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Alexion Announces Positive Top-Line Results Showing Successful Phase 3 Clinical Study of ALXN1210 in Complement Inhibitor Treatment-Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

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-- 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 difference
ALXN1210 vs. Soliris®
[95%
CI: LB,UB]

    Non-inferiority
     

ALXN1210
n=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

___________________

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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 Med. 1995 Nov
9;333(19):1253-8.

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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.

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
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Weitz I, Meyers G, Lamy T, et al. Cross-sectional validation study
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Parker C, Omine M, Richards S, et al. Diagnosis and management of
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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.

9

Wang H, Chuhjo T, Yasue S, et al. Clinical significance of a minor
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Iwanga M, Furukawa K, Amenomori T, et al. Paroxysmal nocturnal
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marrow failure syndromes and the presence of glycophosphatidyl
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