C5 Complement Inhibitor Research Articles

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.

Targeting complement dysregulation: eculizumab in scleroderma renal crisis management-a case-based review.

Systemic sclerosis (SSc) poses significant challenges in clinical management, especially when complicated by scleroderma renal crisis (SRC), a rare but life-threatening manifestation. Here, we report a 41-year-old female patient with SSc who presented with SRC and concurrent thrombotic microangiopathy. Her condition persisted despite conventional treatments such as plasma exchange and renin-angiotensin-aldosterone system blockade. In particular, treatment with eculizumab, a C5 complement inhibitor, led to a rapid improvement in platelet count, reduction in lactate dehydrogenase levels, and complete recovery of renal function. Genetic testing revealed a variant of unknown significance in the thrombomodulin (THBD) gene, which is associated with the complement system. This case highlights the complex interplay between complement dysregulation and SRC, and highlights the promising role of eculizumab in refractory cases. Further investigation of complement involvement and the efficacy of eculizumab in SRC warrants attention to improving therapeutic outcomes in this challenging condition.

Phase 3 randomized COMMODORE 2 trial: Crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria naive to complement inhibition.

Crovalimab is a novel C5 complement inhibitor that enables rapid and sustained C5 inhibition with subcutaneous, low-volume self-administration every 4 weeks. COMMODORE 2 (NCT04434092) is a global, randomized, open-label, multicenter, phase 3 trial evaluating the non-inferiority of crovalimab versus eculizumab in patients with paroxysmal nocturnal hemoglobinuria not previously treated with C5 inhibition. C5 inhibitor-naive patients with lactate dehydrogenase (LDH) ≥2 × upper limit of normal (ULN) were randomized 2:1 to crovalimab or eculizumab. Co-primary efficacy endpoints were proportion of patients with hemolysis control (centrally assessed LDH ≤1.5 × ULN) and proportion with transfusion avoidance. Secondary efficacy endpoints were proportions of patients with breakthrough hemolysis, stabilized hemoglobin, and change in FACIT-Fatigue score. The primary treatment period was 24 weeks. Two hundred and four patients were randomized (135 crovalimab; 69 eculizumab). Crovalimab was non-inferior to eculizumab in the co-primary endpoints of hemolysis control (79.3% vs. 79.0%; odds ratio, 1.0 [95% CI, 0.6, 1.8]) and transfusion avoidance (65.7% vs. 68.1%; weighted difference, -2.8 [-15.7, 11.1]), and in the secondary efficacy endpoints of breakthrough hemolysis (10.4% vs. 14.5%; weighted difference, -3.9 [-14.8, 5.3]) and hemoglobin stabilization (63.4% vs. 60.9%; weighted difference, 2.2 [-11.4, 16.3]). A clinically meaningful improvement in FACIT-Fatigue score occurred in both arms. Complete terminal complement activity inhibition was generally maintained with crovalimab. The safety profiles of crovalimab and eculizumab were similar with no meningococcal infections. Most patients who switched from eculizumab to crovalimab after the primary treatment period preferred crovalimab. These data demonstrate the positive benefit-risk profile of crovalimab.

Design and Biological Evaluation of the Long-Acting C5-Inhibited Ornithodoros moubata Complement Inhibitor (OmCI) Modified with Fatty Acid.

Disorder of complement response is a significant pathogenic factor causing some autoimmune and inflammation diseases. The Ornithodoros moubata Complement Inhibitor (OmCI), a small 17 kDa natural protein, was initially extracted from soft tick salivary glands. The protein was found binding to complement C5 specifically, inhibiting the activation of the complement pathway, which is a successful therapeutic basis of complement-mediated diseases. However, a short half-life due to rapid renal clearance is a common limitation of small proteins for clinical application. In this study, we extended the half-life of OmCI by modifying it with fatty acid, which was a method used to improve the pharmacokinetics of native peptides and proteins. Five OmCI mutants were initially designed, and single-site cysteine mutation was introduced to each of them. After purification, four OmCI mutants were obtained that showed similar in vitro biological activities. Three mutants of them were subsequently coupled with different fatty acids by nucleophilic substitution. In total, 15 modified derivatives were screened and tested for anticomplement activity in vitro. The results showed that coupling with fatty acid would not significantly affect their complement-inhibitory activity (CH50 and AH50). OmCIT90C-CM02 and OmCIT90C-CM05 were validated as the applicable OmCI bioconjugates for further pharmacokinetic assessments, and both showed improved plasma half-life in mice compared with unmodified OmCI (15.86, 17.96 vs 2.57 h). In summary, our data demonstrated that OmCI conjugated with fatty acid could be developed as the potential long-acting C5 complement inhibitor in the clinic.

Poor response to Eculizumab in Caucasian Patients with Treatment Refractory Generalized Myasthenia Gravis: A case series

Background
 Eculizumab, a C5 complement inhibitor, has been approved for management of patients with treatment refractory Acetylcholine receptor positive (AChR+) Generalized Myasthenia Gravis (gMG). Though majority of patients receiving eculizumab experience clinical improvement, a small number of patients may have poor response.
 
 Objective 
 To report three cases of poor response to eculizumab in young caucasian patients with treatment refractory gMG.
 
 Methods
 Case Series
 
 Results 
 All three patients were young, caucasian, thymectomized, females with MGFA class III, treatment refractory MG on multiple immunosuppressant medications. All three patients had initial worsening of MG- ADL score, 1 month post eculizumab, followed by an unchanged MG ADL and MGC score, 3 months after eculizumab therapy. No changes were noted in the number of acute exacerbations of MG, pre and post eculizumab therapy. All patients were eventually started on maintenance Plasma-exchange (PLEX) therapy, post eculizumab failure and had clinical improvement in MG-ADL and MGC scores and reduction in the number of acute exacerbations of disease.
 
 Conclusion
 The exact mechanism contributing to poor clinical response to eculizumab in gMG patients remains unclear. Further studies are warranted to undermine the underlying pathogenesis.

Microangiopathy in multiple myeloma: a case of carfilzomib-induced secondary thrombotic microangiopathy successfully treated with plasma exchange and complement inhibition

BackgroundThrombotic microangiopathy (TMA) is a potentially organ and life-threatening condition affecting patients with multiple myeloma (MM). Cases of proteasome inhibitor-induced TMA and specifically carfilzomib-induced TMA have been rarely reported and standards for diagnostic workup and treatment are not available.Case presentationWe describe a case of a male MM patient under salvage therapy including proteasome inhibitor carfilzomib following chemotherapy and autologous stem cell transplantation. The patient then developed acute kidney injury with clinical and laboratory signs of TMA. Hemodialysis became necessary and treatment with plasma exchange was initiated followed by therapy with C5 complement inhibitor eculizumab which led to amelioration of kidney function and hemolysis parameters.ConclusionWe report a patient with suspected proteasome inhibitor-induced secondary thrombotic microangiopathy that has been successfully treated with plasma exchange and eculizumab, a monoclonal antibody targeting complement factor C5.

Myasthenia in adults, children, and adolescents: what's new?

Therapy of myasthenia gravis (MG) is increasingly oriented to the patient's antibody status. In addition to symptomatic therapy, steroids, classic long-term immunosuppressive therapies and thymectomy are regularly used. In recent years, new therapeutic approaches have been developed that particularly benefit acetylcholine receptor (AChR) antibody (Abs) positive patients with highly active disease. While the C5 complement inhibitor eculizumab was reserved for treatment-refractory generalized courses of AChR-Abs positive MG, two new drugs, the neonatal Fc receptor inhibitor efgartigimod and the more advanced C5 complement inhibitor ravulizumab, have recently been approved as add-on therapy for AChR-Abs positive generalized MG (gMG). In highly active courses of MG with Abs against the muscle-specific receptor tyrosine kinase (MuSK), the use of rituximab should be considered early in the course of the disease. The efficacy of the new drugs in children and adolescents with juvenile MG (JMG) is currently being tested in clinical trials. The new guideline recommends the use of modern immunomodulators based on astep-by-step approach depending on disease activity. With the German Myasthenia Register (MyaReg), the changing therapeutic landscape and quality of life of patients with myasthenic syndromes can be assessed, thus providing real-world data on the care of MG patients. Despite treatment based on the previous guideline, many MG patients suffer considerable impairment to their quality of life. With the new immunomodulators, there is the possibility of early intensified immunotherapy, which, in contrast to long-term immunosuppressants, can lead to arapid improvement in the course of the disease.

Complement Activation Is Associated with Endothelial Damage in Hematopoietic Stem Cell Transplant Associated-Thrombotic Microangiopathy

Introduction: Hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) is a life-threatening complication of HSCT. Identification of at-risk patients is challenging, leading to delays in diagnosis and poor outcomes. Degradation of the glycocalyx and dysregulated complement activation are integral to the pathophysiology. The glycocalyx components thrombomodulin (TM) and syndecan-1 (SYND1) are shed during cell damage, and detection in patient plasma may serve as biomarkers of endothelial cell (EC) dysfunction. Therapeutic intervention to preserve glycocalyx integrity may protect the endothelium and also improve the clinical outcome during HSCT-TMA. Additionally, plasma Ba, an alternative complement pathway (AP) activation product, has been identified as a prognostic biomarker of HSCT-TMA. Our objective was to explore the link between excessive AP activation and endothelial damage in the context of HSCT-TMA and to potentially identify biomarkers to aid in its diagnosis. Methods: Biomarker levels of soluble TM, SYND1, and Ba were measured in plasma of pediatric HSCT patients with and without (controls) TMA obtained from Texas Children's Hospital. Sample acquisition was approved by Baylor College of Medicine Institutional Review Board. Biomarkers were also measured in a pre-clinical in vivo model of inflammation-mediated complement activation similar to HSCT-TMA, in which C57BL/6J mice were injected with lipopolysaccharide (LPS) to induce complement activation, followed by treatment with AP (anti-fB IgG) and terminal complement pathway (anti-C5 IgG) inhibitors or an IgG isotype control. Finally, as the immunosuppressant cyclosporin A (CsA) is a known trigger of HSCT-TMA, the role of complement in CsA-mediated damage in human ECs (HMEC-1 cells and HUVECs) was assessed in vitro. ECs were incubated with CsA followed by normal human serum (NHS) in the presence or absence of the C5 complement inhibitor eculizumab. TM was then measured by fluorescent staining on the cell surface and quantified using mean fluorescence intensity (MFI). Results: HSCT-TMA patients (n=11), compared to HSCT control patients (n=7), had significantly elevated levels of biomarkers of glycocalyx damage (TM: 18.3 ± 10.9 ng/mL and 6.6 ± 2.9 ng/mL, respectively; P<0.01; SYND1: 175.3 ± 177.0 ng/mL and 35.8 ± 18.9, respectively; P<0.05). A strong positive correlation between TM and SYND1 was observed (Pearson r=0.89). Plasma Ba was also significantly elevated in patients with TMA compared to those without (1790.0 ± 1262.0 ng/mL and 652.1 ± 233.5 ng/mL, respectively; P<0.05), and correlated positively with both TM and SYND1 levels (Pearson r=0.72 and 0.50, respectively). We have previously shown in an in vivo model of inflammation-mediated complement activation that LPS-injected mice, compared to saline-injected control mice, had significantly increased plasma Ba levels. Here we demonstrated LPS-injected mice (which also received IgG isotype control) had higher circulating levels of TM than untreated mice (35.1 ± 5.8 ng/mL [n=6] and 10.9 ± 1.6 ng/mL [n=6], respectively; P<0.0001). Inhibition of alternative (anti-fB IgG) and terminal (anti-C5 IgG) pathways of complement significantly attenuated TM levels (compared to isotype control [35.1 ± 5.8 ng/mL]; anti-FB: 25.2 ± 5.3 ng/mL, P<0.01; anti-C5: 26.2 ± 4.9 ng/mL, P<0.05, Fig. 1). TM was positively correlated with Ba (Pearson r=0.68). In vitro treatment of HMEC-1 cells with CsA led to deposition of iC3b and C5b-9, and C5 inhibition with eculizumab significantly reduced C5b-9 deposition (P< 0.0001) but had no effect on iC3b deposition. Treatment of HUVECs with CsA also reduced surface expression of TM (P<0.0001), and TM loss was partially restored by eculizumab (P<0.05, Fig 2). Conclusion: Plasma biomarkers of endothelial damage were elevated in patients with HSCT-TMA and in mice with inflammatory-mediated complement activation. Furthermore, AP activation positively correlated with biomarkers of endothelial damage. Blockade of complement activation significantly reduced markers of endothelial damage in both in vivo and in vitro models. These results provide further evidence linking complement activation and endothelial damage in HSCT-TMA and suggest that the use of these biomarkers may aid in the diagnosis of HSCT-TMA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Coronavirus Disease 2019-Associated Thrombotic Microangiopathy: Literature Review.

Coronavirus disease 2019 (COVID-19) can lead to clinically significant multisystem disorders that also affect the kidney. According to recent data, renal injury in the form of thrombotic microangiopathy (TMA) in native kidneys ranks third in frequency. Our review of global literature revealed 46 cases of TMA in association with COVID-19. Among identified cases, 18 patients presented as thrombotic thrombocytopenic purpura (TTP) and 28 cases presented as atypical hemolytic uremic syndrome (aHUS). Altogether, seven patients with aHUS had previously proven pathogenic or likely pathogenic genetic complement abnormalities. TMA occurred at the time of viremia or even after viral clearance. Infection with COVID-19 resulted in almost no or only mild respiratory symptoms in the majority of patients, while digestive symptoms occurred in almost one-third of patients. Regarding the clinical presentation of COVID-19-associated TMA, the cases showed no major deviations from the known presentation. Patients with TTP were treated with plasma exchange (88.9%) or fresh frozen plasma (11.1%), corticosteroids (88.9%), rituximab (38.9%), and caplacizumab (11.1%). Furthermore, 53.6% of patients with aHUS underwent plasma exchange with or without steroid as initial therapy, and 57.1% of patients received a C5 complement inhibitor. Mortality in the studied cohort was 16.7% for patients with TTP and 10.7% for patients with aHUS. The exact role of COVID-19 in the setting of COVID-19-associated TMA remains unclear. COVID-19 likely represents a second hit of aHUS or TTP that manifests in genetically predisposed individuals. Early identification of the TMA subtype and appropriate prompt and specific treatment could lead to good outcomes comparable to survival and recovery statistics for TMA of all causes.

Clinical Utility and Potential Cost Savings of Pharmacologic Monitoring of Eculizumab for Complement-Mediated Thrombotic Microangiopathy

One of the treatment options for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome, is the administration of the C5 complement inhibitor eculizumab. In vivo studies have reported a complete complement blockade with eculizumab serum concentrations above 50 μg/mL in the case of atypical hemolytic uremic syndrome. The eculizumab trough levels and C5 functional activity were monitored in patients with CM-TMA being treated with eculizumab. For those with eculizumab trough concentrations of more than 100 μg/mL, the frequency of eculizumab 1200-mg doses was decreased. In this article, we describe the pharmacologic monitoring data with the use of C5 functional activity and mass spectrometric assessments of eculizumab to allow for a tailored eculizumab schedule for 10 patients with CM-TMA. In 9 out of 10 (90%) patients with a standard administration schedule, eculizumab trough concentrations were more than 100 μg/mL. At the time of the last eculizumab follow-up (median, 250 days; range, 85-898 days), the interval between eculizumab infusions was extended to every 3-6 weeks for 8 patients; no disease relapse was found with the modified dosing interval. Altering the administration of maintenance eculizumab from every 2-3 weeks to 3-6 weeks yields a savings of $78,185 per patient for a 6-month eculizumab treatment course. Although larger standardized cohorts are necessary to confirm these findings, our data suggest that monitoring eculizumab levels in conjunction with C5 assessment allows for safe modification of eculizumab dosing and results in considerable cost savings.

No HELLP at all: Post-partum atypical hemolytic uremic syndrome treated with Eculizumab: A case report

Atypical hemolytic uremic syndrome (aHUS) is a rare condition among thrombotic microangiopathies (TMA). Pregnancy is a known precipitating factor of complement mediated TMA. The occurrence of microangiopathic hemolytic anemia, thrombocytopenia and acute kidney injury presents diagnostic and therapeutic challenges. Diverse causes include hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome) in pregnant women. In pregnancy or postpartum, the occurrence of aHUS is a critical complication requiring urgent diagnosis and treatment. aHUS is considered to be the result of the underlying condition, with the understanding that therapy is focused on the underlying condition. Five documented cases of pregnancy-associated aHUS treated with Eculizumab have been reported, making the condition extremely rare. We present the case of a pregnant woman with HELLP syndrome induced aHUS. The patient presented with evidence of dysregulation of the complement system and renal insufficiency. Since the initiation of Eculizumab, a C5 complement inhibitor, the development of renal insufficiency diminished and the patient became dialysis independent.

Atypical HUS Unmasked by Infection and Calcineurin Inhibitors Post Lung Transplant

<h3>Introduction</h3> Lung transplant recipients are maintained on multiple lifelong immunosuppressive medications including steroids, calcineurin inhibitors (CNI), and antimetabolite (AM) medications. We report a unique case of a double lung transplant (DLT) recipient developing thrombotic microangiopathy (TMA) from atypical hemolytic uremic syndrome (aHUS) unmasked by infection and CNI therapy. <h3>Case Report</h3> 63-year-old male developed delirium and thrombocytopenia after initiation of CNI therapy with tacrolimus post DLT. Evaluation was otherwise negative and patient improved with cessation of therapy. CNI was switched to cyclosporine without further issues. Four-week biopsy was negative for acute cellular rejection. Five days later, he presented with hypoxia, dyspnea, dizziness, confusion, and impaired gait. His immunosuppressive regimen included prednisone & cyclosporine. His AM therapy was held for leukopenia. All testing and imaging were negative apart from bronchial lavage cultures positive for pseudomonas, klebsiella, and parainfluenza. Appropriate antibiotics and antiviral therapies were started. He developed delirium, acute kidney injury, hemolysis, and thrombocytopenia. Impression was CNI-induced TMA, and CNI was held. All additional work up was negative including shiga-like toxin producing E.Coli. He failed to improve with removal of offending agent and concern was for aHUS given complement panel was suggestive of alternative pathway dysregulation (absent AH50, normal C4 and decreased factors B and H). Patient did not respond to plasmapheresis, and eculizumab was started. He remained thrombocytopenic with positive hemolytic parameters despite 2 doses of therapy. Complement genetic panel testing is pending. Treatment is now held due to respiratory failure and septic shock. <h3>Summary</h3> aHUS is a rare form of TMA, associated with excess activation of the alternate complement pathway which is part of innate immunity. It usually responds to treatment with eculizumab, an anti-C5 monoclonal antibody that inhibits terminal complement complex generation. Our case is inconsistent with secondary HUS from drugs or solid organ transplant and has failed standard aHUS therapy. This is a complex and uniquely challenging case, limited second line options are available including a recently approved long-acting C5 complement inhibitor, which is under review at our institution.

Comparative effectiveness of pegcetacoplan versus ravulizumab in patients with paroxysmal nocturnal hemoglobinuria previously treated with eculizumab: a matching-adjusted indirect comparison

Objective In the absence of a head-to-head study, we assessed the comparative effectiveness of pegcetacoplan, a targeted C3 complement inhibitor, vs. ravulizumab, a C5 complement inhibitor, among patients with paroxysmal nocturnal hemoglobinuria (PNH) previously treated with eculizumab using matching-adjusted indirect comparison methodology. Methods Individual patient data from the PEGASUS study (NCT03500549) comparing pegcetacoplan and eculizumab enabled adjustment for baseline differences compared with published results from the ALXN1210-PNH-302 study (NCT03056040), comparing ravulizumab and eculizumab. Adjusted differences and 95% confidence intervals (CIs) were computed via weighted Wald tests for comparisons of pegcetacoplan vs. ravulizumab, anchored to the common comparator eculizumab. Results Sixty-eight patients from PEGASUS (36 pegcetacoplan; 32 eculizumab) and 195 from ALXN1210-PNH-302 (97 ravulizumab; 98 eculizumab) were included. Compared with ravulizumab, treatment with pegcetacoplan was associated with more transfusion avoidance (adjusted difference [95% CI] = +71.4% [53.5%, 89.3%]), hemoglobin level stabilization (+75.5% [56.4%, 94.6%]), lactate dehydrogenase (LDH) level normalization (+64.0% [41.8%, 86.1%]), and fewer blood transfusions (−5.7 units [−7.2, −4.2]). Additionally, patients who received pegcetacoplan experienced clinically meaningful improvements in fatigue (+8.2 points [3.8, 12.6]), global health status (+9.6 points [0.1, 19.0]), physical functioning (+11.5 points [3.6, 19.5]), and fatigue symptoms (−13.3 points [−23.7, −3.0]), compared with ravulizumab. Mean change from baseline in LDH level was not significantly different for pegcetacoplan vs. ravulizumab. Conclusions Results suggest that among patients previously treated with eculizumab, clinical, hematological, and quality of life endpoints were better for patients who received the C3 complement inhibitor pegcetacoplan vs. patients who received ravulizumab, a C5 complement inhibitor.

Cellular changes in eculizumab early responders with generalized myasthenia gravis

Eculizumab (ECU), a C5 complement inhibitor, is approved to treat acetylcholine receptor autoantibody positive generalized myasthenia gravis (AChR MG). The clinical effect of ECU relies on inhibition of the terminal complement complex; however, the effect of ECU on lymphocytes is largely unknown. We evaluated innate and adaptive immunity among AChR MG patients (N = 3) before ECU and ≥3 months later while on stable therapy, and found reduced activation markers in memory CD4+ T cell subsets, increased regulatory T cell populations, and reduced frequencies of CXCR5+HLA-DR+CCR7+ Tfh subsets and CD11b+ migratory memory B cells. We observed increases within CD8+ T cell subsets that were terminally differentiated and senescent. Our data suggest complement inhibition with ECU modulates the adaptive immunity in patients with MG, consistent with preclinical data showing changes in complement-mediated signaling by T- and antigen-presenting cells. These findings extend our understanding of ECU's mechanism of action when treating patients with MG.

Coversin, a Novel C5 Complement Inhibitor, Is Safe and Effective in the Treatment of PNH: Results of a Phase II Clinical Trial

Background:GPI-anchored proteins play a critical role in protecting red cells from complement mediated lysis. An acquired deficiency in Paroxysmal Nocturnal Haemoglobinuria (PNH) leads to intravascular haemolysis. Until the advent of eculizumab, a monoclonal antibody which prevents the cleavage of C5 to C5a and C5b, PNH was associated with considerable morbidity and a poor long-term prognosis. However, eculizumab is administered by health care professionals by intravenous infusion which may interfere with the life-styles, occupations and personal privacy of patients. Interval dosing has led to concerns by some related to breakthrough haemolysis. Coversin is a protein suitable for small-volume subcutaneous (SC) injection and can be self-administered by patients.Aims:The aims of this study were to assess the safety and tolerability of Coversin, the efficacy of the dosing regime and whether self-injection by patients is well-accepted.Methods:Under the trial protocol of a Phase 2 single arm open label trial of Coversin patients, either newly diagnosed with PNH or who have not previously had access to complement inhibitors, were treated for 90 days. Coversin was supplied as a lyophilised powder, reconstituted with water for injection to give a buffered aqueous solution of Coversin 30mg/mL. The aim of the trial was to recruit 8 adult patients with a diagnosis of PNH confirmed by flow cytometry.Treatment commenced with an ablating regime (AR) consisting of a fixed dose of 60mg followed by 1 - 3 doses of 30mg q12 hours delivered by SC injection. After being suitably instructed patients were encouraged to self-inject the drug. Following the AR, a dose of 15 or 22.5mg q12 hours was given. On day 28, they switched to 30 or 45mg q24 hours for the remainder of the trial. Those patients not satisfactorily controlled could be updosed or switched to the same dose divided into 2 doses administered q12 hours. All patients who completed the trial and wished to do so, continued to receive Coversin under a long-term safety and efficacy protocol.A primary end point was LDH <1.8X ULN at the local laboratory at day 28. Secondary endpoints included LDH (xULN) at 60 and 90 days, terminal complement activity assessed by CH50 ELISA (Quidel®), haemoglobin stabilisation, reduction in requirement for blood transfusions, sheep erythrocyte haemolysis assay, PK (free and bound Coversin levels), anti-drug antibodies (ADA) and quality of life.Results:Results will be presented for all patients who were enrolled. The patients who completed the trial to date (07/31/17) experienced a reduction in serum LDH and PNH symptoms, stabilisation of haemoglobin levels, no transfusions during the trial (three of the four patients received transfusions in the 3 months prior to enrolment), no serious adverse events related to Coversin, tolerated the drug well, and for those experiencing them, the injection site reactions observed were mild to moderate, self-limiting and diminished with time. There has been no evidence of the formation of neutralising antibodies.Summary/Conclusion:Coversin may be an effective alternative for patients with PNH who prefer the independence of self-administration. The relatively short dose interval may also help to reduce breakthrough events. DisclosuresHill:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Weston-Davies:Akari Therapeutics Plc: Employment, Equity Ownership. Nunn:Akari Therapeutics Plc: Employment, Equity Ownership. Robak:Pharmacyclics LLC, an AbbVie Company: Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Akari Therapeutics Plc: Research Funding. Windyga:Akari Therapeutics Plc: Research Funding. Hellmann:Akari Therapeutics Plc: Research Funding. Kulasekararaj:Akari Therapeutics Plc: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria; Ra Pharmaceuticals: Consultancy, Honoraria; Achillion pharmaceuticals: Consultancy, Honoraria. Griffin:Alexion Pharmaceuticals, Inc.: Honoraria. Munir:Janssen: Honoraria; Gilled: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; AbbVie: Honoraria; Roche: Honoraria.

PRO77 Preliminary Characterization of Eculizumab Treatment Patterns, Preceding Disease Triggers and Supportive Therapies in Atypical Hemolytic Uremic Syndrome: A US Claims Database Analysis

Patients with atypical hemolytic uremic syndrome (aHUS) may require ongoing treatment of varying duration. The C5 complement inhibitor eculizumab provides transformative benefits in aHUS; however, knowledge gaps remain regarding treatment patterns/preferences. To address this, we sought to characterize real-world eculizumab use, disease triggers, dialysis and plasma exchange/infusion (PE/PI) in patients with aHUS using US claims data.

#92: What Is the Optimal Management of Patients Immunosuppressed with the Anti-compliment Monoclonal Antibody, Eculizumab? A Case Report and Review

Abstract Background Patients with deficiencies of terminal components of complement are at hundreds to thousands fold increased risk of severe and fatal Neisseria spp. infections compared with the general population. Eculizumab is a newly approved monoclonal antibody C5 complement inhibitor. It is indicated for the treatment of atypical hemolytic uremic syndrome (atypical HUS), myasthenia gravis, and paroxysmal nocturnal hemoglobinuria. Because of the complement-depleting effect of Eculizumab dosing (Soliris®, Alexion Pharmaceuticals, Munich, Germany), patients are immunosuppressed for specific infectious pathogens (including Neisseria species) against which protection partially relies on normal complement activity. Because Eculizumab treatment is associated with a dramatically increased risk of Neisseria species. infections, recommendations for Neisseria meningitidis vaccination and antibiotic prophylaxis are contained in Eculizumab prescribing information. However, the most appropriate prevention of infections after Eculizumab has yet to be determined. Methods Case report and literature review. Results A previously healthy 7-year-old male was diagnosed with atypical HUS which included renal failure progressing to dialysis, persistent thrombocytopenia, hemolytic anemia, and hemoglobinuria. Stool cultures and a stool multiplex PCR panel did not detect Shiga-like producing E. coli nor E. coli O157/H7. Eculizumab dosing was therefore planned and Infectious Diseases consultation was obtained for appropriate preventions. The FDA Prescribing Information recommends Neisseria meningitidis vaccination before starting Eculizumab or, if immediate Eculizumab is necessary, to use antibiotic prophylaxis until 2 weeks after vaccination. The accepted protective titer after meningococcal vaccination is population based and uses the serum bactericidal assay (SBA). An antibody titer of &amp;gt;1:4 (human compliment) or 1:8 (rabbit complement) is considered protective. However, this “gold standard” assay incorporates the use of exogenous human or rabbit complement. The protective SBA titers in subjects with terminal complement component deficiencies may not be properly assessed using these same SBA titer protective thresholds. Furthermore, serious meningococcal infections have occurred after appropriate vaccination in patients receiving chronic Eculizumab treatments (ie for paroxysmal nocturnal hemoglobinuria). Finally, SBA protective levels after single Neisseria meningitidis vaccination have not been achieved in majorities of patients with renal failure receiving dialysis and or transplant immunosuppression. Conclusions The current Eculizumab prescribing information recommendations for vaccination and antimicrobial prophylaxis may be inadequate to prevent serious Neisseria infections. Repeated Neisseria meningitidis vaccination and extended antibiotic prophylaxis may afford better protection in patients chronically dosed with Eculizumab.

Overview of current and emerging therapies for amytrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating, fatal neuromuscular disease. Most patients die within 2 to 5 years of diagnosis. The disease stems from death of upper and lower motor neurons leading to degeneration of motor pathways and the paralytic effects of the disease. The economic cost of the disease is not clear, with estimates ranging from about $64,000 per year to $200,000. Two drugs, riluzole and edaravone, are currently FDA approved for the treatment of ALS, and each provides modest benefits in mortality and/or function. Recent developments in the understanding of the underlying pathophysiologic processes that contribute to ALS have led to the development of numerous investigational therapies, with several now in phase 3 trials. This article highlights the oral tyrosine kinase inhibitor masitinib; the antisense drug tofersen; the humanized monoclonal antibody C5 complement inhibitor ravulizumab-cwvz; and mesenchymal stem cell (MSC)-neurotrophic factor (NTF) cells, a proprietary platform that induces autologous bone marrow-derived MSCs to secrete high levels of NTFs.

P1845HISTORY AND FUTURE PERSPECTIVES OF PAROXYSMAL NOCTURNAL HEMOGLOBINURIA

Abstract Background and Aims Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder that affects about 1-1,5 cases per million individuals, characterized by hemolysis, peripheral blood cytopenia, bone marrow dysfunction, thrombosis, renal impairment and arterial and pulmonary hypertension. The first case of PNH was probably described in 1793 by a surgeon, Dr Charles Stewart, in the medical commentaries “Account of a singular periodical discharge of blood from the urethra”. In the following decades several cases have been reported by the most eminent physicians and scientists of the time. Method In 1882 Paul Strübing was the first to identify PNH as a new disease entity. Hijmans in 1911 considered the possibility that the complement system mediated the hemolysis of PNH erythrocytes and in the same year, Italian scientists Ettore Marchiafava and Nazari scrupulously described the pathogenesis of the affection. In the 1925 Enneking introduced for the first time the name “paroxysmal nocturnal hemoglobinuria”, to define this pathology. Results Despite the increased knowledge of this syndrome, therapies for PNH were still only experimental and symptomatic, with the use of antimicrobial agents, corticosteroids and blood transfusions. The natural history of PNH changed remarkably only in the 2007, with the introduction of Eculizumab complement blockade agent. The Ravulizumab, a long-acting C5 complement inhibitor approved on December 2018 by the U.S. food and drug Administration (FDA), and on July 2019 by the European Commission, represent a new promising instrument for PNH treatment. Conclusion Second generation of anti-complement agents are currently under investigation, representing future promising instruments for the treatment of PNH.

Will Complement Inhibition Be the New Target in Treating COVID-19-Related Systemic Thrombosis?

Will Complement Inhibition Be the New Target in Treating COVID-19-Related Systemic Thrombosis?