25 March 2024
Ultomiris
approved in the
US for the treatment of adults with neuromyelitis optica spectrum
disorder (NMOSD)
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, characterised 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.
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 defence 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, multicentre 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
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 generalised myasthenia gravis
(gMG).
Ultomiris is
also approved in the US, EU, Japan and other countries for the
treatment of certain adults with paroxysmal nocturnal
haemoglobinuria (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 haemolytic uraemic 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
programme, Ultomiris is being assessed for
the treatment of additional haematology 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
commercialisation of life-changing medicines. Alexion focuses its
research efforts on novel molecules and targets in the complement
cascade and its development efforts on haematology, nephrology,
neurology, metabolic disorders, cardiology and ophthalmology.
Headquartered in Boston, Massachusetts, Alexion has offices around
the globe and serves patients in 70 countries.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is
a global, science-led biopharmaceutical company that focuses on the
discovery, development, and commercialisation 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 astrazeneca.com
and follow the Company on social media
@AstraZeneca.
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References
1. Ultomiris
(ravulizumab-cwvz) US prescribing information; 2024.
2. Pittock, SJ, et al. Ravulizumab in aquaporin-4-positive
neuromyelitis optica spectrum disorder. Ann
Neurol, 2023; 93: 1053-1068.
3. Wingerchuk DM, et al. The spectrum of neuromyelitis optica.
Lancet Neurol.
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Neurol. 2017;264(10):2088-2094.
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and seronegative neuromyelitis optica: a multicentre study of 175
patients. J
Neuroinflammation. 2012;9:14.
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Incidence and Prevalence of NMOSD in Australia and New Zealand. J
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South East Wales. Eur J
Neurol. 2012;19(4): 655-659.
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cell membrane. Prog Histochem
Cytochem. 2004;39(1):1-83.
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17. Quek AML, et al. Effects of age and sex on aquaporin-4
autoimmunity. Arch Neurol.
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18. Tüzün E, et al. Enhanced complement consumption in
neuromyelitis optica and Behcet's disease patients. J Neuroimmunol.
2011;233(1-2):211-215.
19. 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.
20. Jarius S, et al.. The History of Neuromyelitis Optica.
J Neuroinflammation.
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21. 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.
22. 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.
Adrian Kemp
Company Secretary
AstraZeneca PLC