-- ALXN1210 Achieved Non-Inferiority to Soliris® (Eculizumab) on Co-Primary Endpoints of Transfusion Avoidance and Lactate Dehydrogenase Normalization, and All Four Key Secondary Endpoints --
-- Safety Profile of ALXN1210 Consistent with That Seen for Soliris® --
-- Regulatory Submissions Planned in
-- Conference Call/Webcast Scheduled for Today,
|Endpoint||Treatment effect [95% CI: LB,UB]||
|Transfusion avoidance||73.6% [65.9%,81.3%]||66.1% [57.7%,74.6%]||6.8% [-4.7%,18.1%]a||LB > -20%||Yes|
|LDH normalization||53.6% [45.9%,61.2%]||49.4% [41.7%,57.0%]||1.19 [0.80,1.77]b||LB > 0.39||Yes|
|Change in LDH levels||-76.8% [-80.0%,-73.7%]||-76.0% [-79.2%,-72.8%]||-0.83% [-5.2%,3.6%]c,†||UB < 20%||Yes|
|Improvement in FACIT scale||7.1 [5.6,8.6]||6.4 [4.9,8.0]||0.67 [-1.2,2.6]c||LB > -5.0||Yes|
|Breakthrough hemolysis||4.0% [0.6%,7.4%]||10.7% [5.2%,16.3%]||-6.7% [-14.2%,0.18%]a,†||UB < 20%||Yes|
|Stabilization of Hb levels||68.0% [59.8%,76.2%]||64.5% [55.9%,73.0%]||2.9% [-8.8%,14.6%]a||LB > -20%||Yes|
LDH: lactate dehydrogenase; FACIT: Functional Assessment of Chronic Illness Therapy; Hb: hemoglobin; CI: confidence interval; LB: lower bound; UB: upper bound
Non-inferiority is achieved if the LB or UB of the 95% CI of the treatment difference meets the pre-defined requirement. Since non-inferiority was achieved across both co-primary and all four key secondary endpoints, the protocol allowed for superiority testing. Testing for superiority followed a closed-testing procedure, using a 2-sided 0.05 test for each parameter, and followed the pre-specified order per protocol: breakthrough hemolysis, change in LDH levels vs. Baseline, LDH normalization, improvement in FACIT scale, stabilization of Hb levels, transfusion avoidance. As breakthrough hemolysis did not achieve statistical significance (p-value = 0.074), no other endpoints were tested.
Difference in proportion of patients; b) Odds ratio;c) Difference in change vs. Baseline
Negative value meaning a difference in favor of ALXN1210
Since non-inferiority was achieved across both co-primary and all four key secondary endpoints, the protocol allowed for superiority testing. The hierarchical testing order pre-specified breakthrough hemolysis as the first endpoint tested for superiority. Although ALXN1210 did not achieve superiority, a numeric trend in favor of ALXN1210 was observed for breakthrough hemolysis (4.0% [0.6%,7.4%] vs. 10.7% [5.2%,16.3%] for Soliris®) with a p-value of 0.074. The study also confirmed that ALXN1210 provides immediate and complete ( > 99%) inhibition of the complement C5 protein that is sustained over the entire 8 week dosing interval. Additionally, treatment with ALXN1210 reduced mean LDH levels to approximately the upper limit of normal (1.0-1.1 times ULN) between months one and six.
"We are very pleased with these positive data for ALXN1210 in the first
and only head-to-head study versus Soliris, and the results reinforce
our ambition to establish ALXN1210 as the new standard of care for
patients with PNH. The data are also consistent with our hypothesis that
immediate, complete, and sustained C5 inhibition is critical for
patients with this potentially life-threatening disease," said
"Having a new treatment option that achieves transfusion avoidance, and
provides rapid and sustained normalization of LDH levels when
administered 6 times a year could be a meaningful improvement for
patients with PNH who currently need 26 infusions per year," said
ALXN1210 was generally well tolerated with a safety profile that is consistent with that seen for Soliris®. The most frequently observed adverse event was headache. The most frequently observed serious adverse event was pyrexia. One patient in the Soliris® arm died from lung cancer (unrelated to Soliris® treatment) during the extension phase of the study. Two patients withdrew from the Soliris® arm for reasons unrelated to treatment. One anti-drug antibody was observed for ALXN1210 and one for Soliris®. No neutralizing antibodies and no apparent effects on efficacy, safety, pharmacokinetics, or pharmacodynamics were detected. There were no cases of meningococcal infection observed in either the ALXN1210 or Soliris® arms. Meningococcal infections are a known risk with terminal complement inhibition, and specific risk-mitigation plans have been in place for ten years for Soliris® to minimize the risk for patients.
Detailed results from this Phase 3 study will be presented at a future medical congress.
About the ALXN1210-PNH-301 Study
This Phase 3, randomized, open-label, active-controlled, multinational, and multicenter study evaluated the efficacy and safety of ALXN1210 compared to Soliris® administered by intravenous (IV) infusion to adult patients (≥ 18 years of age) with PNH who are naïve to complement inhibitor treatment. The study enrolled 246 adult patients with a confirmed diagnosis of PNH who had never been treated with a complement inhibitor and presented with LDH levels ≥ 1.5 times the upper limit of normal (ULN) at the time of screening, as well as with one or more of the following PNH-related signs or symptoms within 3 months of screening: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin < 10 g/dL), history of a major adverse vascular event (MAVE, including thrombosis), dysphagia, or erectile dysfunction; or history of packed red blood cell (pRBC) transfusion due to PNH. Patients in the ALXN1210 arm received a single loading dose of ALXN1210, followed by regular maintenance weight-based dosing every 8 weeks. Patients in the Soliris® arm received 4 weekly induction doses, followed by regular maintenance dosing every 2 weeks. Both arms were treated for 26 weeks. The study was designed to evaluate the non-inferiority of ALXN1210 compared to Soliris®.
The co-primary endpoints were the proportion of patients who remain transfusion-free and do not require a transfusion per protocol-specified guidelines through day 183 and the normalization of LDH levels as directly measured every two weeks by LDH levels ≤ 1 times ULN from day 29 through day 183. Key secondary endpoints included the percentage change from baseline in LDH levels to day 183, change from baseline in quality of life as assessed by the FACIT-Fatigue scale to day 183, proportion of patients with breakthrough hemolysis, and proportion of patients with stabilized hemoglobin levels (defined as avoidance of a ≥ 2 g/dL decrease in hemoglobin level from baseline in the absence of transfusion through day 183). Breakthrough hemolysis was defined as at least one new or worsening symptom or sign of intravascular hemolysis: fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia [hemoglobin < 10 g/dL], MAVE (including thrombosis), dysphagia, or erectile dysfunction in the presence of an elevated LDH level ≥ 2 times ULN, after prior LDH level reduction to < 1.5 times ULN on therapy. Blood samples for the determination of free and total complement C5 protein were collected before and after administration of study drug once a week during the first 4 weeks and every two weeks after that.
All patients enrolled in an extension study of up to 2 years, during which they will receive ALXN1210 every 8 weeks.
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
ALXN1210 has received Orphan Drug Designation (ODD) for the treatment of
patients with PNH in the
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
Soliris® has received Orphan Drug Designation (ODD) for the
treatment of patients with PNH in the
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
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.
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.
This press release contains forward-looking statements, including
statements related to
Hill A, Richards SJ, Hillmen P. Recent developments in the
understanding and management of paroxysmal nocturnal
Hillmen P, Lewis SM, Bessler M, et al. Natural history of
paroxysmal nocturnal hemoglobinuria. NEngl J Med. 1995
Socié G, Mary JY, de Gramont A, et al. Paroxysmal nocturnal
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Hill A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal hemoglobinuria. Blood. 2013;121:4985-4996.
Nishimura J, Kanakura Y, Ware RE, et al. Clinical course and flow
cytometric analysis of paroxysmal nocturnal hemoglobinuria in
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.
Parker C, Omine M, Richards S, et al. Diagnosis and management of
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Hillmen P, Muus P, Duhrsen U, et al. Effect of the complement
inhibitor eculizumab on thromboembolism in patients with
paroxysmal nocturnal hemoglobinuria. Blood. 2007
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.
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.
Maciejewski JP, Rivera C, Kook H, et al. Relationship between bone
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Arne Naeveke, PhD, 475-230-3774
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