remains enigmatic however. seen thrombospondin repeats C6, C7, C8, C9, suggested plays folding domain.12 interesting know whether glycans interact MBL; MBL MASP-3, local environment activation, ensuring does become at density. typically erudite fashion, Liszewski Atkinson13 set scene mechanisms. start reminder primitive probably arose intracellular stored vesicles, go consider evolution, maintenance host, "vacuum cleaner" debris. years, number authors questioned dogma water-hydrolysed (now known C3(H2O)) triggering activation.14-16 Over 40 C3b-like properties,17 Pangburn revisits narrative.3 addresses, through kinetic considerations, extremely low nascent fluid-phase convertase engage surface, suggests facilitatory example, distortion interacts groups,18 "trace activation" LP CP convertases, play part. Interestingly, non-canonical proteolytic example neutrophil proteases released inflammatory sites, considered. Rodriguez Cordoba19 brings clarity highly complex subject, genetics components. wide-ranging contribution, discusses "classical" aspects, exploration variants, uniquely inherited complotype associations.20 reminds relevance eQTLs, topic engaged 20 ago analyzing basis wide individual levels.21 Ekdahl al18 impact biomaterials encountered extracorporeal circuits improve compatibility biomaterials, "non-self" restricted circuit, spill patient, adverse clinical consequences. greatest arisen field Much controversy what proposed, what, context, meant "intracellular." noted above, evolved primordial organisms lacking circulation, possibly within vesicles organism challenged. From perspective, described less radical otherwise appear. King Blom needed structure canonical activities environment.22 consequence C3-dependent potential. context worth noting FI-mediated cleavage subsequently C3c C3dg, often referred event, C3b. Surface-bound iC3b C3dg active, activities. These, well products C3a detail Zarantonello al.23 important defence acquired defective breakdown. non-essential existence colonies C3-deficient guinea pigs development C3−/− mice. implications AP/AL-directed extensive cross-talk coagulation pathways. occurs points cascades, apparent level Beginning hemostasis Noris Galbusera drive home inter-relationship two systems, malfunction thrombotic conditions.24 thrombocytopenic purpura (TTP), commonly dysregulated component. again relevant therapeutics. Shaughnessy al7 always question complementologists, widely immunologists clinicians, critical bacterial infection, complement-dependent killing considers strategies utilize evade appreciated designed inactivate highlighting countering "close-proximity" sites inflammation. downstream antibody-mediated injury autoimmune Greater however, revealed centrally involved autoantibodies. cases, evidence genetic variants genes patients ("experiments nature").25-29 These clues health disease, including fighting cause tissue outlined theory itself owes origin close observation patient congenital factor I. insights—that activated insufficient allows proceed unchecked—capture biology features explain varying etiologies. Unlike cellular system, require recognition molecule, rather based interplay encounter balance negative regulators. Close study human shown variations essentially all AP/AL-related shift major influence infectious diseases, homeostasis metabolism, cancer. introduction AP/AL-driven Peters, gives personal view journey takes mechanistic roles seminal ground-breaking target complement-mediated disease.30 come reviewed al,7 deficiencies activating (FB, properdin) strong factors infections. therefore, arm line Dysregulated hand, multiple net activation/regulation may zero-sum game: decrease advantageous protecting body comes cost increasing tendency towards Michael Holers shows models pathology even initiated autoantibodies classical lectin pathways.31 Indeed, damage autoantibody-mediated almost completely dependent amplification; include rheumatoid arthritis systemic lupus erythematosus. Perhaps unexpected—and significant—discoveries pathogenesis anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Complement abundantly deposited kidneys affected patients, levels do significantly change disease.32 Jennette AP/AL-deficient mouse model inhibition protective.33 led trials inhibitory drugs now approved treatment ANCA-associated success story biomedical research, pre-clinical life-threatening disease. detailed analyses samples conditions, investigators explore Gibson al34 issue, developed observations patients. men, respect allowed confirm defects identified causally shown, associated C3G similar transgenically expressed rodents.35, 36 Studies test approach instrumental bringing therapeutics clinic. necessity reliable accurate assays defining should underestimated—without them danger inappropriately treated, outcomes misinterpreted. Thurman Fremeaux-Bacci37 today's armamentarium Daina al38 linking various kidney prototypical atypical hemolytic uremic syndrome (aHUS) glomerulopathy (C3G). A range underlying aHUS genes, proteins. too, among strongest yet penetrance incomplete. Patients who share same impairments develop all. additional modify AP-mediated predispose inflammation limited kidneys. Harrison39 physiologic susceptible pathologic striking instances impaired paroxysmal nocturnal hemoglobinuria (PNH). PNH caused clonal expansion erythrocytes (decay accelerating factor; DAF) CD59. pathophysiology Risitano al.40 block clinically PNH. Furthermore, rapid easily measured biomarkers (increase hematocrit, lactate dehydrogenase levels), well-suited testing drugs. downside available trials; plus efficacy available, makes trial difficult. landscape inhibitors show revealing insights biology. simply passive Elegant Sacks performed transplant demonstrating production determinant rejection.41 Although liver generally considered source extrahepatic tubular cells, creates microenvironment favors collectin-11 produced stressed epithelial binds L-fucose displayed activates complement.42 Nauser.43 collectin-11-L fucose represent locally kidney. fulminant dysregulation subtle contribute common age-related macular degeneration. Jong al44 50% degeneration, vision loss. AMD risk, several Unfortunately, ophthalmology trials. point out multifactorial challenges conducting least administered intra-ocularly. yielded promising results, use treat actively investigated. Hinted at, developed, thought ARMS2/HTRA1 also, extracellular matrix remodeling, eye consequent Consideration pregnancy-associated disorders dealt Smith-Jackson Harrison.45 illustrates dilemma faced treating Not pathology, processes, issue crucial successful therapy. 1990, Fearon published paper journal Science where utility domain (CR1, CD35), soluble recombinant protein, ameliorate following reperfusion ischemic rat myocardium.46 potency CR1 (sCR1) controlling C5 pathways concentrations were orders magnitude lower physiological, counterparts, C4BP. Soluble (TP10) remarkable effect ischemia/reperfusion (I/R) injury, reducing infarct size, inhibiting MAC formation vascular endothelium, decreasing infiltration. TP10 showed favorable safety profile marked era anti-complement path next greatly facilitated identification loop, clearly defined identified. al40 simplicity resulted test-bed indeed, today. central types impacted erythrocyte translated laboratory hemolysis Many AP-blocking tested vitro, anti-C3b H1747 mini-FH,48 entered drug anti-C5 monoclonal antibody, eculizumab (FDA approval 2007), introduced extensively explored Schmidt Smith.49 blockade profound course unexpectedly convertases. phenomenon extravascular treated 2009 al50 expanded here Due erythrocytes, face continues opsonization resulting coating fragments facilitate erythro-phagocytosis spaces spleen. Treatment clone sizes lysed MAC; unclear. Smith describe series suggesting due potential, conformational changes (termed "priming") presence C5-blockers.49 article focuses anti-C5, protein modulators FHR axis6, 19 natural control FI. better understood approved, attention turned "proximal" keen pathogenic plethora fueled disease.31, 34 molecules occurred huge explosion clear demonstration renal C3G, association blinding degeneration (AMD),44 drove industrial sector. Kolev pegcetacoplan, C3-blocker currently (EMPAVELI™ PNH).51 Pegcetacoplan blocking nor non-convertase enzymes. Intriguingly, pegcetacoplan modulates retaining ex vivo assays; residual (CH50). finding pertinent risk. subcutaneously, small molecule orally bioavailable development. LMW Schubart al52 eloquently rationale inhibitors. Supplementation FI strategy trialled clinic initially supplementation gene therapy approaches. Dreismann al53 emerging level. Gene deliver localized spaces, outer retina eye, compartmentalization continuous supply "biofactory" AMD. elimination bacteria, 50 immune-complex diseases.54 interesting, AP/AL-mediated (PNH aHUS). fact primer suitable complement-inhibitory addition, standard immunosuppressive primary process little specifically Specific categorically entry likely advance models, few monogenic, majority etiology. Even compelling involvement, genotype part story. Phenotype compounded non-complement factors, environmental. (or efficacy) experiments associations. experience mounts, undoubtedly gain Importantly, gained drugs, "elephant room", inhibition, defined. objective chronic restore "normal" totally. Where real, targeted therapies solution. individuals highlighted Reviews something today, believe exciting times lie ahead, hope benefit specialists fields wish specialty. RAH owner director Pharma Consulting Ltd. employed Novartis AG 2001 2013, 2013 2022 held consultancy agreements Novartis. employee Gyroscope Therapeutics, company; opinions entirely her own co-authors necessarily Therapeutics consulted companies developing received research funding JMT consultant Q32 Bio, Inc., company holds stock receive royalty income Inc. No original contained manuscript.

Язык: Английский

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Heme Interactions as Regulators of the Alternative Pathway Complement Responses and Implications for Heme-Associated Pathologies

Current Issues in Molecular Biology, Год журнала: 2023, Номер 45(6), С. 5198 - 5214

Опубликована: Июнь 16, 2023

Heme (Fe2+-protoporphyrin IX) is a pigment of life, and as prosthetic group in several hemoproteins, it contributes to diverse critical cellular processes. While its intracellular levels are tightly regulated by networks heme-binding proteins (HeBPs), labile heme can be hazardous through oxidative In blood plasma, scavenged hemopexin (HPX), albumin other proteins, while also interacts directly with complement components C1q, C3 factor I. These direct interactions block the classical pathway (CP) distort alternative (AP). Errors or flaws metabolism, causing uncontrolled stress, lead severe hematological disorders. Direct extracellular (APCCs) may implicated molecularly conditions at sites abnormal cell damage vascular injury. such disorders, deregulated AP could associated heme-mediated disruption physiological heparan sulphate–CFH coat stressed cells induction local hemostatic responses. Within this conceptual frame, computational evaluation HBMs (heme-binding motifs) aimed determine how APCCs whether these affected genetic variation within putative HBMs. Combined analysis database mining identified all 16 examined, 10 exhibiting disease-associated (SNPs) and/or epigenetic (PTMs). Overall, article indicates that among pleiotropic roles reviewed, induce differential AP-mediated hemostasis-driven pathologies certain individuals.

Язык: Английский

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Analysis of Costs per Responder in US Adults with Paroxysmal Nocturnal Hemoglobinuria with a Suboptimal Response to Prior Eculizumab Treatment

Hematology Reports, Год журнала: 2023, Номер 15(4), С. 578 - 591

Опубликована: Окт. 13, 2023

European Society for Blood and Marrow Transplantation (EBMT) hematologic response categories comprehensively assess complement inhibitor responses in patients with paroxysmal nocturnal hemoglobinuria (PNH). Using data from the 16-week randomized controlled period of phase 3 PEGASUS trial (N = 80), we estimated treatment cost per responder by EBMT category pegcetacoplan eculizumab adults PNH a suboptimal to eculizumab. Average drug costs responder, number needed treat, incremental were using dosages administered during (base case). A US payer perspective (2020 dollars) was used. Scenario analyses conducted various costs, dosages, durations, patient populations, settings. In total, 30 41 (73%) who switched 2 39 (5%) continued had good, major, or complete (good-to-complete responders) at Week 16. weekly good-to-complete USD 15,923 216,100 eculizumab; average 11,651 11,082, respectively. similar across inhibitor-naïve populations consistently lower than Switching allowed more attain costs. These results apply prior only.

Язык: Английский

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Komplementinhibitoren in der Therapie der PNH: neue Substanzen - neue Optionen

InFo Hämatologie + Onkologie, Год журнала: 2024, Номер 27(4), С. 20 - 24

Опубликована: Апрель 1, 2024

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A Cell-Based Assay to Measure the Activity of the Complement Convertases

Kidney International Reports, Год журнала: 2024, Номер 9(7), С. 2260 - 2268

Опубликована: Май 4, 2024

IntroductionThe complement system serves as a crucial defense mechanism against invading pathogens, but dysregulation of this can result in harmful consequences. Central to the cascade are classical/lectin and alternative pathway convertases. Aberrant regulation convertases is often implicated development rare complement-related diseases. However, analyzing convertase activity poses significant challenge due their labile nature intricate interactions with serum proteins.MethodsIn study, we propose novel assay for functional evaluation these complexes. Our approach leverages widely available human lymphoma cell line, which, when sensitized antibodies, triggers activation classical substantial amplification by pathway. The combined action two C5 blockers eculizumab crovalimab let proceed up level not further. In next step, inhibitors washed away guinea pig EDTA buffer supports lytic sites on platform pre-existing convertases.ResultsThe detects recombinant gain-of-function components both types within or plasma. Furthermore, demonstrate assay's practical utility nephrological patients harboring C3 genetic variants illustrate its capacity distinguish between asymptomatic relatives carrying same pathogenic variant.ConclusionsWe provided proof concept new that overactivity individuals character unknown significance ubiquitous proteins like C3.

Язык: Английский

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Exploring treatment strategies for paroxysmal nocturnal hemoglobinuria: an overview of registered clinical trials

Current Medical Research and Opinion, Год журнала: 2024, Номер 40(6), С. 935 - 945

Опубликована: Май 10, 2024

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease in which blood cells lack anchored proteins that regulate the complement system. The erythrocytes are then destroyed because of uncontrolled activity, leading to intravascular hemolysis (IVH) and high risk thrombosis outcome. A huge alteration treatment was development terminal inhibitors, with achievement IVH blockade, reduction or abolishment red cell (RBC) transfusions, thromboembolic events prevention. However, patients treated these inhibitors can still present extravascular (EVH) caused by C3 activation residual clinically relevant levels breakthrough (BTH). Proximal turned out be key solution this problem targeting components proximal pathway, avoiding intra hemolysis. FDA approved eculizumab, ravulizumab (terminal inhibitors), pegcetacoplan, iptacopan, danicopan (proximal inhibitors) as for PNH so far. Various clinical trials underway find most effective method treat PNH. This review aimed summarize 71 registered

Язык: Английский

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