Interim results demonstrate statistically
significant improvement compared to placebo in hemoglobin levels
from baseline to week 12
A prespecified interim analysis of the ALPHA Phase III trial
evaluating danicopan (ALXN2040), an investigational, oral factor D
inhibitor, as an add-on to C5 inhibitor therapy ULTOMIRIS®
(ravulizumab-cwvz) or SOLIRIS® (eculizumab) showed positive
high-level results in patients with paroxysmal nocturnal
hemoglobinuria (PNH) who experience clinically significant
extravascular hemolysis (EVH).
The trial met its primary endpoint of change in hemoglobin from
baseline at 12 weeks and key secondary endpoints, including
transfusion avoidance and change in Functional Assessment of
Chronic Illness Therapy (FACIT) Fatigue score. Danicopan plus
ULTOMIRIS or SOLIRIS demonstrated superiority compared to placebo
plus ULTOMIRIS or SOLIRIS for this specific patient population,
with statistically significant and clinically meaningful
improvements in hemoglobin levels, transfusion avoidance and FACIT
Fatigue scores from baseline.
PNH is a rare and severe blood disorder characterized by the
destruction of red blood cells, known as intravascular hemolysis
(IVH), and white blood cell and platelet activation that can cause
thrombosis (blood clots) and result in organ damage and potentially
premature death.1-3
Marc Dunoyer, Chief Executive Officer, Alexion, said: “Alexion
has relentlessly innovated for the PNH community, pioneering with
SOLIRIS, the first treatment for PNH, and establishing ULTOMIRIS as
a standard of care. We are proud of our continued innovation to
advance new ways of targeting the complement cascade to help
address the needs of patients living with this debilitating
disease. These are the first positive Phase III results for an oral
factor D inhibitor and demonstrate the potential for danicopan
add-on therapy to improve signs and symptoms and reduce the need
for transfusions for the limited proportion of people living with
PNH who experience clinically significant EVH.”
Professor Jong-Wook Lee, MD, PhD, Department of Hematology at
Seoul St. Mary's Hospital of The Catholic University of Korea, and
investigator in the ALPHA trial, said: “C5 inhibitors are a proven
treatment option for patients living with PNH, yet a small
percentage may continue to experience anemia and burden of
transfusion due to clinically significant EVH, however it is not
life-threatening. These data show that danicopan has the potential
to resolve clinically significant EVH while allowing patients to
remain on standard of care treatment with ULTOMIRIS or
SOLIRIS.”
Danicopan was generally well tolerated and there were no
clinically meaningful differences in safety results observed
between the danicopan plus C5 inhibitor group and control
group.
Alexion, AstraZeneca Rare Disease, will present these data at a
forthcoming medical meeting and intends to proceed with regulatory
submissions in the coming months.
INDICATION(S) & IMPORTANT SAFETY INFORMATION for
ULTOMIRIS® (ravulizumab-cwvz)
What is ULTOMIRIS?
ULTOMIRIS is a prescription medicine used to treat:
- adults and children 1 month of age and older with a disease
called Paroxysmal Nocturnal Hemoglobinuria (PNH).
- adults and children 1 month of age and older with a disease
called atypical Hemolytic Uremic Syndrome (aHUS). ULTOMIRIS is not
used in treating people with Shiga toxin E. coli related hemolytic
uremic syndrome (STEC-HUS).
- adults with a disease called generalized myasthenia gravis
(gMG) who are anti-acetylcholine receptor (AChR) antibody
positive.
It is not known if ULTOMIRIS is safe and effective in children
younger than 1 month of age.
IMPORTANT SAFETY INFORMATION
What is the most important information I should know about
ULTOMIRIS?
ULTOMIRIS is a medicine that affects your immune system and
can lower the ability of your immune system to fight
infections.
- ULTOMIRIS increases your chance of getting serious and
life-threatening meningococcal infections that may quickly become
life-threatening and cause death if not recognized and treated
early.
- You must receive meningococcal vaccines at least 2 weeks before
your first dose of ULTOMIRIS if you are not vaccinated.
- If your doctor decided that urgent treatment with ULTOMIRIS is
needed, you should receive meningococcal vaccination as soon as
possible.
- If you have not been vaccinated and ULTOMIRIS therapy must be
initiated immediately, you should also receive 2 weeks of
antibiotics with your vaccinations.
- If you had a meningococcal vaccine in the past, you might need
additional vaccination. Your doctor will decide if you need
additional vaccination.
- Meningococcal vaccines reduce but do not prevent all
meningococcal infections. Call your doctor or get emergency medical
care right away if you get any of these signs and symptoms of a
meningococcal infection: headache with nausea or vomiting, headache
and fever, headache with a stiff neck or stiff back, fever, fever
and a rash, confusion, muscle aches with flu-like symptoms and eyes
sensitive to light.
Your doctor will give you a Patient Safety Card about the
risk of meningococcal infection. Carry it with you at all times
during treatment and for 8 months after your last ULTOMIRIS dose.
It is important to show this card to any doctor or nurse to help
them diagnose and treat you quickly.
ULTOMIRIS is only available through a program called the
ULTOMIRIS REMS. Before you can receive ULTOMIRIS, your doctor
must: enroll in the ULTOMIRIS REMS program; counsel you about the
risk of meningococcal infection; give you information and a
Patient Safety Card about the symptoms and your risk of
meningococcal infection (as discussed above); and make sure that
you are vaccinated with a meningococcal vaccine, and if needed, get
revaccinated with the meningococcal vaccine. Ask your doctor if you
are not sure if you need to be revaccinated.
ULTOMIRIS may also increase the risk of other types of
serious infections. Make sure your child receives vaccinations
against Streptococcus pneumoniae and Haemophilus influenzae type b
(Hib) if treated with ULTOMIRIS. Call your doctor right away if you
have any new signs or symptoms of infection.
Who should not receive ULTOMIRIS?
Do not receive ULTOMIRIS if you have a meningococcal
infection or have not been vaccinated against meningococcal
infection unless your doctor decides that urgent treatment with
ULTOMIRIS is needed.
Before you receive ULTOMIRIS, tell your doctor about all of
your medical conditions, including if you: have an infection or
fever, are pregnant or plan to become pregnant, and are
breastfeeding or plan to breastfeed. It is not known if ULTOMIRIS
will harm your unborn baby or if it passes into your breast milk.
You should not breastfeed during treatment and for 8 months after
your final dose of ULTOMIRIS.
Tell your doctor about all the vaccines you receive and
medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements which could affect your
treatment.
If you have PNH and you stop receiving ULTOMIRIS, your doctor
will need to monitor you closely for at least 16 weeks after you
stop ULTOMIRIS. Stopping ULTOMIRIS may cause breakdown of your red
blood cells due to PNH. Symptoms or problems that can happen due to
red blood cell breakdown include: drop in your red blood cell
count, tiredness, blood in your urine, stomach-area (abdomen) pain,
shortness of breath, blood clots, trouble swallowing, and erectile
dysfunction (ED) in males.
If you have aHUS, your doctor will need to monitor you
closely for at least 12 months after stopping treatment for signs
of worsening aHUS or problems related to a type of abnormal
clotting and breakdown of your red blood cells called thrombotic
microangiopathy (TMA). Symptoms or problems that can happen with
TMA may include: confusion or loss of consciousness, seizures,
chest pain (angina), difficulty breathing and blood clots or
stroke.
What are the possible side effects of ULTOMIRIS?
ULTOMIRIS can cause serious side effects including
infusion-related reactions. Symptoms of an infusion-related
reaction with ULTOMIRIS may include lower back pain, tiredness,
feeling faint, discomfort in your arms or legs, or bad taste. Tell
your doctor or nurse right away if you develop these symptoms, or
any other symptoms during your ULTOMIRIS infusion that may mean you
are having a serious infusion reaction, including: chest pain,
trouble breathing or shortness of breath, swelling of your face,
tongue, or throat, and feel faint or pass out.
The most common side effects of ULTOMIRIS in people treated
for PNH are upper respiratory tract infection and headache.
The most common side effects of ULTOMIRIS in people with aHUS
are upper respiratory tract infection, diarrhea, nausea, vomiting,
headache, high blood pressure and fever.
The most common side effects of ULTOMIRIS in people with gMG
are diarrhea and upper respiratory tract infection.
Tell your doctor about any side effect that bothers you or that
does not go away. These are not all the possible side effects of
ULTOMIRIS. For more information, ask your doctor or pharmacist.
Call your doctor right away if you miss an ULTOMIRIS infusion or
for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
Please see the accompanying full Prescribing
Information and Medication Guide for ULTOMIRIS, including
Boxed WARNING regarding serious and life-threatening meningococcal
infections/sepsis.
INDICATIONS & IMPORTANT SAFETY INFORMATION FOR SOLIRIS®
(eculizumab) [injection for intravenous use 300mg/30mL
vial]
What is SOLIRIS?
SOLIRIS is a prescription medicine used to treat:
- patients with a disease called Paroxysmal Nocturnal
Hemoglobinuria (PNH).
- adults and children with a disease called atypical Hemolytic
Uremic Syndrome (aHUS). SOLIRIS is not for use in treating people
with Shiga toxin E. coli related hemolytic uremic syndrome
(STEC-HUS).
- adults with a disease called generalized myasthenia gravis
(gMG) who are anti-acetylcholine receptor (AChR) antibody
positive.
- adults with a disease called neuromyelitis optica spectrum
disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody
positive.
It is not known if SOLIRIS is safe and effective in children
with PNH, gMG, or NMOSD.
IMPORTANT SAFETY INFORMATION
What is the most important information I should know about
SOLIRIS?
SOLIRIS is a medicine that affects your immune system and can
lower the ability of your immune system to fight
infections.
- SOLIRIS increases your chance of getting serious and
life-threatening meningococcal infections that may quickly become
life-threatening and cause death if not recognized and treated
early.
- You must receive meningococcal vaccines at least 2 weeks before
your first dose of SOLIRIS if you are not vaccinated.
- If your doctor decided that urgent treatment with SOLIRIS is
needed, you should receive meningococcal vaccination as soon as
possible.
- If you have not been vaccinated and SOLIRIS therapy must be
initiated immediately, you should also receive 2 weeks of
antibiotics with your vaccinations.
- If you had a meningococcal vaccine in the past, you might need
additional vaccination. Your doctor will decide if you need
additional vaccination.
- Meningococcal vaccines reduce but do not prevent all
meningococcal infections. Call your doctor or get emergency medical
care right away if you get any of these signs and symptoms of a
meningococcal infection: headache with nausea or vomiting, headache
and fever, headache with a stiff neck or stiff back, fever, fever
and a rash, confusion, muscle aches with flu-like symptoms, and
eyes sensitive to light.
Your doctor will give you a Patient Safety Card about the
risk of meningococcal infection. Carry it with you at all times
during treatment and for 3 months after your last SOLIRIS dose. It
is important to show this card to any doctor or nurse to help them
diagnose and treat you quickly.
SOLIRIS is only available through a program called the
SOLIRIS REMS. Before you can receive SOLIRIS, your doctor must
enroll in the SOLIRIS REMS program; counsel you about the risk of
meningococcal infection; give you information and a Patient
Safety Card about the symptoms and your risk of meningococcal
infection (as discussed above); and make sure that you are
vaccinated with the meningococcal vaccine and, if needed, get
revaccinated with the meningococcal vaccine. Ask your doctor if you
are not sure if you need to be revaccinated.
SOLIRIS may also increase the risk of other types of serious
infections. Make sure your child receives vaccinations against
Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) if
treated with SOLIRIS. Certain people may be at risk of serious
infections with gonorrhea. Certain fungal infections (Aspergillus)
may occur if you take SOLIRIS and have a weak immune system or a
low white blood cell count.
Who should not receive SOLIRIS?
Do not receive SOLIRIS if you have a meningococcal infection
or have not been vaccinated against meningitis infection unless
your doctor decides that urgent treatment with SOLIRIS is
needed.
Before you receive SOLIRIS, tell your doctor about all of
your medical conditions, including if you: have an infection or
fever, are pregnant or plan to become pregnant, and are
breastfeeding or plan to breastfeed. It is not known if SOLIRIS
will harm your unborn baby or if it passes into your breast
milk.
Tell your doctor about all the vaccines you receive and
medicines you take, including prescription and over-the-counter
medicines, vitamins, and herbal supplements which could affect your
treatment. It is important that you have all recommended
vaccinations before you start SOLIRIS, receive 2 weeks of
antibiotics if you immediately start SOLIRIS, and stay up-to-date
with all recommended vaccinations during treatment with
SOLIRIS.
If you have PNH, your doctor will need to monitor you closely
for at least 8 weeks after stopping SOLIRIS. Stopping treatment
with SOLIRIS may cause breakdown of your red blood cells due to
PNH. Symptoms or problems that can happen due to red blood cell
breakdown include: drop in the number of your red blood cell count,
drop in your platelet count, confusion, kidney problems, blood
clots, difficulty breathing, and chest pain.
If you have aHUS, your doctor will need to monitor you
closely during and for at least 12 weeks after stopping treatment
for signs of worsening aHUS symptoms or problems related to
abnormal clotting (thrombotic microangiopathy). Symptoms or
problems that can happen with abnormal clotting may include:
stroke, confusion, seizure, chest pain (angina), difficulty
breathing, kidney problems, swelling in arms or legs, and a drop in
your platelet count.
What are the possible side effects of SOLIRIS?
SOLIRIS can cause serious side effects including serious
allergic reactions. Tell your doctor or nurse right away if you
get any of these symptoms during your SOLIRIS infusion: chest pain;
trouble breathing or shortness of breath; swelling of your face,
tongue, or throat; and feel faint or pass out. If you have an
allergic reaction to SOLIRIS, your doctor may need to infuse
SOLIRIS more slowly, or stop SOLIRIS.
The most common side effects in people with PNH treated with
SOLIRIS include: headache, pain or swelling of your nose or
throat (nasopharyngitis), back pain, and nausea.
The most common side effects in people with aHUS treated with
SOLIRIS include: headache, diarrhea, high blood pressure
(hypertension), common cold (upper respiratory infection),
stomach-area (abdominal) pain, vomiting, pain or swelling of your
nose or throat (nasopharyngitis), low red blood cell count
(anemia), cough, swelling of legs or feet (peripheral edema),
nausea, urinary tract infections, and fever.
The most common side effects in people with gMG treated with
SOLIRIS include: muscle and joint (musculoskeletal) pain.
The most common side effects in people with NMOSD treated
with SOLIRIS include: common cold (upper respiratory
infection); pain or swelling of your nose or throat
(nasopharyngitis); diarrhea; back pain; dizziness; flu-like
symptoms (influenza), including fever, headache, tiredness, cough,
sore throat, and body aches; joint pain (arthralgia); throat
irritation (pharyngitis); and bruising (contusion).
Tell your doctor about any side effect that bothers you or that
does not go away. These are not all the possible side effects of
SOLIRIS. For more information, ask your doctor or pharmacist. Call
your doctor for medical advice about side effects. You are
encouraged to report negative side effects of prescription drugs to
the FDA. Visit MedWatch, or call 1-800-FDA-1088.
Please see the full Prescribing Information and Medication
Guide for SOLIRIS, including Boxed WARNING regarding serious and
life-threatening meningococcal infections.
Notes
PNH
PNH is a rare, chronic, progressive and potentially
life-threatening blood disorder. It is characterized by red blood
cell destruction within blood vessels (also known as intravascular
hemolysis) and white blood cell and platelet activation, which can
result in thrombosis (blood clots).1-3
PNH is caused by an acquired genetic mutation that may happen
any time after birth and results in the production of abnormal
blood cells that are missing important protective blood cell
surface proteins. These missing proteins enable the complement
system, which is part of the immune system and is essential to the
body’s defense against infection, to ‘attack’ and destroy or
activate these abnormal blood cells.1 Living with PNH can be
debilitating, and signs and symptoms may include blood clots,
abdominal pain, difficulty swallowing, erectile dysfunction,
shortness of breath, excessive fatigue, anemia and dark-colored
urine.1,4,5
Clinically Significant EVH
EVH, the removal of red blood cells outside of the blood
vessels, can sometimes occur in PNH patients who are treated with
C5 inhibitors. Since C5 inhibition enables PNH red blood cells to
survive and circulate, EVH may occur when these now surviving PNH
red blood cells are marked by proteins in the complement system for
removal by the spleen and liver.1,3,6 PNH patients with EVH may
continue to experience anemia, which can have various causes, and
may require blood transfusions.6 A small subset of people living
with PNH who are treated with a C5 inhibitor experience clinically
significant EVH, which can result in continued symptoms of anemia
and require blood transfusions.
ALPHA
ALPHA is a pivotal, global Phase III trial designed to evaluate
the efficacy of danicopan as an add-on to C5 inhibitor therapy
ULTOMIRIS® (ravulizumab-cwvz) or SOLIRIS®
(eculizumab) in patients with PNH who experience clinically
significant EVH. In the double-blind, placebo controlled,
multiple-dose trial, patients were enrolled and randomized to
receive danicopan or placebo (2:1) in addition to their ongoing C5
inhibitor therapy for 12 weeks. Prespecified interim analysis for
efficacy was planned once 75 percent (N~63) of participants
completed 12 weeks of treatment period 1. At 12 weeks, patients on
placebo plus C5 inhibitor are switched to danicopan plus a C5
inhibitor and patients on danicopan plus a C5 inhibitor remain on
treatment for an additional 12 weeks.
Patients who complete both treatment periods (24 weeks) have the
option to participate in a long-term extension period and continue
to receive danicopan in addition to C5 inhibitor therapy.
Danicopan (ALXN2040)
Danicopan is an investigational oral medicine in development as
an add-on to C5 inhibitor therapy ULTOMIRIS®
(ravulizumab-cwvz) or SOLIRIS® (eculizumab) for patients
with PNH who experience clinically significant EVH. It is designed
to selectively inhibit factor D, a complement system protein that
plays a key role in the amplification of the complement system
response. Danicopan has been granted Breakthrough Therapy
designation by the US Food and Drug Administration and PRIority
MEdicines (PRIME) status by the European Medicines Agency.
Danicopan has also been granted Orphan Drug Designation in the US
and orphan designation in the EU for the treatment of PNH. Alexion
is also evaluating danicopan as a potential monotherapy for
geographic atrophy in a Phase II clinical trial.
ULTOMIRIS
ULTOMIRIS (ravulizumab-cwvz), the first and only long-acting C5
complement inhibitor, offers immediate, complete and sustained
complement inhibition. The medication works by inhibiting the C5
protein in the terminal complement cascade, a part of the body’s
immune system. When activated in an uncontrolled manner, the
complement cascade over-responds, leading the body to attack its
own healthy cells. ULTOMIRIS is administered intravenously every
eight weeks in adult patients, following a loading dose.
ULTOMIRIS is approved in the US and Japan for the treatment of
certain adults with gMG.
ULTOMIRIS is also approved in the US, EU and Japan for the
treatment of certain adults with PNH and for certain children with
PNH in the US and EU.
Additionally, ULTOMIRIS is approved in the US, EU and Japan for
certain adults and children with aHUS to inhibit
complement-mediated thrombotic microangiopathy.
As part of a broad development program, ULTOMIRIS is being
assessed for the treatment of additional hematology and neurology
indications.
SOLIRIS
SOLIRIS (eculizumab) is a first-in-class C5 complement
inhibitor. The medication works by inhibiting the C5 protein in the
terminal complement cascade, a part of the body’s immune system.
When activated in an uncontrolled manner, the terminal complement
cascade over-responds, leading the body to attack its own healthy
cells. SOLIRIS is administered intravenously every two weeks,
following an introductory dosing period.
SOLIRIS is approved in the US, EU and Japan for the treatment of
PNH, aHUS, certain adults with gMG and certain adults with
NMOSD.
SOLIRIS is not indicated for the treatment of patients with
STEC-HUS.
Alexion
Alexion, AstraZeneca Rare Disease, is the group within
AstraZeneca focused on rare diseases, created following the 2021
acquisition of Alexion Pharmaceuticals, Inc. As a leader in rare
diseases for 30 years, Alexion is focused on serving patients and
families affected by rare diseases and devastating conditions
through the discovery, development and commercialization of
life-changing medicines. Alexion focuses its research efforts on
novel molecules and targets in the complement cascade and its
development efforts on hematology, nephrology, neurology, metabolic
disorders, cardiology and ophthalmology. Headquartered in Boston,
Massachusetts, Alexion has offices around the globe and serves
patients in more than 50 countries. For more information, please
visit www.alexion.com.
About AstraZeneca
AstraZeneca is a global, science-led biopharmaceutical company
that focuses on the discovery, development and commercialization of
prescription medicines in Oncology, Rare Diseases and
BioPharmaceuticals, including Cardiovascular, Renal &
Metabolism, and Respiratory & Immunology. Based in Cambridge,
UK, AstraZeneca operates in over 100 countries and its innovative
medicines are used by millions of patients worldwide. For more
information, please visit www.astrazeneca-us.com and follow us on
Twitter @AstraZenecaUS.
References
- Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood.
2014;124(18):2804-2811.
- Griffin M, Hillmen P, Munir T, et al. Significant hemolysis is
not required for thrombosis in paroxysmal nocturnal hemoglobinuria.
Haematologica. 2019;104(3):e94-e96.
- Hillmen P., et al. The Complement Inhibitor Eculizumab in
Paroxysmal Nocturnal Hemoglobinuria. N Engl J Med.
2006;355(12):1233-43.
- Hillmen, P., et al. Effect of the complement inhibitor
eculizumab on thromboembolism on patients with paroxysmal nocturnal
hemoglobinuria. Blood. 2007;110(12):4123-4128.
- Kulasekararaj, A. G., et al. Ravulizumab (ALXN1210) vs
eculizumab in C5-inhibitor-experienced adult patients with PNH: the
302 study. Blood. 2019;133(6):540–549.
- Brodsky RA. A complementary new drug for PNH. Blood.
2020;135(12):884–885.
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Media Inquiries Todd Siesky +1 475 434 8140
Alexion Media Mailbox: media@alexion.com
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