-- 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 the United
States, European Union, and Japan in the Second Half of 2018 --
-- Conference Call/Webcast Scheduled for Today,
Thursday, March 15, 2018 at 8:30 a.m. EDT --
Alexion Pharmaceuticals, Inc. (NASDAQ: ALXN) announced today
that the pivotal Phase 3 study of ALXN1210, the Company’s
investigational long-acting C5 complement inhibitor, demonstrated
non-inferiority to Soliris® (eculizumab) in complement inhibitor
treatment-naïve patients with paroxysmal nocturnal hemoglobinuria
(PNH) based on the co-primary endpoints of transfusion avoidance
and normalization of lactate dehydrogenase (LDH) levels, a direct
marker of complement-mediated hemolysis in PNH. The study also
demonstrated non-inferiority on all four key secondary endpoints:
percentage change from baseline in LDH levels, change from baseline
in quality of life as assessed by the Functional Assessment of
Chronic Illness Therapy (FACIT)-Fatigue scale, proportion of
patients with breakthrough hemolysis, and proportion of patients
with stabilized hemoglobin levels. In addition, numeric results for
all six endpoints favored ALXN1210. There were no notable
differences in the safety profiles for ALXN1210 and Soliris®.
Endpoint Treatment
effect [95% CI: LB,UB]
Treatment differenceALXN1210 vs.
Soliris®[95% CI: LB,UB]
Non-inferiority
ALXN1210n=125
Soliris®n=121
Requirement
Achieved*
Primary
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 Secondary
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.
a)
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 John Orloff, M.D.,
Executive Vice President and Head of Research & Development at
Alexion. “Soliris has established a high bar for efficacy.
Achieving non-inferiority on both co-primary and all key secondary
endpoints, as well as seeing numeric results in favor of ALXN1210,
in such a rigorous study met a very high hurdle. We look forward to
regulatory submissions of ALXN1210 in PNH in the U.S., EU, and
Japan in the second half of 2018.”
“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 Jong Wook Lee, M.D., Professor of Internal
Medicine, Seoul St. Mary's Hospital, The Catholic University of
Korea, Seoul, Korea, and an investigator in the ALXN1210 study.
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.
Conference Call
Alexion will host a conference call/webcast today, Thursday,
March 15, 2018 at 8:30 a.m. EDT to discuss the study data. To
participate in this call, dial (866) 762-3111 (USA) or +1 (210)
874-7712 (International), passcode 7686417, shortly before 8:30
a.m. EDT. A replay of the call will be available for a limited
period of time following the call. The replay number is (855)
859-2056 (USA) or +1 (404) 537-3406 (International), passcode
7686417. The audio webcast can be accessed on the Investors page of
Alexion’s website at: http://ir.alexion.com.
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
About ALXN1210
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 a Phase 3 clinical study in complement
inhibitor-naïve patients with PNH, intravenous treatment with
ALXN1210 every 8 weeks demonstrated non-inferiority to treatment
with Soliris® every 2 weeks. ALXN1210 is also currently being
evaluated in a Phase 3 clinical study in patients with PNH who have
been treated with Soliris® and 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 single, pharmacokinetics (PK)-based Phase 3 clinical
study of ALXN1210 delivered subcutaneously once per week as a
potential treatment for patients with PNH and aHUS. Alexion also
plans to initiate the development of ALXN1210 as a potential
treatment for patients with generalized MG (gMG) and patients with
immunoglobulin A nephropathy (IgAN).
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.
About Alexion
Alexion is a global biopharmaceutical company focused on serving
patients and families affected by rare diseases through the
innovation, development, and commercialization of life-changing
therapies. Alexion is the global leader in complement inhibition
and 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). In addition, Alexion 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). As the leader in complement biology for over 20 years,
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. This press release and further information
about Alexion can be found at: www.alexion.com.
[ALXN-G]
Forward-Looking Statement
This press release contains forward-looking statements,
including statements related to Alexion's development plans for
ALXN1210, the potential medical benefits of ALXN1210 for the
treatment of PNH, and Alexion's future clinical, regulatory, and
commercial plans for ALXN1210. Forward-looking statements are
subject to factors that may cause Alexion's results and plans to
differ from those expected, including for example, decisions of
regulatory authorities regarding the adequacy of our research,
marketing approval or material limitations on the marketing of our
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, 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 payors (including
governmental agencies) will not reimburse or continue to reimburse
for the use of our products at acceptable rates or at all, the
possibility that expected tax benefits will not be realized,
assessment of impact of recent accounting pronouncements, potential
declines in sovereign credit ratings or sovereign defaults in
countries where we sell our products, 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 anticipated regulatory filings are delayed, the risk that
estimates regarding the number of patients with the diseases that
our products treat are inaccurate, the risks of changing foreign
exchange rates, risks relating to the potential effects of
Alexion's restructuring and relocation of its corporate
headquarters, 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 Annual Report on Form 10-K for
the period ended December 31, 2017 and in our other filings with
the SEC. Alexion does not intend to update any of these
forward-looking statements to reflect events or circumstances after
the date hereof, except when a duty arises under law.
References
___________________
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. NEngl J
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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
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(Baltimore) 2004 May;83(3):193-207.
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Weitz I, Meyers G, Lamy T, et al.
Cross-sectional validation study of patient-reported outcomes in
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Parker C, Omine M, Richards S, et al.
Diagnosis and management of paroxysmal nocturnal hemoglobinuria.
Blood. 2005 Dec 1;106(12):3699-709.
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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 Dec
1;110(12):4123-8.
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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.
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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.
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Maciejewski JP, Rivera C, Kook H, et al.
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J Haematol. 2001;115:1015-1022.
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Alexion Pharmaceuticals, Inc.MediaArne Naeveke, PhD,
475-230-3774Kim Diamond, 475-230-3775orInvestorsSusan Altschuller,
PhD, 475-230-3534Elena Ridloff, CFA, 475-230-3601
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