-- EU Filing Accepted and Under Review --
Alexion Pharmaceuticals, Inc. (ALXN) announced today that the U.S. Food and Drug Administration (FDA) has accepted for review the Company’s Biologics License Application (BLA) for approval of ALXN1210, the Company’s investigational long-acting C5 complement inhibitor, for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). The FDA set a Prescription Drug User Fee Act (PDUFA) date of February 18, 2019, as part of an expedited eight-month review instead of the standard 12-month review following Alexion’s use of a rare disease priority review voucher. The application is supported by comprehensive data from two rigorous Phase 3 clinical trials.
“We are working with the FDA to facilitate a smooth review,” said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. “Building on comprehensive results from the largest-ever Phase 3 development program in PNH, 11 years of proven efficacy and safety with Soliris®, and 25 years of leadership in complement biology, we are on track with our efforts to establish ALXN1210 as the new standard of care for patients with PNH.”
If approved, ALXN1210 would be the first and only long-acting complement inhibitor for patients with PNH, providing immediate and complete inhibition of the C5 complement protein that is sustained over an eight-week dosing interval. The Phase 3 clinical development program of ALXN1210 is the largest-ever Phase 3 program in PNH. The studies enrolled a very broad and diverse population of more than 440 patients, which included patients who had never been treated with a complement inhibitor and patients who were stable on Soliris® and switched to ALXN1210. Topline data were disclosed in press releases on March 15, 2018 and April 26, 2018, respectively.
In addition to the submission in the U.S. on June 18 and the submission in the European Union (EU) on June 28, Alexion is preparing a submission for a New Drug Application for ALXN1210 as a treatment for patients with PNH in Japan in the second half of the year. The European Medicines Agency (EMA) has accepted and is reviewing the submission for the EU. ALXN1210 has received Orphan Drug Designation (ODD) in the U.S. and EU for the treatment of patients with PNH.
About Paroxysmal Nocturnal Hemoglobinuria (PNH)
Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, debilitating, and potentially life-threatening ultra-rare blood disorder that can strike men and women of all races, backgrounds, and ages without warning, with an average age of onset in the early 30s.1,2,3 PNH often goes unrecognized, with delays in diagnosis ranging from one to more than 10 years.2 In patients with PNH, chronic, uncontrolled activation of the complement system, a component of the body’s immune system, results in hemolysis (the destruction of red blood cells)4, which in turn can result in progressive anemia, fatigue, dark urine, and shortness of breath.5,6,7 The most devastating consequence of chronic hemolysis is thrombosis (the formation of blood clots), which can damage vital organs and cause premature death.8 Historically, it had been estimated that one in three patients with PNH did not survive more than five years from the time of diagnosis.2 PNH is more common among patients with disorders of the bone marrow, including aplastic anemia (AA) and myelodysplastic syndromes (MDS).9,10,11 In certain patients with thrombosis of unknown origin, PNH may be an underlying cause.4
ALXN1210 is an innovative, long-acting C5 inhibitor discovered and developed by Alexion that works by inhibiting the C5 protein in the terminal complement cascade, a part of the body’s immune system that, when activated in an uncontrolled manner, plays a role in severe ultra-rare disorders like paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor (AchR) antibody-positive myasthenia gravis (MG). In Phase 3 clinical studies in complement inhibitor-naïve patients with PNH, and patients with PNH who had been stable on Soliris®, intravenous treatment with ALXN1210 every eight weeks demonstrated non-inferiority to intravenous treatment with Soliris® every two weeks, with numeric results for all primary and key secondary endpoints favoring ALXN1210. ALXN1210 is also currently being evaluated in a Phase 3 clinical study in complement inhibitor-naïve patients with aHUS, administered intravenously every eight weeks. In addition, Alexion plans to initiate a Phase 3 clinical study of ALXN1210 delivered subcutaneously once per week as a potential treatment for patients with PNH and aHUS.
ALXN1210 has received Orphan Drug Designation (ODD) for the treatment of patients with PNH in the U.S. and EU, and for the subcutaneous treatment of patients with aHUS in the U.S.
About Soliris® (eculizumab)
Soliris® is a first-in-class complement inhibitor that works by inhibiting the C5 protein in the terminal part of the complement cascade, a part of the immune system that, when activated in an uncontrolled manner, plays a role in severe rare and ultra-rare disorders like paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor (AchR) antibody-positive myasthenia gravis (MG). Soliris® is approved in the U.S., EU, Japan, and other countries as the first and only treatment for patients with PNH and aHUS, in the EU as the first and only treatment of refractory generalized MG (gMG) in adults who are anti-AchR antibody-positive, in the U.S. for the treatment of adult patients with gMG who are anti-AchR antibody-positive, and in Japan for the treatment of patients with gMG who are AChR antibody-positive and whose symptoms are difficult to control with high-dose intravenous immunoglobulin (IVIG) therapy or plasmapheresis (PLEX). Soliris® is not indicated for the treatment of patients with Shiga-toxin E. coli-related hemolytic uremic syndrome (STEC-HUS).
Soliris® has received Orphan Drug Designation (ODD) for the treatment of patients with PNH in the U.S., EU, Japan, and many other countries, for the treatment of patients with aHUS in the U.S., EU, and many other countries, for the treatment of patients with MG in the U.S. and EU, and for the treatment of patients with refractory gMG in Japan. Alexion and Soliris® have received some of the pharmaceutical industry's highest honors for the medical innovation in complement inhibition: the Prix Galien USA (2008, Best Biotechnology Product) and France (2009, Rare Disease Treatment).
For more information on Soliris®, please see full prescribing information for Soliris®, including BOXED WARNING regarding risk of serious meningococcal infection, available at www.soliris.net.
Important Soliris® Safety Information
The U.S. prescribing information for Soliris® includes the following warnings and precautions: Life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris®. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Comply with the most current Centers for Disease Control (CDC)’s Advisory Committee on Immunization Practices (ACIP) recommendations for meningococcal vaccination in patients with complement deficiencies. Immunize patients with meningococcal vaccines at least two weeks prior to administering the first dose of Soliris®, unless the risks of delaying Soliris® therapy outweigh the risk of developing a meningococcal infection. Monitor patients for early signs of meningococcal infections and evaluate immediately if infection is suspected. Soliris® is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS). Under the Soliris® REMS, prescribers must enroll in the program. Enrollment in the Soliris® REMS program and additional information are available by telephone: 1-888-SOLIRIS (1-888-765-4747) or at www.solirisrems.com.
Patients may have increased susceptibility to infections, especially with encapsulated bacteria. Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with Soliris® may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenza type b (Hib). Soliris® treatment of patients with PNH should not alter anticoagulant management because the effect of withdrawal of anticoagulant therapy during Soliris® treatment has not been established. Administration of Soliris® may result in infusion reactions, including anaphylaxis or other hypersensitivity reactions.
In patients with PNH, the most frequently reported adverse events observed with Soliris® treatment in clinical studies were headache, nasopharyngitis, back pain, and nausea. In patients with aHUS, the most frequently reported adverse events observed with Soliris® treatment in clinical studies were headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, and pyrexia. In patients with gMG who are anti-AchR antibody-positive, the most frequently reported adverse reaction observed with Soliris® treatment in the placebo-controlled clinical study (≥10%) was musculoskeletal pain.
Alexion is a global biopharmaceutical company focused on serving patients and families affected by rare diseases through the discovery, development, and commercialization of life-changing therapies. As the global leader in complement biology and inhibition for more than 20 years, Alexion has developed and commercializes the first and only approved complement inhibitor to treat patients with paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), and anti-acetylcholine receptor (AchR) antibody-positive generalized myasthenia gravis (gMG). Alexion also has two highly innovative enzyme replacement therapies for patients with life-threatening and ultra-rare metabolic disorders, hypophosphatasia (HPP) and lysosomal acid lipase deficiency (LAL-D). In addition, the company is developing two late-stage therapies, a second complement inhibitor and a copper-binding agent for Wilson disease. Alexion focuses its research efforts on novel molecules and targets in the complement cascade, and its development efforts on the core therapeutic areas of hematology, nephrology, neurology, and metabolic disorders. Alexion has been named to the Forbes list of the World's Most Innovative Companies seven years in a row and is headquartered in Boston, Massachusetts' Innovation District. The company also has offices around the globe and serves patients in more than 50 countries. This press release and further information about Alexion can be found at: www.alexion.com.
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including statements related to: the future planned submission of regulatory applications for review and approval by regulatory authorities in certain countries (including Japan) for ALXN1210 for treatment of patients with PNH, the timing of anticipated future submissions of regulatory applications for ALXN1210 for review and approval by certain governmental authorities, future plans to work with regulatory authorities to facilitate a smooth review of the ALXN1210 marketing authorization application, making ALXN1210 the new standard of care for patients with PNH, plans for future clinical studies of ALXN1210 delivered subcutaneously as a potential treatment for patients with PNH and aHUS, and the potential medical benefits of ALXN1210 for the treatment of PNH and other diseases. Forward-looking statements are subject to factors that may cause Alexion's results and plans to differ materially from those expected by these forward looking statements, including for example: the inability to submit regulatory applications for ALXN1210 for review and approval by certain governmental authorities in the timeframes expected due to delays or future product information (or other reasons), the inability to timely provide (or provide at all) the product safety and efficacy information required by regulatory authorities for products for certain indications, our products not gaining acceptance among patients (and providers or third party payers) for certain indications (due to cost or otherwise), the inability to develop future clinical study programs for certain product delivery mechanisms (or the failure of those programs to meet safety and efficacy goals), the inability to timely and cost-effectively develop programs for existing products for new indications (or the failure to obtain regulatory approval for use in such new indications), decisions of regulatory authorities regarding the adequacy of our research, marketing approval or material limitations on the marketing of our products (or the indications of such products), delays, interruptions, or failures in the manufacture and supply of our products and our product candidates, failure to satisfactorily address matters raised by the FDA and other regulatory agencies, the possibility that results of clinical trials are not predictive of safety and efficacy results of our products in broader patient populations, the possibility that current rates of adoption of our products are not sustained (or do not meet expected future rates), the possibility that clinical trials of our product candidates could be delayed, the adequacy of our pharmacovigilance and drug safety reporting processes, the risk that third party payers (including governmental agencies) will not reimburse or continue to reimburse for the use of our products (or proposed future products) at acceptable rates or at all, delay of collection or reduction in reimbursement due to adverse economic conditions or changes in government and private insurer regulations and approaches to reimbursement, uncertainties surrounding legal proceedings, company investigations and government investigations, including investigations of Alexion by the U.S. Securities and Exchange Commission (SEC) and U.S. Department of Justice, the risk that other anticipated regulatory filings are delayed, the risk that estimates regarding the number of patients with the diseases that our products treat are inaccurate, and a variety of other risks set forth from time to time in Alexion's filings with the SEC, including but not limited to the risks discussed in Alexion's Quarterly Report on Form 10-Q for the period ended June 30, 2018 and in Alexion's other filings with the SEC. Alexion disclaims any obligation to update any of these forward-looking statements to reflect events or circumstances after the date hereof, except when a duty arises under law.
1 Hill A, Richards SJ, Hillmen P. Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria. Br J Haematol. 2007 May;137(3):181-92.
2 Hillmen P, Lewis SM, Bessler M, et al. Natural history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995 Nov 9;333(19):1253-8.
3 Socié G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term follow-up and prognostic factors. Lancet. 1996;348:573-577.
4 Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121:4985-4996.
5 Nishimura J, Kanakura Y, Ware RE, et al. Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan. Medicine (Baltimore) 2004 May;83(3):193-207.
6 Weitz I, Meyers G, Lamy T, et al. Cross-sectional validation study of patient-reported outcomes in patients with paroxysmal nocturnal haemoglobinuria. Intern Med J. 2013;43:298-307.
7 Parker C, Omine M, Richards S, et al. Diagnosis and management of paroxysmal nocturnal hemoglobinuria. Blood. 2005 Dec 1;106(12):3699-709.
8 Hillmen P, Muus P, Duhrsen U, et al. Effect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood. 2007 Dec 1;110(12):4123-8.
9 Wang H, Chuhjo T, Yasue S, et al. Clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria-type cells in bone marrow failure syndrome. Blood. 2002;100 (12):3897-3902.
10 Iwanga M, Furukawa K, Amenomori T, et al. Paroxysmal nocturnal haemoglobinuria clones in patients with myelodysplastic syndromes. Br J Haematol. 1998;102(2):465-474.
11 Maciejewski JP, Rivera C, Kook H, et al. Relationship between bone marrow failure syndromes and the presence of glycophosphatidyl inositol-anchored protein-deficient clones. Br J Haematol. 2001;115:1015-1022.