Early Clinical Experience and Basic Science Support Further Investigation of Soliris® (eculizumab) for the Treatment of Patients with Thrombotic Microangiopathy
Case Reports and Basic Science Presented at International Conference
on HUS, PNH and MPGN
CHESHIRE, Conn., Jun 15, 2010 (BUSINESS WIRE) -- Researchers reported today that Soliris(R) (eculizumab), a
first-in-class terminal complement inhibitor developed by Alexion
Pharmaceuticals, Inc. (Nasdaq: ALXN), may provide clinical benefits to
patients with thrombotic microangiopathy (TMA) resulting from
uncontrolled complement activation. TMA, the formation of blood clots in
capillaries and small arteries, can lead to life-threatening damage in
multiple organs including kidney failure, thrombocytopenia (abnormally
low platelet count) and anemia.
TMA is common among patients with certain ultra-rare, severe complement
inhibitor deficiency diseases, including atypical Hemolytic Uremic
Syndrome (aHUS), Membranoproliferative Glomerulonephritis (MPGN),
Catastrophic Antiphospholipid Syndrome (CAPS) and Paroxysmal Nocturnal
Hemoglobinuria (PNH). Research examining the role of Soliris in these
disorders was the subject of 10 presentations at the 2nd
International Conference on HUS-MPGN-PNH held in Innsbruck, Austria on
June 13-15, 2010.
"aHUS, MPGN, CAPS and PNH are diseases characterized by uncontrolled
complement activation that share a common pathology of TMA. Research
shows that these defects in the body's complement system often result in
devastating and life-threatening clinical consequences," said Dr. Lothar
Bernd Zimmerhackl, President of the Conference and Professor at the
Medical University of Innsbruck. "As we gain more clinical experience
and learn more about these diseases, terminal complement inhibition with
eculizumab is a promising treatment strategy, since it targets a central
mechanism of TMA."
Soliris has been approved by healthcare authorities in the United
States, European Union, Japan and other countries as the first treatment
for patients with PNH, a rare, debilitating and life-threatening blood
disorder defined by hemolysis, or the destruction of red blood cells.
Soliris is not approved for the treatment of aHUS, MPGN, CAPS or
diarrhea-associated HUS (D+HUS).
"Research presented this week in Innsbruck suggests that Soliris has the
potential to benefit patients with a variety of ultra-rare genetic
diseases characterized by the presence of TMA," said Leonard Bell, M.D.,
Chief Executive Officer of Alexion. "Our primary focus is to diligently
bring Soliris to patients with PNH in a growing number of countries
worldwide. We recognize the often devastating outcomes for patients who
have very few and limited therapeutic options, and we are committed to
evaluating the safety and efficacy of Soliris in these diseases where we
believe complement inhibition could have a dramatic impact on patients'
lives."
Early Clinical Experience with Soliris in Atypical HUS
Researchers
reported several case studies of patients with atypical Hemolytic Uremic
Syndrome (aHUS) treated with Soliris. As previously announced, Alexion
has completed enrollment in four prospective, open-label clinical
studies investigating Soliris as a potential treatment for patients with
aHUS, and preliminary results from these studies are expected later this
year. Presentations at the conference included:
-
"Eculizumab in Atypical Hemolytic Uremic Syndrome: Long-Term
Clinical Course and Histological Findings," S. Tschumi.
A
nine year-old girl with aHUS requiring plasma exchange was switched to
treatment with Soliris (600 mg every two weeks). Nine months after
starting Soliris, kidney function remained stable, anti-hypertensive
medications were reduced, cardiac thickening was reduced, and quality
of life was substantially improved. A renal biopsy performed at two
months after starting Soliris showed that there was no evidence of TMA.
-
"Remission of Plasma-Resistant Atypical Hemolytic Uremic Syndrome
Relapse on Kidney Graft with Eculizumab," G. Ardissino.
A six
year-old boy with aHUS received a kidney transplant. Two months after
the transplant, aHUS exacerbated without any apparent antecedent
precipitant resulting in kidney failure requiring dialysis, despite
plasma exchange. Soliris treatment was commenced and was associated
with improvement in kidney function allowing cessation of dialysis.
Investigators noted that Soliris appeared safe in this individual.
-
"Maintenance of Renal Function Under Eculizumab Despite
Discontinuation of Plasma Exchange After a Third Transplantation for
Atypical Hemolytic Uremic Syndrome Associated with a CFH Mutation,"
J.C. Davin.
A 17-year old patient with aHUS and history of
multiple severe brain ischemic events underwent a third kidney
transplant and was started on plasma exchange therapy. The patient
experienced repetitive aHUS exacerbations and also became severely
intolerant of plasma with severe allergic reactions. The patient was
started on Soliris treatment at the dose of 1200 mg every two weeks
and plasma exchange was discontinued. The patient tolerated Soliris
well during fifteen months of treatment. During this ongoing treatment
her plasma creatinine was stable, and neither aHUS exacerbation nor
side-effects have been observed.
-
"Effectiveness of Eculizumab in a Plasma Infusion Dependent Patient
with Atypical Hemolytic Uremic Syndrome Associated with Heterozygous
Combined De Novo Mutations in Factor H Gene," A.L. Lapeyraque.
A
seven year-old girl with aHUS had been treated prophylactically with
plasma infusions and with increased plasma infusion frequency after
exacerbations. After plasma infusions were determined to be
ineffective, the patient was started on Soliris treatment. The patient
experienced immediate and complete inhibition of terminal complement
activation. Already during the first week of treatment, her platelet
count increased, hemolysis and blood pressure normalized and renal
function recovered. The patient is chronically treated with 600 mg of
Soliris every two weeks for over six months with no evidence of
platelet consumption or hemolysis.
-
"Successful Kidney Transplantation in Four Patients With Factor H
Deficiency-HUS," G. Ardissino.
Four patients with Factor H
deficiency HUS (FHD-HUS) had kidney transplants following one plasma
exchange before transplant and prophylactic plasma exchanges and
plasma infusion after transplant. Two out of the four patients
experienced aHUS recurrence despite prophylactic plasma therapy. One
patient was managed with Soliris and was reported to have achieved
immediate recovery from the recurrence.
Rationale for Terminal Complement Inhibition in Patients with MPGN
MPGN
is a rare and progressive renal disease that is typically found in
children and young adults. There are two types of MPGN: MPGN type I and
MPGN type II which is also known as Dense Deposit Disease (DDD). In both
types, a dysregulation in the alternative pathway of the complement
system is considered to play a role in the pathogenesis. Presentations
included:
-
"Treatment of a Patient with Dense Deposit Disease with Eculizumab
(Soliris)," M. Vivarelli, F. Emma.
Results were reported on a
17-year-old patient who was diagnosed with DDD with normal renal
function but significant proteinuria (3-5 grams/24 hrs). To date, the
patient has been treated with Soliris for 16 months. The reported
results indicate that Soliris treatment was associated with a
significant increase in serum protein and albumin, as well as a
decrease in both the urine protein/creatinine ratio and 24 hour
protein. His creatinine and blood pressure remain normal. The
investigators reported no drug-related adverse effects while on
Soliris over the 16-month treatment period and concluded that Soliris
may be an important therapeutic option for patients with DDD.
-
"Membrano Proliferative Glomerulonephritis: 3 Case Reports," S.
Hartl.
Researchers report on three patients with MPGN, two
with MPGN type I and one with MPGN type II or DDD, with different
clinical courses and biopsy results. The activation of the complement
system and antibodies against the C3 convertase play an important role
in all three patients. The researchers suggest that the C5 convertase
might be a sophisticated target in MPGN and a clinical trial with the
anti-C5 antibody Soliris might be an important step in advancing the
treatment in this severe disease. An international registry has been
set-up to be the basis for further clinical trials using Soliris in
patients with MPGN.
-
"A Novel Disease Mechanism for MPGN II/DDD: Increased CFHR1
Expression Results in Competitive Loss of CFH Cofactor Activity," C.
Licht.
Researchers present a case of an 11 year-old boy with
DDD who, despite treatment, progressed to end stage kidney disease
within months and was started on peritoneal dialysis. After four
years, he received a transplant but developed disease recurrence
within one week. Plasma therapy was transiently successful, but after
nine months the treatment effect was lost and renal function again
severely deteriorated resulting in severe and uncontrollable
hypertension requiring kidney removal. A genetic analysis identified 3
copies of CFHR1. The researchers identified that a surplus of CFHR1
could play a role in disease recurrence early post treatment, and that
more efficient treatment strategies like targeted complement blockade
are required for patients with DDD.
Other Clinical Experience with Soliris in TMA Diseases: PNH, CAPS and
D+HUS
Several encouraging case studies were reported and
provide further insight into the potential benefits of Soliris in
treating patients with other TMA-related diseases, including PNH, CAPS,
and D+HUS.
-
"Current Experience with Eculizumab and Future Aspects," M. Riedl
on behalf of L.B. Zimmerhackl.
The report from Dr.
Zimmerhackl's group highlighted a recent publication in the New
England Journal of Medicine (1) that described the investigational use
of Soliris to achieve the first reported successful kidney transplant
for a patient suffering from CAPS, another ultra rare life-threatening
disease characterized by multi-organ failure as a consequence of TMA.
-
"Eculizumab in Diarrhea-Associated Hemolytic Uremic Syndrome," C.
Mache.
A 28 year-old patient with positive serology for E.
coli 0157, acute renal failure with hemolysis and platelet
consumption, decreased early complement protein levels, and no
identifiable complement mutation was treated with hemodialysis,
steroids and frequent plasma exchange. With no improvement and
continued dialysis requirement during 30 days of this treatment,
Soliris treatment was commenced. The patient's platelet count was
normalized after 29 days, serum haptoglobin levels after 85 days, and
serum LDH after 99 days. In addition, renal function had improved
permitting termination of hemodialysis after 22 days. At the time of
this conference (five months post initiation of therapy), Soliris is
still sustaining suppression of TMA, and maintaining renal function
with a serum creatinine of 2.3 mg/dL.
-
"Rescue Therapy with Eculizumab Fails to Prevent Graft Loss in a
Renal Transplant Patient with Factor I Mutation: Chronic Rejection or
Recurrence?" S. Loos.
A patient with D-HUS (presumably aHUS),
who had already had 2 failed kidney transplants, each with evidence of
aHUS-associated TMA on kidney biopsy, was transplanted a third time
with chronic plasma therapy in 2008. In 2009, the patient progressed
to kidney failure despite intravenous steroids and addition of further
immunosuppressive medications. At that time, the kidney biopsy showed
interstitial fibrosis without biopsy evidence of TMA or humoral
rejection in the kidney. The kidney allograft function had already
declined significantly, and treatment with Soliris was commenced. This
case highlights the problem of defining HUS recurrence in failing
renal transplant.
About PNH
PNH is a rare blood disorder that strikes people of all ages, with an
average age of onset in the early 30s. (2) Approximately 10 percent of
all patients first develop symptoms at 21 years of age or younger. (3)
PNH develops without warning and can occur in men and women of all
races, backgrounds and ages. PNH often goes unrecognized, with delays in
diagnosis ranging from one to more than 10 years. (4) It is estimated
that approximately one-third of patients with PNH do not survive more
than five years from the time of diagnosis. (4) PNH has been identified
more commonly among patients with disorders of the bone marrow,
including aplastic anemia (AA) and myelodysplastic syndromes (MDS).
(5,6, 7) In patients with thrombosis of unknown origin, PNH may be an
underlying cause. (2) More information on PNH is available at www.pnhsource.com.
About aHUS
Atypical hemolytic-uremic syndrome (aHUS) is an ultra-rare, chronic and
progressive genetic disorder characterized by sudden clinical
deterioration - life-threatening blood clots throughout the body leading
to renal failure, thrombocytopenia, and hemolytic anemia. These clinical
abnormalities are the hallmark of thrombotic microangiopathy.
Patients with aHUS experience poor outcomes. Approximately 60 percent of
patients with the most common mutation experience renal failure,
dialysis, or death within one year of the first clinical episode. (9,
10) Following kidney transplantation, recurrent aHUS causes kidney
failure in up to 60 to 90 percent of patients. (11) As in PNH, aHUS is
caused by a deficiency in normally occurring complement inhibitor
proteins. Typically, patients with aHUS have genetic mutations in one of
several complement inhibitor proteins that lead to uncontrolled
complement activation. Excessive complement activation is associated
with severe inflammation of the blood vessels and blood clotting through
the activation of white blood cells, platelets, and the endothelial cell
lining of blood vessels. (8)
About Soliris
Soliris (eculizumab) is a first-in-class terminal complement inhibitor
developed from the laboratory through regulatory approval by Alexion.
Soliris has been approved by the healthcare authorities in the U.S.,
European Union, Japan and other countries as the first treatment for
patients with PNH, a rare, debilitating and life-threatening blood
disorder defined by hemolysis, or the destruction of red blood cells.
Prior to these approvals, there was no therapy specifically available
for the treatment of PNH. Soliris is not approved for treatment of
atypical Hemolytic Uremic Syndrome (aHUS), Membranoproliferative
Glomerulonephritis (MPGN), Catastrophic Antiphospholipid Syndrome (CAPS)
or diarrhea-associated HUS (D+HUS).
Patients with PNH in more than 20 countries now have access to Soliris
therapy through national or private healthcare providers. As the first
terminal complement inhibitor to be approved in countries around the
world, Soliris represents a long-sought breakthrough in medical
innovation. Alexion's innovative approach to complement inhibition has
received some of 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 on Soliris is available at www.soliris.net.
Important Safety Information
Soliris is generally well tolerated in patients with PNH. The most
frequent adverse events observed in clinical studies of patients with
PNH were headache, nasopharyngitis (runny nose), back pain and nausea.
Treatment with Soliris should not alter anticoagulant management because
the effect of withdrawal of anticoagulant therapy during Soliris
treatment has not been established.
The U.S. product label for Soliris also includes a boxed warning:
"Soliris increases the risk of meningococcal infections. Meningococcal
infection may become rapidly life-threatening or fatal if not recognized
and treated early. Vaccinate patients with a meningococcal vaccine at
least two weeks prior to receiving the first dose of Soliris;
revaccinate according to current medical guidelines for vaccine use.
Monitor patients for early signs of meningococcal infections, evaluate
immediately if infection is suspected, and treat with antibiotics if
necessary." During PNH clinical studies, two out of 196 vaccinated PNH
patients treated with Soliris experienced a serious meningococcal
infection. Prior to beginning Soliris therapy, all patients and their
prescribing physicians are encouraged to enroll in the PNH Registry,
which is part of a special risk-management program that involves initial
and continuing education and long-term monitoring for detection of new
safety findings.
About Alexion
Alexion Pharmaceuticals, Inc. is a biopharmaceutical company working to
develop and deliver life-changing drug therapies for patients with
serious and life-threatening medical conditions. Alexion is engaged in
the discovery, development and commercialization of therapeutic products
aimed at treating patients with a wide array of severe disease states,
including hematologic and kidney diseases, transplant, other
inflammatory disorders, and cancer. Soliris is Alexion's first marketed
product. Alexion is evaluating other potential indications for Soliris
as well as other formulations of eculizumab for additional clinical
indications, and is pursuing development of other antibody product
candidates in early stages of development. This press release and
further information about Alexion Pharmaceuticals, Inc. can be found at: www.alexionpharma.com.
[ALXN-G]
Safe Harbor Statement
This news release contains forward-looking statements, including
statements related to anticipated clinical development milestones and
potential health and medical benefits of Soliris (eculizumab) for the
treatment of patients with Paroxysmal Nocturnal Hemoglobinuria, and the
potential treatment of patients with atypical Hemolytic Uremic Syndrome
(aHUS), Membranoproliferative Glomerulonephritis (MPGN), Catastrophic
Antiphospholipid Syndrome (CAPS) or diarrhea-associated HUS (D+HUS).
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 its
current or potential new indications, delays in arranging satisfactory
manufacturing capability and establishing commercial infrastructure, the
possibility that results of published reports or clinical trials are not
predictive of safety and efficacy results of Soliris in broader patient
populations, the risk that clinical trials may not be completed
successfully, the possibility that initial results of commercialization
are not predictive of future rates of adoption of Soliris, the risk that
third parties won't agree to license any necessary intellectual property
to Alexion on reasonable terms or at all, the risk that third party
payors will not reimburse for the use of Soliris at acceptable rates or
at all, 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 Quarterly Report on
Form 10-Q for the period ended March 31, 2010, and in Alexion's other
filings with the 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
(1) Lonze B, Singer A, Montgomery, R. Eculizumab and Renal
Transplantation in a Patient with CAPS. N Engl J Med. 2010: 362:18.
(2) Socié G, Mary J Yves, de Gramont A, et al. Paroxysmal nocturnal
haemoglobinuria: long-term follow-up and prognostic factors. Lancet.
1996: 348:573-577.
(3) Parker C, Omine M, Richards S, et al. Diagnosis and management of
paroxysmal nocturnal hemoglobinuria. Blood. 2005;106 (12):3699-3709.
(4) Hillmen P, Lewis SM, Bessler M, Luzzatto L, Dacie JV. Natural
history of paroxysmal nocturnal hemoglobinuria. N Engl J Med. 1995;
333:1253-1258.
(5) Wang H, Chuhjo T, Yasue S, Omine M, Naka S. Clinical significance of
a minor population of paroxysmal nocturnal hemoglobinuria-type cells in
bone marrow failure syndrome. Blood. 2002;100 (12):3897-3902.
(6) 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.
(7) Maciejewski JP, Risitano AM, Sloand EM, et al. Relationship between
bone marrow failure syndromes and the presence of glycophosphatidyl
inositol-anchored protein-deficient clones. Br J Haematol.
2001;115:1015-1022.
(8) Ståhl A, Vaziri-Sani F, Heinen S, Kristoffersson A-C, Gydell K-H,
Raafat R, Gutierrez A, Beringer O, Zipfel PF, and Karpman D. Factor H
dysfunction in patients with atypical hemolytic uremic syndrome
contributes to complement deposition on platelets and their activation.
Blood. 2008;111:5307-5315.
(9) Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F,
Bettinaglio P, et al. Genetics of HUS: the impact of MCP, CFH, and IF
mutations on clinical presentation, response to treatment, and outcome.
Blood. 2006 Aug 15;108(4):1267-79).
(10) Noris M and Remuzzi G. Atypical Hemolytic-Uremic Syndrome. N Engl J
Med 2009;361:1676-87.
(11) Loirat C, Noris M, Fremeaux-Bacchi V. Complement and the atypical
hemolytic uremic syndrome in children. Pediatr Nephrol. 2008
Nov;23(11):1957-72.
SOURCE: Alexion Pharmaceuticals, Inc.
Alexion Pharmaceuticals, Inc.
Irving Adler, 203-271-8210
Sr. Director, Corporate Communications
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