Alexion Pharmaceuticals (Nasdaq:ALXN) today announced the initiation of
a single, multinational, placebo-controlled trial to evaluate the safety
and efficacy of eculizumab (Soliris®) in patients with
relapsing neuromyelitis optica (NMO), a life-threatening, ultra-rare
neurologic disorder. Alexion also initiated a single, multinational,
placebo-controlled trial in patients with refractory generalized
myasthenia gravis (MG), another rare and debilitating neurologic
Both NMO and MG are disorders caused by uncontrolled complement
activation. In patients with NMO, chronic, uncontrolled complement
activation results in severe damage to the central nervous system (CNS),
predominantly impacting the optic nerve and spinal cord. This
devastating disease is characterized by severe weakness, paralysis,
respiratory failure, loss of bowel and bladder function, blindness and
premature death. Currently, there are no approved treatments for NMO. In
patients with MG, uncontrolled complement activation due to antibodies
directed at the neuromuscular junction can ultimately lead to profound
and debilitating weakness of various muscle groups throughout the body.
Patients with generalized MG develop significant muscle weakness,
impairing their ability to walk, speak clearly, swallow and, in some
cases, to breathe normally.
"Since complement activation plays a pivotal role in the pathophysiology
of both NMO and MG, the mechanism of action of eculizumab, as a terminal
complement inhibitor, suggests it may have the potential to help
patients living with these rare and devastating disorders," said Martin
Mackay, Ph.D., executive vice president and global head of R&D at
Alexion. "We look forward to enrolling patients in these
placebo-controlled studies to confirm the clinical benefits of
eculizumab in the treatment of NMO and MG, which would be an important
development for these underserved patient populations."
Soliris is currently approved in the United States, European Union,
Japan and other countries for the treatment of patients with paroxysmal
nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome
(aHUS), two debilitating, ultra-rare and life-threatening disorders
caused by chronic uncontrolled complement activation. Soliris is not
approved in any country for the treatment of NMO or MG.
About The NMO Study
The trial is a multinational, double-blind, placebo-controlled study
with the primary objective of assessing the efficacy of eculizumab
compared to placebo in patients with relapsing NMO, based on the time to
first relapse and relapse risk reduction. Secondary endpoints include
safety and tolerability as well as additional efficacy outcome measures.
Patient enrollment and dosing have commenced in this trial. Recruitment
is open to adults with a diagnosis of NMO or NMO spectrum disorder with
relapsing disease. More information about the NMO trial is available at www.clinicaltrials.gov
under the identifier NCT01892345.
This trial is based on results from an investigator-initiated study
which was recently published in the Lancet Neurology journal. In
that study, treatment with eculizumab was associated with a significant
reduction in the frequency of relapses (recurring attacks) in patients
with severe, relapsing NMO.1
In June 2013 the U.S. Food and Drug Administration (FDA) granted
eculizumab an orphan drug designation for the treatment of NMO.
Eculizumab was also granted orphan medicinal product designation from
the Committee for Orphan Medicinal Products (COMP) of the European
Medicines Agency (EMA) for the treatment of NMO in August 2013.
About The MG Study
The trial is a multinational, double-blind, parallel-group,
placebo-controlled study with the primary objective to assess the
efficacy of eculizumab compared to placebo on patients' motor function,
as measured by the improvement in MG- Activities of Daily Living
(MG-ADL) score at 26 weeks. Secondary endpoints include safety and
tolerability as well as additional efficacy measures. Patient screening
has commenced in this study. Recruitment is open to adults with a
diagnosis of refractory generalized MG, with an MG-ADL total score of at
least 6 demonstrating continued muscle weakness despite treatment. More
information about the MG trial is available at www.clinicaltrials.gov
under the identifier NCT01997229.
This trial is based on preliminary evidence from a Company-sponsored
Phase 2 pilot study in a small group of 14 patients that evaluated the
safety and efficacy of eculizumab in the treatment of refractory
generalized MG.2 In the pilot study, 86% (6/7) of patients
receiving a 16-week course of eculizumab therapy achieved at least a
3-point reduction in the total Quantitative Myasthenia Gravis (QMG)
score, compared to 57% (4/7) of patients treated with placebo.
Similarly, 86% (6/7) of patients in the eculizumab arm had at least a
2-point improvement in MG-ADL, compared to 57% (4/7) in the placebo arm;
the mean change in MG-ADL was -4.1 points in the eculizumab-treated
patients. Since a 2-point change in MG-ADL is considered clinically
meaningful,3 the 4.1-point change in the pilot study suggests
a robust treatment effect. Eculizumab therapy was well tolerated inthe
About Neuromyelitis Optica (NMO)
In patients with neuromyelitis optica (NMO), binding of NMO-IgG antibody
to astrocytes results in uncontrolled complement activation and
destruction of myelin-producing cells, leading to severe damage to the
central nervous system and predominantly impacting the spinal cord and
optic nerve.4-6 The disease is characterized by severe
weakness, paralysis, respiratory failure, loss of bowel and bladder
function, blindness and premature death.7-9 Patients with NMO
have a life-long exposure to the uncontrolled terminal complement
activation due to chronic autoimmune attack, and most patients
experience an unpredictable, relapsing course of disease with cumulative
disability, as each attack adds to the neurologic disability.8,10,11
Fifty percent of relapsing NMO patients have been reported to sustain
permanent severe disability, including paralysis and blindness, within
five years of disease onset.12 Most NMO-related deaths result
from respiratory complications from NMO attacks.12,13 The
disease primarily affects women, with a female to male ratio as high as
a 9:1.14 Currently, there are no approved treatments for NMO.
About Myasthenia Gravis (MG)
Myasthenia gravis (MG) is a rare, debilitating neurologic disorder
caused by auto-antibodies that recognize a specific target in the
nerve-muscle junction, which results in life-long uncontrolled terminal
complement activation causing tissue damage and interference with
signaling between nerve and muscle fibers.15,16 Patients with
MG initially experience weakness in their ocular (eye) muscles, and the
disease typically progresses to the more severe and generalized form to
include weakness of head, trunk, limb and respiratory muscles. Symptoms
can include drooping eyelid, weakness in the arms and legs, slurred
speech, difficulty chewing or swallowing, and difficulty breathing.
About Soliris® (eculizumab)
Soliris® (eculizumab) is a first-in-class terminal complement
inhibitor developed from the laboratory through regulatory approval and
commercialization by Alexion. Soliris is approved in the U.S. (2007),
European Union (2007), Japan (2010) and other countries as the first and
only treatment for patients with paroxysmal nocturnal hemoglobinuria
(PNH), a debilitating, ultra-rare and life-threatening blood disorder,
characterized by complement-mediated hemolysis (destruction of red blood
cells). Soliris is indicated to reduce hemolysis. Soliris is also
approved in the U.S. (2011), the European Union (2011), Japan (2013) and
other countries as the first and only treatment for patients with
atypical hemolytic uremic syndrome (aHUS), a debilitating, ultra-rare
and life-threatening genetic disorder characterized by
complement-mediated thrombotic microangiopathy, or TMA (blood clots in
small vessels). Soliris is not approved for the treatment of NMO or MG
in any country.
Alexion's breakthrough approach in terminal complement inhibition has
received the pharmaceutical industry's highest honors: the 2008 Prix
Galien USA Award for Best Biotechnology Product with broad implications
for future biomedical research and the 2009 Prix Galien France Award in
the category of Drugs for Rare Diseases. More information, including the
full prescribing information on Soliris, is available at www.soliris.net.
Important Safety Information
The U.S. product label for Soliris includes a boxed warning:
"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 Advisory Committee on Immunization
Practices (ACIP) recommendations for meningococcal vaccination in
patients with complement deficiencies. Immunize patients with a
meningococcal vaccine 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. (See Serious
Meningococcal Infections (5.1) for additional guidance on the management
of 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:
In patients with PNH, the most frequently reported adverse events
observed with Soliris treatment in clinical studies were headache,
nasopharyngitis (runny nose), back pain and nausea. 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 aHUS, the most frequently
reported adverse events observed with Soliris treatment in clinical
studies were hypertension, upper respiratory tract infection, diarrhea,
headache, anemia, vomiting, nausea, urinary tract infection, and
leukopenia. Please see full prescribing information for Soliris,
including boxed WARNING regarding risk of serious meningococcal
Alexion is a biopharmaceutical company focused on serving patients with
severe and rare disorders through the innovation, development and
commercialization of life-transforming therapeutic products. Alexion is
the global leader in complement inhibition and has developed and markets
Soliris® (eculizumab) as a treatment for patients with PNH
and aHUS, two debilitating, ultra-rare and life-threatening disorders
caused by chronic uncontrolled complement activation. Soliris is
currently approved in nearly 50 countries for the treatment of PNH, and
in the United States, European Union, Japan and other countries for the
treatment of aHUS. Alexion is evaluating other potential indications for
Soliris in additional severe and ultra-rare disorders beyond PNH and
aHUS, and is developing other highly innovative biotechnology product
candidates across multiple therapeutic areas. This press release and
further information about Alexion can be found at: www.alexionpharma.com.
Safe Harbor Statement
This news release contains forward-looking statements, including
statements related to potential medical benefits of Soliris®
(eculizumab) for the treatment of neuromyelitis optica (NMO) and
myasthenia gravis (MG). 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 marketing approval or material limitations on the marketing of
Soliris for NMO or MG, delays in arranging satisfactory manufacturing
capabilities, the possibility that results of clinical trials are not
predictive of safety and efficacy results of Soliris for NMO or MG in
broader or different patient populations, decisions of regulatory
authorities to require additional testing, the risk that estimates
regarding the number of patients with NMO or MG and observations
regarding the natural history of patients with NMO or MG are inaccurate,
and a variety of other risks set forth from time to time in Alexion's
filings with the Securities and Exchange Commission, including but not
limited to the risks discussed in Alexion's Annual Report on Form 10-K
for the period ended Dec. 31, 2013. 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.
1 Pittock S, Lennon VA, McKeon A, et al. Eculizumab in
AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an
open-label pilot study. Lancet Neurol 2013;12(6):554-62.
2 Howard JF, Jr., Barohn RJ, Cutter GR, et al. A randomized,
double-blind, placebo-controlled phase II study of eculizumab in
patients with refractory generalized myasthenia gravis. Muscle Nerve
3 Howard JF, Jr. Clinical overview of MG. Myasthenia Gravis
Foundation of America, 2006. http://www.myasthenia.org/HealthProfessionals/ClinicalOverviewofMG.aspx.
4 Jarius S, Wildemann B. AQP4 antibodies in neuromyelitis
optica: diagnostic and pathogenetic relevance. Nat Rev Neuro.
5 Hinson SR, Romero MF, Popescu BFG, et al. Molecular
outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in
astrocytes. Proc Nat Acad Sci 2012;109(4):1245-50.
6 Hinson SR, Pittock SJ, Lucchinetti CF, et al. Pathogenic
potential of IgG binding to water channel extracellular domain in
neuromyelitis optica. Neurology 2007;69:2221-31.
7 Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ,
Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neuro.
8 Wingerchuk DM. Diagnosis and treatment of neuromyelitis
optica. Neurologis. 2007;13(1):2-11.
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Treat Options Neurol 2008;10(1):55-66.
10 Tuzun E, Kurtuncu M, Turkoglu R, et al. Enhanced
complement consumption in neuromyelitis optica and Behcet's disease
patients. J Neuroimmunol 2011;233(1-2):211-5.
11 Kuroda H, Fujihara K, Takano R, et al. Increase of
complement fragment C5a in cerebrospinal fluid during exacerbation of
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12 Wingerchuk DM, Hogancamp WF,O'Brien PC, Weinshenker BG.
The clinical course of neuromyelitis optica (Devic's syndrome).
13 Kitley J, Leite MI, Nakashima I, et al. Prognostic factors
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past, present, and future. J Clin Invest 2006;116(11):2843-54.
16 Tüzün E, Huda R, Christadoss P. Complement and cytokine
based therapeutic strategies in myasthenia gravis. J Autoimmun
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