C5 Inhibitor Research Articles

The Role of the Complement System in Autoimmune Diseases and Therapeutic Targeting

The complement system, a critical component of the innate immune system, plays a dual role in immune defense and pathogenesis, particularly in autoimmune diseases. Comprising over 30 proteins, the complement system facilitates pathogen clearance, inflammation, and immune modulation. However, its dysregulation can lead to uncontrolled activation and contribute to the development and progression of various autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), antiphospholipid syndrome (APS), and vasculitis. In these diseases, excessive complement activation triggers inflammation, immune cell recruitment, and tissue damage, exacerbating the autoimmune response. This review provides an in-depth analysis of the complement system’s role in autoimmune diseases, exploring how its three activation pathways—classical, lectin, and alternative—contribute to disease pathogenesis. It also discusses key complement proteins such as C3, C5, and the membrane attack complex (MAC) in promoting inflammatory responses in these conditions. Moreover, the review highlights recent advances in therapeutic strategies targeting the complement system, including the development of C5 inhibitors like eculizumab and C3 inhibitors, which show promise in treating complement-mediated autoimmune diseases. These therapies aim to reduce inflammation and tissue destruction, offering new approaches for managing autoimmune disorders. Understanding complement dysregulation is crucial for the development of more effective treatments in the future. Keywords: Complement system, Autoimmune diseases, Complement activation, Inflammation, Therapeutic targeting

Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria is a rare blood disorder characterized by life-threatening hemolysis and thrombosis. Complement C5 inhibitor therapy improves symptoms and life prognosis; however, it can result in insufficient hemolysis control, with residual intravascular hemolysis and extravascular hemolysis in some patients. Pegcetacoplan, the first complement C3 inhibitor approved for patients with paroxysmal nocturnal hemoglobinuria, targets both intravascular and extravascular hemolysis. This analysis evaluated population pharmacokinetic/pharmacodynamic profiles of pegcetacoplan. Pooled clinical study data were used to predict pegcetacoplan concentrations and biomarker responses indicative of hemolysis (hemoglobin and lactate dehydrogenase) over time, including the impact of patient characteristics and prior or concurrent complement C5 inhibitor treatment, to support the approved dose of subcutaneous pegcetacoplan 1080 mg twice weekly. The population pharmacokinetoc analysis included 284 subjects, and the pharmacokinetic/pharmacodynamic analysis included 165 subjects. Subcutaneous pegcetacoplan 1080 mg twice weekly resulted in rapid serum exposures and robust biomarker response within 4 weeks after treatment initiation. Steady-state serum concentrations demonstrated consistent exposure (median ≥ 600 µg/mL) with minimal peak-to-trough variation. The median effective half-life was 8.6 days in patients with paroxysmal nocturnal hemoglobinuria. Body weight significantly impacted pegcetacoplan exposure, and other covariates impacted hemoglobin (sex and creatinine clearance) or lactate dehydrogenase (prior or concurrent complement C5 inhibitor treatment); however, effects were not clinically meaningful. The approved dose of pegcetacoplan is predicted to produce rapid and sustained exposure and robust hemoglobin and lactate dehydrogenase responses in adult patients with paroxysmal nocturnal hemoglobinuria, with no initial dose adjustments required for any specific patient population.

Safety of Crovalimab Versus Eculizumab in Patients With Paroxysmal Nocturnal Haemoglobinuria (PNH): Pooled Results From the Phase 3 COMMODORE Studies.

To evaluate the tolerability of crovalimab versus eculizumab in C5 inhibitor (C5i)-naive and -experienced patients with PNH from COMMODORE 2, 3 and 1 (NCT04434092, NCT04654468 and NCT04432584). Pooled safety data were assessed in the total crovalimab and eculizumab populations and by C5i-naive versus C5i-switched status in patients receiving crovalimab. Analyses include 6.5 months of additional follow-up from the COMMODORE 2 and 1 primary analyses. COMMODORE safety data (crovalimab, 393 patients [naive, 192 patients; switched, 201 patients]; eculizumab, 111 patients) were analysed. The total patient years (PY) were 503.9 and 51.1 in the total crovalimab and eculizumab populations, respectively, with 471 and 581 adverse events (AEs) per 100 PY. Serious infection rates were 8.9 and 13.7 AEs per 100 PY, respectively; no meningococcal infections were reported. Fatal AEs occurred in eight (2%) patients receiving crovalimab (naive, six patients; switched, two patients) and one (1%) receiving eculizumab, all treatment unrelated. In C5i-switched patients, 39 (19%) had transient immune complex reactions (risk when switching between C5i and crovalimab); the majority were Grades 1-2 arthralgia and rash, and 16 (8%) had Grade 3 events. Crovalimab's safety profile was consistent with eculizumab's and was generally comparable between C5i-naive and C5i-switched patients.

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.

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.

Incremental Effectiveness of Iptacopan Compared with C5 Inhibitors in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from a Modelling Analysis

Incremental Effectiveness of Iptacopan Compared with C5 Inhibitors in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria: Results from a Modelling Analysis

Two-decade battle with myasthenia gravis: A breakthrough case report on the long-term success with eculizumab and ravulizumab treatment.

This unique case of generalized myasthenia gravis shows sustained stability of a patient's condition for 3 years with eculizumab/ravulizumab treatment following 16 years of refractory disease. It highlights the long-term effectiveness of C5 inhibitors in a real-world setting, aiding physicians in their decision-making for refractory cases and treatment discontinuation scenarios.

Beyond Recycling Antibodies: Crovalimab's Molecular Design Enables Four-Weekly Subcutaneous Injections for PNH Treatment.

The advent of recycling antibodies, leveraging pH-dependent antigen binding and optimized FcRn interaction, has advanced the field of antibody therapies, enabling extended durability and reduced dosages. Eculizumab (Soliris®) demonstrated the efficacy of C5 inhibitors for paroxysmal nocturnal hemoglobinuria (PNH), while its derivative, ravulizumab (Ultomiris®), recognized as a recycling antibody, extended the dosing intervals. However, limitations including intravenous administration and inefficacy in patients with the R885H single-nucleotide polymorphism (SNP) in C5 could necessitate alternative solutions. Crovalimab (PiaSky®), a next-generation recycling antibody, overcomes these challenges with innovative charge engineering, achieving the enhanced cellular uptake of C5-crovalimab complexes and targeting a unique C5 epitope, allowing for efficacy regardless of the R885H SNP. This study highlights crovalimab's distinctive molecular features, showing its eliminated binding to Fcγ receptors and C1q, alongside its optimized antigen binding characteristics. The impact of charge engineering was reconfirmed in mice, demonstrating faster C5 clearance than recycling antibodies. Notably, in the maintenance dosing regimen, crovalimab neutralizes approximately seven C5 molecules per antibody on average. Furthermore, its design also reduces the viscosity to facilitate high-concentration formulations suitable for subcutaneous delivery. Consequently, crovalimab offers a four-weekly subcutaneous injection regimen for PNH, marking a substantial improvement in treatment convenience and potentially transforming patients' quality of life.

Efficacy and Safety of Ravulizumab in IgA Nephropathy: A Phase 2 Randomized Double-Blind Placebo-Controlled Trial.

Key Points This phase 2, double-blind, randomized controlled trial evaluated the complement C5 inhibitor, ravulizumab, in adults with IgA nephropathy.A 30.1% (90% confidence interval, 13.7% to 43.5%) relative reduction in proteinuria for ravulizumab versus placebo was observed at approximately 6 months.Treatment with ravulizumab was well tolerated. Background The complement system plays a central role in the pathogenesis of IgA nephropathy. We present findings from a phase 2 trial of ravulizumab, a complement C5 inhibitor. Methods The Study of Ravulizumab in Proliferative Lupus Nephritis or IgA Nephropathy (NCT04564339) was a randomized, double-blind, placebo-controlled trial of ravulizumab in addition to standard of care. Adults with IgA nephropathy, proteinuria ≥1 g/d, and eGFR ≥30 ml/min per 1.73 m2, and on stable renin-angiotensin blockade were randomized 2:1 to ravulizumab (intravenous every 8 weeks) or placebo for 26 weeks. From week 26–50, all participants received open-label ravulizumab. The primary end point was percentage change in proteinuria from baseline (BL) to week 26. Secondary end points included change in proteinuria at week 50 and eGFR. Safety, pharmacokinetics, and pharmacodynamics were evaluated. Results Forty-three patients were randomized to ravulizumab and 23 to placebo. At week 26, a statistically significant reduction in proteinuria was observed with ravulizumab versus placebo: −41.9% (95% confidence interval [CI], −50.2% to −32.0%) change in urine protein with ravulizumab and −16.8% (95% CI, −31.8% to 1.6%) change with placebo (30.1% treatment effect; P = 0.005). At week 50, there was a −44.8% (95% CI, −55.1% to −32.1%) change from BL in urine protein with ravulizumab, and in patients who crossed over from placebo to ravulizumab at week 26, the change from BL (week 0) to week 50 was −45.1% (−58.0% to −28.4%). The least squares mean change in eGFR from BL to week 26 with ravulizumab was 0.2 (95% CI, −2.3 to 2.7) ml/min per 1.73 m2 and with placebo was −4.5 (−7.9 to −1.1) ml/min per 1.73 m2. From BL to week 50, the least squares mean change in eGFR with ravulizumab was −3.9 (95% CI, −6.4 to−1.3) ml/min per 1.73 m2, and in patients who crossed over from placebo to ravulizumab at week 26, it was −6.3 (−9.7 to −2.9) ml/min per 1.73 m2. Ravulizumab was well tolerated, with an adverse event profile similar to that for placebo. Conclusions An early, sustained, and clinically meaningful reduction in proteinuria and trend toward stabilization of eGFR were observed with ravulizumab versus placebo. A phase 3 trial (NCT06291376) is enrolling. Clinical Trial registry name and registration number: Study of Ravulizumab in Proliferative Lupus Nephritis or IgA Nephropathy, NCT04564339.

Cost-effectiveness of iptacopan for paroxysmal nocturnal hemoglobinuria

AbstractIptacopan, a novel oral factor B inhibitor, recently obtained US Food and Drug Administration approval for treating paroxysmal nocturnal hemoglobinuria, a rare blood disorder characterized by persistent complement-mediated hemolytic anemia. The standard-of-care (SOC) has traditionally relied on complement C5 inhibitors eculizumab and ravulizumab, which are limited by persistent anemia from extravascular hemolysis and requirement for intravenous infusion. Recent publication of phase 3 studies in this arena reinforces iptacopan as an effective anticomplement monotherapy compared with SOC. Given ongoing price negotiations and limited literature showing its cost-ineffectiveness in the anti-C5–treated population, we conducted a comprehensive cost-effectiveness analysis of iptacopan monotherapy in anti-C5–treated patients from the societal perspective, as compared with C5 inhibition. The primary outcomes were the incremental net monetary benefit across a lifetime horizon and the cost-effective maximum monthly threshold price of iptacopan monotherapy compared with the SOC. The secondary outcome was time saved for patients and nurses with the use of oral iptacopan therapy. Iptacopan monotherapy and SOC accrued 12.6 and 10.8 quality-adjusted life-years at costs of $9.52 million and $13.5 million, respectively. Iptacopan remained cost saving across extensive sensitivity and all scenario analyses, including alternative parameterization for anemia resolution and aggregated individual-level utilities and transition probability matrix. Across all probabilistic sensitivity analyses, iptacopan therapy was favored over SOC in 100% of 10 000 Monte Carlo iterations. Cost-saving thresholds for iptacopan vs anti-C5 in are ∼1.1, 1.4, and 1.4 in Brazil, Japan, and the United States, respectively. Iptacopan monotherapy can improve quality-adjusted life expectancy for patients while saving health care costs across jurisdictions.

Outcomes from the International Society of Nephrology Hemolytic Uremic Syndromes International Forum

The haemolytic uraemic syndromes (HUS) are a heterogeneous group of conditions only some of which are mediated by complement (CaHUS). We report the outcome of the 2023 International Society of Nephrology HUS International Forum where a global panel of experts considered the current state of the art, identified areas of uncertainty, and proposed optimal solutions. Areas of uncertainty and areas for future research included: the nomenclature of HUS; novel complement testing strategies; identification of biomarkers; genetic predisposition to aHUS; optimal dosing and withdrawal strategies for C5 inhibitors; treatment of kidney transplantation recipients; disparity of access to treatment; and the next generation of complement inhibitors in CaHUS. The current rationale for optimal patient management is described.

Eculizumab as first-line treatment for patients with severe presentation of complement factor H antibody-mediated hemolytic uremic syndrome.

Complement factor H (FH) antibody-mediated hemolytic uremic syndrome (HUS) has varying prevalence globally. Plasmapheresis and immunosuppressive drugs are the standard treatment. Recently, eculizumab has been reported as an effective alternative. This study aims to report four children with FH antibody-mediated HUS managed with eculizumab plus immunosuppression as first-line therapy. A retrospective chart review was conducted for children aged ≤ 18years old with complement-mediated HUS in two referral centers. Patients with FH antibody-mediated HUS treated with eculizumab as first-line therapy were included. Four children (aged 6-11years old) were included. Dialysis was necessary in three patients. Eculizumab was administered 5-23days after onset. None of them received plasmapheresis. Prednisone and mycophenolate mofetil were added after receiving positive FH antibody results. Hematological signs and kidney function improved after the second eculizumab dose. Eculizumab was discontinued in three patients after 6months. One patient required rituximab due to persistent high FH antibody titers; discontinuation of eculizumab occurred after 15months without recurrence. No treatment-related complications were observed. During a mean 12-month follow-up (range 6-24months), no relapses were recorded and all patients ended with normal GFR. Our data suggest that a short course of 6months of C5 inhibitor might be sufficient to reverse thrombotic microangiopathy symptoms and improve kidney function in patients with severe FH antibody-mediated HUS. Simultaneously, adding immunosuppressive agents might reduce the risk of relapse and allow cessation of C5 inhibition in a shorter period of time.

Using genetics to explore complement C5 as a druggable protein in periodontitis.

An excessively activated or dysregulated complement system has been proven to be a vital contributor to the pathogenesis of periodontitis. It has been previously hypothesized that inhibiting the activity of complement component C5 by targeting the C5a receptor is a powerful candidate for treating periodontitis. Here, we apply the drug target instrumental variable (IV) approach to investigate the therapeutic effect of genetically proxied inhibition of C5 on periodontitis. In our primary analysis, we used 26 independent 'cis' single nucleotide polymorphisms as IVs from the vicinity of the encoding locus of C5 that are associated with plasma C5 levels. In a secondary analysis, we assess the validity of our primary findings, exploring the involvement of alternative downstream biomarkers, interleukin 17 (IL-17), interleukin 1β (IL-1β), and tumor necrosis factor (TNF). Summary statistics of plasma levels (C5, IL-17, IL-1β, and TNF) were obtained from a genome-wide association study (GWAS) of 35,559 European descent individuals. We extracted association statistics from a GWAS of 17,353 clinical periodontitis cases and 28,210 European controls. Wald ratios were combined using inverse-variance weighted meta-analysis. In our primary approach, inhibiting C5 reduced the risk of periodontitis (Odds ratio 0.89 per 1 standard deviation reduction in C5; 95% confidence Interval 0.80-0.98, p value=0.022). Our secondary analysis suggests an involvement of IL-17 within the potential causal pathway, but was inconclusive for other biomarkers. The findings from our study suggest that C5 inhibition may reduce the risk of periodontitis, prioritizing C5 inhibitors as a potential adjunctive therapeutic intervention in this disease.

Time to response with ravulizumab, a long-acting terminal complement inhibitor, in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis.

The efficacy and safety of ravulizumab, a terminal complement C5 inhibitor, in adults with anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG) were demonstrated in the CHAMPION MG study (NCT03920293). This analysis aimed to characterize the latency to onset of a clinically meaningful therapeutic effect for ravulizumab. Post hoc analysis of data collected for up to 60 weeks from CHAMPION MG was performed to assess the timing of response to ravulizumab. Response was analyzed based on reductions of ≥2 and ≥3 points (minimal clinically important differences [MCIDs]) in Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG) total scores, respectively, and on more rigorous reductions of ≥3 and ≥5 points, respectively. Time to first response was assessed using the Kaplan-Meier product-limit method. The median (95% confidence interval) time to first response was 2.1 (2.1-2.6) and 4.1 (2.3-10.0) weeks for reductions of ≥2 and ≥3 points in MG-ADL total score, respectively (n = 139), and 4.1 (2.1-10.0) and 18.3 (11.0-33.4) weeks for reductions of ≥3 and ≥5 points in QMG total score, respectively (n = 134). Cumulative response rates at Week 60 (data cut-off) were 88% and 82% for ≥2- and ≥3-point MG-ADL score reductions, respectively, and 86% and 59% for ≥3- and ≥5-point QMG score reductions, respectively. The median times to MCID with ravulizumab treatment in patients with AChR Ab+ gMG were ~2 weeks and ~4 weeks based on MCID MG-ADL and QMG total score reductions, respectively.

Complement-mediated hemolytic uremic syndrome associated with postpartum hemorrhage: case series and systematic review of individual participant data

BackgroundPostpartum hemorrhage is considered a risk factor for pregnancy-associated complement-mediated hemolytic uremic syndrome (CM-HUS; previously known as atypical hemolytic uremic syndrome) but has not been systematically studied. MethodsA systematic review of individual participant data from case series and reports in addition to a case series from our institution. Search terms were “thrombotic microangiopathy,” “atypical hemolytic uremic syndrome,” and “complement mediated” combined with “pregnancy,” “postpartum,” and/or postpartum hemorrhage. Cases of thrombotic microangiopathy other than CM-HUS were excluded. Outcomes were clinical and laboratory characteristics of postpartum hemorrhage-associated CM-HUS, treatment, and outcomes. ResultsThirty-three studies including 48 women with postpartum hemorrhage-associated CM-HUS and 3 patients from our institution were included in the study. Most women presented at term (28/45; 62%), delivered by cesarean section (21/41; 51%), and had pregnancy complications, mainly preeclampsia (16/51; 31%) or fetal demise (/51; 18%). Hematological and renal abnormalities usually appeared within the first 24 hours postdelivery. The median platelet count was 46 × 109/L (IQR, 45), and the median maximal lactate dehydrogenase was 2638 U/L (IQR, 1866). Renal function normalized in 20/23 (87%) women treated with C5 inhibitors with or without plasma exchange; in 7/11 (63%) women treated with plasma exchange alone, but only in 3/17 (18%) patients treated with supportive care. Patients treated with C5 inhibitors and/or plasma exchange achieved significantly better renal outcomes compared with supportive care alone (P < .001). ConclusionCM-HUS is a rare complication following postpartum hemorrhage and occurs mainly in women with preeclampsia and/or following cesarean section. Patients treated with C5 inhibitors and/or plasma exchange had a better renal prognosis compared with patients who received supportive treatment alone.

Iptacopan (Fabhalta) for Paroxysmal Nocturnal Hemoglobinuria

The FDA has approved the complement factor B inhibitor iptacopan (Fabhalta – Novartis) for treatment of paroxysmal nocturnal hemoglobinuria (PNH) in adults. Iptacopan is the first oral drug to be approved in the US for this indication. Three parenterally administered drugs, the complement C5 inhibitors eculizumab (Soliris) and ravulizumab (Ultomiris) and the complement C3 inhibitor pegcetacoplan (Empaveli), are also approved for treatment of PNH.

Complement is increased in treatment resistant rectal cancer and modulates radioresistance

Resistance to neoadjuvant chemoradiation therapy (neo-CRT) is a significant clinical problem in the treatment of locally advanced rectal cancer. Identification of novel therapeutic targets and biomarkers predicting therapeutic response is required to improve patient outcomes. Increasing evidence supports a role for the complement system in resistance to anti-cancer therapy. In this study, increased expression of complement effectors C3 and C5 and increased production of anaphylatoxins, C3a and C5a, was observed in radioresistant rectal cancer cells. Modulation of the central complement effector, C3, was demonstrated to functionally alter the radioresponse, with C3 overexpression significantly enhancing radioresistance, whilst C3 inhibition significantly increased sensitivity to a clinically-relevant dose of radiation. Inhibition of C3 was demonstrated to increase DNA damage and alter cell cycle distribution, mediating a shift towards a radiosensitive cell cycle phenotype suggesting a role for C3 in reprogramming of the tumoural radioresponse. Expression of the complement effectors C3 and C5 was significantly increased in human rectal tumour tissue, as was expression of CFB, a component of the alternative pathway of activation. Elevated levels of C3a and C5b-9 in pre-treatment sera from rectal cancer patients was associated with subsequent poor responses to neo-CRT and poorer survival. Together these data demonstrate a role for complement in the radioresistance of rectal cancer and identify key complement components as potential biomarkers predicting response to neo-CRT and outcome in rectal cancer.

Genetic Associations of Lipids and Lipid-Modifying Drug Targets With Type 2 Diabetes in the Chinese Population

BackgroundDyslipidemia is a recognized risk factor for type 2 diabetes (T2D), yet the genetic basis and causal nature remain unclear, particularly in Chinese populations. ObjectivesThe authors investigated the causal effects of genetically predicted lipid levels on T2D risk and explored the potential effects of lipid-modifying drugs. MethodsLeveraging data from the Kunshan Community cohort in China, we analyzed the associations between low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol, and triglycerides (TGs) with T2D risk using genetic risk scores, 1-sample univariable, multivariable, and nonlinear Mendelian randomization (MR) analyses. Two-sample MR using summary-level data from Global Lipid Genetics Consortium and Biobank Japan was used for validation. Drug-target MR was used to examine the impact of lipid-modifying drug targets on T2D. ResultsLower genetic risk scores of LDL-C (OR per SD: 0.97 [95% CI: 0.95-0.99]; P = 0.010) and TGs (0.96 [95%CI: 0.94-0.98]; P = 0.002) were associated with increased T2D risk. Univariable MR revealed that genetically predicted lower LDL-C (0.78 [95% CI: 0.65-0.93]; P = 0.006) and TG levels (0.76 [95% CI: 0.66-0.89]; P < 0.001) were linked to a higher T2D risk, validated by 2-sample MR. Multivariable MR demonstrated a direct inverse association between LDL-C (0.80 [95% CI: 0.66-0.97]; P = 0.020) and TG (0.80 [95% CI: 0.66-0.97]; P = 0.022) with T2D. No evidence was found for nonlinearity. Among lipid-modifying drugs, genetic mimicry of apolipoprotein C3 (APOC3) inhibition increased T2D risk (OR per 1 mmol/L reduction in TG: 1.38 [95% CI: 1.10-1.75]; P = 0.007). ConclusionsOur findings suggested potential adverse effects of lower LDL-C, TG levels, as well as long-term use of APOC3 inhibitors on T2D risk in Chinese populations. These findings highlight the need for cautious lipid management strategies in T2D prevention.

Sutimlimab for Cold Agglutinin Disease.

Cold agglutinin disease (CAD) is a rare type of autoimmune hemolytic anemia (AIHA) distinct from warm antibody AIHA. One of the ways it is distinct is that CAD is usually not responsive to corticosteroids compared with warm antibody AIHA. Historically, CAD therapy has been limited to immunotherapy or chemoimmunotherapy with varying responses. Cold agglutinin disease also poses a risk for thrombosis and mortality. For patients, fatigue tends to be a common symptom of CAD. The hallmark of CAD is complement-mediated hemolysis, which makes complement inhibitors a critical therapeutic option for patients. Previously, eculizumab, a C5 inhibitor, had limited therapeutic effect for CAD. More recently, sutimlimab, a C1s inhibitor, was shown in two phase III studies to be an efficacious treatment for CAD, improving hemoglobin, hemolysis, and fatigue. However, there is a paucity of medical literature on CAD and on sutimlimab in particular that is geared toward advanced practice providers (APPs). This article aims to provide APPs with a background in CAD and a focus on sutimlimab, assisting these providers in caring for patients with CAD receiving this therapy.

Navigating the Complement Pathway to Optimize PNH Treatment with Pegcetacoplan and Other Currently Approved Complement Inhibitors.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and potentially life-threatening hematologic disorder caused by a somatic mutation in a relevant portion of hematopoietic stem cells. Mutation of the phosphatidylinositol glycan biosynthesis class A (PIGA) gene prevents the expression of cell-surface proteins, including the complement regulatory proteins CD55 and CD59. With decreased or a lack of CD55 and CD59 expression on their membranes, PNH red blood cells become susceptible to complement-mediated hemolysis (symptoms of which include anemia, dysphagia, abdominal pain, and fatigue), leading to thrombosis. State-of-the-art PNH treatments act by inhibiting the dysregulated complement at distinct points in the activation pathway: late at the C5 level (C5 inhibitors, eculizumab, ravulizumab, and crovalimab), centrally at the C3 level (C3/C3b inhibitors and pegcetacoplan), and early at the initiation and amplification of the alternative pathway (factor B inhibitor, iptacopan; factor D inhibitor, danicopan). Through their differing mechanisms of action, these treatments elicit varying profiles of disease control and offer valuable insights into the molecular underpinnings of PNH. This narrative review provides an overview of the mechanisms of action of the six complement inhibitors currently approved for PNH, with a focus on the C3/C3b-targeted therapy, pegcetacoplan.