-- Data Demonstrate Rapid and Sustained
Reduction of Plasma Lactate Dehydrogenase (LDH) --
Alexion Pharmaceuticals, Inc. (NASDAQ:ALXN) announced today the
presentation of comprehensive dose-ranging data from two Phase 1b/2
studies of ALXN1210, the Company’s investigational long-acting C5
complement inhibitor, in patients with paroxysmal nocturnal
hemoglobinuria (PNH), a chronic, progressive, debilitating and
potentially life-threatening ultra-rare blood disorder
characterized by complement-mediated hemolysis.1,2 Treatment with
ALXN1210 for up to eight months resulted in rapid and sustained
reduction of plasma lactate dehydrogenase (LDH) levels, a direct
marker of hemolysis, with reductions in mean LDH levels from
Baseline (BL) ranging from 73% to 88%. ALXN1210 was generally well
tolerated with a safety profile that is consistent with that seen
historically in patients with complement inhibition.3 The data were
presented at the 59th American Society of Hematology (ASH) Annual
Meeting & Exposition in Atlanta. All patients from the Phase 1b
study and from Cohorts 1, 2, and 3 of the Phase 2 study have been
successfully transitioned to the Phase 3 dosing regimen, after
which plasma LDH levels have remained suppressed.
“It is encouraging to see rapid and sustained reduction in
plasma LDH levels in these dose optimization studies,” said
Alexander R�th, M.D. from the Department of Hematology, West German
Cancer Center, University Hospital Essen, Essen, Germany and an
investigator in the Phase 1b/2 studies. “These comprehensive
results provide robust preliminary evidence for the efficacy and
safety of ALXN1210 as a future treatment for patients with
PNH.”
“The strength of these data and exposure-response analyses,
along with the totality of data for ALXN1210 and discussions with
global regulators, allowed us to determine an eight-week,
weight-based dosing regimen that targets complete C5 inhibition and
rapid and sustained suppression of LDH,” said John Orloff, M.D.,
Executive Vice President and Head of Research & Development at
Alexion. “We have completed enrollment in our two multinational
Phase 3 PNH studies, with nearly 450 patients enrolled, and expect
data from these studies in the second quarter of 2018.”
Optimization of Dose Regimen for ALXN1210, a Novel Complement
C5 Inhibitor, in Patients with Paroxysmal Nocturnal Hemoglobinuria
(PNH): Results of Two Phase 1b/2 Studies3
The researchers presented results from two open-label Phase 1b/2
studies designed to provide dose ranging data to optimize the
dosing regimen for the Phase 3 development of ALXN1210 as a
treatment for patients with PNH based on exposure-response
assessments. The studies included a total of 39 adult patients with
PNH (Study 103, n=13; Study 201, n=26) who were naïve to complement
inhibition. The primary efficacy endpoint was the change from BL in
mean plasma LDH levels to day 169 in Study 103 and day 253 in Study
201. The secondary efficacy endpoints were changes from BL in free
hemoglobin, haptoglobin, and reticulocytes. Post hoc efficacy
analyses evaluated the proportion of patients achieving LDH levels
within the normal range and the incidence of breakthrough hemolysis
(days 29-253). LDH BL was defined as the average of values at
screening, prior to the first ALXN1210 infusion. For other
parameters, BL was defined as the most recent value prior to the
first infusion. Study 103 evaluated two escalating intravenous (IV)
dosing regimens of ALXN1210, and Study 201 evaluated four IV
regimens with different doses and intervals. The results
demonstrated exposure-response relationships, and further
substantiate and extend previously presented results.4,5,6,7
Study 201 Study 103 LDH at Protocol-Specified
Endpointa Cohort 1
1000 mg q4w
n=6
Cohort 2
1600 mg q6w
n=6
Cohort 3
2400 mg q8w
n=7
Cohort 4
5400 mg q12w
n=7
Cohort 1
900 mg q4w
n=6
Cohort 2
1800 mg q4w
n=7
% LDH reduction from BL, mean (SD)b 72.9 (12.1) 77.8
(6.5) 85.0 (4.4) 87.6 (6.9) 86.0 (3.2)
84.7 (3.8) LDH levels, U/L, mean (SD) 230.0 (44.0)
266.0 (54.3) 306.1 (130.7) 276.4 (196.9) 232.0
(82.3) 227.9 (50.6) LDH normalization (D29-D253)c LDH
normalized, n/N (%) 5/6 (83) 3/6 (50) 4/7 (57)
5/7 (71) 4/6 (67) 6/7 (86) LDH >1.5 x ULN,
n/N (%) 4/6 (67) 3/6 (50) 2/7 (29)
3/7(43) 2/6 (33) 1/7 (14) LDH >2 x ULN, n/N (%)
2/6 (33) 1/6 (17) 2/7 (29) 1/7 (14)
1/6 (17) 0/7 (0) Breakthrough hemolysis (D29-253)d
Incidence of breakthrough hemolysis through day 253, n/N (%)
2/6 (33.3) 1/6 (16.7) 2/7 (28.6) 1/7 (14.3)
1/6 (16.7) 0/7 (0)
BL: baseline; SD: standard deviation; D: day; LDH: lactate
dehydrogenase; ULN: upper limit of normalq4w: every 4 weeks; q6w:
every 6 weeks; q8w: every 8 weeks; q12w: every 12 weeksa LDH
parameters at protocol-specified endpoint: Study 103, day 169/24
weeks; Study 201, day 253/36 weeks.b Primary efficacy endpoint.c
Patients meeting each parameter at least once after day 29 through
day 253.d Defined as at least 1 symptom or sign of intravascular
hemolysis (fatigue, abdominal pain, shortness of breath [dyspnea],
anemia [hemoglobin <10 g/dL and hemoglobin< baseline
hemoglobin], major adverse vascular event [including thrombosis],
dysphagia, or erectile dysfunction) within ±7 days of an elevated
LDH ≥2 x ULN after prior LDH reduction to <1.5 x ULN on
therapy.
The most frequent related treatment-emergent adverse event
(TEAE) was headache. No patient stopped treatment or withdrew from
the studies, and there were no deaths. Two patients in Study 201
experienced meningococcal infections but recovered completely and
continued receiving ALXN1210. Meningococcal infections are a known
risk with terminal complement inhibition, and specific
risk-management plans have been in place for ten years for Soliris®
(eculizumab) to minimize the risk for patients.
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.1,2,8 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)9, which in turn
can result in progressive anemia, fatigue, dark urine and shortness
of breath.10,11,12 The most devastating consequence of chronic
hemolysis is thrombosis (the formation of blood clots), which can
damage vital organs and cause premature death.13 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).14,15,16 In certain patients with thrombosis of unknown
origin, PNH may be an underlying cause.9
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 early studies, ALXN1210 demonstrated rapid,
complete, and sustained reduction of free C5 levels, as well as
rapid and sustained reduction of plasma lactate dehydrogenase (LDH)
levels, a direct marker of hemolysis (the destruction of red blood
cells).4,5,6,7 ALXN1210 is currently being evaluated in Phase 3
clinical studies as a potential treatment for patients PNH and
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.
ALXN1210 has received Orphan Drug Designation (ODD) for the
intravenous 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, and in the U.S. for the
treatment of adult patients with gMG who are anti-AchR
antibody-positive. Alexion’s new drug application in Japan for
Soliris as a treatment for patients with anti-AchR
antibody-positive refractory gMG has been accepted for review by
the Japanese Ministry of Health, Labour, and Welfare (MHLW).
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 the potential medical benefits of
ALXN1210 for the treatment of PNH. 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 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 the current rates of adoption of Soliris in
paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic
uremic syndrome (aHUS), or other diseases are not sustained, 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, 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 (DOJ), the risk that anticipated regulatory
filings are delayed, the risk that estimates regarding the number
of patients with PNH, aHUS, gMG, hypophosphatasia (HPP) and
lysosomal acid lipase deficiency (LAL-D) are inaccurate, the risks
of changing foreign exchange rates, risks relating to the potential
effects of the Company'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 Quarterly Report on
Form 10-Q for the period ended September 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
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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):1253-8.3 Roeth A,
Rottinghaus ST, Hill A, et al. Optimization of Dose Regimen for
ALXN1210, a Novel Complement C5 Inhibitor, in Patients with
Paroxysmal Nocturnal Hemoglobinuria (PNH): Results of 2 Phase 1b/2
Studies. Poster 3482. December 11, 2017, American Society of
Hematology (ASH) Meeting, Atlanta, GA, USA4 Sheridan D, Yu Z-X,
Zhang Y, et al. Design and preclinical characterization of
ALXN1210: A next generation anti-C5 monoclonal antibody with
improved pharmacokinetics and duration of action. Immunobiology.
2016 Oct 221:11585 Sahelijo L, Mujeebuddin A, Mitchell D, et al.
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pharmacokinetics and exposure-response relationships of ALXN1210, a
humanized monoclonal antibody to C5, with marked half-life
extension and potential for significantly longer dosing intervals.
Blood. 2015;126 (23):4777.6 Lee JW, Bachman E, Aguzzi R, et al.
ALXN1210, A Long-Acting C5 Inhibitor, Results in Rapid and
Sustained Reduction of LDH With a Monthly Dosing Interval in
Patients With PNH: Preliminary Data From a Dose-Escalation Study.
Haematologia (Budap). 2016;101(Suppl 1):414-5.7 Lee JW, Bachman E,
Aguzzi R, et al. Immediate, Complete, and Sustained Inhibition of
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with Paroxysmal Nocturnal Hemoglobinuria (PNH): Interim Analysis of
a Dose-Escalation Study. Blood. 2016;128:24288 Socié G, Mary JY, de
Gramont A, et al. Paroxysmal nocturnal haemoglobinuria: long-term
follow-up and prognostic factors. Lancet. 1996;348:573-577.9 Hill
A, Kelly RJ, Hillmen P. Thrombosis in paroxysmal nocturnal
hemoglobinuria. Blood. 2013;121:4985-4996.10 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 May;83(3):193-207.11 Weitz I, Meyers G,
Lamy T, et al. Cross-sectional validation study of patient-reported
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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):4123-8.14 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):3897-3902.15 Iwanga M,
Furukawa K, Amenomori T, et al. Paroxysmal nocturnal
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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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