Eculizumab: Difference between revisions
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{{ | {{Drugbox | ||
| | | Verifiedfields = changed | ||
| source | | verifiedrevid = 461092423 | ||
| target | | image = | ||
| | |||
| | <!--Monoclonal antibody data--> | ||
| | | type = mab | ||
| | | mab_type = mab | ||
| | | source = zu/o | ||
| | | target = [[Complement system|Complement]] protein [[Complement component 5|C5]] | ||
| | |||
| bioavailability | <!--Clinical data--> | ||
| protein_bound | | tradename = Soliris | ||
| metabolism | | Drugs.com = {{drugs.com|monograph|eculizumab}} | ||
| licence_EU = Soliris | |||
| licence_US = Eculizumab | |||
| pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | |||
| pregnancy_US = C | |||
| pregnancy_category = | |||
| legal_AU = <!-- Unscheduled / S2 / S3 / S4 / S5 / S6 / S7 / S8 / S9 --> | |||
| legal_CA = <!-- / Schedule I, II, III, IV, V, VI, VII, VIII --> | |||
| legal_UK = POM | |||
| legal_US = Rx-only | |||
| legal_status = | |||
| routes_of_administration = [[Intravenous therapy|Intravenous infusion]] | |||
<!--Pharmacokinetic data--> | |||
| bioavailability = | |||
| protein_bound = | |||
| metabolism = | |||
| elimination_half-life = 8 to 15 days (mean 11 days) | | elimination_half-life = 8 to 15 days (mean 11 days) | ||
| excretion | | excretion = | ||
| | <!--Identifiers--> | ||
| | | CAS_number_Ref = {{cascite|correct|??}} | ||
| | | CAS_number = 219685-50-4 | ||
| | | ATC_prefix = L04 | ||
| | | ATC_suffix = AA25 | ||
| | | PubChem = | ||
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | |||
| | | DrugBank = DB01257 | ||
| UNII_Ref = {{fdacite|correct|FDA}} | |||
| UNII = A3ULP0F556 | |||
| ChEMBL_Ref = {{ebicite|changed|EBI}} | |||
| ChEMBL = 1201828 | |||
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | |||
| ChemSpiderID = NA | |||
<!--Chemical data--> | |||
| chemical_formula = | |||
| molecular_weight = 148 [[Atomic mass unit|kDa]] | |||
}} | }} | ||
'''Eculizumab''' ([[International Nonproprietary Name| | __NOTOC__ | ||
Eculizumab was | {{CMG}} | ||
==Overview== | |||
'''Eculizumab''' ([[International Nonproprietary Name|INN]] and [[United States Adopted Name|USAN]]; trade name '''Soliris''') is a humanized [[monoclonal antibody]] that is a first-in-class terminal [[complement system|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]]).<ref name=Hillmen2006>{{cite journal|last=Hillmen, Young, Schubert|first=P, N, J, et al|title=The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria|journal=N Engl J Med|year=2006|volume=355|issue=12|pages=1233–1243|doi=10.1056/NEJMMoa061648|pmid=16990386|first2=NS|first3=J|first4=RA|first5=G|first6=P|first7=A|first8=J|first9=MO|first10=R|first11=P|first12=AM|first13=A|first14=H|first15=CL|first16=J|first17=SA|first18=CF|first19=RP|first20=L}}</ref> It costs approximately £245,700 for ongoing treatment, but there is variance depending on clinical response.<ref>http://www.medicinescomplete.com/mc/bnf/current/PHP5923-soliris.htm?q=soliris&t=search&ss=text&p=1#PHP5923-soliris</ref> | |||
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.<ref name=Nris2010>{{cite journal|last=Noris, Caprioli, Bresin|first=M, J, E, et al.|title=Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype|journal=Clin J Am Soc Nephrol|year=2010|volume=5|pages=1844–1859|doi=10.2215/CJN.02210310|first2=J.|first3=E.|first4=C.|first5=G.|first6=S.|first7=E.|first8=C.|first9=F.|first10=A.|first11=R.|first12=R.|first13=R.|first14=I.|first15=E. M.|first16=P. F.|first17=T. H.|first18=G.|issue=10|pmid=20595690|pmc=2974386}}</ref><ref name=Caprioli2006>{{cite journal|last=Caprioli, Noris, Brioschi|first=J, M, S, et al|title=Genetics of HUS: the impact of MPC, CFH, and IF mutations on clinical presentation, response to treatment, and outcome|journal=Blood|year=2006|volume=108|pages=1267–1279|doi=10.1182/blood-2005-10-007252|issue=4|pmid=16621965|first2=M|first3=S|first4=G|first5=F|first6=P|first7=C|first8=E|first9=L|first10=S|first11=F|first12=S|first13=G|first14=CJ|first15=MK|first16=D|first17=JP|first18=G|pmc=1895874}}</ref> | |||
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.<ref name=Hillmen2006 /><ref name=Hillman2004>{{cite journal|last=Hillman, Hall, Marsh|first=P, C, JC, et al|title=Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria|journal=N Eng J Med|year=2004|volume=350|pages=552–559|doi=10.1056/NEJMoa031688|first2=Claire|first3=Judith C.W.|first4=Modupe|first5=Michael P.|first6=Beth E.|first7=Matthew J.|first8=Stephen J.|first9=Scott A.|first10=Christopher F.|first11=Russell P.|issue=6}}</ref><ref name=Ray2000>{{cite journal|last=Ray, Burrows, Ginsberg, Burrows|first=JG, RF, JS, EA|title=Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient|journal=Haemostasis|year=2000|volume=30|pages=103–107}}</ref><ref name=Kelly2011>{{cite journal|last=Kelly, Hill, Arnold|first=RJ, A, LM, et al|title=Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival|journal=Blood|year=2011|volume=117|pages=6786–6792|doi=10.1182/blood-2011-02-333997|pmid=21460245|first2=A|first3=LM|first4=GL|first5=SJ|first6=M|first7=LD|first8=DR|first9=WM|first10=P|issue=25}}</ref> Clinical trials in patients with aHUS demonstrated inhibition of thrombotic microangiopathy (TMA),<ref name=Soliris2011>{{cite journal |title=7.Soliris® (eculizumab) prescribing information |year=2011 |url=http://www.soliris.net/sites/default/files/assets/soliris_pi.pdf |location=Cheshire, CT: Alexion Pharmaceuticals |deadurl=no |accessdate=15 December 2013}}</ref> the formation of blood clots in small blood vessels throughout the body,<ref name=Hillmen2006 /><ref name=Caprioli2006 /><ref name=Hillman2004 /> including normalization of platelets and [[lactate dehydrogenase]] (LDH), as well as maintenance or improvement in renal function.<ref name=Soliris2011/> | |||
Eculizumab was discovered and 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. | |||
==Medical Uses== | |||
===Paroxysmal Nocturnal Hemoglobinuria=== | |||
In those with [[paroxysmal nocturnal hemoglobinuria]] despite best historical care (e.g., anticoagulation therapy, transfusions), 35% of patients with PNH die within 5 years of diagnosis.<ref name=Hillmen1995>{{cite journal|last=Hillmen, Lewis, Bessler, Luzzatto, Dacie|first=P, SM, M, L, JV|title=Natural history of paroxysmal nocturnal hemoglobinuria|journal=N Engl J Med|year=1995|volume=333|issue=19|pages=1253–1258|doi=10.1056/NEJM199511093331904|pmid=7566002|first2=SM|first3=M|first4=L|first5=JV}}</ref> Thromboembolism (TE) is the leading cause of death in PNH patients, accounting for 40% to 67% of PNH-related mortality.<ref name=Hillmen2007>{{cite journal|last=Hillmen, Muus, Duhrsen|first=P, P, U, et al|title=Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria|journal=Blood|year=2007|volume=110|issue=12|pages=4123–4128|doi=10.1182/blood-2007-06-095646|pmid=17702897|first2=P|first3=U|first4=AM|first5=J|first6=L|first7=H|first8=J|first9=RA|first10=A|first11=G|first12=M|first13=SA|first14=L|first15=RP|first16=NS}}</ref><ref name=Brodsky2005>{{cite journal|last1=Brodsky|first1=RA|title=Paroxysmal nocturnal hemoglobinuria |journal=Hematology: Basic Principles and Practice|year=2005|pages=419–427|author2=Hoffman R, Benz EJ Jr, Shattil SJ, et al|publisher=Elsevier Churchill Livingstone|location=Philadelphia, PA}}</ref> Patients with PNH are 62 times more likely to have a venous thromboembolism than the general population, which is higher than any other hyper-coagulable disease.<ref name=Hill2006>{{cite journal|last=Hill, Ridley, Esser|first=A, SH, D, et al|title=Protection of erythrocytes from human complement-mediated lysis by membrane-targeted recombinant soluble CD59: A new approach to PNH therapy|journal=Blood|year=2006|volume=107|issue=5|pages=2131–2137|doi=10.1182/blood-2005-02-0782|pmid=16322479|first2=SH|first3=D|first4=RG|first5=MJ|first6=P|first7=S|first8=GP|first9=SJ|first10=J|first11=RA|first12=P}}</ref><ref name=DeStefano2002>{{cite journal|last=DeStafano, Rossi, Paciaroni, Leone|first=V, E, K, G|title=Screening for inherited thrombophilia: indications and therapeutic implications|journal=Haematologica|year=2002|volume=107|issue=5|pages=1095–1108}}</ref> Both venous and arterial thromboembolism can occur in patients with PNH.<ref name=Hill2007>{{cite journal|last=Hill, Richards, Hillmen|first=A, SJ, P|title=Recent developments in the understanding and management of paroxysmal nocturnal hemoglobinuria|journal=Br J Haematol|year=2007|volume=137|pages=181–192|doi=10.1111/j.1365-2141.2007.06554.x|pmid=17408457|first2=SJ|first3=P|issue=3}}</ref> Although [[deep vein thrombosis]] and [[pulmonary embolism]] are the most common clinical presentations,<ref name=Hillmen2007 /> 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.<ref name=Lee2010>{{cite journal|last=Lee, Jang, Lee|first=JW, JH, JH, et al|title=High prevalence and mortality associated with thromboembolism in Asian patients with paroxysmal nocturnal hemoglobinuria (PNH)|journal=Haematologica|year=2010|volume=95|issue=Suppl 2|pages=205, abstr.0505}}</ref> For patients who experience TE and survive, the risk of subsequent TEs is increased,<ref name=Hillmen2007/> and the risk of death increases 5- to 15-fold for PNH patients with no previous TE.<ref name=Lee2010 /> Notably, data suggest 60% of patients with PNH have evidence of undiagnosed thrombosis.<ref name=Hill2006 /> In one analysis, thromboembolism was observed in a significantly higher rate of PNH patients with LDH levels over 1.5 times the upper limit of normal.<ref name=Kim2010>{{cite journal|last=Kim, Lee, Kim, Lee, Chung|first=JS, JW, BK, J|title=The use of the complement inhibitor eculizumab (Soliris) for treating Korean patients with paroxysmal nocturnal hemoglobinuria|journal=Korean J Hematol|year=2010|volume=45|issue=4|pages=269–74|doi=10.5045/kjh.2010.45.4.269|pmid=21253430|first2=JW|first3=BK|first4=JH|first5=J|pmc=3023054}}</ref> | |||
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. Notably, there was a rapid and meaningful improvement in fatigue and quality of life for the treated patients. No serious treatment-related adverse events were reported.<ref name=Hillmen2006 /> | |||
Significantly, data from three independent clinical studies—a Phase II pilot study,<ref name=Hillman2004 /> the Phase III TRIUMPH study,<ref name=Hillmen2006 /> and the Phase III SHEPHERD study<ref name=Ray2000 />—demonstrated a greater than 90% reduction in thromboembolic events, the most serious complication of PNH and a major cause of death in this disease. All PNH patients in clinical trials derived a benefit from eculizumab therapy; many benefits occurred rapidly, while others showed improvement over time.<ref name=Soliris2011 /> | |||
===aHUS=== | |||
Historically, 33-40% of patients with aHUS died or progressed to ESRD with the first clinical manifestation of the disease.<ref name=Nris2010 /><ref name=Caprioli2006 /> 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).<ref name=Caprioli2006/> 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.<ref name=George2010>{{cite journal|last=George|first=JN|title=How I treat patients with thrombotic thrombocytopenic purpura|journal=Blood|year=2010|volume=116|pages=4060–4069|doi=10.1182/blood-2010-07-271445|issue=20|pmid=20686117}}</ref><ref name=Mache2009>{{cite journal|last=Mache, Acham-Roschitz, Fremeaux-Bacchi|first=CJ, B, V, et al|title=Complement inhibitor eculizumab in atypical hemolytic uremic syndrome|journal=CJASN-- Cling J Amer Soc Nephrol|year=2009|volume=4|pages=1312–1316|doi=10.2215/CJN.01090209|first2=B.|first3=V.|first4=M.|first5=P. F.|first6=S.|first7=U.|first8=E.|issue=8}}</ref> 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.<ref name=Caprioli2006 /> | |||
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.<ref name=Soliris2011 /> 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)[21], 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).<ref name=Licht2011>{{cite journal|last=Licht, Muus, Legendre|first=C, P, C, et al|title=Eculizumab is an effective long-term treatment in patients with atypical hemolytic-uremic syndrome (aHUS) previously receiving chronic plasma exchange/infusion (PE/PI): extenstion study results|journal=Presented ath: 53rd Annual Society of Hematology Annual Meeting and Exposition|quote=December 10-13, 2011 |pages=Poster TH- P0366|location=San Diego, CA}}</ref> TMA-related endpoints in these trials included the following:<ref name=Soliris2011 /><ref name=Licht2011/><ref name=Greenbaum2011>{{cite journal|last=Greenbaum, Babu, Furman|first=L, S, R,et al|title=Continued improvements in renal function with sustained eculizumab in patients aith atypical hemolytic uremic syndrome (aHUS)|journal=Presented at the American Society of Nephrology Kidney Week 2011|quote=November 8-13, 2011 |pages=Pster TH-P0367|location=Philadelphia, PA}}</ref> | |||
*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 [[creatinine]]for 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.<ref name=Soliris2011 /><ref name=Greenbaum2011/> | |||
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.<ref name=Soliris2011 /><ref name=Licht2011 /> | |||
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.<ref name=Legendre2012>{{cite journal|last=Legendre, Greenbaum, Babu|first=C, L, S, et al|title=Eculizumab (ECU) is atypical hemolytic uremic syndrome (aHUS) patients (PTS) with progressing TMA: continued improvements at 2-year follow-up|journal=Presented at: American Society of Nephrological Kidney Week 2012|quote=October 30-November 4, 2012|location=San Diego, CA}}</ref> 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.<ref name=Licht2012>{{cite journal|last=Licht, Muus, Legendre|first=C, P, C, et al|title=Eculizumab (ECU) is effective in atypical hemolytic uremic syndrome (aHUS) patients (PTS) with a long disease duration and chronic kidney disease (CKD): 2-year data|journal=Presented at: American Society of Nephrology Kidney Week|quote=October 30-November 4, 2012 |location=San Diego, CA}}</ref> | |||
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.<ref name=Soliris2011 /> | |||
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.<ref name=Hodgkins2012>{{cite journal|last=Hodgkins, Bobrowski, Lane, Langman|first=KS, AE, JC, CB|title=Clinical grand rounds: atypical hemolytic uremic syndrome|journal=Amer J Nephrol|year=2012|volume=35|pages=394–400|doi=10.1159/000337954|first2=Amy E.|first3=Jerome C.|first4=Craig B.|issue=5}}</ref> 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.<ref name=Gruppo2011>{{cite journal|last=Gruppo, Dixon|first=RA, BP|title=Long-term outcome in a pediatric patient with atypical hemolytic uremic syndrome (aHUS) with sustained eculizumab (ECU) treatment|journal=Presented at: 53rd annual meeting and exposition of the american society of hematology|quote=December 10-13, 2011 |pages=Abstract 44320|location=San Diego, CA}}</ref> | |||
==Adverse Effects== | |||
In PNH clinical trials, the most frequently reported [[adverse events]] (AEs) were [[headache]] (44%), [[nasopharyngitis]] (23%), back pain (19%), [[nausea]] (16%), [[fatigue (medical)|fatigue]] (12%), and cough (12%).<ref name=Soliris2011 /> 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%).<ref name=Soliris2011 /> | |||
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.<ref name=Soliris2011 /> Clinicians are therefore advised to comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies. 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. If urgent eculizumab therapy is indicated in an [[unvaccinated]] patient, the meningococcal vaccine should be administered as soon as possible.<ref name=Soliris2011 /> However, current meningococcal vaccines do not protect against strains of meningococcus with a serogroup B antigen,<ref name=bouts2011>{{cite journal|last=Bouts, Monnens, Davin, Struijk, Spanjaard|first=A, L, J-C, G, L|title=Insufficient protection by Neisseria meningitidis vaccination alone during eculizumab therpay|journal=Pediatr Nephrol|year=2011|volume=26|pages=1919–1920|doi=10.1007/s00467-011-1929-3|pmid=21643943|url=http://www.springerlink.com/content/g65212358332j273/|pmc=3163808|first2=Leo|first3=Jean-Claude|first4=Geertrude|first5=Lodewijk|issue=10}}</ref> and thus may not be sufficient to protect patients. In clinical trials, 33 of 67 patients with aHUS were treated with eculizumab less than 2 weeks after meningococcal vaccination, and 31 of these 33 patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after vaccination. Patients should be monitored for early sign of meningococcal infection, and should be evaluated immediately if infection is suspected.<ref name=Soliris2011 /> | |||
Eculizumab treatment is recommended to continue for the patient’s lifetime, unless discontinuation of therapy is clinically indicated.<ref name=European2012>{{cite web|title=European Medicines Agency|url=http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000791/WC500054208.pdf|work=European Public Assessment Report (EPAR) for Soliris (eculizumab) Appendix I Summary of Product Characteristics|year=2012}}</ref> After discontinuing eculizumab, patients with PNH should be monitored for at least 8 weeks to detect [[hemolysis]]. Patients with aHUS should be monitored for signs and symptoms of TMA complications for at least 12 weeks. 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. If TMA complications occur after eculizumab discontinuation, the clinician should consider reinstitution of eculizumab treatment, PE/PI, or appropriate organ-specific supportive measures.<ref name=Soliris2011 /> | |||
==Mechanism of action== | |||
Eculizumab is a recombinant humanized monoclonal IgG2/4 antibody<ref name=Rother2007>{{cite journal|last=Rother, Rollins, Mojcik|first=RP, SA, CF, et al|title=Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria|journal=Nat Biotechnol|year=2007|volume=25|pages=1256–1264|doi=10.1038/nbt1344|pmid=17989688|first2=SA|first3=CF|first4=RA|first5=L|issue=11}}</ref> 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.<ref name=Brodsky2009>{{cite journal|last1=Brodsky|first1=RA|title=Paroxysmal nocturnal hemoglobinuria|journal=Hematology: Basic Principles and Practice|year=2009|pages=385–395|author2=Hoffman R, Benz EJ Jr, Shattil S, et al.|publisher=Churchill Livingstone|location=Philadelphia, PA}}</ref> | |||
Eculizumab inhibits the cleavage of [[Complement component 5|C5]] to [[Complement component 5a|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.<ref name=Brodsky2009 /> | |||
===PNH=== | |||
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).<ref name=Brodsky2009 /> | |||
===aHUS=== | |||
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, [[endothelial]]cell damage, and systemic, persistent TMA.<ref name=Soliris2011 /> | |||
==Biochemistry== | |||
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).<ref name=Dmytrijuk2008>{{cite journal|last=Dmytrijuk, Robie-Suh, Cohen, Rieves, Weiss, Pazdur|first=A, K, MH, D, K, R|title=FDA report eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria|journal=The Oncologist|year=2008|volume=13|issue=9|pages=993–1000|doi=10.1634/theoncologist.2008-0086|pmid=18784156|url=http://theoncologist.alphamedpress.org/content/13/9/993.full.pdf+html|first2=K.|first3=M. H.|first4=D.|first5=K.|first6=R.}}</ref> | |||
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 [[Blood plasma|plasma]].<ref name=Dmytrijuk2008 /> | |||
==Research== | |||
===STEC-HUS=== | |||
There are case reports of eculizumab being used to treat [[Escherichia coli O157:H7|Shiga-toxin-producing Escherichia coli]] [[hemolytic-uremic syndrome]] (STEC-HUS),<ref name=Lapeyraque2011>{{cite journal|last=Lapeyraque, Malina, Fremeaux-Bacchi|first=A-L, M, V, et al|title=Eculizumab in Severe Shiga-Toxin- Associated HUS|journal=N Engl J Med|year=2011|volume=364|pages=2561–2563|doi=10.1056/NEJMc1100859|url=http://www.nejm.org/doi/full/10.1056/NEJMc1100859|first2=Michal|first3=Véronique|first4=Tobias|first5=Michael|first6=Mehdi|first7=François|first8=Marie-José|first9=Françoise|first10=Patrick|first11=Franz|issue=26|pmid=21612462}}</ref> 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|Shiga-toxin]] has been shown to trigger uncontrolled complement activity through direct activation of the alternative complement pathway<ref name=Morigi2011>{{cite journal|last=Morigi, Galbusera, Gastoldi|first=M, M, S, et al|title=Alternative pathway activation of complement by shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis|journal=J Immunol|year=2011|volume=187|pages=172–180|doi=10.4049/jimmunol.1100491|pmid=21642543|first2=M|first3=S|first4=M|first5=S|first6=A|first7=C|first8=M|first9=M|first10=M|first11=D|first12=F|first13=G|first14=C|issue=1}}</ref><ref name=Thurman2009>{{cite journal|last=Thurman, Marians, Emlen|first=JM, R, W, et al|title=Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome|journal=Clin J Am Soc Nephrol|year=2009|volume=4|pages=1920–1924|doi=10.2215/CJN.02730409|pmid=19820137|first2=R|first3=W|first4=S|first5=C|first6=H|first7=VM|first8=M|first9=M|first10=C|first11=E|first12=H|issue=12|pmc=2798880}}</ref> as well as by binding to and inactivating the regulatory protein [[complement factor H]].<ref name=Orth2009>{{cite journal|last=Orth, Khan, Naim|first=D, AB, A, et al|title=Shiga toxin activated complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome|journal=J Immunol|volume=182|pages=6394–6400|doi=10.4049/jimmunol.0900151|pmid=19414792|year=2009|first2=AB|first3=A|first4=K|first5=J|first6=H|first7=M|first8=SJ|first9=AJ|first10=S|first11=H|first12=MP|first13=LB|first14=R|issue=10}}</ref> | |||
===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.<ref name=PressRelease2009>{{cite news|title=Study Should New Approach to Prevent Antibody-Mediated Damage in Kidney Transplants|url=http://www.eurekalert.org/pub_releases/2009-06/mc-ssn060109.php|newspaper=Mayo Clinic (press release)|date=June 2, 2009}}</ref> 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.<ref name=Stegall2010>{{cite journal|last=Stegall, Diwan, Cornell|first=MD, TS, L, et al|title=Terminal complement inhibition decreases early acute humoral rejection in sensitized renal transplant patientes|journal=Trasplantation|year=2010|volume=90|pages=127|doi=10.1097/00007890-201007272-00246|first2=T. S.|first3=L.|first4=J. M.|first5=P. G.|first6=F.|first7=S.|first8=M. J.|first9=W. K.|first10=J. M.}}</ref> 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.<ref name=Locke2009>{{cite journal|last=Locke, Magro, Singer|first=JE, CM, AL, et al|title=The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection|journal=Am J Transplant|year=2009|volume=9|pages=231–235|doi=10.1111/j.1600-6143.2008.02451.x|pmid=18976298|first2=CM|first3=AL|first4=DL|first5=M|first6=AT|first7=KE|first8=E|first9=LM|first10=JK|first11=ZA|first12=DS|first13=AA|first14=RA|issue=1}}</ref> | |||
===Myasthenia Gravis=== | |||
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.<ref>Complement associated pathogenic mechanisms in myasthenia gravis, Erdem Tüzün et al, 2013</ref> 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.<ref name=PressRealse2011>{{cite news|title=34. Phase 2 study of eculizumab (Soliris®) in patients with severe and refractory generalized myasthenia gravis presented at MGFR annual meeting|url=http://www.alxn.com/News/article.aspx?relid=605575.|newspaper=Alexion Pharmaceuticals Inc. (press release)|date=September 14, 2011|location=Cheshire, CT}}</ref> | |||
===Neuromyelitis Optica=== | |||
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.<ref name=ClinicalTrial2012>{{cite web|title=An open label study of the effects of eculizumab in neuromyelitis optica." Bethesda, MD; National Institutes of Health, US Department of Health and Human Services|url=http://www.clinicaltrials.gov/ct2/show/NCT00904826?term=NCT00904826&rank=1.|work=ClinicalTrials.gov|year=2012}}</ref> | |||
===Membranoproliferative Glumerulonephritis (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.<ref name=Sethi2012>{{cite journal|last=Sethi, Fervenza|first=S, FC|title=Membranoproliferative glomerulonephritis - a new look at an old entity|journal=N Engl J Med|year=2012|volume=366|pages=1119–1131 |url=http://www.nejm.org/doi/full/10.1056/NEJMra1108178 |doi=10.1056/NEJMra1108178|first2=Fernando C.|issue=12|pmid=22435371 }}</ref> Some cases of the disease are thought to result from complement dysregulation.<ref name=Sethi2012/><ref name=Nephroticsyndrome>{{cite web|title=Nephrotic syndrome|url=http://www.merckmanuals.com/home/kidney_and_urinary_tract_disorders/kidney_filtering_disorders/nephrotic_syndrome.html#v761916|work=The Merk Manual Home Health Handbook|author=Merk & Co., Inc.|location=Whitehouse station, NJ}}</ref><ref name=Licht2009>{{cite journal|last=Licht, Fremeaux-Bacchi|first=C, V|title=Hereditary and acquired complement dysregulation in membranoproliferative glomerulonephritis|journal=Thromb Haemost|year=2009|volume=101|pages=271–278|pmid=19190809|first2=V|issue=2}}</ref><ref name=Radhakrishan2012>{{cite journal|last=Radhakrishnan, Lunn, Kirschfink|first=S, A, M, et al|title=Eculizumab and refractory membranoproliferative glomerulonephritis|journal=N Eng J Med|year=2012|volume=366|pages=1165–1166|doi=10.1056/NEJMc1106619|first2=Andrew|first3=Michael|first4=Paul|first5=Diane|first6=Valerie|first7=Fred|first8=Christoph|issue=12}}</ref> 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]].<ref name="Licht2009" /><ref name="Radhakrishan2012" /> | |||
===Dense-Deposit Disease (DDD)=== | |||
[[Dense deposit disease|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]].<ref name=Sethi2012 /> DDD frequently progresses to ESRD and disease recurrence after kidney transplantation.<ref name=Vivarelli2012>{{cite journal|last=Vivarelli, Pasini, Emma|first=M, A, F|title=Eculizumab for the treatment of dense-deposit disease|journal=N Engl J Med|year=2012|volume=366|pages=1161–1165|doi=10.1056/NEJMc1111953|first2=Andrea|first3=Francesco|issue=12}}</ref> 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.<ref name=Daina2012>{{cite journal|last=Daina, Noris, Remuzzi|first=E, M, G|title=Eculizumab in a patient with dense-deposit disease|journal=N Engl J Med|year=2012|volume=366|pages=1161–1163|doi=10.1056/NEJMc1112273|pmid=22435382|first2=M|first3=G|issue=12}}</ref> 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.<ref name="Vivarelli2012" /> 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.<ref name=Bomback2012>{{cite journal|last=Bomback, Smith, Barile|first=AS, RJ, GR|title=Eculizumab for dense deposit disease and C3 glomerulonephritis|journal=Clin J Am Soc Nephrol|year=2012|volume=7|series=5|pages=748–756|doi=10.2215/CJN.12901211|pmid=22403278|first2=RJ|first3=GR|first4=Y|first5=EC|first6=L|first7=MB|first8=GS|first9=VD|first10=PA|first11=J|first12=GB|issue=5|pmc=3338285}}</ref> | |||
===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.<ref name=Roth2009>{{cite journal|last=Roth, Huttmann, Rother, Duhrsen, Philipp|first=A, A, RP, U, T|title=Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease|journal=Blood|year=2009|volume=113|issue=16|pages=3885–3886|doi=10.1182/blood-2009-01-196329|pmid=19372265|url=http://bloodjournal.hematologylibrary.org/content/113/16/3885.full|first2=A.|first3=R. P.|first4=U.|first5=T.}}</ref> | |||
===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.<ref name=ClinicalTrials2011>{{cite web|title=Eculizumab to enable renal transplantation in patient with history of catastrophic antipholopid antibody syndrome|url=http://clinicaltrials.gov/ct2/show/NCT01029587?term=eculizumab+AND+catastrophic+antiphospholipid+syndrome&rank=1|work=ClinicalTrials.gov|author=National Institutes of Health, US Department of Health and Human Services|location=Bethesda, MD|year=2011}}</ref> 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.<ref name=Lonze2010>{{cite journal|last=Lonze, Singer, Montgomery|first=BE, AL, RA|title=Eculizumab and renal transplantation in a patient with CAPS|journal=N Engl J Med|year=2010|volume=362|pages=1744–1745|doi=10.1056/NEJMc0910965|pmid=20445191|first2=AL|first3=RA|issue=18}}</ref><ref name=Shapira2012>{{cite journal|last=Shapira, Andrade, Allen, Salmon|first=I, D, SL, JE|title=Induction of durable remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab|journal=Arthritis Rheum|year=2012|volume=64|issue=8|pages=2719–2723|doi=10.1002/art.34440|pmid=22354668|first2=D|first3=SL|first4=JE}}</ref> | |||
==References== | ==References== | ||
{{ | {{Reflist|2}} | ||
==External | ==External Links== | ||
*[http://www.healthvalue.net/globulerougeexplose.html Flash animation of eculizumab mechanism of action] | *[http://www.healthvalue.net/globulerougeexplose.html Flash animation of eculizumab mechanism of action] | ||
*[http://soliris.net/ US homepage] | |||
[[Category:Drugs]] | |||
[[Category: | |||
Revision as of 15:08, 12 February 2014
Monoclonal antibody | |
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Type | Whole antibody |
Source | Template:Infobox drug/mab source |
Target | Complement protein C5 |
Clinical data | |
Trade names | Soliris |
AHFS/Drugs.com | Monograph |
[[Regulation of therapeutic goods |Template:Engvar data]] |
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Routes of administration | Intravenous infusion |
ATC code | |
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Pharmacokinetic data | |
Elimination half-life | 8 to 15 days (mean 11 days) |
Identifiers | |
CAS Number | |
DrugBank | |
ChemSpider | |
UNII | |
ChEMBL | |
E number | {{#property:P628}} |
ECHA InfoCard | {{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value). |
Chemical and physical data | |
Molar mass | 148 kDa |
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
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).[1] It costs approximately £245,700 for ongoing treatment, but there is variance depending on clinical response.[2]
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.[3][4]
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.[1][5][6][7] Clinical trials in patients with aHUS demonstrated inhibition of thrombotic microangiopathy (TMA),[8] the formation of blood clots in small blood vessels throughout the body,[1][4][5] including normalization of platelets and lactate dehydrogenase (LDH), as well as maintenance or improvement in renal function.[8]
Eculizumab was discovered and 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.
Medical Uses
Paroxysmal Nocturnal Hemoglobinuria
In those with paroxysmal nocturnal hemoglobinuria despite best historical care (e.g., anticoagulation therapy, transfusions), 35% of patients with PNH die within 5 years of diagnosis.[9] Thromboembolism (TE) is the leading cause of death in PNH patients, accounting for 40% to 67% of PNH-related mortality.[10][11] Patients with PNH are 62 times more likely to have a venous thromboembolism than the general population, which is higher than any other hyper-coagulable disease.[12][13] Both venous and arterial thromboembolism can occur in patients with PNH.[14] Although deep vein thrombosis and pulmonary embolism are the most common clinical presentations,[10] 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.[15] For patients who experience TE and survive, the risk of subsequent TEs is increased,[10] and the risk of death increases 5- to 15-fold for PNH patients with no previous TE.[15] Notably, data suggest 60% of patients with PNH have evidence of undiagnosed thrombosis.[12] In one analysis, thromboembolism was observed in a significantly higher rate of PNH patients with LDH levels over 1.5 times the upper limit of normal.[16]
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. Notably, there was a rapid and meaningful improvement in fatigue and quality of life for the treated patients. No serious treatment-related adverse events were reported.[1]
Significantly, data from three independent clinical studies—a Phase II pilot study,[5] the Phase III TRIUMPH study,[1] and the Phase III SHEPHERD study[6]—demonstrated a greater than 90% reduction in thromboembolic events, the most serious complication of PNH and a major cause of death in this disease. All PNH patients in clinical trials derived a benefit from eculizumab therapy; many benefits occurred rapidly, while others showed improvement over time.[8]
aHUS
Historically, 33-40% of patients with aHUS died or progressed to ESRD with the first clinical manifestation of the disease.[3][4] 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).[4] 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.[17][18] 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.[4]
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.[8] 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)[21], 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).[19] TMA-related endpoints in these trials included the following:[8][19][20]
- 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.[8][20]
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.[8][19]
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.[21] 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.[22]
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.[8]
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.[23] 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.[24]
Adverse Effects
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%).[8] 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%).[8]
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.[8] Clinicians are therefore advised to comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies. 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. If urgent eculizumab therapy is indicated in an unvaccinated patient, the meningococcal vaccine should be administered as soon as possible.[8] However, current meningococcal vaccines do not protect against strains of meningococcus with a serogroup B antigen,[25] and thus may not be sufficient to protect patients. In clinical trials, 33 of 67 patients with aHUS were treated with eculizumab less than 2 weeks after meningococcal vaccination, and 31 of these 33 patients received antibiotics for prophylaxis of meningococcal infection until at least 2 weeks after vaccination. Patients should be monitored for early sign of meningococcal infection, and should be evaluated immediately if infection is suspected.[8]
Eculizumab treatment is recommended to continue for the patient’s lifetime, unless discontinuation of therapy is clinically indicated.[26] After discontinuing eculizumab, patients with PNH should be monitored for at least 8 weeks to detect hemolysis. Patients with aHUS should be monitored for signs and symptoms of TMA complications for at least 12 weeks. 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. If TMA complications occur after eculizumab discontinuation, the clinician should consider reinstitution of eculizumab treatment, PE/PI, or appropriate organ-specific supportive measures.[8]
Mechanism of action
Eculizumab is a recombinant humanized monoclonal IgG2/4 antibody[27] 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.[28]
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.[28]
PNH
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).[28]
aHUS
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.[8]
Biochemistry
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).[29]
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.[29]
Research
STEC-HUS
There are case reports of eculizumab being used to treat Shiga-toxin-producing Escherichia coli hemolytic-uremic syndrome (STEC-HUS),[30] 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[31][32] as well as by binding to and inactivating the regulatory protein complement factor H.[33]
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.[34] 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.[35] 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.[36]
Myasthenia Gravis
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.[37] 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.[38]
Neuromyelitis Optica
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.[39]
Membranoproliferative Glumerulonephritis (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.[40] Some cases of the disease are thought to result from complement dysregulation.[40][41][42][43] 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.[42][43]
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.[40] DDD frequently progresses to ESRD and disease recurrence after kidney transplantation.[44] 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.[45] 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.[44] 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.[46]
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.[47]
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.[48] 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.[49][50]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 Hillmen, Young, Schubert, P, N, J; et al. (2006). "The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria". N Engl J Med. 355 (12): 1233–1243. doi:10.1056/NEJMMoa061648. PMID 16990386.
|first2=
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in Authors list (help);|first3=
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in Authors list (help);|first5=
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in Authors list (help);|first6=
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in Authors list (help);|first7=
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in Authors list (help);|first8=
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in Authors list (help);|first9=
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in Authors list (help);|first10=
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in Authors list (help);|first11=
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in Authors list (help);|first12=
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in Authors list (help);|first13=
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in Authors list (help);|first14=
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in Authors list (help);|first15=
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in Authors list (help);|first16=
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in Authors list (help);|first17=
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in Authors list (help) - ↑ http://www.medicinescomplete.com/mc/bnf/current/PHP5923-soliris.htm?q=soliris&t=search&ss=text&p=1#PHP5923-soliris
- ↑ 3.0 3.1 Noris, Caprioli, Bresin, M, J, E; et al. (2010). "Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype". Clin J Am Soc Nephrol. 5 (10): 1844–1859. doi:10.2215/CJN.02210310. PMC 2974386. PMID 20595690.
|first2=
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in Authors list (help);|first5=
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in Authors list (help);|first6=
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in Authors list (help);|first7=
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in Authors list (help);|first8=
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in Authors list (help);|first9=
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in Authors list (help);|first10=
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in Authors list (help);|first11=
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in Authors list (help);|first12=
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in Authors list (help);|first13=
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in Authors list (help);|first15=
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missing|last16=
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in Authors list (help) - ↑ 4.0 4.1 4.2 4.3 4.4 Caprioli, Noris, Brioschi, J, M, S; et al. (2006). "Genetics of HUS: the impact of MPC, CFH, and IF mutations on clinical presentation, response to treatment, and outcome". Blood. 108 (4): 1267–1279. doi:10.1182/blood-2005-10-007252. PMC 1895874. PMID 16621965.
|first2=
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in Authors list (help);|first8=
missing|last8=
in Authors list (help);|first9=
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in Authors list (help);|first10=
missing|last10=
in Authors list (help);|first11=
missing|last11=
in Authors list (help);|first12=
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in Authors list (help);|first13=
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in Authors list (help);|first14=
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in Authors list (help);|first15=
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in Authors list (help);|first16=
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in Authors list (help) - ↑ 5.0 5.1 5.2 Hillman, Hall, Marsh, P, C, JC; et al. (2004). "Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria". N Eng J Med. 350 (6): 552–559. doi:10.1056/NEJMoa031688.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help);|first4=
missing|last4=
in Authors list (help);|first5=
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in Authors list (help);|first6=
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in Authors list (help);|first7=
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in Authors list (help);|first8=
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in Authors list (help) - ↑ 6.0 6.1 Ray, Burrows, Ginsberg, Burrows, JG, RF, JS, EA (2000). "Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient". Haemostasis. 30: 103–107.
- ↑ Kelly, Hill, Arnold, RJ, A, LM; et al. (2011). "Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival". Blood. 117 (25): 6786–6792. doi:10.1182/blood-2011-02-333997. PMID 21460245.
|first2=
missing|last2=
in Authors list (help);|first3=
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in Authors list (help);|first4=
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in Authors list (help);|first5=
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in Authors list (help);|first7=
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in Authors list (help) - ↑ 8.00 8.01 8.02 8.03 8.04 8.05 8.06 8.07 8.08 8.09 8.10 8.11 8.12 8.13 8.14 "7.Soliris® (eculizumab) prescribing information" (PDF). Cheshire, CT: Alexion Pharmaceuticals. 2011. Retrieved 15 December 2013.
- ↑ Hillmen, Lewis, Bessler, Luzzatto, Dacie, P, SM, M, L, JV (1995). "Natural history of paroxysmal nocturnal hemoglobinuria". N Engl J Med. 333 (19): 1253–1258. doi:10.1056/NEJM199511093331904. PMID 7566002.
|first2=
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missing|last3=
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missing|last5=
in Authors list (help) - ↑ 10.0 10.1 10.2 Hillmen, Muus, Duhrsen, P, P, U; et al. (2007). "Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria". Blood. 110 (12): 4123–4128. doi:10.1182/blood-2007-06-095646. PMID 17702897.
|first2=
missing|last2=
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missing|last3=
in Authors list (help);|first4=
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in Authors list (help);|first6=
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in Authors list (help);|first7=
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in Authors list (help);|first8=
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in Authors list (help);|first9=
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in Authors list (help);|first10=
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in Authors list (help);|first11=
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in Authors list (help);|first13=
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in Authors list (help) - ↑ Brodsky, RA; Hoffman R, Benz EJ Jr, Shattil SJ; et al. (2005). "Paroxysmal nocturnal hemoglobinuria". Hematology: Basic Principles and Practice. Philadelphia, PA: Elsevier Churchill Livingstone: 419–427.
- ↑ 12.0 12.1 Hill, Ridley, Esser, A, SH, D; et al. (2006). "Protection of erythrocytes from human complement-mediated lysis by membrane-targeted recombinant soluble CD59: A new approach to PNH therapy". Blood. 107 (5): 2131–2137. doi:10.1182/blood-2005-02-0782. PMID 16322479.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help);|first4=
missing|last4=
in Authors list (help);|first5=
missing|last5=
in Authors list (help);|first6=
missing|last6=
in Authors list (help);|first7=
missing|last7=
in Authors list (help);|first8=
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in Authors list (help);|first9=
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in Authors list (help) - ↑ DeStafano, Rossi, Paciaroni, Leone, V, E, K, G (2002). "Screening for inherited thrombophilia: indications and therapeutic implications". Haematologica. 107 (5): 1095–1108.
- ↑ Hill, Richards, Hillmen, A, SJ, P (2007). "Recent developments in the understanding and management of paroxysmal nocturnal hemoglobinuria". Br J Haematol. 137 (3): 181–192. doi:10.1111/j.1365-2141.2007.06554.x. PMID 17408457.
|first2=
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in Authors list (help) - ↑ 15.0 15.1 Lee, Jang, Lee, JW, JH, JH; et al. (2010). "High prevalence and mortality associated with thromboembolism in Asian patients with paroxysmal nocturnal hemoglobinuria (PNH)". Haematologica. 95 (Suppl 2): 205, abstr.0505.
- ↑ Kim, Lee, Kim, Lee, Chung, JS, JW, BK, J (2010). "The use of the complement inhibitor eculizumab (Soliris) for treating Korean patients with paroxysmal nocturnal hemoglobinuria". Korean J Hematol. 45 (4): 269–74. doi:10.5045/kjh.2010.45.4.269. PMC 3023054. PMID 21253430.
|first2=
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in Authors list (help) - ↑ George, JN (2010). "How I treat patients with thrombotic thrombocytopenic purpura". Blood. 116 (20): 4060–4069. doi:10.1182/blood-2010-07-271445. PMID 20686117.
- ↑ Mache, Acham-Roschitz, Fremeaux-Bacchi, CJ, B, V; et al. (2009). "Complement inhibitor eculizumab in atypical hemolytic uremic syndrome". CJASN-- Cling J Amer Soc Nephrol. 4 (8): 1312–1316. doi:10.2215/CJN.01090209.
|first2=
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in Authors list (help);|first3=
missing|last3=
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in Authors list (help);|first5=
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missing|last7=
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missing|last8=
in Authors list (help) - ↑ 19.0 19.1 19.2 Licht, Muus, Legendre, C, P, C; et al. "Eculizumab is an effective long-term treatment in patients with atypical hemolytic-uremic syndrome (aHUS) previously receiving chronic plasma exchange/infusion (PE/PI): extenstion study results". Presented ath: 53rd Annual Society of Hematology Annual Meeting and Exposition. San Diego, CA: Poster TH- P0366.
December 10-13, 2011
- ↑ 20.0 20.1 Greenbaum, Babu, Furman, L, S, R; et al. "Continued improvements in renal function with sustained eculizumab in patients aith atypical hemolytic uremic syndrome (aHUS)". Presented at the American Society of Nephrology Kidney Week 2011. Philadelphia, PA: Pster TH-P0367.
November 8-13, 2011
- ↑ Legendre, Greenbaum, Babu, C, L, S; et al. "Eculizumab (ECU) is atypical hemolytic uremic syndrome (aHUS) patients (PTS) with progressing TMA: continued improvements at 2-year follow-up". Presented at: American Society of Nephrological Kidney Week 2012. San Diego, CA.
October 30-November 4, 2012
- ↑ Licht, Muus, Legendre, C, P, C; et al. "Eculizumab (ECU) is effective in atypical hemolytic uremic syndrome (aHUS) patients (PTS) with a long disease duration and chronic kidney disease (CKD): 2-year data". Presented at: American Society of Nephrology Kidney Week. San Diego, CA.
October 30-November 4, 2012
- ↑ Hodgkins, Bobrowski, Lane, Langman, KS, AE, JC, CB (2012). "Clinical grand rounds: atypical hemolytic uremic syndrome". Amer J Nephrol. 35 (5): 394–400. doi:10.1159/000337954.
|first2=
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in Authors list (help) - ↑ Gruppo, Dixon, RA, BP. "Long-term outcome in a pediatric patient with atypical hemolytic uremic syndrome (aHUS) with sustained eculizumab (ECU) treatment". Presented at: 53rd annual meeting and exposition of the american society of hematology. San Diego, CA: Abstract 44320.
December 10-13, 2011
- ↑ Bouts, Monnens, Davin, Struijk, Spanjaard, A, L, J-C, G, L (2011). "Insufficient protection by Neisseria meningitidis vaccination alone during eculizumab therpay". Pediatr Nephrol. 26 (10): 1919–1920. doi:10.1007/s00467-011-1929-3. PMC 3163808. PMID 21643943.
|first2=
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missing|last5=
in Authors list (help) - ↑ "European Medicines Agency" (PDF). European Public Assessment Report (EPAR) for Soliris (eculizumab) Appendix I Summary of Product Characteristics. 2012.
- ↑ Rother, Rollins, Mojcik, RP, SA, CF; et al. (2007). "Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria". Nat Biotechnol. 25 (11): 1256–1264. doi:10.1038/nbt1344. PMID 17989688.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help);|first4=
missing|last4=
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missing|last5=
in Authors list (help) - ↑ 28.0 28.1 28.2 Brodsky, RA; Hoffman R, Benz EJ Jr, Shattil S; et al. (2009). "Paroxysmal nocturnal hemoglobinuria". Hematology: Basic Principles and Practice. Philadelphia, PA: Churchill Livingstone: 385–395.
- ↑ 29.0 29.1 Dmytrijuk, Robie-Suh, Cohen, Rieves, Weiss, Pazdur, A, K, MH, D, K, R (2008). "FDA report eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria". The Oncologist. 13 (9): 993–1000. doi:10.1634/theoncologist.2008-0086. PMID 18784156.
|first2=
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in Authors list (help) - ↑ Lapeyraque, Malina, Fremeaux-Bacchi, A-L, M, V; et al. (2011). "Eculizumab in Severe Shiga-Toxin- Associated HUS". N Engl J Med. 364 (26): 2561–2563. doi:10.1056/NEJMc1100859. PMID 21612462.
|first2=
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in Authors list (help);|first3=
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in Authors list (help) - ↑ Morigi, Galbusera, Gastoldi, M, M, S; et al. (2011). "Alternative pathway activation of complement by shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis". J Immunol. 187 (1): 172–180. doi:10.4049/jimmunol.1100491. PMID 21642543.
|first2=
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in Authors list (help) - ↑ Thurman, Marians, Emlen, JM, R, W; et al. (2009). "Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome". Clin J Am Soc Nephrol. 4 (12): 1920–1924. doi:10.2215/CJN.02730409. PMC 2798880. PMID 19820137.
|first2=
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in Authors list (help);|first3=
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in Authors list (help);|first4=
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missing|last12=
in Authors list (help) - ↑ Orth, Khan, Naim, D, AB, A; et al. (2009). "Shiga toxin activated complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome". J Immunol. 182 (10): 6394–6400. doi:10.4049/jimmunol.0900151. PMID 19414792.
|first2=
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in Authors list (help);|first14=
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in Authors list (help) - ↑ "Study Should New Approach to Prevent Antibody-Mediated Damage in Kidney Transplants". Mayo Clinic (press release). June 2, 2009.
- ↑ Stegall, Diwan, Cornell, MD, TS, L; et al. (2010). "Terminal complement inhibition decreases early acute humoral rejection in sensitized renal transplant patientes". Trasplantation. 90: 127. doi:10.1097/00007890-201007272-00246.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help);|first4=
missing|last4=
in Authors list (help);|first5=
missing|last5=
in Authors list (help);|first6=
missing|last6=
in Authors list (help);|first7=
missing|last7=
in Authors list (help);|first8=
missing|last8=
in Authors list (help);|first9=
missing|last9=
in Authors list (help);|first10=
missing|last10=
in Authors list (help) - ↑ Locke, Magro, Singer, JE, CM, AL; et al. (2009). "The use of antibody to complement protein C5 for salvage treatment of severe antibody-mediated rejection". Am J Transplant. 9 (1): 231–235. doi:10.1111/j.1600-6143.2008.02451.x. PMID 18976298.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help);|first4=
missing|last4=
in Authors list (help);|first5=
missing|last5=
in Authors list (help);|first6=
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in Authors list (help);|first7=
missing|last7=
in Authors list (help);|first8=
missing|last8=
in Authors list (help);|first9=
missing|last9=
in Authors list (help);|first10=
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in Authors list (help);|first11=
missing|last11=
in Authors list (help);|first12=
missing|last12=
in Authors list (help);|first13=
missing|last13=
in Authors list (help);|first14=
missing|last14=
in Authors list (help) - ↑ Complement associated pathogenic mechanisms in myasthenia gravis, Erdem Tüzün et al, 2013
- ↑ "34. Phase 2 study of eculizumab (Soliris®) in patients with severe and refractory generalized myasthenia gravis presented at MGFR annual meeting". Alexion Pharmaceuticals Inc. (press release). Cheshire, CT. September 14, 2011. horizontal tab character in
|title=
at position 4 (help) - ↑ "An open label study of the effects of eculizumab in neuromyelitis optica." Bethesda, MD; National Institutes of Health, US Department of Health and Human Services". ClinicalTrials.gov. 2012.
- ↑ 40.0 40.1 40.2 Sethi, Fervenza, S, FC (2012). "Membranoproliferative glomerulonephritis - a new look at an old entity". N Engl J Med. 366 (12): 1119–1131. doi:10.1056/NEJMra1108178. PMID 22435371.
|first2=
missing|last2=
in Authors list (help) - ↑ Merk & Co., Inc. "Nephrotic syndrome". The Merk Manual Home Health Handbook. Whitehouse station, NJ.
- ↑ 42.0 42.1 Licht, Fremeaux-Bacchi, C, V (2009). "Hereditary and acquired complement dysregulation in membranoproliferative glomerulonephritis". Thromb Haemost. 101 (2): 271–278. PMID 19190809.
|first2=
missing|last2=
in Authors list (help) - ↑ 43.0 43.1 Radhakrishnan, Lunn, Kirschfink, S, A, M; et al. (2012). "Eculizumab and refractory membranoproliferative glomerulonephritis". N Eng J Med. 366 (12): 1165–1166. doi:10.1056/NEJMc1106619.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help);|first4=
missing|last4=
in Authors list (help);|first5=
missing|last5=
in Authors list (help);|first6=
missing|last6=
in Authors list (help);|first7=
missing|last7=
in Authors list (help);|first8=
missing|last8=
in Authors list (help) - ↑ 44.0 44.1 Vivarelli, Pasini, Emma, M, A, F (2012). "Eculizumab for the treatment of dense-deposit disease". N Engl J Med. 366 (12): 1161–1165. doi:10.1056/NEJMc1111953.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help) - ↑ Daina, Noris, Remuzzi, E, M, G (2012). "Eculizumab in a patient with dense-deposit disease". N Engl J Med. 366 (12): 1161–1163. doi:10.1056/NEJMc1112273. PMID 22435382.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help) - ↑ Bomback, Smith, Barile, AS, RJ, GR (2012). "Eculizumab for dense deposit disease and C3 glomerulonephritis". Clin J Am Soc Nephrol. 5. 7 (5): 748–756. doi:10.2215/CJN.12901211. PMC 3338285. PMID 22403278.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help);|first4=
missing|last4=
in Authors list (help);|first5=
missing|last5=
in Authors list (help);|first6=
missing|last6=
in Authors list (help);|first7=
missing|last7=
in Authors list (help);|first8=
missing|last8=
in Authors list (help);|first9=
missing|last9=
in Authors list (help);|first10=
missing|last10=
in Authors list (help);|first11=
missing|last11=
in Authors list (help);|first12=
missing|last12=
in Authors list (help) - ↑ Roth, Huttmann, Rother, Duhrsen, Philipp, A, A, RP, U, T (2009). "Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease". Blood. 113 (16): 3885–3886. doi:10.1182/blood-2009-01-196329. PMID 19372265.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help);|first4=
missing|last4=
in Authors list (help);|first5=
missing|last5=
in Authors list (help) - ↑ National Institutes of Health, US Department of Health and Human Services (2011). "Eculizumab to enable renal transplantation in patient with history of catastrophic antipholopid antibody syndrome". ClinicalTrials.gov. Bethesda, MD.
- ↑ Lonze, Singer, Montgomery, BE, AL, RA (2010). "Eculizumab and renal transplantation in a patient with CAPS". N Engl J Med. 362 (18): 1744–1745. doi:10.1056/NEJMc0910965. PMID 20445191.
|first2=
missing|last2=
in Authors list (help);|first3=
missing|last3=
in Authors list (help) - ↑ Shapira, Andrade, Allen, Salmon, I, D, SL, JE (2012). "Induction of durable remission in recurrent catastrophic antiphospholipid syndrome via inhibition of terminal complement with eculizumab". Arthritis Rheum. 64 (8): 2719–2723. doi:10.1002/art.34440. PMID 22354668.
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in Authors list (help)
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