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Positive Phase 3 Extension Data For ULTOMIRIS (Ravulizumab) In Patients With Paroxysmal Nocturnal Hemoglobinuria (PNH) Presented At European Hematology Association (EHA) Congress

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Monday, June 17, 2019

BOSTON - Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) announced the presentation of new data demonstrating that ULTOMIRIS®(ravulizumab), the first and only long-acting C5 complement inhibitor administered every eight weeks, provided consistent efficacy and safety through 52 weeks in the extension of the Phase 3 study of ULTOMIRIS and SOLIRIS® (eculizumab) in complement inhibitor-naïve, adult patients with paroxysmal nocturnal hemoglobinuria (PNH). Sustained efficacy of ULTOMIRIS was observed on the co-primary endpoints of transfusion avoidance and normalization of lactate dehydrogenase (LDH) levels and the secondary endpoints of LDH level reduction and breakthrough hemolysis (BTH). In an additional sub-study, nearly all patients preferred ULTOMIRIS over SOLIRIS. The data will be presented at the Annual Congress of the European Hematology Association (EHA), taking place June 13-19, 2019 in Amsterdam, Netherlands.

LDH level normalization and reduction are direct markers for reduced hemolysis in PNH, a severe, ultra-rare disease characterized by complement-mediated intravascular hemolysis. PNH can cause a wide range of debilitating symptoms and complications, including thrombosis, which can occur throughout the body and result in organ damage and premature death. Incomplete inhibition of the C5 complement protein can increase the risk of BTH and related serious complications.

“The confirmation of consistent efficacy and safety through 52 weeks with only six or seven infusions per year instead of 26 with SOLIRIS makes ULTOMIRIS a very compelling new therapy for patients with PNH,” said Professor Hubert Schrezenmeier, M.D., Medical Director of the Institute of Transfusion Medicine and the Institute for Clinical Transfusion Medicine and Immunogenetics, German Red Cross Blood Transfusion Service Baden-Württemberg-Hessen and University Hospital Ulm, Germany, study investigator and presenting author. “I am impressed with the continuing complete C5 inhibition in all patients receiving ULTOMIRIS and the absence of breakthrough hemolysis associated with incomplete C5 inhibition. This makes me hopeful that we can reduce the potentially devastating consequences of returning PNH symptoms.”

All patients in the initial ULTOMIRIS group of the extension study maintained complete C5 inhibition through 52 weeks, and no patient experienced BTH associated with incomplete C5 inhibition. All patients who had experienced incomplete C5 inhibition while receiving SOLIRIS in the first 26 weeks achieved complete C5 inhibition after the switch to ULTOMIRIS in the extension phase. No patient experienced BTH associated with incomplete C5 inhibition between weeks 27 and 52 after switching to ULTOMIRIS compared to six percent while receiving SOLIRIS in the first 26 weeks.

“We continue to expand the body of clinical evidence supporting the potential of ULTOMIRIS to become the new standard of care for patients with PNH,” said John Orloff, M.D., Executive Vice President and Head of Research & Development at Alexion. “SOLIRIS, the first approved therapy for PNH, was a breakthrough for patients for whom only supportive care had been available before. With ULTOMIRIS, we want to enable patients to live their lives more freely thanks to maximal hemolysis control with established safety and reduced treatment burden.”

The most common adverse events occurred less frequently in the extension phase than during the initial treatment phase where the safety profile of ULTOMIRIS was consistent with that of SOLIRIS. The most common treatment-emergent adverse events in the extension phase were upper respiratory tract infection (in the initial ULTOMIRIS arm) and nasopharyngitis (in the initial SOLIRIS arm). The most frequently observed serious adverse event was pyrexia. One patient in the initial SOLIRIS arm died from lung cancer (unrelated to SOLIRIS treatment). There was no case of meningococcal infection observed.

ULTOMIRIS was studied in the largest-ever Phase 3 program in PNH. The entire clinical development program for ULTOMIRIS in PNH to date represents more than 800 patient years of experience.

Additional data to be presented at the EHA congress indicate a very strong patient preference for ULTOMIRIS over SOLIRIS. According to results from a sub-study in the ULTOMIRIS Phase 3 extension in patients who had been stable on SOLIRIS before, nearly all patients (93%) preferred ULTOMIRIS due to reduced infusion frequency, ability to plan activities, overall quality of life, convenience of treatment, and effectiveness of medication until the next infusion compared to SOLIRIS.

New results from the International PNH Registry will also be presented at the EHA congress. These data suggest that a change in clone size does not change the increased risk of major adverse vascular events in PNH,17 and that complement inhibition with SOLIRIS does not change the effectiveness of concomitant immunosuppressive therapy in patients with PNH and aplastic anemia (AA).

The U.S. Food and Drug Administration (FDA) approved ULTOMIRIS for adult patients with PNH on December 21, 2018. The European Commission (EC) is reviewing the recommendation by the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) from April 26, 2019 to approve ULTOMIRIS as a treatment for adult patients with PNH and typically delivers its final decision within two months. The Japanese Ministry of Health, Labour and Welfare (MHLW) is reviewing the recommendation by the Pharmaceuticals and Medical Devices Agency’s (PMDA) Drug Committee (BUKAI) to approve ULTOMIRIS as a treatment for patients with PNH and is anticipated to deliver a decision in late June.

About the extension  of the Phase 3 study in complement-naïve, adult patients with PNH 
At the end of the 26-week Phase 3 study, all patients (246; 125 on ULTOMIRIS, 121 on SOLIRIS) had the option to receive ULTOMIRIS every eight weeks for up to two years. The aim of this extension study is to monitor the durability of efficacy in the initial ULTOMIRIS group, the efficacy of ULTOMIRIS in the initial SOLIRIS group after the switch to ULTOMIRIS and the safety of ULTOMIRIS in all patients. A total of 243 patients (124 from the initial ULTOMIRIS group, 119 from the initial SOLIRIS group) were followed. Results for the co-primary endpoints of transfusion avoidance and LDH level normalization and the secondary endpoints of percentage change from baseline in LDH levels and proportion of patients with BTH are provided descriptively. Complete C5 inhibition was defined as plasma levels of free C5 ≤0.5 μg/ml.

About the patient preference study 
At the end of the 26-week Phase 3 study in adult patients with PNH who had been clinically stable on SOLIRIS for at least 6 months, all patients (195) were given the option to continue receiving ULTOMIRIS every eight weeks for up to two years. The patient preference study enrolled patients from the extension study who had received at least two doses of ULTOMIRIS. Patient treatment preference was evaluated at one time point using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). The 11 questions included one question on overall treatment preference, nine questions on preference based on treatment characteristics, one question on the most important treatment characteristic for the overall treatment preference, four questions on aspects of treatment with SOLIRIS and four matching questions for ULTOMIRIS. Of 98 patients enrolled, 95 patients from eight countries (European Union, North America, and Australia) completed PNH-PPQs per protocol.

About Paroxysmal Nocturnal Hemoglobinuria (PNH) 
Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic, progressive, debilitating and life-threatening ultra-rare blood disorder characterized by intravascular hemolysis (destruction of red blood cells) that is mediated by an uncontrolled activation of the complement system, a part of the immune system.PNH can strike men and women of all races, backgrounds and ages without warning, with an average age of onset in the early 30s. PNH often goes unrecognized, with delays in diagnosis ranging from one to more than five years. Patients with PNH may experience a wide range of signs and symptoms, such as fatigue, difficulty swallowing, shortness of breath, abdominal pain, erectile dysfunction, dark-colored urine and anemia. The most devastating consequence of chronic intravascular hemolysis is thrombosis, which can occur in blood vessels throughout the body, damage vital organs and cause premature death. The first thrombotic event can be fatal. Despite historical supportive care, including transfusion and anticoagulation management, 20 to 35 percent of patients with PNH die within five to 10 years of diagnosis. Patients with certain types of hemolytic anemia, bone marrow disorders and unexplained venous or arterial thrombosis are at increased risk of PNH.

ULTOMIRIS (ravulizumab-cwvz), the first and only long-acting C5 inhibitor administered every eight weeks, is approved in the U.S. as a treatment for adults with paroxysmal nocturnal hemoglobinuria (PNH). ULTOMIRIS works by inhibiting the C5 protein in the terminal complement cascade, a part of the body’s immune system. The terminal complement cascade, when activated in an uncontrolled manner, plays a role in severe ultra-rare disorders like PNH, atypical hemolytic uremic syndrome (aHUS), anti-acetylcholine receptor (AchR) antibody-positive myasthenia gravis (MG) and anti-aquaporin-4 (AQP4) auto-antibody-positive neuromyelitis optica spectrum disorder (NMOSD). Regulatory authorities in the European Union (EU) and Japan are reviewing applications for the approval of ULTOMIRIS as a treatment for adult patients and patients with PNH, respectively. In Phase 3 clinical studies in complement inhibitor-naïve patients with PNH and patients with PNH who had been stable on SOLIRIS®(eculizumab), intravenous treatment with ULTOMIRIS every eight weeks demonstrated non-inferiority to intravenous treatment with SOLIRIS every two weeks on all endpoints.

The Phase 3 study of ULTOMIRIS, administered intravenously every eight weeks in adult patients with aHUSmet its primary objective. Alexion has submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) for approval of ULTOMIRIS as a treatment for patients with aHUS and plans to submit similar applications in the EU and Japan later in 2019. ULTOMIRIS is also currently being evaluated in a Phase 3 clinical study in children and adolescents with aHUS, administered intravenously every eight weeks. Alexion has initiated a Phase 3 study of ULTOMIRIS, intravenously administered every eight weeks, as a potential treatment for patients with generalized MG (gMG), and is planning to initiate a Phase 3 in patients with NMOSD. In addition, Alexion has initiated Phase 3 studies of ULTOMIRIS delivered subcutaneously once per week as a potential treatment for patients with PNH and aHUS.

ULTOMIRIS has received Orphan Drug Designation (ODD) for the treatment of patients with PNH in the U.S. and Japan and for the subcutaneous treatment of patients with aHUS in the U.S.

About Alexion 
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 two approved complement inhibitors to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) as well as the first and only approved complement inhibitor to treat atypical hemolytic uremic syndrome (aHUS) and anti-acetylcholine receptor (AchR) antibody-positive generalized myasthenia gravis (gMG), and is also developing it for patients with neuromyelitis optica spectrum disorder (NMOSD). 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 several mid-to-late-stage therapies, including a second complement inhibitor, a copper-binding agent for Wilson disease and an anti-neonatal Fc receptor (FcRn) antibody for rare Immunoglobulin G (IgG)-mediated diseases as well as several early-stage therapies, including one for light chain (AL) amyloidosis and a second anti-FcRn therapy. 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:


Source: Alexion
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