Age-related macular degeneration
A phase II trial of intravenously infused eculizumab for the treatment of non-exudative age-related macular degeneration was conducted by the University of Miami; Alexion Pharmaceuticals appeared to be a collaborator (COMPLETE; NCT00935883). However, in its Form 10-K (filed 06 February 2015), Alexion did not list this programme among its active clinical programmes, indicating that development for age-related macular degeneration has been discontinued.
Alexion Pharmaceuticals was developing an intravitreal formulation of eculizumab for the treatment of age-related macular degeneration. According to Alexion's pipeline, it appears the new formulation of eculizumab has completed phase I clinical development.
The asthma indication was not mentioned for eculizumab in Alexion's list of clinical programmes in the company's Form 10-K (filed 23 February 2010). Development for this indication appears to have been discontinued.
Intravenous and nebulised formulations of eculizumab were being investigated for the treatment of asthma. A randomised, double-blind, placebo-controlled, crossover phase II trial of intravenously infused eculizumab was completed in late 2008 for the prevention of mild allergic asthma (C07-002; NCT00485576). A total of 21 patients were enrolled at two sites in Canada  .
A surrogate anti-C5 monoclonal antibody of eculizumab was effectively delivered to the lungs and showed favourable results in preclinical models of acute severe allergic asthma. The data also indicated that such anti-C5 antibodies could be successfully aerosolised for therapeutic use   .
In April 2020, Alexion Pharmaceuticals announced that emergency Expanded Access Programs (EAP) has been opened in France and the US (ECU-COV-401; NCT04355494). The program will allow participants with severe COVID-2019 infection related penumonia, acute lung injury or acute respiratory distress syndome to be treated with eculizumab   .
In March 2020, Alexion reported that they provided eculizumab to patients with COVID-2019 infections and severe pneumonia as an experimental emergency treatment. The company contacted Biomedical Advanced Research and Development Authority (BARDA) office, the Department of Defense (DoD) to discuss potential use of eculizumab in patients with COVID-2019 infections  .
In June 2015, the UK's NICE published a summary on the off-label use of eculizumab for the treatment of dense deposit disease (type II membranoproliferative glomerulonephritis [different to membranous glomerulonephritis]). The summary specifically suggests the use of eculizumab to prevent the recurrence of dense deposit disease  .
Independent investigators were conducting phase II development of eculizumab for the treatment of dense deposit disease in collaboration with Alexion. However, in the company's Form 10-K filed 06 February 2015, this programme was no longer listed.
Gullain Barre Syndrome
In November 2016 Chiba University, in collaboration with Alexion Pharmaceuticals, completed a phase II trial that assessed the safety and efficacy of eculizumab in patients with Gullain Barre Syndrome (100069; NCT02493725; UMIN000018171). The randomised, double-blind, placebo-controlled trial was initiated in July 015 and enrolled 34 patients in Japan  .
Haemolytic uraemic syndrome (HUS)
In May 2014, regular approval for eculizumab was granted by the US FDA under a sBLA for the treatment of adult and paediatric patients with a treatment of atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. The full approval was granted based on the two-year outcome data from two additional long-term prospective clinical trials. The revised label specifies longer term clinical benefit associated with sustained treatment with eculizumab and the use of eculizumab prior to the use of supportive care with either plasma exchange or plasma. Eculizumab was initially approved by the US FDA for aHUS in children and adults, in September 2011, under an accelerated approval process. This was the first FDA-approved product for the treatment of aHUS. The new indication was approved with an extension of the existing Risk Evaluation and Mitigation Strategy    .
Alexion received a positive opinion from the CHMP for an updated EU label to include data on the benefits of long-term treatment and the risks associated with treatment discontinuation in patients with atypical haemolytic uraemic syndrome, in February 2015. The data in support of this label change included results of the M11-001 trial  . Eculizumab was granted a centralised EU marketing authorisation by the EMA for the treatment of aHUS in children and adults, in November 2011    . Alexion had submitted the marketing applications for eculizumab in the treatment of aHUS to the FDA and the EMA in April 2011  . The US and EU submissions included results from two 26-week phase II trials in adults and adolescents with aHUS. Both trials met their primary endpoints and positive final data was published in the New England Journal of Medicine   .
In the UK (where the drug is available for the treatment of aHUS), there was controversy over whether eculizumab should be used, after the Ministers of Health decided not to follow a positive recommendation issued by the Advisory Group for National Specialised Services (AGNSS). AGNSS was set up by the UK Government to evaluate therapies for patients with very rare disorders. The decision not to follow the recommendation of AGNSS was made in January 2013, approximately a year and a half after the European Commission issued approval for this indication. The UK Ministers of Health referred consideration of the drug for this indication to the National Institute for Health and Clinical Excellence (NICE)  . The National Health Service (NHS) in the UK made eculizumab available on an interim basis, pending the results of appraisal by the NICE. In March 2014, the NICE issued draft guidance (produced by its Highly Specialised Technologies programme) concerning use of eculizumab for the treatment of aHUS. The agency accepted that eculizumab is an effective treatment for aHUS, but asked Alexion to explain the high cost of the drug. NICE estimated that routine use of eculizumab would cost the NHS approximately £58 million in the first year; the cost over 5 years is estimated at more than £80 million. The independent advisory committee of NICE requested clarification from Alexion concerning the manufacturing and research and development costs of a medicine for a very rare condition, and also asked NHS England to clarify treatment costs for a highly specialised technology. The information obtained in response to this request was discussed in April 2014 at a meeting of the Evaluation Committee   . In September 2014, NICE reaffirmed its earlier positive assessment on eculizumab for the treatment of aHUS and issued a recommendation that it be nationally commissioned for patients with aHUS, but subject to certain conditions. These conditions included the establishment of a centre to coordinate the use of eculizumab, and monitoring systems to record patients diagnosed with the disease  . A final draft guidance from NICE was issued in November 2014, under which eculizumab was recommended for commissioning for all patients in England with aHUS   . NICE issued final guidance in January 2015, recommending eculizumab for the treatment of aHUS. This is the first guidance to be issue under NICE's Highly Specialised Technologies programme for very rare conditions  .
Handok launched eculizumab for atypical haemolytic uraemic syndrome in Korea, in 2012  .
In September 2013, the Ministry of Health, Labour and Welfare in Japan approved the use of eculizumab for the treatment of all patients with aHUS  .
Alexion announced in March 2013 that Health Canada has approved eculizumab for use in adolescents and adults with aHUS to inhibit complement-mediated thrombotic microangiopathy. The agency has also approved eculizumab for use in paediatric patients with aHUS, under the Notice of Compliance with Conditions (NOC/c) policy (based on retrospective data). In fulfilment of the required conditions, Alexion will conduct an additional prospective study in paediatric patients with aHUS and will provide further data from all continuing and future trials of the drug in patients with aHUS  .
In April 2012, Alexion initiated a phase IV trial to asses the post-marketing safety and disease progression of eculizumab in patients with atypical haemolytic uraemic syndrome (M11-001; NCT01522183). The observational trial was conducted in 2 000 patients in the US  .
In September 2013, Alexion completed a phase II trial that characterised the overall safety and tolerability of eculizumab in patients with atypical haemolytic uraemic syndrome (C11-005J; NCT01757431). The open-label trial was initiated in May 2012, and enrolled two patients in Japan  .
In August 2009, Alexion commenced enrolment in four open-label pivotal phase II trials of eculizumab in patients with aHUS from sites in North America and Europe (C08-003 A/B NCT00838513, NCT00844428; C08-002A/B NCT00844545, NCT00844844). NCT00844844 and NCTNCT00844545 trials were completed in July 2013 and enrolled plasma therapy-resistant patients with atypical haemolytic uraemic syndrome. NCT00844428 and NCT000838513 trials were completed in December 2013 and enrolled plasma therapy-sensitive patients with aHUS     . Enrolment of patients in all four trials was completed in April 2010; in total, 37 adult and adolescent patients with aHUS were enrolled in these trials   . In June 2014, Alexion Pharmaceuticals released data from three subgroup analysis from prospective clinical trials and survival model data from a registrational trial  .
In February 2014, an additional phase II trial in adults with aHUS was completed in the US, Belgium, France, Germany, Italy, Spain and the UK (C10-004; NCT01194973). The open-label trial was initiated in July 2010 and enrolled 41 patients. In December 2014, Alexion presented post-hoc analysis data from the C10-004 and C10-003 phase II trials at the 56th Annual Meeting of the American Society of Haematology (ASH-2014). The pooled data of these two trials demonstrated that, eculizumab treatment significantly improved the haematologic and renal parameters in adults and paediatric patients, regardless of genetic mutation, with no unexpected safety concerns  . Alexion has reported 26-week and one year data from this trial. Data from subgroup analysis and combined analysis with C10-003 trial have also been reported    .
A phase II trial investigated the efficacy and tolerability of eculizumab in 22 paediatric aHUS patients. Patients were recruited from centres in the US, Canada, and the EU (C10-003; NCT01193348). Results were reported in November 2013. Alexion has reported efficacy and safety data from a subgroup analysis     .
In June 2011, Alexion initiated a phase II open-label trial of eculizumab in Germany for the treatment of patients with Shiga-toxin producing E. coli haemolytic uraemic syndrome (STEC-HUS), resulting from a recent enterohaemorrhagic E. coli (EHEC) outbreak. Alexion had been supplying eculizumab throughout the crisis, which started in May 2011. The purpose of the trial is to provide the therapy in a controlled manner and to collect data systematically, which could be useful to treat STEC-HUS in the future. All patients receiving eculizumab in the STEC-HUS outbreak were to be included in the trial, which was authorised by the German regulatory authorities  . Dosing in the trial was completed in the first quarter of 2012. Positive 8-week (primary endpoint) and 28-week efficacy data have been reported     . Alexion reported in July 2013 that it had obtain and analysed longer-term control clinical outcome data from the epidemiology study in approximately 400 patients with STEC-HUS who received only the best supportive care during the German epidemic  . In October 2013, Alexion Pharmaceuticals stated that it continue to analyse longer-term control clinical outcome data from this study  . Eculizumab is not indicated for the treatment of patients with STEC-HUS.
In August 2009, the European Commission granted Alexion Pharmaceuticals' eculizumab orphan drug status in the treatment of aHUS  . Eculizumab also obtained orphan drug status in the EU for the treatment of infection-associated HUS, such as STEC-HUS. The FDA has granted eculizumab orphan drug status for the treatment of aHUS and STEC-HUS.
Haemolytic anaemias and antiphospholipid syndrome
Alexion has tested eculizumab in a patient with autoimmune haemolytic anaemia (also known as cold agglutinin disease or CAD); a disease characterised by autoimmune attacks on red blood cells, leading to severe complement activation and haemolysis, anaemia and poor quality of life. Eculizumab treatment was associated with reduced haemolysis, absence of the need for blood transfusions, and improved symptoms of fatigue and anaemia. As of June 2013, Alexion has continued to mention CAD among its development programmes for eculizumab, which was underway as an investigator-initiated clinical trial. However, in the company's Form 10-K filed 06 February 2015, this programme was no longer listed.
Alexion was also developing a clinical programme to investigate the use of eculizumab for the treatment of catastrophic antiphospholipid syndrome (CAPS), a disorder in which uncontrollable blood clotting often leads to multiple organ failure; however, no recent development has been reported   .
Heart transplant rejection
Alexion reported on its pipeline that eculizumab was in preclinical development for the prevention of heart transplant rejection. However, it is unclear whether development is ongoing as this indication was not present on Alexion's Form 10-K (filed 17 February 2011).
Alexion completed a phase II efficacy study with eculizumab in 115 non-lupus patients with membranous glomerulonephritis in the US. In February 2002, Alexion commenced dosing in a follow-on open-label extension of the phase II study. However, Alexion discontinued development in this indication in order to focus its resources on development for paroxysmal nocturnal haemoglobinuria.
The FDA granted eculizumab fast-track designation in membranous glomerulonephritis in early 2000 and the drug has orphan drug status in the US for idiopathic membranous glomerular nephropathy.
Motor neuron disease
Independent investigators were conducting a phase II trial of eculizumab for the treatment of multifocal motor neuropathy, in collaboration with Alexion. However, in the company's Form 10-K filed 06 February 2015, this programme was no longer listed.
In October 2017, the US FDA approved eculizumab (Soliris®) as a treatment for adult patients with generalised myasthenia gravis (gMG), who are anti-acetylcholine receptor (AchR) antibody-positive  . In March 2017, the US FDA accepted Alexion's sBLA to extend the indication for eculizumab as a treatment of anti-acetylcholine receptor (AChR) antibody-positive refractory generalised myasthenia gravis patients and assigned a PDUFA date. The application was submitted to the US FDA in January 2017. The submission is supported by the comprehensive data from the phase III REGAIN study [see below]    .
In August 2017, the European Commission approved the use of eculizumab for the treatment of refractory generalised myasthenia gravis (gMG) in patients who are anti-acetylcholine receptor (AChR) antibody-positive  . In June 2017, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion for the approval. The submission was completed in January 2017 and was based on comprehensive data from the phase III REGAIN study   
In December 2017, Alexion announced that the Ministry of Health, Labour and Welfare (MHLW) in Japan approved eculizumab (Soliris®) for the treatment of patients with gMG, who are AChR antibody-positive and whose symptoms are difficult to control with high-dose intravenous immunoglobulin therapy or plasmapheresis  . In June 2017, MHLW accepted for review Alexion's sNDA, filed in March 2017, to extend the indication for eculizumab as a treatment of AChR antibody-positive gMG patients. The application was based on the results from the phase III REGAIN study [see below]   .
In December 2018, Alexion Pharmaceuticals initiated a pivotal phase III trial to investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of eculizumab, in paediatric patients with refractory generalised myasthenia gravis (P200-2018; ECU-MG-303; EudraCT2016-001384-37; NCT03759366). The trial intends to enrol approximately 12 patients in the US and Japan. Change from baseline in the Quantitative Myasthenia Gravis (QMG) score over time irrespective of rescue treatment will be assessed as the primary endpoint  .
According to top-line results released by Alexion in June 2016, the phase III REGAIN trial failed to meet its primary efficacy endpoint, however, there were clinically meaningful improvements in MG-ADL and QMG measures in patients treated with eculizumab compared with placebo  . New secondary efficacy endpoint results were released by Alexion Pharmaceuticals in July 2016  . Alexion, in December 2013, initiated the randomised, double-blind, placebo-controlled, pivotal phase III trial, to assess the efficacy and safety of eculizumab in patients with refractory generalised myasthenia gravis (REGAIN; ECU-MG301; NCT01997229; EudraCT2013-003589-15) (Alexion Pharmaceuticals, 10-Q filed in July 2015). The global trial enrolled 92 patients in the US, Canada, Japan, Sweden, Italy, Denmark, Spain, UK, Belgium, Germany, the Netherlands, Greece, South Korea, Turkey, Hungary, France, Czech Republic, Brazil, Australia and Finland. The company further reported that it had exceeded the target enrolment in the REGAIN phase III trial. The trial was completed in June 2016      . In March 2019, Alexion completed an open-label extension phase III trial that evaluated the long-term safety and efficacy of eculizumab in patients with refractory generalised myasthenia gravis (ECU-MG302; EudraCT2013-002191-41; NEUR3784; NCT02301624). The open-label trial was initiated in October 2014, and enrolled 117 participants in Italy, the UK, Belgium, Germany, Sweden, Hungary, Spain, the Netherlands, Denmark, Czech Republic, and Finland. Earlier, in September 2017, interim efficacy results from the extension trial were released by the company   . Additional interim results were presented by the company at the 71st Annual Meeting of the American Academy of Neurology (AAN-2019)  .
A randomised, double-blind, cross-over phase II trial was initiated by Alexion in October 2008 to determine whether eculizumab is safe and effective in the treatment of patients with myasthenia gravis when combined with various immunosuppressants, such as prednisone, methotrexate, mycophenolate mofetil, ciclosporin and cyclophosphamide (NCT00727194). Patients with moderate to severe muscle weakness despite previous treatment will receive weekly intravenous eculizumab at 600mg for four doses, followed by a 900mg dose every two weeks for seven doses in the first treatment period (16 weeks), followed by corresponding placebo treatment (16 weeks), or patients will receive the reverse sequence (i.e. placebo in the first treatment period, followed by eculizumab in the second); washout period between treatments is 5 weeks. Primary efficacy will be evaluated by adverse event profiles and Quantitative Myasthenia Gravis (QMG) score. Enrolment of 14 patients in the US, Canada, and UK has been completed and results have been released   .
In August 2014, the European Commission granted orphan drug status to eculizumab for the treatment of myasthenia gravis in the EU  . Eculizumab was granted orphan drug designation by the US FDA in June 2014 for the treatment of myasthenia gravis  . Eculizumab was also granted orphan drug designation in Japan for the treatment of myasthenia gravis  .
Collaborative preclinical studies conducted with researchers at Case Western Reserve University demonstrated that a surrogate anti-C5 antibody prevented experimentally acquired myasthenia gravis and inhibited progression of disease in two thirds of the rodents evaluated.
Neuromyelitis optica (NMO)
In June 2019, the U.S. Food and Drug Administration approved the sBLA for eculizumab for the treatment of patients with neuromyelitis optica spectrum disorder who are Anti-Aquaporin-4 (AQP4) antibody positive  . In February 2019, US FDA accepted the supplemental Biologics License Application (sBLA) and ganted priority review  . The sBLA was submitted based on the results from the phase III PREVENT study [see below]  .
In November 2019, the Ministry of Health, Labour and Welfare in Japan approved the extension of the current marketing authorization of eculizumab to include the prevention of relapse in patients with anti-aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD), including neuromyelitis optica. The approval was based on results from the phase III PREVENT study [see below]. Prior to April 2019, an application seeking approval was submitted by Alexion Pharmaceuticals in Japan   .
In August 2019, the European Commission approved the extension of the current marketing authorization of eculizumab for the treatment of neuromyelitis optica spectrum disorder in adults  . Earlier, in July 2019, the Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion to extend the current marketing authorization of eculizumab to include the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adult patients who are anti-aquaporin-4 (AQP4) antibody positive with a relapsing course of the disease. The European Commission will review the CHMP opinion and the final decision is planned within two months  . In February 2019, Alexion Pharmaceuticals submiited regulatory application in the European Union for the approval of eculizumab for the treatment of neuromyelitis optica spectrum disorder, in the US. The submission was based on the results from the phase III PREVENT study [see below]  .
In June 2013, eculizumab received orphan drug designation from the US FDA for the treatment of neuromyelitis optica  . The Committee for Orphan Medicinal Products of the European Medicines Agency issued a positive opinion for eculizumab in the treatment of neuromyelitis optica in July 2013. The recommendation for orphan designation was to be considered by the European Commission for final approval  . Orphan designation for eculizumab in NMO was subsequently granted by the European Commission in August 2013  . Eculizumab was granted orphan drug designation for this indication in Japan in November 2014  .
Pooled long-term efficacy and safety data from the phase III PREVENT and ECU-NMO-302 trials [see below] were presented at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-2019), in September 2019. Updated safety data from the pooled analysis were presented at the 72nd Annual Meeting of the American Academy of Neurology (AAN-2020), in April 2020   .
In September 2018, Alexion reported that the pivotal phase III PREVENT trial met its primary endpoint of time to first adjudicated on-trial relapse, demonstrating that treatment with eculizumab reduced the risk of NMO relapse (ECU-NMO-301; NCT01892345; EudraCT2013-001150-10; 14-001640; UKCRN15423; CCRN2595). Based on the positive results of the trial the company intends to file regulatory applications in the US, EU, and Japan  . The randomised, double-blind, placebo-controlled trial that investigated the efficacy of eculizumab in patients with relapsing NMO was completed in July 2018. The trial was initiated in January 2014 and enrolled 143 patients in the US, Australia, Canada, Croatia, Colombia, Czech Republic, Denmark, France, Germany, Hong Kong, Italy, Japan, Malaysia, South Korea, Russia, Singapore, Spain, Taiwan, Turkey, the UK, Argentina, Austria and Thailand. In March 2020, data from the trial were presented at the 72nd Annual Meeting of the American Academy of Neurology (AAN-2020). Positive results from the trial were released by Alexion Pharmaceuticals in May 2019      .
Alexion, in January 2015 initiated an open-label extension trial to investigate long-term safety and efficacy of eculizumab in patients with relapsing neuromyelitis optica spectrum disorder (ECU-NMO-302; NCT02003144; EudraCT2013-001151-12). The open-label trial intends to recruit approximately 119 patients in the US, Australia, Canada, Colombia, Croatia, Czech Republic, Denmark, Hong Kong, Italy, Japan, Malaysia, South Korea, Russia, Spain, Taiwan, Thailand, Turkey, and the UK  .
In December 2019, Alexion Pharmaceuticals initiated a phase II/III trial to evaluate the safety and efficacy of eculizumab in pediatric participants (aged 2 to < 18 years) with relapsing neuromyelitis optica spectrum disorder (NCT04155424; ECU-NMO-303; EudraCT2019-001829-26). The open label trial intends to enrol approximately 15 patients in Japan and may be extends in the US, Canada, Italy, South Korea, Spain, Germany  .
Results from an investigator-sponsored open-label phase I/II trial of eculizumab in patients with NMO were presented at the American Neurological Association Annual Meeting (ANA-2012) in October 2012  . This trial was conducted by the Mayo Clinic and involved 14 patients (NCT00904826). In two of Alexion's Form 10-K filings (2010 and 2011) eculizumab was listed as being in phase II development for NMO  .
Paroxysmal nocturnal haemoglobinuria (PNH)
Eculizumab was launched as Soliris® in the US after marketing approval was granted by the FDA in March 2007. The product is indicated for the treatment of all patients with PNH, but carries a boxed warning that eculizumab increases the incidence of meningococcal infections. The BLA submission and approval was based on data from the pivotal phase III TRIUMPH trial      .
The CHMP issued a positive opinion to update the indication for eculizumab to include treatment of paroxysmal nocturnal haemoglobinuria in patients with high disease activity regardless of history of transfusion, in February 2015. The filing was based on results of the M07-001 trial  . In June 2007, eculizumab received approval from the European Commission for the treatment of patients with PNH in the EU. The MAA was reviewed under the centralised procedure and was evaluated under an accelerated assessment procedure. Eculizumab was initially made available to patients in Europe on a named-patient basis while reimbursement, price approval and funding processes were being established. Alexion subsequently began commercial sales in select European markets during the fourth quarter of 2007. Furthermore, the British government notified Alexion in September 2008 that eculizumab was to qualify for reimbursement on national level, beginning in the second quarter of 2009    . The EMA granted a positive opinion recommending unlimited validity for eculizumab in March 2012  . In May 2013, the EMA's European public assessment report (EPAR) for Soliris® was amended to include treatment for both adults and children with PNH  .
The Japanese Ministry of Health, Labour and Welfare approved eculizumab for the treatment of PNH in April 2010. Approval was based on an NDA submitted by Alexion during April 2009, and which was supported by data from the phase III AEGIS trial. In June 2010, the company announced that the product will be launched in the third quarter of 2010, in the same month the product was granted reimbursement status through Japan's National Health Insurance system     . An application for marketing authorisation for this indication has also been submitted in Switzerland; Alexion reported in its Form 10-K (filed 23 February 2010) that approval was granted in Switzerland in 2010. Approval was also granted in South Korea early in 2010.
Eculizumab was approved under priority review by Health Canada's Biologics and Genetic Therapies Directorate (BGTD) in January 2009 for the treatment of all patients with PNH. The marketing application contained data from the TRIUMPH, SHEPHERD and E05-001 trials  . Alexion launched eculizumab for the treatment of PNH in Canada in July 2009. Alexion Pharma Canada has also launched the OneSource™ Program, when a specific OneSource™ Case Manager gets assigned to a patient who enrols in the programme. The patient will receive an immediate and over time support, ranging from disease education to coordinated care with the Physician's office  .
In February 2009, eculizumab was also approved under priority review by the Therapeutic Goods Administration (TGA) in Australia for the treatment of all patients with PNH. A division of Alexion based in Sydney was working with Australian healthcare authorities to obtain reimbursement for the product and had expected to have a decision on pricing structure by the end of 2009  .
Handok launched eculizumab for the treatment of paroxysmal nocturnal haemoglobinuria in Korea, in 2012  .
Alexion Pharmaceuticals initiated an expanded access programme EMBRACE, for eculizumab, for the treatment of paroxysmal nocturnal haemoglobinuria in the US (C06-002; NCT00438789).
In January 2007, Alexion initiated a phase IV trial to assess the safety and efficacy of eculizumab in patients with paroxysmal nocturnal haemoglobinuria (M07-001; NCT01374360). The trial is expected to enrol approximately 2 000 patients in Argentina, Australia, Belgium, Canada, Finland, France, Germany, Netherlands, Norway, Spain, Sweden, Switzerland, the UK and the US  .
In October 2008, Alexion Pharmaceuticals completed a phase III trial which evaluated the long-term safety of eculizumab in patients with transfusion dependent haemolytic paroxysmal nocturnal haemoglobinuria (E05-001; NCT00122317). This open-label extension trial (TRIUMPH, SHEPHERD or X03-001; see below) enrolled 187 patients in the US, Australia, Belgium, Canada, France, Germany, Ireland, Italy, the Netherlands, Spain, Sweden and the UK, and was initiated in May 2005  .
Results from the phase III TRIUMPH trial (NCT00112983; EudraCT2004-000646-20) demonstrated that all primary and secondary endpoints were achieved with statistical significance  . This randomised, double-blind, placebo-controlled trial evaluated haemoglobin stabilisation and transfusion reduction efficacy and safety of eculizumab IV infusion in approximately 75 patients with PNH  .
Patient follow-up consultations in the phase III SHEPHERD trial were completed in October 2006 (EudraCT2004-002795-42; C04-002). The open-label study, which was initiated in February 2005, conducted to collect additional safety data from eculizumab among haemolytic PNH patients who have undergone transfusion. A total of 85 patients received treatment for 12 months in Germany, Ireland, Italy, Spain, Sweden, and the UK. Data presented by Alexion demonstrated that eculizumab therapy reduced haemolysis, and improved fatigue, quality of life and anaemia in a population of patients with minimal transfusion requirements and/or evidence of thrombocytopenia. Additionally, 1-year data showed that the trial met both its primary endpoints     .
Patient enrolment in a single registration trial, known as AEGIS, was completed by Alexion in October 2008. The trial evaluated the safety, efficacy and pharmacology of eculizumab as a treatment for patients with PNH in Japan. The study was initiated in January 2008 after study approval was granted by the Pharmaceutical and Medical Device Administration (PMDA). A total of 29 patients will be dosed with eculizumab for 12 weeks after enrolment. The inclusion criteria for the AEGIS study was similar to those used in the previously conducted phase III, SHEPHERD study. Results have been reported and are consistent with earlier studies    .
In November 2011, Alexion Pharmaceuticals completed a phase I/II trial that investigated the appropriate dose regimens, pharmacokinetics, pharmacodynamics, safety and efficacy of eculizumab IV infusion in paediatric and adolescent patients (aged 2 to 17 years) with paroxysmal nocturnal haemoglobinuria (M07-005;EudraCT2009-010402-11; NCT00867932). The open-label, single-group, non-randomised trial was initiated in May 2009, and recruited seven patients in the US  .
Results presented at the European Haematology Association Congress 2009 demonstrated eculizumab to significantly reduce haemolysis in never-transfused patients with PNH and in patients with PNH and thrombocytopenia, showed sustained platelet recovery following treatment with eculizumab  .
A pilot, open-label phase Ib trial evaluating eculizumab in 11 patients with PNH has been completed in the UK. All patients in the trial chose to participate in two consecutive one year extension studies. One-year and 2-year cumulative results have been presented. The positive findings further supported further clinical development of eculizumab for PNH   .
Eculizumab has been granted orphan drug status in the US, EU, Australia, Canada and Japan for the treatment of PNH    . According to Alexion's Form 10-K (filed 17 February 2011), eculizumab has also been granted orphan drug status in South Korea for the treatment of PNH.
Renal transplant rejection
Eculizumab is in phase II development for the treatment of antibody mediated rejection (AMR) following renal transplantation, and prevention of AMR presensitised renal transplant (living and deceased donor) rejection (Alexion's 2014 annual report filed in February 2015).
In company-sponsored trials, Alexion was evaluating the effectiveness of eculizumab in preventing antibody mediated rejection (AMR), also known as acute humoral rejection (AHR), in patients undergoing kidney transplant. The clinical protocols for two trials were approved by the US FDA and EMA  . The company initiated a phase II living-donor study in November 2011 (NCT01399593). The study enrolled 102 patients in the US, Australia, the UK, France, Germany, Italy, the Netherlands, Norway, Sweden and Spain. The primary composite endpoint of Week 9 post-transplantation treatment failure rate did not reach statistical significance, according to results reported in January 2015; however, the trial was terminated in July 2016   . In May 2017, Alexion Pharmaceuticals completed a phase II deceased-donor study that assessed the safety and efficacy of eculizumab in the prevention of AMR in sensitised patients receiving deceased-donor kidney transplant (NCT01567085; EudraCT2010-019631-35; C10-002; 362145; ACTRN12612000333819). Interim results from this trial, reported in September 2013, suggested that the primary endpoint of 9-week treatment failure rate had been met. The trial was initiated in May 2012 and enrolled 80 patients in Australia, France, Italy, Spain, Sweden and the UK. In May 2015, positive results were reported from the study         .
In June 2015, a investigator sponsored phase I/II trial investigating the safety and efficacy of eculizumab when added to conventional treatment was terminated due to poor enrolment (ABOi; NCT01095887). The phase I/II trial was initiated in March 2010, to evaluate the prevention of antibody-mediated rejection in ABO blood group incompatible living donor kidney transplantation in 6 patients enrolled at study centre in the US  . Another investigator-sponsored phase I/II trial by the Mayo Clinic investigating the addition of eculizumab to conventional anti-rejection treatment in kidney transplant patients was terminated in October 2017(NCT01106027; 09-005627DD). The trial was initiated in March 2010 and intended to enrol approximately 40 patients receiving positive cross-match deceased donor kidney transplant in the US  . Alexion is a collaborator in both these trials.
In August 2017, the Mayo Clinic completed a phase II trial that evaluated the safety and efficacy of a dosing regimen of eculizumab, when added to conventional therapy, in preventing antibody-mediated rejection (AMR) in positive cross-match living-donor kidney transplantation (NCT00670774; 07-007208). Eculizumab was given 1h pre-transplantation, then once-weekly for 4 weeks, and then again at weeks 5, 7 and 9. It was hypothesised that the blockade of terminal complement activation at the time of transplant, in combination with conventional treatment, will reduce the incidence of rejection. Alexion appeared to be a collaborator in this trial. The open-label trial enrolled 31 patients with anti-HLA antibodies specific to their living donor in the US   .
The Brigham and Women's Hospital, in collaboration with Alexion, initiated a phase II trial in November 2013 to investigate the efficacy and tolerability of eculizumab versus plasmapheresis + immune globulin in approximately 21 patients with acute, grade II or grade III, antibody-mediated, renal transplant rejection (NCT01895127). However, the trial was terminated in April 2016 due to lack of efficacy  .
In April 2014, the European Commission granted orphan drug designation to eculizumab for the prevention of graft rejection following solid organ transplantation  .
At the American Transplant Congress in May 2009, Alexion presented early clinical and laboratory data on the potential role of terminal complement inhibition with eculizumab in the treatment of a subset of kidney transplant patients who are at high risk for antibody-mediated rejection  .
In a rodent model of transplantation, eculizumab induced inhibition of terminal complement and successfully prevented antibody mediated rejection. Furthermore, addition of anti-C5 antibody to standard anti-cellular therapy resulted in a significant increase in graft survival, compared with graft survival in animals treated with anti-cellular therapy alone. Eculizumab was also noted to prevent antibody mediated rejection even in the presence of high levels of circulating anti-donor antibodies.
Delayed-graft function (DGF)
In December 2016, Alexion released top-line results from the phase II/III PROTECT study showing that the trial did not meet its primary endpoint of incidence of delayed graft function, with a two-dose regimen of eculizumab, in patients with renal transplants (NCT02145182, EudraCT2013-004650-25, ECU-DGF201). Alexion completed the randomised, parallel-group, double-blind, placebo-controlled trial in November 2016. The trial was initiated in August 2014, and enrolled 286 patients in the US, Germany, Czech Republic, Canada, France, Italy, Australia and Spain        .
In May 2019, Alexion Pharmaceuticals in collaboration with Icahn School of Medicine at Mount Sinai terminated a double-blind, placebo-controlled, phase II pilot study that was designed to determine the safety and efficacy of eculizumab in the prevention of DGF following deceased-donor renal transplantation (NCT01403389). After interim analysis, the pilot study was terminated and modified to a larger multicenter study (NCT01919346) to better assess efficacy. The trial intended to enrol approximately 20 participants in the US (Alexion Form 2013 10-K)  .
An additional investigator-sponsored phase II trial of eculizumab for the prevention of DGF in renal transplantation was initiated in August 2013, in the US however, the study was discontinued in December 2017, based on results from Alexion PROTECT DGF study (NCT01919346). The trial was sponsored by Dr. P. Heeger of Icahn School of Medicine at Mount Sinai, with Alexion Pharmaceuticals as collaborator. The randomised, double-blind, placebo-controlled trial enrolled 21 patients. The primary outcome measure is need of at least one dialysis treatment in the first week following transplantation  .
In January 2014, eculizumab was granted orphan drug designation by the US FDA for the prevention of delayed graft function in renal transplant patients  . In February 2014, the European Commission granted eculizumab orphan drug designation for the prevention of DGF following solid organ transplantation  .
Preliminary results of a phase IIb trial in rheumatoid arthritis showed that monthly treatment with eculizumab caused a significant, moderate improvement in the ACR20 score over a 6-month period  . This trial, which was the first of two scheduled phase IIb trials of eculizumab in rheumatoid arthritis, enrolled 368 patients in the US and Canada. A 12-month open-label extension study of the phase IIb trial was in progress. However, Alexion discontinued development in this indication to focus its resources on development for paroxysmal nocturnal haemoglobinuria.
Phase I and II trials in rheumatoid arthritis had previously been completed.
The rationale behind evaluating eculizumab in this indication was that activated terminal complement proteins appear to have a central role in the pathogenesis of immune-mediated joint inflammation, indicating that anti-C5 monoclonal antibodies may have therapeutic potential for the treatment of rheumatoid arthritis  .
Eculizumab completed a phase Ib pilot trial in patients with severe psoriasis. Based on preliminary analysis of data from this study, Alexion stated that it may consider further trials of the antibody in patients with psoriasis or psoriatic arthritis. Eculizumab was also in phase Ib trials for bullous pemphigoid. However, Alexion discontinued development in this indication to focus its resources on development for paroxysmal nocturnal haemoglobinuria.
A phase I, pilot trial was completed in patients with dermatomyositis, an inflammatory skin and muscle disorder, for which eculizumab has orphan drug status in the US.
Systemic lupus erythematosus
Eculizumab was undergoing phase II trials in the US in patients with systemic lupus erythematosus. However, Alexion discontinued development in this indication to focus its resources on development for paroxysmal nocturnal haemoglobinuria.
Other investigator sponsored trials
NHS Greater Glasgow and Clyde in collaboration with the University of Glasgow initiated a phase II trial to assess the inhibition of complement activation in Guillain-Barre Syndrome (GN12NE462; NCT02029378; EudraCT2013-000228-33). Primary endpoints were incidence of adverse and serious adverse events and improvement of one or more grade in functional outcome at four weeks. The randomised, double-blind trial was designed to enrol 30 patients in the UK. However, the trial was prematurely ended  .
Eculizumab was being investigated in preclinical studies for the treatment of adult respiratory distress syndrome and immune (idiopathic) thrombocytopenic purpura. However, Alexion discontinued development in these indications to focus its resources on development for paroxysmal nocturnal haemoglobinuria.
In April 2015, the EMA approved the labelling changes made to the EU labels of eculizumab to include information related to the use of drug in patients with paroxysmal nocturnal haemoglobinuria (PNH) regardless of history of transfusion. Additionally, the label was also amended to to include new atypical haemolytic uraemic syndrome (aHUS) long-term efficacy data and the risks associated with the discontinuation of treatment  .
In May 2014, revised label information for the use of eculizumab in the treatment of aHUS in adults and paediatrics was approved. The label changes specify the benefits of chronic and sustained treatment with eculizumab and includes data from two years of treatment, and data on the use of eculizumab prior to supportive care with plasma exchange or plasma  .
The US product label for eculizumab includes a boxed warning stating that eculizumab increases the risk of meningococcal infections. During clinical studies, two out of 196 vaccinated patients with PNH treated with eculizumab experienced a serious meningococcal infection. Its is advised that patients should receive a meningococcal vaccine at least 2 weeks prior to receiving the first dose of eculizumab and then re-vaccinate according to current medical guidelines for vaccine use  . A similar boxed warning appears on the EU label  .