New Data Presented at the American Association
of Neuromuscular & Electrodiagnostic Medicine Annual Meeting
Further Substantiate and Extend Results from Pivotal REGAIN
Study
Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) announced today
results from an interim analysis of an ongoing Phase 3 open-label
extension study of the pivotal, placebo-controlled REGAIN study of
Soliris® (eculizumab) for the treatment of patients with refractory
generalized myasthenia gravis (gMG) who are anti-acetylcholine
receptor (AChR) antibody-positive. The new results show sustained
treatment benefits across a range of MG-specific assessment scales
through an additional 52 weeks for patients who continued to
receive Soliris, and also demonstrate rapid, significant and
sustained improvements through 52 weeks for patients who had
crossed over from placebo in REGAIN to Soliris treatment in the
extension study. The safety profile of Soliris was consistent with
that observed in the REGAIN study. The results are presented at the
annual meeting of the American Association of Neuromuscular &
Electrodiagnostic Medicine (AANEM) in Phoenix, Arizona.
“There is an urgent need for a treatment for patients with
refractory gMG who have attempted multiple therapies and continue
to suffer from severe symptoms and complications,” said Professor
James F. Howard, MD, Department of Neurology at the University of
North Carolina, Chapel Hill, USA, and lead investigator in REGAIN
and its open-label extension study. “These new results build on the
findings of the REGAIN study, and it is encouraging to see the
rapid and sustained benefits of Soliris treatment with patients
recovering functional ability to carry out activities of daily
living, and quality of life.”
Results presented show that the benefits for patients treated
with Soliris in REGAIN through 26 weeks were maintained in the
extension study across all four assessment scales for an additional
52 weeks (78 weeks in total). For patients who received placebo in
REGAIN and then were treated with Soliris in the extension study,
significant treatment benefits occurred within 1 to 4 weeks and
were sustained through 52 weeks across all four assessment
scales.1
Treatment benefits in the REGAIN open-label extension
study1
Assessment scale
Soliris
Soliris/Soliris
Soliris/Soliris Placebo
Placebo/Soliris
Placebo/Soliris
REGAIN – week 26
n=55-56
extension – week 26
n=47-49
extension – week 52
n=20
REGAIN – week 26
n=59
extension – week 26
n=55-56
extension – week 52
n=20
MG-ADL -4.4 [-5.6, -3.3] -5.2
[-6.3, -4.2] -4.4 [-6.0, -2.7]
-2.3 [-3.2, -1.5] -4.9
[-5.8, -4.0] -5.3 [-6.8 -3.7]
QMG -5.0
[-6.4, -3.6] -5.2 [-6.7, -3.6] -4.5 [-6.7, -2.3] -1.7 [-2.7, -0.6]
-4.8 [-6.4, -3.3] -6.4 [-8.8 -4.0]
MGC -8.4 [-10.7, -6.2]
-10.0 [-12.3, -7.8] -8.8 [-11.9, -5.6] -5.0 [-6.8, -3.2] -10.0
[-12.0, -8.0] -10.0 [-13.3,-6.7]
MG-QoL 15 -12.8 [-16.6,
-9.0] -15.2 [-19.0, -11.3] -14.9 [-21.7, -8.1] -5.4 [-7.8, -2.9]
-12.9 [-16.6, -9.1] -16.2 [-21.3,-11.1]
Treatment effects measured in decreased mean scores (using
repeated measures from baseline) at given time points compared to
baseline at enrollment in the REGAIN study (summarized for patients
who enrolled in the extension study) [95% confidence intervals]
MG-ADL – MG-Activities of Daily Living, a patient-reported
assessment of functional ability to carry out daily activitiesQMG –
Quantitative MG, a clinical assessment of muscle strength by
physiciansMGC – MG Composite, a patient- and physician-reported
assessment of functional ability and signs and symptoms of MGMG-QoL
15 – MG Quality of Life 15, a patient-reported assessment of
MG-specific quality of life
“We are grateful to the patients and investigators who continue
to participate in this ongoing extension study that further
substantiates the rapid and sustained benefits of complement
inhibition for this debilitating, chronic and progressive
neurological disorder,” said John Orloff, M.D., Executive Vice
President and Head of Research & Development at Alexion.
Patients with refractory gMG represent an ultra-rare subset of
patients2-5 who have difficulties walking, talking, swallowing and
breathing normally despite multiple therapies for MG. Exacerbations
and crises of their disease may require hospitalization and
intensive care and may be life-threatening.6-8 Chronic uncontrolled
activation of the complement cascade, a part of the immune system,
can play a major role in the debilitating symptoms and potentially
life-threatening complications of the disease.9-11
Soliris is the first and only complement inhibitor, and the only
complement-based therapy approved in the European Union (EU) for
the treatment of patients with refractory gMG who are anti-AChR
antibody-positive. Alexion’s supplemental Biologics License
Application (sBLA) in the U.S. and a supplemental new drug
application in Japan for Soliris for similar indications have been
accepted for review by the U.S. Food and Drug Administration (FDA)
and the Japanese Ministry of Health, Labour and Welfare (MHLW),
respectively. Soliris has received Orphan Drug Designation (ODD)
for the treatment of patients with MG in the U.S. and EU, and for
the treatment of patients with refractory gMG in Japan.
About the Open-Label Extension Study (MG-302)
94% (117/125) of patients who completed the REGAIN study
enrolled in the open-label extension, of which 56 continued to
receive Soliris (Soliris/Soliris group) and 61 were switched from
placebo to Soliris (placebo/Soliris group) within two weeks of
completing the REGAIN study. Patients were not informed of prior
treatment assignment in REGAIN through a four-week blinded
induction phase, after which all patients received ongoing
open-label treatment with Soliris (1,200 mg/dose) every two weeks.
For this interim analysis, 49 patients in the Soliris/Soliris group
and 56 patients in the placebo/Soliris group completed week 26
assessments; 20 patients in each group completed week 52
assessments. Patient numbers for scores at week 26 may differ
slightly because a total score could not be computed when an
assessment was missed or data were not complete. Mean scores over
time were calculated using repeated measures from baseline. The
study is ongoing and planned to continue until January 2019.
About REGAIN (MG-301)
This was a randomized, double-blind, placebo-controlled,
multicenter Phase 3 clinical study that evaluated the efficacy and
safety of Soliris over 26 weeks in 125 patients with refractory gMG
who had a confirmed diagnosis of MG with positive serologic test
for antibodies against AChR. Patients initially received 900 mg of
Soliris or placebo weekly for 4 weeks followed by 1,200 mg of
Soliris or placebo 1 week later, and then 1,200 mg of Soliris or
placebo every 2 weeks. The primary efficacy endpoint of change from
baseline in MG-ADL total score at week 26, as well as the three
secondary endpoints —changes from baseline in QMG, MGC, and MG-QoL
15—were assessed using a worst-rank analysis. The study narrowly
missed statistical significance on the primary endpoint (p=0.0698).
However, 18 out of 22 pre-specified endpoints and analyses showed
results with p-values <0.05 across the four assessment scales,
supporting early, sustained and substantial responses. The safety
profile was consistent with what has been reported for Soliris
during the past 10 years in patients with paroxysmal nocturnal
hemoglobinuria (PNH) and atypical hemolytic uremic syndrome
(aHUS).
The REGAIN study (MG-301) and its open-label extension study
(MG-302) are sponsored by Alexion.
About Refractory Generalized Myasthenia Gravis
Patients with refractory generalized myasthenia gravis (gMG) who
are anti-acetylcholine receptor (AChR) antibody-positive represent
an ultra-rare subset of MG patients2-4 who continue to suffer from
severe disease symptoms and complications despite therapies
currently used for MG.2,3,12
MG is a debilitating, chronic and progressive autoimmune
neuromuscular disease that can occur at any age but most commonly
begins for women before the age of 40 and men after the age of
60.6,7,13,14 It typically begins with weakness in the muscles that
control the movements of the eyes and eyelids, and often progresses
to the more severe and generalized form, known as gMG with weakness
of the head, neck, trunk, limb and respiratory muscles.14
While most patients with gMG can be managed with therapies for
MG, 10% to 15% of patients are considered refractory—meaning they
fail to respond adequately to or cannot tolerate multiple therapies
for MG and continue to suffer profound muscle weakness, and severe
disease symptoms that limit function.2,4,12 Patients with
refractory gMG can suffer from slurred speech; choking; impaired
swallowing; double or blurred vision; disabling fatigue; immobility
requiring assistance; shortness of breath, and episodes of
respiratory failure. Complications, exacerbations and myasthenic
crises can require hospital and intensive care unit admissions with
prolonged stays and can be life-threatening.6-8
In patients with anti-AChR antibody-positive MG, the body’s own
immune system turns on itself to produce antibodies against AChR, a
receptor located on muscle cells in the neuromuscular junction
(NMJ) and used by nerve cells to communicate with the muscles these
nerves control.6,7 The binding of these antibodies to AChR
activates the complement cascade, another part of the immune
system, which leads to a localized destruction of the muscle
membrane at the NMJ. As a result, the communication between nerve
and muscle is impaired, which in turn leads to a loss of normal
muscle function.9-11,15
About Soliris® (eculizumab)
Soliris® is a first-in-class complement inhibitor that works by
inhibiting the terminal part of the complement cascade, a part of
the immune system that, when activated in an uncontrolled manner,
plays a role in serious ultra-rare disorders like paroxysmal
nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome
(aHUS) and anti-acetylcholine receptor (AChR) antibody-positive
refractory generalized myasthenia gravis (gMG).
Soliris is approved in the U.S., EU, Japan and other countries
as the first and only treatment for patients with PNH and aHUS, and
in the EU as the first and only treatment for refractory gMG in
patients who are anti-AChR antibody-positive. Soliris is not
indicated for the treatment of patients with Shiga-toxin E.
coli-related hemolytic uremic syndrome (STEC-HUS). 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.
About Alexion
Alexion is a global biopharmaceutical company focused on
developing and delivering life-transforming therapies for patients
with devastating and rare disorders. 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 refractory 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 news release contains forward-looking statements, including
statements related to the potential medical benefits of Soliris®
(eculizumab) for the treatment of generalized myasthenia gravis
(gMG), and Alexion's future clinical, regulatory and commercial
plans for Soliris for the treatment of myasthenia gravis.
Forward-looking statements are subject to factors that may cause
Alexion's results and plans to differ from those expected,
including for example, the risks and uncertainties of drug
development, decisions of regulatory authorities regarding the
adequacy of our research, marketing approval or material
limitations on the marketing of eculizumab for the treatment of
gMG, 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
clinical trials of our product candidates could be delayed, the
adequacy of our pharmacovigilance and drug safety reporting
processes, the risk that third party payers (including governmental
agencies) will not reimburse or continue to reimburse for the use
of our products at acceptable rates or at all, the outcome of
challenges and opposition proceedings to our intellectual property,
assertion or potential assertion by third parties that the
manufacture, use or sale of our products infringes their
intellectual property, risks regarding government investigations,
including investigations of Alexion by the SEC and DOJ, the risk
that anticipated regulatory filings are delayed, the risk that
estimates regarding the number of patients with gMG are inaccurate,
and a variety of other risks set forth from time to time in
Alexion's filings with the U.S. Securities and Exchange Commission,
including but not limited to the risks discussed in Alexion's
Quarterly Report on Form 10-Q for the period ended June 30, 2017
and in our other filings with the U.S. Securities and Exchange
Commission. 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
- Howard JF, Wang JJ, O’Brien F,
Mantegazza R and the REGAIN study group. Efficacy of eculizumab is
maintained beyond 26 weeks in patients with AChR+ refractory
generalized myasthenia gravis (gMG). Poster (abstract 211), annual
meeting of the American Association of Neuromuscular &
Electrodiagnostic Medicine (AANEM), September 14, 2017.
- Silvestri N, Wolfe G.
Treatment-refractory myasthenia gravis. J. Clin Neuromuscul Dis.
2014;15(4):167-178.
- Howard J. Targeting the Complement
System in Refractory Myasthenia Gravis. Supplement to Neurology
Reviews. February 2016.
- Suh J., Goldstein JM, Nowak RJ.
Clinical Characteristics of Refractory Myasthenia Gravis Patients.
Yale J Biol Med. 2013;86(2):255-260.
- Regulation (EU) No 536/2014 of the
European Parliament and of the Council of 16 April 2014 on clinical
trials on medicinal products for human use, and repealing Directive
2001/20/EC.
http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32000R0141&qid=1421232987002&from=EN.
Accessed on June 26, 2017.
- Howard JF, 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. 2013;48(1):76-84.
- National Institute of Neurological
Disorders and Stroke. Myasthenia Gravis Fact Sheet. Publication
date May 2017.
http://www.ninds.nih.gov/disorders/myasthenia_gravis/detail_myasthenia_gravis.htm.
- Sathasivam S. Diagnosis and management
of myasthenia gravis. Progress in Neurology and Psychiatry.
January/February 2014.
- Tüzün E, Huda R, Christadoss P.
Complement and cytokine based therapeutic strategies in myasthenia
gravis. JAutoimmun. 2011;37(2):136-143.
- Meriggioli MN, Sanders DB. Muscle
autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev.
Clin.Immunol. 2012;8(5), 427-428.
- Conti-Fine, et al. Myasthenia gravis:
past, present, and future. J Clin Invest. 2006; 116:2843-2354.
- Sanders DB, Wolfe, GI, Benatar M, et
al. International consensus guidance for management of myasthenia
gravis: Executive summary. Neurology. 2016 Jul
26;87(4):419-25.
- Huda R, Tüzün E, Christadoss P.
Targeting complement system to treat myasthenia gravis. Rev.
Neurosci. 2014; 25(4): 575–583.
- Meriggioli MN, Sanders DB. Autoimmune
myasthenia gravis: emerging clinical and biological heterogeneity.
Lancet Neurol. 2009-8(5): 475-490.
- Buzzard, K. A., N. J. Meyer, T. A.
Hardy, D. S. Riminton and S. W. Reddel. Induction intravenous
cyclophosphamide followed by maintenance oral immunosuppression in
refractory myasthenia gravis. Muscle Nerve. 2015;52(2):
204-210.
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Alexion Pharmaceuticals, Inc.MediaArne Naeveke, PhD,
475-230-3774Executive Director, Product
CommunicationsorInvestorsElena Ridloff, CFA, 475-230-3601Vice
President, Investor RelationsorCatherine Hu, 475-230-3599Director,
Investor Relations
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