Analysis of Phase III CHAMPION-MG trial
open-label extension adds to growing body of safety and efficacy
data for ULTOMIRIS in generalized myasthenia gravis
Patients who transitioned from placebo to
ULTOMIRIS showed rapid and sustained response, reinforcing clinical
benefit of C5 inhibition
New, prolonged follow-up results from the Phase III CHAMPION-MG
trial open-label extension (OLE) showed that ULTOMIRIS®
(ravulizumab-cwvz) demonstrated long-term efficacy in adults with
anti-acetylcholine receptor (AChR) antibody-positive generalized
myasthenia gravis (gMG), with improvements in activities of daily
living, muscle strength and quality of life, sustained through 60
weeks.1 ULTOMIRIS was also well tolerated throughout this
analysis.
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Results from the trial were presented on April 5 at the 2022
American Academy of Neurology (AAN) Annual Meeting.
gMG is a rare, debilitating, chronic, autoimmune neuromuscular
disease that leads to a loss of muscle function and severe
weakness.2 Symptoms of gMG may include disabling fatigue, slurred
speech, difficulty swallowing and eating, double or blurred vision,
immobility requiring assistance, shortness of breath, and episodes
of respiratory failure.3-5
Professor James F. Howard, Jr, MD, Department of Neurology at
The University of North Carolina School of Medicine and lead
primary investigator in the CHAMPION-MG trial said: “gMG is a
complex, devastating disease, disrupting many aspects of daily
living, and helping patients improve muscle strength and function
should be essential to any treatment plan. These results reinforce
that C5 inhibition with predictable dosing is an important
treatment option which provides sustained improvement of functional
activities.”
Gianluca Pirozzi, MD, PhD, Senior Vice President, Head of
Development and Safety, Alexion, said: “Alexion has pioneered the
research of complement inhibition as a treatment approach for rare
diseases, and we are continuing to innovate to benefit as many
patients as possible. These data are encouraging because they
suggest ULTOMIRIS has the potential to help a broader range of gMG
patients, including those with milder symptoms, regain control of
their lives and experience sustained clinical benefit through 60
weeks. We are deeply grateful for continued input and collaboration
from the gMG community.”
Upon completion of the randomized control period (RCP) of the
CHAMPION-MG trial, 99.4% of participants (n=161) entered the OLE,
during which all patients received ULTOMIRIS. At the time of data
cut off, 113 patients had reached 60 weeks. Efficacy analysis
included all patients who received ≥1 dose of ULTOMIRIS in the
OLE.1
ULTOMIRIS demonstrated statistically significant improvements
from baseline (defined as initiation of ULTOMIRIS therapy) in
measures of functional activity, muscle strength and quality of
life at 60 weeks of the OLE, including Myasthenia Gravis-Activities
of Daily Living (MG-ADL) total score (-4.0 [95% CI -4.8, -3.1],
p<0.0001). Additionally, patients transitioning from placebo
(n=83) showed rapid response at a similar magnitude and time course
as those who received ULTOMIRIS during the RCP.1
Summary of efficacy results
Changes in scores from RCP baseline among patients who
received ULTOMIRIS for 60 weeksi,ii
Analysis at week 60 of ULTOMIRIS
treatment (n=78)
MG-ADL Total Score
-4.0 [95% CI -4.8, -3.1], p<0.0001
Quantitative Myasthenia Gravis Total
Score
-4.1 [95% CI -5.4, -2.9], p<0.0001
Revised 15-Item Myasthenia Gravis
Quality of Life Score
-5.0 [95% CI -6.9, -3.1], p<0.0001
Neurological Quality of Life Fatigue
Subscale Score
-10.2 [95% CI -15.1, -5.3],
p<0.0001
- Results analyzed using mixed-effect model for repeated
measures, reported as least squares mean change from RCP
baseline
- Eleven patients discontinued OLE prior to the data cut-off
The safety and tolerability were consistent with the known
safety profile of ULTOMIRIS observed in the RCP of CHAMPION-MG and
other approved indications. The most common adverse events (AEs)
(occurring in greater than or equal to 10% of 169 patients treated
with ULTOMIRIS in the RCP and/or OLE) were headache (16.6%) and
diarrhea (13.6%).1
Additional results from the CHAMPION-MG trial and
pharmacokinetics and pharmacodynamics of ULTOMIRIS in gMG were also
presented at the 2022 AAN Annual Meeting.
Regulatory submissions for ULTOMIRIS for the treatment of gMG
are currently under review with multiple health authorities,
including in the United States (US), European Union (EU) and
Japan.
IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNING
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, feeling faint
or discomfort in your arms or legs. 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.
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.
INDICATIONS
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).
It is not known if ULTOMIRIS is safe and effective in children
younger than 1 month of age.
Please see the accompanying full Prescribing Information and
Medication Guide for ULTOMIRIS, including Boxed WARNING regarding
serious and life-threatening meningococcal
infections/sepsis.
Notes
gMG
gMG is a rare autoimmune disorder characterized by loss of
muscle function and severe muscle weakness.2
85% of people with gMG are AChR Ab+, meaning they produce
specific antibodies (anti-AChR) that bind to signal receptors at
the neuromuscular junction (NMJ), the connection point between
nerve cells and the muscles they control. This binding activates
the complement system, which is essential to the body’s defense
against infection, causing the immune system to attack the NMJ.2
This leads to inflammation and a breakdown in communication between
the brain and the muscles.2
gMG can occur at any age, but most commonly begins for women
before the age of 40 and for men after the age of 60.6-8 Initial
symptoms may include slurred speech, double vision, droopy eyelids,
and lack of balance; these can often lead to more severe symptoms
as the disease progresses such as, impaired swallowing, choking,
extreme fatigue, and respiratory failure.4,9
CHAMPION-MG
The global Phase III randomized, double-blind,
placebo-controlled, multicenter 26-week trial evaluated the safety
and efficacy of ULTOMIRIS in adults with gMG who were not
previously treated with a complement inhibitor medicine. The trial
enrolled 175 patients across North America, Europe, Asia-Pacific
and Japan. Participants were required to have a confirmed
myasthenia gravis diagnosis at least six months prior to the
screening visit with a positive serologic test for anti-AChR
antibodies, MG-ADL total score of at least 6 at trial entry and
Myasthenia Gravis Foundation of America Clinical Classification
Class II to IV at screening. There was no requirement for prior
treatment failure, and patients could stay on stable standard of
care medicines, with a few exceptions, for the duration of the
randomized control period.10
Patients were randomized 1:1 to receive ULTOMIRIS or placebo for
a total of 26 weeks. Patients received a single weight-based
loading dose on Day 1, followed by regular weight-based maintenance
dosing beginning on Day 15, every eight weeks. The primary endpoint
of change from baseline in the MG-ADL total score at Week 26 was
assessed along with multiple secondary endpoints evaluating
improvement in disease-related and quality-of-life measures.
Patients who completed the randomized control period were
eligible to continue into an open-label extension period evaluating
the safety and efficacy of ULTOMIRIS, which is ongoing.
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, EU and Japan for the treatment
of certain adults and children with paroxysmal nocturnal
hemoglobinuria (PNH) based on the ALXN1210-PNH-302 and
ALXN1210-PNH-304 Phase III trials.
Additionally, ULTOMIRIS is approved in the US, EU and Japan for
certain adults and children with atypical hemolytic uraemic
syndrome (aHUS) based on the ALXN1210-aHUS-311 and
ALXN1210-aHUS-312 Phase III trials.
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 nearly 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
- Howard, JF., Vu, T., Mantegazza, R., et al. Long-term efficacy
and safety of ravulizumab, a long-acting terminal complement
inhibitor, in adults with anti-acetylcholine receptor
antibody-positive generalized myasthenia gravis: Results from the
phase 3 CHAMPION MG open-label extension. Oral presentation at:
American Academy of Neurology (AAN) Annual Meeting; April 5, 2022;
Session S25.005.
- Howard, J. F., (2017). Myasthenia gravis: the role of
complement at the neuromuscular junction. Annals of The New York
Academy of Sciences, 1412(1), 113-128.
- Howard JF, Barohn RJ, Cutter GR, et al. A randomized,
double-blind, placebo-controlled phase II study of eculizumab in
patients with refractory generalized myasthenia gravis. Muscle
Nerve. 2013;48(1):76-84.
- Myasthenia Gravis Fact Sheet. (2020, April 27). National
Institutes of Neurological Disorders and Stroke. Available here.
Accessed March 2022.
- Sathasivam S. Diagnosis and management of myasthenia gravis.
Wiley Online Library website.
https://onlinelibrary.wiley.com/doi/pdf/10.1002/pnp.315. Accessed
September 25, 2019.
- Myasthenia Gravis. National Organization for Rare Disorders
(NORD). Available here. Accessed March 2022.
- Howard, J. F. (2015). Clinical Overview of MG. Available here.
Accessed March 2022.
- Sanders, D. B., Raja, S. M., Guptill J. T., Hobson-Webb, L. D.,
Juel, V. C., & Massey, J. M. (2020). The Duke myasthenia gravis
clinic registry: I. Description and demographics. Muscle &
Nerve, 63(2), 209-216.
- Ding J., Zhao, S., Ren, K., Dang, D., Li, H., Wu, F., Zhang,
M., Li, Z., & Guo, J. (2020). Prediction of generalization of
ocular myasthenia gravis under immunosuppressive therapy in
Northwest China. BMC Neurology, 20(238).
- ClinicalTrials.gov. Safety and Efficacy Study of Ravulizumab in
Adults With Generalized Myasthenia Gravis. NCT Identifier:
NCT03920293. Available online. Accessed March 2022.
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