First and only long-acting C5 complement
inhibitor offers patients with AQP4 Ab+ NMOSD the potential to live
relapse-free
Unprecedented relapse risk reduction
observed in CHAMPION-NMOSD trial underscores how ULTOMIRIS may
redefine patient journey for rare neurological disease
ULTOMIRIS® (ravulizumab-cwvz) has been approved in the United
States (US) as the first and only long-acting C5 complement
inhibitor for the treatment of adult patients with anti-aquaporin-4
(AQP4) antibody-positive (Ab+) neuromyelitis optica spectrum
disorder (NMOSD).1
The approval by the US Food and Drug Administration (FDA) was
based on positive results from the CHAMPION-NMOSD Phase III trial,
which were published in the Annals of Neurology.2 In the trial,
ULTOMIRIS was compared to an external placebo arm from the pivotal
SOLIRIS® PREVENT clinical trial.
ULTOMIRIS met the primary endpoint of time to first on-trial
relapse as confirmed by an independent adjudication committee. Zero
relapses were observed among ULTOMIRIS patients with a median
treatment duration of 73 weeks (relapse risk reduction: 98.6%,
hazard ratio (95% CI): 0.014 (0.000, 0.103), p<0.0001).2
NMOSD is a rare and debilitating autoimmune disease that affects
the central nervous system (CNS), including the spine and optic
nerves.3-5 Most people living with NMOSD experience unpredictable
relapses, characterized by a new onset of neurologic symptoms or
worsening of existing neurologic symptoms, which tend to be severe
and recurrent and may result in permanent disability.6-8 The
diagnosed prevalence of adults with NMOSD in the US is estimated at
approximately 6,000.9-11
Sean J. Pittock, MD, Director of Mayo Clinic's Center for
Multiple Sclerosis and Autoimmune Neurology and of Mayo's
Neuroimmunology Laboratory and lead primary investigator in the
CHAMPION-NMOSD trial, said: “C5 inhibition has been proven to offer
efficacy in reducing the risk of NMOSD relapses by blocking the
complement system, a part of the immune system, from attacking
healthy cells in the spinal cord, optic nerve and brain. With
today’s FDA approval, patients now have the option of a long-acting
C5 inhibitor treatment that showed zero relapses in the pivotal
CHAMPION-NMOSD trial, supporting the primary goal of relapse
prevention in treating NMOSD.”
Marc Dunoyer, Chief Executive Officer, Alexion, said: “Alexion
has been at the forefront of innovation in NMOSD, striving to offer
patients a future without fear of life-altering or even fatal
relapses. Building on the established efficacy of C5 inhibition for
people living with AQP4 Ab+ NMOSD, we are proud to deliver a
transformative, long-acting treatment option that has the potential
to eliminate relapses with a convenient dosing schedule every eight
weeks. We are grateful to the NMOSD community for their ongoing
collaboration and input, which enables us to advance science for
rare diseases.”
Overall, the safety and tolerability of ULTOMIRIS in the
CHAMPION-NMOSD trial were consistent with previous clinical studies
and real-world use, and no new safety signals were observed. The
most common adverse events (AEs) were COVID-19, headache, back
pain, arthralgia and urinary tract infection.2
ULTOMIRIS is also approved for certain adults with NMOSD in
Japan and the European Union (EU). Regulatory reviews are ongoing
in additional countries.
INDICATION(S) & IMPORTANT SAFETY INFORMATION
INDICATION(S)
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.
- adults with a disease called Neuromyelitis Optica Spectrum
Disorder (NMOSD) who are anti-aquaporin 4 (AQP4) antibody
positive.
It is not known if ULTOMIRIS is safe and effective in children
younger than 1 month of age.
It is not known if ULTOMIRIS is safe and effective for the
treatment of gMG or NMOSD in children.
IMPORTANT SAFETY INFORMATION
What is the most important information I should know about
ULTOMIRIS?
ULTOMIRIS is a medicine that affects your immune system and
may lower the ability of your immune system to fight
infections.
- ULTOMIRIS increases your chance of getting serious
meningococcal infections that may quickly become life-threatening
or cause death if not recognized and treated early.
- You must complete or update meningococcal vaccine(s) at least 2
weeks before your first dose of ULTOMIRIS.
- If you have not completed your meningococcal vaccines and
ULTOMIRIS must be started right away, you should receive the
required vaccine(s) as soon as possible.
- If you have not been vaccinated and ULTOMIRIS must be started
right away, you should also receive antibiotics for as long as your
healthcare provider tells you.
- If you had a meningococcal vaccine in the past, you might need
additional vaccines before starting ULTOMIRIS. Your healthcare
provider will decide if you need additional meningococcal
vaccines.
- Meningococcal vaccines do not prevent all meningococcal
infections. Call your healthcare provider or get emergency
medical care right away if you get any of these signs and symptoms
of a meningococcal infection: fever, fever with high heart
rate, headache and fever, confusion, muscle aches with flu-like
symptoms, fever and a rash, headache with nausea or vomiting,
headache with a stiff neck or stiff back, or eyes sensitive to
light.
Your healthcare provider will give you a Patient Safety Card
about the risk of serious meningococcal infection. Carry it
with you at all times during treatment and for 8 months after your
last ULTOMIRIS dose. Your risk of meningococcal infection may
continue for several months after your last dose of ULTOMIRIS. It
is important to show this card to any healthcare provider who
treats you. This will help them diagnose and treat you quickly.
ULTOMIRIS is only available through a program called the
ULTOMIRIS and SOLIRIS Risk Evaluation and Mitigation Strategy
(REMS). Before you can receive ULTOMIRIS, your healthcare
provider must: enroll in the REMS program; counsel you about the
risk of serious meningococcal infections; give you information
about the signs and symptoms of serious meningococcal infection;
make sure that you are vaccinated against serious infections caused
by meningococcal bacteria, and that you receive antibiotics if you
need to start ULTOMIRIS right away and are not up to date on your
vaccines; give you a Patient Safety Card about your risk of
meningococcal infection.
ULTOMIRIS may also increase the risk of other types of
serious infections, including Streptococcus pneumoniae,
Haemophilus influenzae, and Neisseria gonorrhoeae. Your
child should receive vaccines against Streptococcus pneumoniae and
Haemophilus influenzae type b (Hib) if treated with ULTOMIRIS.
Certain people may be at risk of serious infections with
gonorrhea.
Who should not receive ULTOMIRIS?
Do not receive ULTOMIRIS if you have a serious meningococcal
infection when you are starting ULTOMIRIS.
Before you receive ULTOMIRIS, tell your healthcare provider
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 healthcare provider 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
healthcare provider 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 healthcare provider 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, abdominal
pain, muscle spasms, changes in blood pressure, tiredness, feeling
faint, shaking chills (rigors), discomfort in your arms or legs,
bad taste, or drowsiness. Stop treatment of ULTOMIRIS and tell your
healthcare provider right away if you develop these symptoms, or
any other symptoms during your ULTOMIRIS infusion that may mean you
are having a serious infusion-related 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 treated
for 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 infections.
The most common side effects of ULTOMIRIS in people with
NMOSD are COVID-19 infection, headache, back pain, urinary tract
infection, and joint pain (arthralgia).
Tell your healthcare provider 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 healthcare
provider or pharmacist. Call your healthcare provider 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 meningococcal infections.
Notes
NMOSD
NMOSD is a rare disease in which the immune system is
inappropriately activated to target healthy tissues and cells in
the CNS.3,4 Approximately three-quarters of people with NMOSD are
anti-AQP4 Ab+, meaning they produce antibodies that bind to a
specific protein, aquaporin-4 (AQP4).5,12 This binding can
inappropriately activate the complement system, which is part of
the immune system and is essential to the body’s defense against
infection, to destroy cells in the optic nerve, spinal cord and
brain.3,13,14
It most commonly affects women and begins in the mid-30s. Men
and children may also develop NMOSD, but it is even more rare.15,16
People with NMOSD may experience vision problems, intense pain,
loss of bladder/bowel function, abnormal skin sensations (e.g.,
tingling, prickling or sensitivity to heat/cold) and impact on
coordination and/or movement.5-7,17,18 Most people living with
NMOSD experience unpredictable relapses, also known as attacks.
Each relapse can result in cumulative disability including vision
loss, paralysis and sometimes premature death.6-8 NMOSD is a
distinct disease from other CNS diseases, including multiple
sclerosis. The journey to diagnosis can be long, with the disease
sometimes misdiagnosed.19-21
CHAMPION-NMOSD
CHAMPION-NMOSD is a global Phase III, open-label, multicenter
trial evaluating the safety and efficacy of ULTOMIRIS in adults
with NMOSD. The trial enrolled 58 patients across North America,
Europe, Asia-Pacific and Japan. Participants were required to have
a confirmed NMOSD diagnosis with a positive anti-AQP4 antibody
test, at least one attack or relapse in the twelve months prior to
the screening visit, an Expanded Disability Status Scale Score of 7
or less and body weight of at least 40 kilograms at trial entry.
Participants could stay on stable supportive immunosuppressive
therapy for the duration of the trial.22
Due to the potential long-term functional impact of NMOSD
relapses and available effective treatment options, a direct
placebo comparator arm was precluded for ethical reasons. The
active treatment was compared to an external placebo arm from the
pivotal SOLIRIS PREVENT clinical trial.
Over a median treatment duration of 73 weeks, all enrolled
patients received a single weight-based loading dose of ULTOMIRIS
on Day 1, followed by regular weight-based maintenance dosing
beginning on Day 15, every eight weeks. The primary endpoint was
time to first on-trial relapse, as confirmed by an independent
adjudication committee. The end of the primary treatment period
could have occurred either when all patients completed or
discontinued prior to the Week 26 visit and two or more adjudicated
relapses were observed, or when all patients completed or
discontinued prior to the Week 50 visit if fewer than two
adjudicated relapses were observed. In the trial, there were zero
adjudicated relapses, so the end of the primary treatment period
occurred when the last enrolled participant completed the 50-week
visit.
Patients who completed the primary treatment period were
eligible to continue into a long-term extension period, which is
ongoing.
ULTOMIRIS® (ravulizumab-cwvz)
ULTOMIRIS® (ravulizumab-cwvz), the first and only
long-acting C5 complement inhibitor, provides 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, EU, Japan and other countries
for the treatment of certain adults with generalized myasthenia
gravis (gMG).
ULTOMIRIS is also approved in the US, EU, Japan and other
countries for the treatment of certain adults with paroxysmal
nocturnal hemoglobinuria (PNH) and for certain children with PNH in
the US and EU.
Additionally, ULTOMIRIS is approved in the US, EU, Japan and
other countries for certain adults and children with atypical
hemolytic uremic syndrome to inhibit complement-mediated thrombotic
microangiopathy (aHUS).
Further, ULTOMIRIS is approved in the US, EU and Japan for the
treatment of certain adults with neuromyelitis optica spectrum
disorder (NMOSD).
As part of a broad development program, ULTOMIRIS is being
assessed for the treatment of additional hematology and neurology
indications.
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 more than 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 70 countries. For more information, please visit
www.alexion.com.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) 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. Please visit www.astrazeneca-us.com and follow
the Company on social media @AstraZeneca.
References
- Ultomiris (ravulizumab-cwvz) US prescribing information;
2024.
- Pittock, SJ, et al. Ravulizumab in aquaporin-4–positive
neuromyelitis optica spectrum disorder. Ann Neurol, 2023; 93:
1053-1068.
- Wingerchuk DM, et al. The spectrum of neuromyelitis optica.
Lancet Neurol. 2007;6(9):805-815.
- Wingerchuk DM. Diagnosis and treatment of neuromyelitis optica.
Neurologist. 2007;13(1):2-11.
- Hamid SHM, et al. What proportion of AQP4-IgG-negative NMO
spectrum disorder patients are MOG-IgG positive? A cross sectional
study of 132 patients. J Neurol. 2017;264(10):2088-2094.
- Wingerchuk DM, et al. Neuromyelitis optica. Curr Treat Options
Neurol. 2008;10(1):55-66.
- Kitley J, et al. Prognostic factors and disease course in
aquaporin-4 antibody-positive patients with neuromyelitis optica
spectrum disorder from the United Kingdom and Japan. Brain.
2012;135(6):1834-1849.
- Jarius S, et al. Contrasting disease patterns in seropositive
and seronegative neuromyelitis optica: a multicentre study of 175
patients. J Neuroinflammation. 2012;9:14.
- Papp V, et al. A population-based epidemiological study of
neuromyelitis optica spectrum disorder in Hungary. Eur J Neurol.
2020;27(2):308-317.
- Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity
and neuromyelitis optica spectrum. Ann Neurol.
2016;79:775–783.
- Bukhari W, et al. Incidence and Prevalence of NMOSD in
Australia and New Zealand. J Neurol Neurosurg Psychiatry.
2017;88(8):632-638.
- Wingerchuk DM, et al. The clinical course of neuromyelitis
optica (Devic’s syndrome). Neurology. 1999;53(5):1107-1114.
- Cossburn M, et al. The Prevalence of Neuromyelitis Optica in
South East Wales. Eur J Neurol. 2012;19(4): 655-659.
- Papadopoulos MC, et al. Treatment of neuromyelitis optica:
state-of-the-art and emerging therapies. Nat Rev Neurol.
2014;10(9):493.
- Takata K, et al. Aquaporins: water channel proteins of the cell
membrane. Prog Histochem Cytochem. 2004;39(1):1-83.
- Mori M, et al. Worldwide prevalence of neuromyelitis optica
spectrum disorders. J Neurol Neurosurg Psychiatry.
2018;89(6):555-556.
- Quek AML, et al. Effects of age and sex on aquaporin-4
autoimmunity. Arch Neurol. 2012;69:1039–43.
- Tüzün E, et al. Enhanced complement consumption in
neuromyelitis optica and Behcet’s disease patients. J Neuroimmunol.
2011;233(1-2):211-215.
- Kuroda H, et al. Increase of complement fragment C5a in
cerebrospinal fluid during exacerbation of neuromyelitis optica. J
Neuroimmunol. 2013;254(1-2):178-182.
- Jarius S, et al.. The History of Neuromyelitis Optica. J
Neuroinflammation. 2013;10, 797.
- Mealy MA, et al. Assessment of Patients with Neuromyelitis
Optica Spectrum Disorder Using the EQ-5D. Int J MS care.
2019;21(3), 129–134.
- ClinicalTrials.gov. An Efficacy and Safety Study of Ravulizumab
in Adult Participants With NMOSD. NCT Identifier: NCT04201262.
Available here. Accessed March 2024.
Dr. Pittock has provided consulting services to Alexion.
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