We are a biopharmaceutical company focused on serving patients with severe
and ultra-rare disorders through the innovation, development and commercialization
of life-transforming therapeutic products. Our marketed product Soliris®
(eculizumab) is the first and only therapeutic approved for patients with two
severe and ultra-rare disorders resulting from chronic uncontrolled activation
of the complement component of the immune system: paroxysmal nocturnal hemoglobinuria
(PNH), a life-threatening and ultra-rare genetic blood disorder, and atypical
hemolytic uremic syndrome (aHUS), a life-threatening and ultra-rare genetic
disease. We are also evaluating additional potential indications for Soliris
in severe and ultra-rare diseases in which chronic uncontrolled complement activation
is the underlying mechanism, and we are progressing in various stages of development
with additional biotechnology product candidates as treatments for patients
with severe and ultra-rare disorders. We were incorporated in 1992 and began
commercial sale of Soliris in 2007.
Soliris is designed to inhibit a specific aspect of the complement component
of the immune system and thereby treat inflammation associated with chronic
disorders in the therapeutic areas of hematology, nephrology, transplant rejection
and neurology. Soliris is a humanized monoclonal antibody that effectively blocks
terminal complement activity at the doses currently prescribed. The initial
indication for which we received approval for Soliris is PNH. PNH is an ultra-rare,
debilitating and life-threatening, genetic deficiency blood disorder defined
by chronic uncontrolled complement activation leading to the destruction of
red blood cells (hemolysis). The chronic hemolysis in patients with PNH may
be associated with life-threatening thromboses, recurrent pain, kidney disease,
disabling fatigue, impaired quality of life, severe anemia, pulmonary hypertension,
shortness of breath and intermittent episodes of dark-colored urine (hemoglobinuria).
Soliris was approved for the treatment of PNH by the U.S. Food and Drug Administration
(FDA) and the European Commission (EC) in 2007 and by Japan’s Ministry
of Health, Labour and Welfare (MHLW) in 2010, and has been approved in several
other territories. Additionally, Soliris has been granted orphan drug designation
for the treatment of PNH in the United States, Europe, Japan and several other
territories.
In September 2011, Soliris was approved by the FDA for the treatment of pediatric
and adult patients with aHUS. aHUS is a genetic ultra-rare disease characterized
by chronic uncontrolled complement activation and thrombotic microangiopathy,
the formation of blood clots in small blood vessels throughout the body, causing
a reduction in platelet count (thrombocytopenia) and life-threatening damage
to the kidney, brain, heart and other vital organs. Also, in November 2011,
the EC granted marketing authorization for Soliris to treat pediatric and adult
patients with aHUS in Europe. The FDA and EC have granted Soliris orphan drug
designation for the treatment of patients with aHUS.
Products and Development Programs
The human immune system defends the body from attack or invasion by infectious
agents or pathogens. This is accomplished through a complex system of proteins
and cells, primarily complement proteins, antibodies
and white blood cells, each with a specialized function. Under normal circumstances,
complement proteins, together with antibodies and white blood cells, act to
protect the body by removing:
harmful micro-organisms;
cells containing foreign proteins known as antigens; and
potential disease-causing combinations of antigens and antibodies known as immune
complexes.
When activated by certain stimuli, the immune system triggers a series of enzymatic
and biochemical reactions called the complement cascade that results in an inflammatory
response. This inflammatory response is one of the immune system’s weapons
against foreign pathogens or otherwise diseased tissue. However, under certain
circumstances, the complement cascade may cause excessive or inappropriate activation,
and/or an individual may be deficient in naturally occurring complement inhibitors,
all of which may result in acute and chronic inflammatory conditions and damage
to healthy tissues.
We focus our product development programs on life transforming therapeutics
for diseases for which we believe current treatments are either non-existent
or inadequate. Eculizumab is a humanized antibody known as a C5 terminal complement
inhibitor (C5 Inhibitor), which is designed to selectively block the production
of inflammation-causing proteins of the complement cascade. We believe that
selective suppression of this immune response may provide a significant therapeutic
advantage relative to existing therapies. In addition to PNH and aHUS, for which
the use of eculizumab has been approved in the United States and Europe, we
believe that C5 Inhibitors may be useful in the treatment of a variety of other
serious diseases and conditions resulting from uncontrolled complement activation.
Soliris is designed to inhibit a specific aspect of the complement component
of the immune system and thereby treat inflammation associated with chronic
disorders in the therapeutic areas of hematology, nephrology including transplant
rejection, and neurology. Soliris is a humanized antibody which, administered
at the doses currently prescribed, generally blocks complement activity for
one to two weeks after a single dose.
Soliris was approved for the treatment of PNH by the FDA and the EC in 2007,
by Japan’s MHLW in 2010 and has been approved in several other territories.
Additionally, Soliris was granted orphan drug designation for the treatment
of PNH in the United States, Europe, Japan and several other territories.
Soliris was approved for the treatment of aHUS by the FDA and the EC in 2011.
Soliris was granted orphan drug designation for the treatment of aHUS in the
United States and Europe.
Orphan drug designation generally entitles us to exclusivity for certain periods
of time, subject to limited circumstances. However, if a competitive product
that is the same as Soliris, as defined under the applicable regulations, is
shown to be clinically superior to our product in the treatment of PNH, or if
a competitive product is different from Soliris, as defined under the applicable
regulations, the orphan drug exclusivity we have obtained may not restrict the
approval of such competitive product.
Hematology
Paroxysmal Nocturnal Hemoglobinuria (PNH)
PNH is an ultra-rare, debilitating and life-threatening blood disorder in which
an acquired genetic deficiency causes uncontrolled complement activation which
leads to life-threatening complications. Patients with PNH have an acquired
genetic deficiency in certain protective proteins on the surface of their blood
cells, allowing their own complement system to attack and destroy these blood
cells. Patients with PNH suffer from chronic complement activation of some of
their blood cells and also hemolysis, or destruction of red blood cells caused
by the C5 cleavage product C5b-9. This hemolysis is believed to lead to further
clinical complications including thromboses, kidney disease, liver dysfunction,
disabling fatigue, impaired quality of life, recurrent pain, shortness of breath,
pulmonary hypertension, intermittent episodes of dark colored urine (hemoglobinuria),
and anemia. Approximately one-half of the patients with PNH die from the disease
within 10 to 15 years of diagnosis.
Our marketed product Soliris is the first and only therapy approved for the
treatment of patients with PNH. We continue to work with researchers to expand
the base of knowledge in PNH and the utility of Soliris to treat patients with
PNH. Additionally, we are sponsoring multinational registries to gather information
regarding the natural history of patients with PNH and the longer term outcomes
during Soliris treatment.
Cold Agglutinin Disease (CAD)
We are aware that dosing is ongoing in an investigator-initiated Phase II study
of eculizumab in patients for the treatment of CAD. CAD is a severe, ultra-rare
complement-mediated autoimmune disease characterized by the presence of high
concentrations of circulating complement-activating antibodies directed against
red blood cells. As observed with PNH patients, CAD patients also suffer from
the clinical consequences of severe hemolysis.
As blood is cooled during circulation through the distal parts of the arms and
legs, specific antibodies bind to the red blood cells resulting in activation
of the complement cascade and red blood cell lysis. Clinical manifestations
of CAD include symptoms of chronic hemolysis such as fatigue, dyspnea, weakness,
hemoglobinuria, kidney damage, pallor and jaundice. In the most severe cases,
complications of progressive hemolysis or anemia may result in death. Current
therapies, including cold avoidance, corticosteroids, immunosuppressive drugs,
intravenous immunoglobulin G and chemotherapy agents are largely ineffective
in controlling hemolysis in patients with CAD.
Hematology/Nephrology
Atypical Hemolytic Uremic Syndrome (aHUS)
aHUS is a chronic and life-threatening ultra-rare genetic disease in which uncontrolled
complement activation causes blood clots in small blood vessels throughout the
body (thrombotic microangiopathy, or TMA) leading to kidney failure, stroke,
heart attack and death. Our marketed product Soliris is the first and only therapy
approved for the treatment of patients with aHUS.
In patients with aHUS, deficiency of naturally occurring complement inhibitors
causes uncontrolled complement activation which leads to systemic TMA, the formation
of blood clots in small blood vessels throughout the body causing a reduction
in platelet count (thrombocytopenia) and life-threatening damage to the kidney,
brain, heart and other vital organs. The prognosis for patients with aHUS is
generally poor. Approximately 70% of patients with the most common mutation
experience chronic renal insufficiency, chronic dialysis, or death within one
year after the first clinical manifestation of TMA. aHUS commonly recurs in
patients who undergo renal transplantation and, depending upon the mutation,
the disease can lead to loss of the transplanted kidney in up to approximately
90% of aHUS patients who undergo kidney transplantation.
Approximately 50% of patients diagnosed with aHUS have been identified to have
genetic mutations in at least one of the complement control proteins or neutralizing
autoantibodies to complement regulatory factors, which can lead to uncontrolled
complement activation. Excessive complement activation may contribute to the
blood vessel inflammation and clotting by stimulating activation of white blood
cells, platelets and the endothelial lining of blood vessels.
As a post marketing requirement, we have now completed enrollment in a prospective
open-label trial in adult aHUS and, separately, enrollment has been completed
in a prospective pediatric aHUS study.
Nephrology
Shiga-toxin producing E. Coli Hemolytic Uremic Syndrome (STEC-HUS)
STEC-HUS is a life-threatening, complement-mediated ultra-rare disorder that
results from exposure to Enterohemorrhagic E.Coli, (EHEC). Our STEC-HUS development
program was initiated in connection with the widespread outbreak of EHEC in
Germany in May and June 2011. Many EHEC patients rapidly progressed to STEC-HUS
during this outbreak. As in several other conditions with severe and uncontrolled
complement activation, including aHUS, complement activation in STEC-HUS results
in TMA. Although aHUS and STEC-HUS exhibit similar life-threatening TMA manifestations,
aHUS and STEC-HUS are different disorders. aHUS is a chronic genetic disease
of uncontrolled complement activation, while STEC-HUS is not genetic and follows
an isolated episode of infection. STEC-HUS is an ultra-rare disorder, comprising
only a small sub-set of the already rare population of patients with EHEC. Following
an authorization by the Paul-Ehrlich-Institut, Germanys health care regulatory
body for biologics, and an access program for patients initiated in May 2011,
we initiated an open-label clinical trial to investigate eculizumab as a treatment
for patients with STEC-HUS. Enrollment in this trial has been completed. The
FDA and the EC have each granted orphan designation for eculizumab as a treatment
for patients with STEC-HUS.
MPGN II/C3 Nephropathy
We are aware that independent investigators have completed enrollment in studies
aimed at evaluating eculizumab in patients with membrano-proliferative glomerulonephritis
(MPGN II or dense deposit disease) as well as patients with a similar disease
referred to as C3 nephropathy. MGPN II and C3 nephropathy are ultra-rare forms
of glomerulonephritis, associated with genetic mutations in complement inhibitor
genes leading to sustained uncontrolled complement activation and inflammation.
Clinically, this disease is characterized by the onset of severe proteinuria
(excess protein in the urine), often accompanied by nephrotic syndrome which
is refractory to immunosuppressant therapy. In most cases, the disease progresses
to chronic renal failure, requiring dialysis and renal transplantation.
Acute Humoral Rejection (AHR) in Presensitized Kidney Transplant Patients
Patients undergoing solid organ transplantation may experience severe AHR in
the early post-transplant period. For example, in a patient undergoing a kidney
transplant this may be characterized by the acute onset of renal dysfunction
and rapid progression to destruction of the transplanted kidney.
AHR results when antibodies in the transplant recipient vigorously attack the
blood vessels of the donor kidney. During severe AHR, these donor specific antibodies
bind to the blood vessel lining of the donor organ and initiate activation of
the complement cascade, resulting in severe blood vessel inflammation and clotting.
Administration of a C5 inhibitor in animal models of AHR inhibits complement
activation, tissue damage and transplant rejection.
We initiated enrollment in a multi-national, multi-site controlled clinical
trial of eculizumab in presensitized renal transplant patients at elevated risk
for AHR who will receive living donor grafts, and we have initiated enrollment
in a multi-national, multi-site controlled clinical trial of eculizumab in presensitized
renal transplant patients at elevated risk for AHR who will receive deceased
donor grafts. We are also aware that an independent investigator has started
enrolling patients in a clinical trial to evaluate eculizumab in kidney transplant
patients sensitized to their donor kidney due to an ABO blood group mismatch
between donor and recipient.
Delayed Kidney Transplant Graft Function
We are aware that dosing is ongoing in an investigator-initiated Phase II study
of eculizumab in patients at elevated risk for delayed graft function (DGF)
following kidney transplant.
DGF is the term used to describe the failure of a kidney or other organs to
function immediately after transplantation due to ischemia-reperfusion and immunological
injury. After kidney transplantation, DGF can be considered a form of acute
kidney injury post-transplantation and is an important complication of kidney
transplantation. The frequency of DGF can be as high as 50% in some kidney transplant
settings. DGF complicates post-transplant management, increases morbidity and
prolongs patient hospitalization. In addition to the acute kidney injury, DGF
predisposes the transplanted kidney to both acute and chronic rejection and
increases the risk of chronic allograft nephropathy and premature graft loss.
Studies have indicated that activation of the complement cascade may be a key
early event required for the development of DGF following kidney transplant.
There are currently no accepted or approved therapies for prevention or treatment
of DGF following kidney transplantation.
Neurology
Neuromyelitis Optica (NMO)
NMO is a severe and ultra-rare autoimmune disease of the central nervous system
(CNS) that primarily affects the optic nerves and spinal cord. Individuals with
NMO develop optic neuritis, which causes pain in the eye and vision loss, and
transverse myelitis, which causes weakness, numbness, and sometimes paralysis
of the arms and legs, weakness or paralysis of respiratory muscles sometimes
leading to respiratory failure, along with sensory disturbances and loss of
bladder and bowel control.
Preliminary data from the investigator-initiated Phase II clinical trial of
eculizumab in severe and relapsing NMO patients was presented to the American
Neurological Association (ANA) meeting in October 2012. The study was reported
to have achieved its primary efficacy endpoint with a high degree of clinical
and statistical significance and several key secondary endpoints were also achieved.
Myasthenia Gravis (MG)
MG is an ultra-rare autoimmune syndrome characterized by complement activation
leading to the failure of neuromuscular transmission. Patients with MG initially
experience weakness in their ocular, or eye muscles, and the disease typically
progresses to head, spinal, limb and respiratory muscles. Symptoms can include
drooping eyelids, blurred vision, slurred speech, difficulty chewing or swallowing,
weakness in the arms and legs and difficulty breathing. In an experimental animal
model of MG, administration of a C5 Inhibitor was found to prevent experimentally
acquired MG and to inhibit disease progression.
Preliminary data from a Phase II trial evaluating the safety and efficacy of
eculizumab in patients with severe, refractory MG demonstrated an encouraging
disease improvement signal and was presented at the Myasthenia Gravis Foundation
Annual Meeting in September 2011. We continue to work with investigators to
design the next clinical trial to evaluate eculizumab as a treatment for patients
with severe and refractory MG.
Asfotase Alfa
Hypophosphatasia (HPP)
HPP is an ultra-rare, genetic, and life-threatening metabolic disease characterized
by impaired phosphate and calcium regulation, leading to progressive damage
to multiple vital organs including destruction and deformity of bones, profound
muscle weakness, seizures, impaired renal function, and respiratory failure.
The severe manifestations of the genetic deficiency in HPP affect people of
all ages, and approximately 50% of infants with the disease do not survive past
one year of age. HPP is caused by mutations in the gene encoding the enzyme
Tissue Nonspecific Alkaline Phosphatase. This enzyme normally breaks down metabolic
substrates such as inorganic pyrophosphate and pyridoxal phosphate.
Asfotase alfa, a targeted enzyme replacement therapy in Phase II clinical trials
for patients with HPP, is designed to directly address the morbidities and mortality
of HPP by targeting alkaline phosphatase directly to the deficient tissue. In
this way, asfotase alfa is designed to normalize the genetically defective metabolic
process and prevent or reverse the severe, crippling and life-threatening complications
of dysregulated mineral metabolism in patients with HPP. Initial studies with
asfotase alfa in HPP patients indicate that the treatment significantly decreases
the levels of targeted metabolic substrates. We have initiated a natural history
study in infants with HPP and are currently dosing patients in a separate global
trial of severe infant HPP patients. We acquired asfotase alfa in February 2012
in connection with our acquisition of Enobia.
cPMP
Molybdenum Cofactor Deficiency (MoCD) Disease Type A (MoCD Type A)
MoCD Type A is a rare metabolic disorder characterized by severe and rapidly
progressive neurologic damage and death in newborns. MoCD Type A results from
a genetic deficiency in cyclic Pyranopterin Monophosphate (cPMP), a molecule
that enables production of certain enzymes, the absence of which allows neurotoxic
sulfite to accumulate in the brain. To date, there is no approved therapy available
for MoCD Type A. There has been some early clinical experience with the cPMP
replacement therapy in a small number of children with MoCD Type A. We are currently
conducting pre-Investigational New Drug (IND) toxicology studies with cPMP replacement
therapy.
ALXN 1102/1103
ALXN 1102/1103 is a novel alternative pathway complement inhibitor with a mechanism
of action unique from Soliris. ALXN 1102 is currently being investigated in
a Phase I single dose, dose escalating safety and pharmacology study. ALXN 1103
is being dosed in the same Phase I trial as a subcutaneous formulation.
ALXN 1007
ALXN 1007 is a novel humanized antibody designed to target rare and severe inflammatory
disorders and is a product of our proprietary antibody discovery technologies.
ALXN 1007 is currently being investigated in a Phase I single dose, dose escalating
safety and pharmacology study in healthy volunteers.
Competition
There are currently no approved drugs other than Soliris for the treatment of
PNH and aHUS. However, many companies, including major pharmaceutical and chemical
companies as well as specialized biotechnology companies, are engaged in activities
similar to our activities. Universities, governmental agencies and other public
and private research organizations also conduct research and may market commercial
products on their own or through joint ventures. Many of these entities may
have:
substantially greater financial and other resources;
larger research and development staffs;
lower labor costs; and/or
more extensive marketing and manufacturing organizations.
Many of these companies and organizations have significant experience in preclinical
testing, human clinical trials, product manufacturing, marketing, sales and
distribution and other regulatory approval and commercial procedures. They may
also have a greater number of significant patents and greater legal resources
to seek remedies for cases of alleged infringement of their patents by us to
block, delay or compromise our own drug development process.
We compete with large pharmaceutical companies that produce and market synthetic
compounds and with specialized biotechnology firms in the United States, Europe
and in other countries and regions, as well as a growing number of large pharmaceutical
companies that are applying biotechnology to their operations. A number of biotechnology
and pharmaceutical companies are developing new products for the treatment of
the same diseases being targeted by us; in some instances, these products have
already entered clinical trials or are already being marketed. Other companies
are engaged in research and development based on complement proteins.
Several companies have either publicly announced their intentions to develop
drugs which target the inflammatory effects of complement in the immune system
or have had programs to develop complement inhibitor therapies. We believe that
our potential C5 Inhibitors differ substantially from those of our potential
competitors due to our compounds’ demonstrated ability to specifically
intervene in the complement cascade, for potentially prolonged periods of time.
We believe this action to be the optimal point so that the disease-causing actions
of complement proteins are inhibited, while the normal disease-preventing functions
of complement proteins and other aspects of immune function remain intact.