Complement Inhibitor Research Articles

Pegcetacoplan: the first and only C3-targeted therapy for the treatment of adults with paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder of hematopoietic stem cells, characterized by somatic mutations of the Phosphatidylinositol Glycan Class A Gene, resulting in increased hemolysis. The advent of complement inhibitors has since changed the way clinicians approach treating PNH. Pegcetacoplan is a C3 inhibitor that has shown promise in this field and improved outcomes for patients who have been diagnosed with PNH. This review article will aim to examine the pathophysiology of PNH and the current treatments available, with a focus on pegcetacoplan. It will focus on the pharmacodynamics, pharmocokinetics and evidence in the use of pegcetacoplan in PNH. Electronic sources including PubMed, MEDLINE, were utilized with studies in the last 5 years prioritized, especially the phase 3 Prince and Pegasus studies. The results from phase 3 studies for pegcetacoplan have been promising, showing good efficacy and improvements in patients' conditions. More research is required to evaluate the use of pegcetacoplan, especially in combination with existing treatment in patients who are having suboptimal results. Nonetheless, with more results on the way and new agents to treat PNH in the vicinity, this remains a very exciting time for both clinicians and patients.

Complement Inhibition in Chronic Subdural Hematoma Fluid.

Emerging data suggest a complex pathophysiology of chronic subdural hematoma (CSDH) to which an inflammatory response might contribute. The complement system is activated in acute traumatic setting, although its role in CSDH is unknown. To investigate the complement system in CSDH pathophysiology, we analyzed blood and hematoma fluid biomarkers, as well as immunohistochemistry of the CSDH membrane and dura. We simultaneously collected CSDH fluid and peripheral blood from 20 CSDH patients at the time of surgery. Biopsies of the dura mater and the CSDH capsule were obtained and analyzed by immunohistochemistry for C5b-C9 or C5a deposition. Biomarkers of inflammation and complement activation were analyzed by a 21-multiplex assay, including Adiponectin, Clusterin, Complement factor C9 and CRP. Complement factor C5a was analyzed separately by a commercial R-plex electrochemiluminescence assay. Ten biomarkers differed significantly between peripheral blood and paired CSDH of which two were significantly increased in CSDH fluid (Clusterin and Cystatin C). Eight of the significantly altered biomarkers were significantly decreased in CSDH fluid, including C5a, Complement 9 and Adiponectin. There was no immunoreactivity for C5a or the C5b-C9 membrane attack complex in the dura or CSDH membrane. In CSDH levels of the complement inhibitor Clusterin were increased, whereas levels of C5a and C9 were decreased. Membrane attack complex C5b-C9 was not detected in the membrane or dura surrounding the CSDH. Inhibition of complement could lead to reduced clearance of debris in the CSDH as well as secondary inflammatory reactions.

The Complement System– An Important New Therapeutic Target in IgA Nephropathy

Background: IgA nephropathy is the most common primary glomerular disease worldwide. Until recently, there were not any treatments of proven benefit, and care of patients with IgAN primarily involved supportive measures. Within the past few years, however, multiple new drugs have shown promise in clinical trials. Summary: Several complement inhibitory drugs have demonstrated efficacy at reducing proteinuria, and there is a strong rationale for expecting that these agents will be effective at slowing progression of the disease. Furthermore, anti-complement drugs target a part of the immune system that is not directly blocked by other classes of immunosuppressive agents. One of the new drugs, iptacopan, is a selective inhibitor of the alternative pathway. Preliminary results from a phase 3 study of iptacopan in IgA nephropathy demonstrated that treatment is associated with a rapid reduction in proteinuria, and the drug recently received accelerated approved from the Food and Drug Administration. Additional drugs that have been tested in IgA nephropathy include agents that block the complement cascade at the levels of C3 and C5. Complement activation in the kidneys of IgA nephropathy patients generates biomarkers that can be detected in the blood, urine, and kidney biopsies. If multiple complement inhibitory drugs receive approval for IgA nephropathy, these biomarkers may be useful for selecting the most appropriate drug for an individual patient. Complement biomarkers may also be useful for monitoring a patient’s response to treatment. Key Messages: Several complement inhibitors are currently in clinical trials for IgAN. Iptacopan recently received accelerated approval for the indication and complement inhibitory drugs will likely become an integral part of the treatment for this disease in the near future. As these drugs become available in the clinic, it will be important to develop biomarkers that can guide clinicians to the best drug for an individual patient.

Systemic Administration of a Site-Targeted Complement Inhibitor Attenuates Chronic Stress-Induced Social Behavior Deficits and Neuroinflammation in Mice

Chronic stress, a risk factor for many neuropsychiatric conditions, causes dysregulation in the immune system in both humans and animal models. Additionally, inflammation and synapse loss have been associated with deficits in social behavior. The complement system, a key player of innate immunity, has been linked to social behavior impairments caused by chronic stress. However, it is not known whether complement inhibition can help prevent neuroinflammation and behavioral deficits caused by chronic stress. In this study, we investigated the potential of a site-targeted complement inhibitor to ameliorate chronic stress-induced changes in social behavior and inflammatory markers in the prefrontal cortex (PFC) and hippocampus. Specifically, we investigated the use of C2-Crry, which comprises a natural antibody-derived single-chain antibody (ScFv) targeting domain-designated C2, linked to Crry, a C3 activation inhibitor. The C2 targeting domain recognizes danger-associated molecular patterns consisting of a subset of phospholipids that become exposed following cell stress or injury. We found that systemic administration of C2-Crry attenuated chronic stress-induced social behavioral impairments in mice. Furthermore, C2-Crry administration significantly decreased microglia/macrophage and astrocyte activation markers in the PFC and hippocampus. These findings suggest that site-targeted complement inhibition could offer a promising, safe, and effective strategy for treating chronic stress induced behavioral and immune function disorders.

Redefining Calciphylaxis as a Uniquely Bone Forming Subcutaneous C5b-9-Mediated Microvascular Injury Syndrome Associated With Localized Subcutaneous and Systemic Complement Pathway Activation.

Microvascular thrombosis is key to the pathogenesis of calciphylaxis. C5b-9-mediated microvascular injury reflective of complement pathway activation could be a key pathophysiologic event. We conducted a retrospective multicenter study of 24 patients who have had biopsy-supported calciphylaxis from the 2010-2022 data base from Emory where C5b-9 immunohistochemistry (IHC) had not been conducted and the 2019-2023 data base from Cornell where C5b-9 IHC was done as part of the routine calciphylaxis work up. IHC for C5b-9 on lesional biopsy specimens was assessed and correlated with routine light microscopic findings and clinical features. Most of the patients in our study had uremic calciphylaxis associated with obesity, diabetes, dialysis, hypertension, hyperparathyroidism and elevated serum phosphorus. Most patients did not have defined procoagulant and/or hyperviscosity states. The vascular pathology was predominantly limited to the subcutaneous fat and ranged from a calcific intimal arteriopathy to microvascular thrombosis with endothelial injury with or without endothelial calcification. In most cases (ie, in excess of 80%), there was prominent deposition of C5b-9 within the vasculature including the microvasculature and arteries of the fat at least localized to injured vessels suggesting a causal association. In about 40% of cases, there was evidence of systemic complement pathway activation revealed by concurrent dermal microvascular C5b-9 deposition. Calciphylaxis is characterized by subcuticular vascular changes that reflect an interplay between complement triggered endothelial cell injury, resultant vascular thrombosis, and subsequent abluminal calcification. Complement inhibition therapy defines a potential intervention that should be explored.

Divergent changes in complement pathway gene expression in schizophrenia and bipolar disorder: Links to inflammation and neurogenesis in the subependymal zone

Deficits in neurogenesis markers in the subependymal zone (SEZ) are associated with elevated inflammation in schizophrenia and bipolar disorder. However, the extent to which complement factors are also changed in the SEZ of these major psychiatric disorders and their impact on neurogenesis remains poorly understood. We extracted RNA from the SEZ of 93 brains, including controls (n = 32), schizophrenia (n = 32), and bipolar disorder (n = 29) cases. Quantitative RT-PCR measured 13 complement transcripts encoding initiators, convertases, effectors or inhibitors. Differences in abundance were analysed by diagnosis and inflammatory subgroups (high- or low-inflammation), which were previously defined by SEZ cytokine and inflammation marker expression.Complement mRNAs C1QA (p = 0.011), C1QB (p < 0.001), C1R (p = 0.027), and Factor B (p = 0.025) were increased in high-inflammation schizophrenia versus low-inflammation controls. Conversely, high-inflammation bipolar cases had decreased C1QC (p = 0.011) and C3 (p = 0.003). Complement mRNAs C1R (SCZ, p = 0.010; BD, p = 0.047), C1S (SCZ, p = 0.026; BD, p = 0.017), and Factor B (BD, p = 0.025) were decreased in low-inflammation schizophrenia and bipolar subgroups versus low-inflammation controls. Complement inhibitors varied by subgroup: Factor H was increased in high-inflammation schizophrenia (p < 0.001), and CD59 in high-inflammation bipolar disorder (p = 0.020). Complement activator and inhibitor mRNAs were positively correlated with quiescent neural stem cell marker GFAPD (q < 0.05) but negatively with immature neuron markers DLX6-AS1 (q < 0.05) and DCX (q < 0.05).These findings suggest altered complement cascade expression in the SEZ in high- and low-inflammation schizophrenia and bipolar disorder, with opposite directional changes suggesting distinct molecular pathology. Complement activation may promote stem cell quiescence and reduce differentiation or survival of newborn neurons.

Adult Onset Foveomacular Vitelliform Dystrophy Shows Genetic Overlap With Age-Related Macular Degeneration.

Adult-onset foveomacular vitelliform dystrophy (AFVD) shares phenotypic similarities with age-related macular degeneration (AMD). The genetic factors associated with AFVD are unknown in >80% of cases. This study evaluated the association of known AMD genetic risk variants with AFVD and compared systemic complement activation in these conditions. Clinical, imaging, and genetic data were collected from 50 patients with AFVD (men/women = 25/25, mean age ± SD 73 ± 10 years), 917 patients with AMD (men/women = 377/540, mean age ± SD 77 ± 9 years), and 432 unaffected healthy controls (men/women = 202/230, mean age ± SD 71 ± 8 years). Genotyping focused on 52 single nucleotide polymorphisms (SNPs) linked to AMD. Weighted genetic risk scores (GRS) for 19 complement system associated variants, 7 lipid metabolism associated variants, the remaining 26 variants (other pathways GRS), and for all 52 variants (global score) were derived and correlated with phenotype. Of the 52 SNPs evaluated, CFH (rs570618) and C2/CFB/SKIV2L (rs116503776 and rs114254831) were associated with AFVD compared with healthy controls (odds ratio [OR] = 2.73, 95% confidence interval [CI] = 1.32-5.73, P = 0.01; OR = 0.31, 95% CI = 0.14-0.71, P = 0.0036; and OR = 0.41, 95% CI = 0.22-0.74, P = 0.0025, respectively). MIR6130/RORB (rs10781182) was negatively associated with AFVD compared with the healthy controls (OR = 0.13, CI = 0.06-0.25, P < 0.0001) and AMD (OR = 0.19, CI = 0.10-0.34, P < 0.0001). Regression analysis showed complement GRS was positively associated with AFVD compared with controls (OR = 1.42, 95% CI = 1.04-1.95, P = 0.03), whereas the other pathways' GRS was negatively associated (OR = 0.46, 95% CI = 0.21-0.98, P = 0.04). AMD was positively associated with the complement score, global score, and ARMS2/HTRA1 compared with controls. Non-monogenic AFVD is associated with AMD risk alleles in the complement cascade, but not in other pathways. Further research is needed to explore complement inhibition for AFVD.

Gene therapy for geographic atrophy in age-related macular degeneration: current insights.

Geographic atrophy (GA) is the advanced stage of non-neovascular (dry) age-related macular degeneration, defined by the presence of sharply demarcated atrophic lesions of the outer retina. The complement system is integral to the body's natural immune response, and hence its overactivation can lead to tissue damage and inflammation. It has been shown to play a significant role in GA lesion development and progression, and therefore, complement inhibition is emerging as a promising avenue for therapeutic intervention. With the recent approval by the Food and Drug Administration of drugs like SYFOVRE™ (pegcetacoplan injection) and IZERVAY™ (avacincaptad pegol intravitreal solution), there is hope for the development of interventions capable of slowing down or arresting the progression of GA. In particular, gene therapy intervention is gaining traction for halting GA atrophy at the source of our genes. The concept is to insert a gene into the eye that will act as an ocular "bio-factory," producing a desired protein. This can either lead to overproduction of an already available protein or produce a substance not typically generated in the eye. This review aims to provide an overview of the present understanding of GA, encompassing risk factors, prevalence, pathophysiology, and genetic associations. It will also highlight the current landscape of GA treatment, with particular emphasis on gene therapy intervention.

Coronavirus Disease 2019-Associated Thrombotic Microangiopathy: A Single-Center Experience.

Coronavirus disease 2019 (COVID-19) can lead to various multisystem disorders, including thrombotic microangiopathy (TMA). We present here eight patients with COVID-19-associated TMA who were treated at our center. Our aim was to summarize the demographic and clinical characteristics of the patients and discuss the possible role of COVID-19. One patient presented with thrombotic thrombocytopenic purpura (TTP) and seven with atypical hemolytic-uremic syndrome (aHUS.) Most patients had no obvious symptoms of COVID-19, and TMA occurred after viremia. Two patients had concomitant non-COVID-19-related triggers for TMA: exposure to tacrolimus and everolimus; first presentation of antiphospholipid syndrome. The patient with TTP was treated with therapeutic plasma exchange (TPE), steroids and caplacizumab, resulting in complete hematologic recovery. Six patients with aHUS were treated with TPE with or without steroids, four of whom received a C5 complement inhibitor and one an intravenous immunoglobulin. One patient with aHUS was treated with a C5 complement inhibitor and a steroid. We observed one partial and one complete recovery of renal function, while five patients experienced renal failure. There were no deaths. We believe that COVID-19 may act as a trigger for TMA in patients who have either pre-existing endothelial injury or an underlying predisposition to complement activation, and may also trigger autoimmune diseases. As a consequence of the different underlying pathophysiologies, the treatment of COVID-19-associated TMA requires a specific approach based on the subtype of the syndrome and possible concomitant triggers.

Myasthenia gravis: The evolving therapeutic landscape

Pharmacological options in the management of generalized myasthenia gravis (gMG) have expanded rapidly in the last 7 years. There are now several complement inhibitors and neonatal Fc receptor antagonists on the market in many countries for patient management, following the successful completion of Phase 3 studies. In open-label extensions, these agents have proven to be effective over the longer term extending several years, with benefits such as reduction of corticosteroid requirements being observed. In the communication below, we will briefly summarize recent pharmacologic advancements in the management of gMG and outline how these agents are currently being used and may be used in the future.

Health-related quality of life and symptom-specific functional impairment among patients treated with parenterally administered complement inhibitors for paroxysmal nocturnal hemoglobinuria

AbstractThis study describes the health-related quality of life (HRQoL) and symptom-specific functional impairment of patients with paroxysmal nocturnal hemoglobinuria (PNH) in a real-world setting. US-based adults with PNH treated with a parenterally administered complement inhibitor (PACI) for ≥ 6 months completed an online, cross-sectional, observational survey; a subset of patients also participated in semi-structured qualitative interviews. The survey included the PROMIS® 29 + 2 Profile v2.1 (PROMIS 29 + 2) to measure HRQoL. The FACIT-Fatigue, Neuro-QOL Item Bank v2.0 Cognitive Function Short Form, and PROMIS Item Bank v1.0 Dyspnea Functional Limitations 10a Short Form measured symptom-specific functional impairment. For each patient with PNH who completed the online survey, 3 age- and sex-matched adults from the general population (GP) also completed the survey. The HRQoL and functional impairment of the PNH sample were compared to that of the GP sample. The association between HRQoL/functional impairment and fatigue severity for the PNH sample was also investigated. Compared to the age- and sex-matched GP sample, patients treated with PACIs for PNH had significantly worse HRQoL and greater functional impairment for all measured domains (p &lt; 0.05). Within the PNH sample, statistically significant associations (p &lt; 0.05) were observed between fatigue severity and HRQoL/functional impairment for all outcomes except the PROMIS 29 + 2 Sleep Disturbance domain. Interview participants described fatigue-related impairments in their physical, social, and cognitive functioning. Despite receiving treatment for PNH, patients experienced deficits in HRQoL and functional impairment, suggesting that opportunities to improve patient-relevant outcomes through treatment should be identified.

Management of paroxysmal nocturnal hemoglobinuria with low-level hemolysis in pregnancy- a report of two cases.

Pregnant women with paroxysmal nocturnal hemoglobinuria (PNH) are at high risk for life-threatening thromboembolism. Therapy with the complement inhibitor eculizumab is able to mitigate thrombotic risks in PNH and to improve pregnancy outcomes. However, whether PNH with low-level hemolysis in pregnancy can be safely managed without complement inhibition is unclear.Here, we describe two pregnant patients with PNH in the setting of bone marrow failure and low-level hemolysis with lactate dehydrogenase (LDH) < 1.5 x upper limit of normal [ULN]. In both patients, management consisted solely of prophylactic anticoagulation, without the use of complement inhibition. Both pregnancies ended successfully without thromboembolic complications.We conclude that in pregnant patients with PNH and low-level hemolysis (i.e. LDH < 1.5 x ULN), management with close monitoring and prophylactic anticoagulation only, without use of complement inhibition, might be a reasonable strategy. More data to guide optimal management of pregnant women with PNH are needed.

Normothermic Machine Perfusion Reconstitutes Porcine Kidney Tissue Metabolism But Induces an Inflammatory Response, Which Is Reduced by Complement C5 Inhibition.

Normothermic machine perfusion (NMP) is a clinical strategy to reduce renal ischemia-reperfusion injury (IRI). Optimal NMP should restore metabolism and minimize IRI induced inflammatory responses. Microdialysis was used to evaluate renal metabolism. This study aimed to assess the effect of complement inhibition on NMP induced inflammatory responses. Twenty-two pig kidneys underwent 18h of static cold storage (SCS) followed by 4h of NMP using a closed-circuit system. Kidneys were randomized to receive a C5-inhibitor or placebo during SCS and NMP. Perfusion resulted in rapidly stabilized renal flow, low renal resistance, and urine production. During SCS, tissue microdialysate levels of glucose and pyruvate decreased significantly, whereas glycerol increased (p < 0.001). In the first hour of NMP, glucose and pyruvate increased while glycerol decreased (p < 0.001). After 4h, all metabolites had returned to baseline. Inflammatory markers C3a, soluble C5b-9, TNF, IL-6, IL-1β, IL-8, and IL-10 increased significantly during NMP in perfusate and kidney tissue. C5-inhibition significantly decreased perfusate and urine soluble C5b-9 (p < 0.001; p = 0.002, respectively), and tissue IL-1β (p = 0.049), but did not alter other inflammatory markers. Microdialysis can accurately monitor the effect of NMP on renal metabolism. Closed-circuit NMP induces inflammation, which appeared partly complement-mediated. Targeting additional immune inhibitors should be the next step.

Efficacy and safety of complement inhibitors in patients with geographic atrophy associated with age-related macular degeneration: a network meta-analysis of randomized controlled trials.

Clinical trials in recent years have shown significant effectiveness of complement inhibitors for geographic atrophy (GA) treatment. Two complement inhibitor drugs have been approved by the Food and Drug Administration (FDA). to compare and rank the different complement inhibitors in the treatment of GA secondary to age-related macular degeneration (AMD). A systematic literature search was conducted in the Cochrane Central, Web of Science Core Collection, PubMed, LWW Medical Journals, ClinicalTrials.gov, and WHO ICTRP from inception to October 2023. All randomized clinical trials evaluating the effectiveness of complement inhibitors in patients diagnosed with secondary GA in AMD were identified. This study followed Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) network meta-analysis Checklist of Items and the Cochrane Risk of Bias Assessment Tool for assessing the study quality. Multiple authors independently coded all titles and abstracts, reviewed full-text articles against the inclusion and exclusion criteria, and resolved all discrepancies by consensus. Random-effects network meta-analyses were applied. Bayesian network meta-analysis was performed using the BUGSnet package in R (4.2.0). The primary efficacy outcome was the change in GA lesion size (mm2) from baseline to month 12. The secondary efficacy outcome was the mean change in best-corrected visual acuity (BCVA) from baseline to month 12. Safety outcome measures included the number of subjects with serious adverse events (SAEs) and macular neovascularization (MNV). Ten randomized controlled trials including 4,405 participants and five complement inhibitors were identified. Comparison with sham and SUCRA analysis showed that avacincaptad pegol 2mg (MD: -0.58, 95% CrI: -0.97 to -0.18, SUCRA: 93.55), pegcetacoplan monthly (MD: -0.38, 95% CrI: -0.57 to -0.20, SUCRA: 81.37), and pegcetacoplan every other month (MD: -0.30, 95% CrI: -0.49 to -0.11, SUCRA: 70.16) have significant changes in GA lesion reduction. No treatments showed significant changes in BCVA and SAE compared with sham. Pegcetacoplan monthly (OR: 4.30, 95% CrI: 1.48-16.72) increased the risk of MNV. Avacincaptad pegol 2mg demonstrated favorable outcomes in terms of SAE and MNV. Avacincaptad pegol 2mg is the most effective complement inhibitor with better safety for the treatment of GA secondary to AMD. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022351515, Identifier PROSPERO CRD42022351515.

CD59 double knockout mice express a CD59ba hybrid fusion protein that mediates insulin secretion.

CD59 is a cell-surface inhibitor of the terminal step in the complement cascade. However, in addition to its complement inhibitory function, a non-canonical role of CD59 in pancreatic beta cells has been identified. Two recently discovered intracellular alternative splice forms of CD59, IRIS-1 and IRIS-2, are involved in insulin exocytosis through interactions with SNARE-complex components. In mice, the CD59 gene has undergone duplication and to further explore the role of CD59 in insulin secretion, blood glucose homeostasis was studied in a CD59 double knockout (CD59abKO) mouse model. However, no phenotypic deviation related to insulin secretion or blood glucose homeostasis was observed for the CD59abKO mice. Instead, a CD59ba hybrid transcript formed as a consequence of the mutation induced to generate the model was identified. This hybrid transcript is expressed in pancreatic islets of the CD59abKO mice and is comprised of the remaining exons of the two CD59 genes spliced together. Similar to canonical CD59, the CD59ba hybrid was found to be glycosylated and present on the cell surface when exogenously expressed in INS-1 832/13 cells. Furthermore, INS-1 832/13 cells over-expressing the mouse CD59ba hybrid retained normal insulin secretion following siRNA-mediated knockdown of canonical CD59. Hence, although the CD59ba hybrid has lost the complement inhibitory function, the intracellular insulin secretory function remains. These results provide further information concerning the structural requirements of CD59 in its intracellular role relative to its role as a complement inhibitor. It also highlights the importance of carefully assessing plausible consequences of induced mutations in research models.

Praziquantel and factor H recruitment differentially affect the susceptibility of Schistosoma mansoni to complement-mediated damage.

Schistosomes are highly efficient evaders of human immunity, as evident by their ability to survive in human blood for years. How they protect themselves against the constant attack by a key element of innate immunity, the complement system, has remained unclear. In this study, new light is shed on the interaction between distinct life-cycle stages of Schistosoma mansoni and the human complement system. We demonstrate that schistosomula, the young stage assumed immediately after cercaria penetration of the skin, are extremely vulnerable towards complement-mediated killing as only 10-20% survive. The survival rate increases to 70% already within 30 minutes and reaches close to 100% within two hours. Pathway-specific complement inhibitors revealed the alternative pathway of complement activation as the main contributor to killing and damage of the schistosomula. Moreover, the complement regulator factor H is recruited by the schistosomula in this early stage to evade killing. Surviving parasites appear fully viable despite the ongoing complement attack, as demonstrated by the deposition of C3 fragments. However, when exposed to the widely used schistocidal drug praziquantel, the vulnerability of 24 h-old schistosomula towards complement-mediated killing is notably increased; no such effect was observed for mefloquine or oxamniquine. Similar to the younger life-cycle stages, adult worms remain under complement attack. C3 fragments were found all over the outer surface (tegument), deposited mostly on the ridges and not on the tubercles. The recruitment of factor H merits more detailed studies that pinpoint the molecules involved and elucidate the novel possibilities to intercept the uncovered immune evasion therapeutically. That praziquantel and complement work in synergy is surprising and may in the future result in enhanced understanding of the drug's mechanism of action.

Thrombosis in Paroxysmal Nocturnal Hemoglobinuria (PNH): From Pathogenesis to Treatment.

Paroxysmal Nocturnal Hemoglobinuria (PNH) constitutes a rare bone marrow failure syndrome characterized by hemolytic anemia, thrombotic events (TEs), and bone marrow aplasia of variable degrees. Thrombosis is one of the major clinical manifestations of the disease, affecting up to 40% of individuals with PNH. Venous thrombosis is more prevalent, affecting mainly unusual sites, such as intrabdominal and hepatic veins. TEs might be the first clinical manifestation of PNH. Complement activation, endothelial dysfunction, hemolysis, impaired bioavailability of nitric oxide, and activation of platelets and neutrophils are implicated in the pathogenesis of TEs in PNH patients. Moreover, a vicious cycle involving the coagulation cascade, complement system, and inflammation cytokines, such as interleukin-6, is established. Complement inhibitors, such as eculizumab and ravulizumab (C5 inhibitors), have revolutionized the care of patients with PNH. C5 inhibitors should be initiated in patients with PNH and thrombosis, while they constitute a great prophylactic measure for TEs in those individuals. Anticoagulants, such as warfarin and low-molecular-weight heparin, and, in selected cases, direct oral anticoagulants (DOACs) should be used in combination with C5 inhibitors in patients who develop TEs. Novel complement inhibitors are considered an alternative treatment option, especially for those who develop extravascular or breakthrough hemolysis when terminal inhibitors are administered.

Shedding of membrane complement inhibitors CD59 and CD46 into the circulation is associated with poor prognosis in acute coronary syndrome patients: a cohort study

IntroductionThe role of the complement inhibitory proteins CD46 and CD59 in the immune response to an acute coronary syndrome (ACS) is unknown. We investigated the relationships between the shedding of CD46 and CD59 into the circulation, reflected by plasma levels of soluble CD46 and CD59, and the risk for post-ACS complications.MethodsWe measured plasma sCD46 and sCD59 in a cohort of 546 ACS patients within 24 h after hospital admission, and after 6-weeks in a subgroup of 114 patients. Study outcomes were incident heart failure (HF), major adverse cardiovascular events (MACE) and mortality during a median follow-up period of up to 3.3 years. Echocardiography at 1-year was performed in the follow-up subgroup.ResultsElevated sCD46 and sCD59 were correlated with increased levels of inflammatory mediators and metalloproteinases in plasma, and were associated with increased risk for MACE in Cox proportional hazard models adjusted for cardiovascular risk factors and revascularization [HR 95% CI 1.24 (1.02–1.52), p = 0.034 for sCD46 and 1.18 (1.00–1.38), p = 0.049 for sCD59]. Elevated sCD59 was also associated with higher incidence of HF [HR 95% CI 1.41 (1.15–1.74), p = 0.001], and with lower left ventricular ejection fraction at 1-year post-ACS (Spearman r = − 0.234, p = 0.020). We found no associations between plasma levels of the proteins at 6 weeks and outcomes.ConclusionsShedding of the complement regulators CD46 and CD59 in plasma in the acute phase of ACS is associated with a negative prognosis. Plasma sCD46 and sCD59 could reflect the degree of local immune activation and serve as prognostic biomarkers in ACS patients.

A Thrilling Case of Anemia

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare bone marrow failure disorder that presents with triad of peripheral blood cytopenias, hemolytic anemia and thrombosis. The absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. GPI anchor protein deficiency is due to acquired somatic mutations in phosphatidylinositol glycan class A (PIGA) gene.Terminal complement inhibition with eculizumab and allogeneic bone marrow transplantation (BMT) are the only widely effective therapies for patients with classical PNH. Compared to eculizumab and ravulizumab that block the fifth component of complement (C5), pegcetacoplan blocks the third component of complement (C3).

Iptacopan Treatment Improves Clinical Parameters in a Real-World Cohort with Paroxysmal Nocturnal Hemoglobinuria: Evidence from a Managed Access Program

Background: Paroxysmal nocturnal hemoglobinuria (PNH), a rare acquired hematopoietic stem cell disorder, is life-threatening and associated with complement-mediated hemolysis, thrombosis, and bone marrow failure. While several treatment options for PNH are available, remaining unmet clinical need and access to effective therapies continue to be a challenge for some patients. Iptacopan is the first oral, proximal complement inhibitor that targets Factor B to inhibit the alternative pathway. In 2023, prior to launch, a managed access program (MAP) was initiated to provide iptacopan (200 mg, twice daily) to PNH patients with high unmet clinical need who have exhausted available treatment options. Here, we focus on outcomes of MAP patients with PNH from 23 countries, for whom their physicians had initiated iptacopan treatment. Methods: In the ongoing MAP,patients were eligible for participation if: (i) an unsolicited request was submitted by a licensed physician, (ii) there was a lack of viable alternative therapy for serious/life-threatening conditions, (iii) they were ineligible for clinical trials or unable to participate, (iv) the risk of treatment was justified by potential benefit, (v) they met additional medical criteria by experts or health authorities. Adults (≥18 years) with confirmed PNH diagnosis and who had received the required vaccinations were included. At baseline (BL), physicians included their patients in the MAP by requesting treatment initiation with iptacopan for a duration ranging from 1 to 3 months. Subsequently, requests for retreatment could be made at any time for patients benefiting from treatment, to ensure uninterrupted treatment. Categorical parameters were collected at the time of MAP enrollment (BL) and at request for retreatment (RR) to evaluate hemoglobin range (Hb [g/dL]), lactose dehydrogenase (LDH) above normal range (yes/no), reticulocyte count within normal range (yes/no), number of blood transfusion visits in the past 3 months, fatigue status, overall treatment satisfaction, and treatments received prior to iptacopan therapy. Results: As of June 20, 2024,74 patients were treated with iptacopan, and 5 patients discontinued the MAP for reasons not related to adverse events, such as inactivity or no response from treating physician; 35 patients had complete datasets available at both baseline and RR and were included in the analysis. Patients had a median age of 51.0 years (IQR 41.0-65.0), 21 (60.0%) were female, and 25 (65.7%) were Caucasian and their median exposure to iptacopan was 32 (IQR 22-53; min 5, max 89) days. Within this exposure time, 28 (80%) patients at the time of RR had achieved Hb level ≥10 g/dL vs 16 (45.7%) patients at BL, of which 14 (40.0%) patients at the time of RR achieved Hb level ≥12 g/dL vs 10 (28.6%) patients at BL. In total, 25 (71.4%) patients had LDH levels below 1.5 × upper limit of normal vs 20 (57.1%) patients at BL, and 22 (62.9%) patients achieved reticulocyte count within normal range vs 16 (45.7%) patients at BL. In total, 3 (8.6%) patients at the time of RR had ≥2 blood transfusion visits in the past 3 months vs 11 (31.4%) patients at BL. No patients reported severe fatigue at the time of RR vs 13 (37.1%) patients at BL. Overall, 12 (34.3%) and 17 (48.6%) patients reported being satisfied and very satisfied with their current therapy at the time of RR vs 4 (11.4%) and 6 (17.1%) patients who were satisfied or very satisfied with their therapies at BL, respectively. Overall, 5 (14.3%) patients were complement treatment-naïve, and 30 (85.7%) patients were reported to receive ≥1 prior complement inhibitor therapies including eculizumab (23 [65.7%]), ravulizumab (15 [42.9%]), pegcetacoplan (7 [20.0%]), vemircopan (6 [17.1%]), and others. The safety profile of MAP population was consistent with that reported in randomized clinical trials. Conclusion: This MAP data analysis demonstrates that with 1 month of iptacopan therapy, hematological and patient-oriented parameters were improved in both complement inhibitor-naïve and -experienced patients in this real-world setting. At the time of iptacopan retreatment request, a higher proportion of patients reported near normal Hb levels and reticulocyte count, had a reduced number of transfusion visits, and improved fatigue and treatment satisfaction. Additional long-term results may provide better understanding of iptacopan safety and efficacy in real-world patients with PNH.