|This article needs additional citations for verification. (April 2013)|
|Source||Humanized (from mouse)|
|Target||Complement protein C5|
|Licence data||EMA: , US FDA:|
|Pregnancy cat.||C (US)|
|Legal status||POM (UK) ℞-only (US)|
|Half-life||8 to 15 days (mean 11 days)|
|Mol. mass||148 kDa|
|(what is this?)|
Eculizumab (INN and USAN; trade name Soliris) is a humanized monoclonal antibody that is a first-in-class terminal complement inhibitor and the first therapy approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a rare, progressive, and sometimes life-threatening disease characterized by excessive destruction of red blood cells (hemolysis) and excessive blood clotting. Eculizumab also is the first agent approved for the treatment of atypical hemolytic uremic syndrome (aHUS), an ultra-rare genetic disease that causes abnormal blood clots to form in small blood vessels throughout the body, leading to kidney failure, damage to other vital organs and premature death. It costs approximately £245,700 for ongoing treatment. 
In clinical trials in patients with PNH, eculizumab was associated with reductions in chronic hemolysis, thromboembolic events, and transfusion requirements, as well as improvements in PNH symptoms, quality of life, and survival. Clinical trials in patients with aHUS demonstrated inhibition of thrombotic microangiopathy (TMA), the formation of blood clots in small blood vessels throughout the body, including normalization of platelets and lactate dehydrogenase (LDH), as well as maintenance or improvement in renal function.
Eculizumab was developed by Alexion Pharmaceuticals and is manufactured by Alexion. It was approved by the United States Food and Drug Administration (FDA) on March 16, 2007 for the treatment of PNH, and on September 23, 2011 for the treatment of aHUS. It was approved by the European Medicines Agency for the treatment of PNH on June 20, 2007, and on November 24, 2011 for the treatment of aHUS. Eculizumab is currently being investigated as a potential treatment for other severe, ultra-rare disorders.
- 1 Medical uses
- 2 Adverse effects
- 3 Mechanism of action
- 4 Biochemistry
- 5 Research
- 6 References
- 7 External links
Paroxysmal nocturnal hemoglobinuria
Historically, 35% of people with paroxysmal nocturnal hemoglobinuria treated with the best available care (e.g., anticoagulation therapy, transfusions), died within 5 years of diagnosis. Thromboembolism (TE) is the leading cause of death in PNH patients, accounting for 40% to 67% of PNH-related mortality. Patients with PNH are 62 times more likely to have a venous thromboembolism than the general population, which is higher than any other hyper-coaguable disease. Both venous and arterial thromboembolism can occur in patients with PNH. Although deep vein thrombosis and pulmonary embolism are the most common clinical presentations, thrombosis in atypical sites (including Budd-Chiari, renal, and dermal thrombosis) is more common among PNH patients than in the general population. In a national registry, 39% of TEs in patients with PNH occurred in arterial sites. For patients who experience TE and survive, the risk of subsequent TEs is increased, and the risk of death increases 5- to 15-fold for PNH patients with no previous TE. Sixty percent of patients with PNH have evidence of undiagnosed thrombosis.
Data from three independent clinical studies—a Phase II pilot study, the Phase III TRIUMPH study, and the Phase III SHEPHERD study—demonstrated a greater than 90% reduction in thromboembolic events, the most serious complication of PNH and a major cause of death in this disease. Many PNH patients in clinical trials derived a benefit from eculizumab therapy; many benefits occurred rapidly, while others showed improvement over time.
Eculizumab protects blood cells against immune destruction by inhibiting the complement system. In the TRIUMPH study, a double-blind, randomized, placebo-controlled, Phase III trial involving 87 patients, eculizumab was associated with an 86% reduction in intravascular hemolysis, as measured by LDH reduction, as well as a 73% reduction in transfusions across all subgroups. There was a rapid and meaningful improvement in fatigue and quality of life for the treated patients. 
Historically, 33-40% of patients with aHUS died or progressed to ESRD with the first clinical manifestation of the disease. Moreover, 65% of all patients with aHUS will die, require kidney dialysis, or have permanent renal damage within one year of diagnosis despite administration of plasma exchange or plasma infusion (PE/PI). Prior to the availability of eculizumab, management of aHUS did not specifically target chronic uncontrolled complement activation, the underlying cause of systemic TMA in aHUS. Not only is PE/PI ineffective in arresting platelet activation and systemic TMA, but it also causes poor outcomes and carries the risk of serious – and sometimes fatal – complications. Even those patients who survive the first clinical manifestations of aHUS continue to experience TMA and remain at risk of progressive failure of vital organs or sudden death.
Eculizumab has been shown to inhibit terminal complement activity in children and adults with aHUS, and to eliminate the need for PE/PI and new dialysis. The efficacy and safety of eculizumab in aHUS have been studied in two prospective studies, one involving 17 patients with progressing TMA (median age 28 years, range 17-68) who were resistant to or intolerant of PE/PI (Study 1), and the other involving 20 patients with long duration of aHUS (median age 28 years, range 13–63; median duration from diagnosis of aHUS to screening 48 months) who were receiving chronic PE/PI (Study 2). TMA-related endpoints in these trials included the following:
- platelet count change from baseline
- hematologic normalization (maintenance of normal platelet counts and lactate dehydrogenase [LDH] levels for at least four weeks)
- complete TMA response (hematologic normalization plus at least a 25% reduction in serum creatininefor a minimum of four weeks)
- TMA-event free status (absence for at least 12 weeks of a decrease in platelet count of >25% from baseline, PE/PI, and new dialysis requirement)
- daily TMA intervention rate (defined as the number of PE/PI interventions and the number of new dialyses required per patient per day)
- time course of changes in renal function as measured by eGFR
- proportion of patients with improvement by ≥ 1 chronic kidney disease (CKD) stage, eGFR increase by ≥ 15 mL/min/1.73m2 or serum creatinine decrease by ≥25%
In Study 1, eculizumab inhibited complement-mediated TMA activity in all 17 patients through 26 weeks. Efficacy findings included a significant and sustained increase in platelet count through Week 26. Thirteen patients (76%) achieved hematologic normalization, and 15 patients (88%) achieved TMA event-free status. Renal function, as measured by eGFR, improved in nine patients (53%); the median duration of eGFR improvement was 251 days. Additionally, four of the five patients requiring dialysis at study entry were able to discontinue dialysis for the duration of eculizumab treatment. Quality of life (QoL) was significantly improved, with 80% of patients achieving a clinically meaningful change through Week 26; this increased to 87% through 1 year.
Similar results were reported in Study 2, in which 16 patients (80%) achieved TMA event-free status and 18 (90%) achieved hematologic normalization. All patients discontinued PE/PI and no new dialysis was required. Eculizumab was associated with mean increases in platelet count and eGFR from baseline to 26 weeks. QoL was also improved, with 8 of 11 (73%) evaluable patients exceeding the clinically meaningful threshold through a median duration of 62 weeks.
After completing the initial 26-week treatment period, most patients in each of the prospective studies continued to receive eculizumab by enrolling in an extension study. Two-year follow-up data from the extension studies suggest that eculizumab provides sustained inhibition of complement-mediated TMA and significant, continuous, time-dependent improvement in renal function. In the extension to Study 1, in which 13 patients were treated for a median duration of 100 weeks, chronic eculizumab treatment resulted in a continued increase in platelet counts and greater percentages of patients achieving key renal endpoints compared to those completing 26 weeks of therapy. Additionally, at a median duration of almost 2 years, all patients receiving chronic eculizumab therapy remain alive. In the extension to Study 2, in which 20 patients were treated for a median duration of 114 weeks, 19 (95%) achieved TMA event-free status, and the percentages of patients reaching the key renal endpoints were also higher than at Week 26. No patient on chronic eculizumab therapy in the extension to Study 2 required PE/PI or progressed to ESRD or dialysis.
Efficacy results from a single-arm retrospective study, in which 30 patients (including 19 pediatric patients aged 2 months to 17 years) were treated for a median of 16 weeks, were generally consistent with those from the two prospective studies. Among the pediatric patients, eculizumab reduced signs of TMA activity, as shown by an increase in mean platelet counts from baseline. Seventeen (89%) pediatric patients achieved platelet count normalization, 8 (42%) attained hematologic normalization, 8 (42%) had a complete TMA response, and 9 (47%) experienced improvement in eGFR from baseline. Four of 8 pediatric patients (50%) discontinued dialysis during the study period, and none required new dialysis while on eculizumab therapy.
In addition to the above single-arm studies, there are dozens of published case reports of the use of eculizumab in patients with aHUS, including several reporting complete or partial recovery of renal function with no need for subsequent kidney replacement therapy. One pediatric patient, who was initially diagnosed shortly after birth and experienced four episodes of clinical TMA complications within 18 months following discontinuation of PE/PI, has been treated with eculizumab for 36 months as of December 2011, with no evidence of aHUS clinical manifestation, adverse events, or serious infections; this is the longest reported event-free period in the clinical literature.
In PNH clinical trials, the most frequently reported adverse events (AEs) were headache (44%), nasopharyngitis (23%), back pain (19%), nausea (16%), fatigue (12%), and cough (12%). In two prospective clinical trials in aHUS, the most commonly reported AEs were hypertension (35%), upper respiratory infection (35%), diarrhea (32%), headache (30%), anemia (24%), vomiting (22%), and nausea (19%). Twenty of 37 patients (54%) in the aHUS trials experienced a serious adverse event (SAE); the most commonly reported SAEs were hypertension (16%) and infections (14%).
Eculizumab inhibits terminal complement activation and therefore makes patients vulnerable to infection with encapsulated organisms. Life-threatening and fatal meningococcal infections have occurred in patients who received eculizumab. Due to the increased risk of meningococcal infections, meningococcal vaccination is recommended at least 2 weeks prior to receiving eculizumab, unless the risks of delaying eculizumab therapy outweigh the risk of developing a meningococcal infection, in which case the meningococcal vaccine should be administered as soon as possible. However, current meningococcal vaccines do not protect against strains of meningococcus with a serogroup B antigen, and thus may not be sufficient to protect patients.
Eculizumab treatment is recommended to continue for the patient’s lifetime, unless discontinuation of therapy is clinically indicated. In aHUS clinical studies, 18 patients (five in the prospective studies) discontinued eculizumab treatment; TMA complications occurred following a missed dose in five patients, and eculizumab was reinstated in four of these five patients.
Mechanism of action
Eculizumab is a recombinant humanized monoclonal IgG2/4 antibody that selectively targets and inhibits the terminal portion of the complement cascade. The complement system is a branch of the body’s immune system that destroys and removes foreign particles. When complement proteins are activated and bind to the surfaces of foreign particles, it triggers a cascade by which one complement protein induces the activation of the next protein in the sequence. The complement proteins then create holes or pores in the invading organisms, leading to their destruction. While complement plays an important role in protecting the body from foreign organisms, it can also destroy healthy cells and tissue.
Eculizumab specifically binds to the terminal Complement component 5, or C5, which acts at a late stage in the complement cascade. When activated, C5 is involved in activating host cells, thereby attracting pro-inflammatory immune cells, while also destroying cells by triggering pore formation. By inhibiting the complement cascade at this point, the normal, disease-preventing functions of proximal complement system are largely preserved, while the properties of C5 that promote inflammation and cell destruction are impeded.
Eculizumab inhibits the cleavage of C5 to C5a (a potent anaphylatoxin with prothrombotic and proinflammatory properties) and C5b by the C5 convertase, which prevents the generation of the terminal complement complex C5b-9 (which also has prothrombotic and proinflammatory effects). Both C5a and C5b-9 cause the terminal complement-mediated events that are characteristic of PNH and aHUS.
An acquired genetic mutation in patients with PNH leads to the generation from bone marrow of abnormal cell lines (known as PNH cells) that are deficient in protective complement inhibitors on the cell surface. PNH red blood cells undergo lysis due to constant attack by the body’s complement (immune) system. Eculizumab inhibits terminal complement-mediated chronic hemolysis in people with (PNH).
Eculizumab inhibits complement-mediated thrombotic microangiopathy (TMA) in patients with aHUS, a disease in which a deficiency of natural complement regulatory factors leads to chronic uncontrolled complement activation. This results in platelet activation, endothelialcell damage, and systemic, persistent TMA.
Eculizumab is a humanized monoclonal antibody against the complement protein C5. It is an immunoglobulin G-kappa (IgGκ) consisting of human constant regions and murine complementarity-determining regions grafted onto human framework light and heavy chain variable regions. The compound contains two 448-amino acid heavy chains and two 214-amino acid light chains, and has a molecular weight of approximately 148 kilodaltons (kDa).
The metabolism of eculizumab is thought to occur via lysosomal enzymes that cleave the antibody to generate small peptides and amino acids. The volume of distribution of eculizumab in humans approximates that of plasma.
There are case reports of eculizumab being used to treat Shiga-toxin-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS), such as occurred during the May 2011 outbreak of enteroaggretative E. coli infections in Germany (the STEC-HUS commonly seen in North America is of the enterohemorrhagic type). Eculizumab was given to block complement activation, which plays a role in the pathogenesis of both STEC-HUS and aHUS. Specifically, Shiga-toxin has been shown to trigger uncontrolled complement activity through direct activation of the alternative complement pathway as well as by binding to and inactivating the regulatory protein complement factor H.
Acute humoral rejection (AHR)/ antibody-mediated rejection (AMR)
Preliminary results from a Mayo Clinic research study show that eculizumab prevents acute humoral rejection (AHR, also known as antibody-mediated rejection (AMR)) of kidney allografts by inhibiting activation of the complement system by antigen-antibody complexes. Specifically, eculizumab treatment led to a significant decrease in the incidence of early AHR, compared to a historical control group that received no eculizumab. Eculizumab also reportedly maintained stable allograft function and simplified the management of kidney transplant patients by decreasing the need for post-transplant plasma exchange and splenectomy. Researchers at Johns Hopkins University have also reported a case in which eculizumab was combined with plasmapheresis and intravenous immunoglobulin to salvage a kidney undergoing severe AMR. In this case, eculizumab, by inhibiting the cleavage of complement protein C5 to the C5a and C5b receptors, was associated with a marked decrease in membrane attack complex (C5b-9) deposition in the kidney.
Eculizumab has been shown to produce a clinically meaningful benefit in patients with severe and refractory generalized myasthenia gravis, a rare neurological disorder caused by uncontrolled complement activation resulting from auto-antibodies that recognize a specific target in the nerve-muscle junction. In a Phase II study involving 14 patients, eculizumab was superior to placebo in improving disease severity scores, and the improvement was achieved more rapidly with eculizumab than with placebo.
An open-label study is investigating the effects of eculizumab in patients with neuromyelitis optica, a complement-mediated inflammatory disease of the brain tissues that can potentiate immune attack on the optic nerves (leading to optic neuritis), spinal cord (causing transverse myelitis), and brain.
Membranoproliferative glomerulonephritis (MPGN)
Membranoproliferative glomerulonephritis (MPGN, previously known as mesangiocapillary glomerulonephritis) is an uncommon cause of chronic nephritis that primarily affects children but can occur at any age. Its clinical presentation and course can range from benign and slowly progressive to rapidly progressive. Patients may thus present with hematuria (blood in the urine), proteinuria (excess protein in the urine), renal impairment, and hypertension. MPGN frequently progresses to end-stage renal disease (ESRD) and disease recurrence following kidney transplantation. Some cases of the disease are thought to result from complement dysregulation. Canadian researchers have reported a case in which eculizumab produced “a dramatic response” in a 16-year-old girl with MPGN, as evidenced by amelioration of neurologic complications, normalization of kidney function, and improvements in thrombocytopenia, anemia, proteinuria, and hypoalbuminemia.
Dense-deposit disease (DDD)
Dense-deposit disease (DDD), previously considered a subtype of MPGN (sometimes known as MPGN II), is characterized by dense deposits of immunoglobulins, complement factors, or both in the basement membrane of the glomerulus. DDD frequently progresses to ESRD and disease recurrence after kidney transplantation. In a March 22, 2012 letter to the New England Journal of Medicine, a group of Italian researchers reported a case involving an 11-year-old girl with DDD who was treated with eculizumab, which led to normalization of serum total protein and albumin, decreased creatinine, and decline of proteinuria to below the nephrotic range. The same issue of the New England Journal of Medicine also featured a letter from another group of Italian researchers, who reported a case in which a 17-year-old patient with DDD experienced improvements in proteinuria, plasma protein levels, and renal function, along with reductions in the size of dense deposits, after treatment with eculizumab. After treatment was interrupted after 18 months, proteinuria rapidly increased; eculizumab therapy was resumed 6 months later, and was associated with a reduction in proteinuria. In a Phase I trial involving three patients with DDD and three with C3 glomerulonephritis who were treated with eculizumab every other week for 1 year, two patients showed significantly reduced serum creatinine, one achieved a marked reduction in proteinuria, and one had stable laboratory parameters but histopathologic improvements. The investigators surmised that pre-treatment elevation of serum membrane attack complex may predict response to eculizumab in DDD and C3 glomerulonephritis, both of which comprise C3 glomerulopathy.
Cold agglutinin disease
There are also reports of eculizumab being used to treat cold agglutinin disease. In one patient case report, eculizumab led to a sustained reduction of hemolysis, disappearance of further exacerbations, complete elimination of transfusion requirements, and improvement of symptoms and quality of life.
Catastrophic antiphospholipid syndrome (CAPS)
Catastrophic antiphospholipid syndrome (CAPS) is a rare condition in which blood clots form in multiple organs simultaneously, possibly leading to multi-organ system failure and death. The kidneys are the most frequently affected organ system in CAPS, and patients who survive a CAPS episode commonly experience permanent kidney failure. There are reports in the literature suggesting that eculizumab therapy may be useful in CAPS by virtue of its blockade of complement activity, prevention of acute progressive thrombotic events, reversal of thrombocytopenia, and control of serum antiphospholipid antibody levels.
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