# AstraZeneca Ultomiris granted approval in US for treatment of adults with neuromyelitis optica spectrum disorder

- Link: https://www.directorstalkinterviews.com/astrazeneca-ultomiris-granted-approval-in-us-for-treatment-of-adults-with-neuromyelitis-optica-spectrum-disorder/4121149025
- Published: 2024-03-25T07:17:35+00:00
- Author: Ethan Davis

**_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.  

**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.

**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_.
2007;6(9):805-815. 

4.   Wingerchuk DM. Diagnosis and treatment of neuromyelitis optica. _Neurologist_.
2007;13(1):2-11. 

5.   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. 

6.   Wingerchuk DM, et al. Neuromyelitis optica. _Curr Treat Options Neurol_. 2008;10(
1):55-66. 

7.   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. 

8.   Jarius S, et al. Contrasting disease patterns in seropositive and seronegative
neuromyelitis optica: a multicentre study of 175 patients. _J Neuroinflammation_.
2012;9:14. 

9.   Papp V, et al. A population-based epidemiological study of neuromyelitis optica
spectrum disorder in Hungary. Eur J Neurol. 2020;27(2):308-317.

10.  Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis
optica spectrum. Ann Neurol. 2016;79:775-783.

11.  Bukhari W, et al. Incidence and Prevalence of NMOSD in Australia and New Zealand.
J Neurol Neurosurg Psychiatry. 2017;88(8):632-638.

12.  Wingerchuk DM, et al. The clinical course of neuromyelitis optica (Devic’s 
syndrome). _Neurology_. 1999;53(5):1107-1114. 

13.  Cossburn M, et al. The Prevalence of Neuromyelitis Optica in South East Wales.
_Eur J Neurol_. 2012;19(4): 655-659. 

14.  Papadopoulos MC, et al. Treatment of neuromyelitis optica: state-of-the-art
and emerging therapies. _Nat Rev Neurol_. 2014;10(9):493. 

15.  Takata K, et al. Aquaporins: water channel proteins of the cell membrane. _Prog
Histochem Cytochem_. 2004;39(1):1-83. 

16.  Mori M, et al. Worldwide prevalence of neuromyelitis optica spectrum disorders.
_J Neurol Neurosurg Psychiatry_. 2018;89(6):555-556.

17.  Quek AML, et al. Effects of age and sex on aquaporin-4 autoimmunity. _Arch 
Neurol_. 2012;69:1039-43. 

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_.
2013;10, 797. 

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.

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