REG - AstraZeneca PLC - Update on US review of Ultomiris for NMOSD

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RNS Number : 5427L  AstraZeneca PLC  06 September 2023

6 September 2023

Update on US regulatory review of Ultomiris in NMOSD

 

The US Food and Drug Administration (FDA) has issued a complete response
letter (CRL) regarding the supplemental Biologics License Application (sBLA)
for long-acting C5 complement inhibitor Ultomiris (ravulizumab-cwvz) for the
treatment of adult patients with neuromyelitis optica spectrum disorder
(NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive (Ab+).

 

The CRL did not request additional analysis or reanalysis of the Phase III
CHAMPION-NMOSD trial data included in the sBLA submission and did not raise
concerns about the efficacy or safety data from the trial.(1)

 

The FDA requested modifications to enhance the Ultomiris Risk Evaluation and
Mitigation Strategy (REMS) to further validate patients' meningococcal
vaccination status or prophylactic administration of antibiotics prior to
treatment.

 

Alexion, AstraZeneca Rare Disease is working closely with the FDA regarding
next steps for the REMS modifications and remains committed to bringing
Ultomiris to people living with NMOSD in the US as quickly as possible.

 

Ultomiris is currently approved for the treatment of certain adults with NMOSD
in the European Union (EU), Japan and other countries.

 

Ultomiris is approved by the FDA for the treatment of adult patients with
generalised myasthenia gravis (gMG) who are anti-acetylcholine receptor (AChR)
Ab+, and certain adults and children with paroxysmal nocturnal haemoglobinuria
(PNH) or atypical haemolytic uraemic syndrome (aHUS).

 

Notes

 

NMOSD

NMOSD is a rare disease in which the immune system is inappropriately
activated to target healthy tissues and cells in the central nervous system
(CNS).(2,3) Approximately three-quarters of people with NMOSD are anti-AQP4
Ab+, meaning they produce antibodies that bind to a specific protein,
aquaporin-4 (AQP4).(4) 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.(2,5,6)

It most commonly affects women and begins in the mid-30s. Men and children may
also develop NMOSD, but it is even more rare.(7,8) 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.(9-13 )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.(10,11,14) NMOSD is a distinct
disease from other CNS diseases, including multiple sclerosis. The journey to
diagnosis can be long, with the disease sometimes misdiagnosed.(15-17)

 

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.(18)

 

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 and Japan for the treatment of certain
adults with generalised myasthenia gravis.

 

Ultomiris is also approved in the US, EU and Japan 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 and Japan for certain adults
and children with atypical haemolytic uraemic syndrome to inhibit
complement-mediated thrombotic microangiopathy.

 

Further, Ultomiris is approved in the 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
more than 50 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 (http://www.astrazeneca.com/) and follow the
Company on social media @AstraZeneca
(https://www.linkedin.com/company/astrazeneca/mycompany/verification/) .

 

Contacts

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(https://www.astrazeneca.com/investor-relations.html#Contacts) . For Media
contacts, click here (https://www.astrazeneca.com/media-centre/contacts.html)
.

 

References

1.   Pittock SJ, et al. Efficacy and safety of ravulizumab in adults with
anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder:
outcomes from the phase 3 CHAMPION-NMOSD trial. Oral Presentation at: American
Academy of Neurology Annual Meeting, April 23, 2023; Presentation S5.002
(https://index.mirasmart.com/aan2023/SearchResults.php?Program_Number=S5.002)
.

2.   Wingerchuk DM, et al. The spectrum of neuromyelitis optica. Lancet
Neurol. 2007;6(9):805-815.

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

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

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

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

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

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

9.   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.

10.  Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Treat Options
Neurol. 2008;10(1):55-66.

11.  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.

12.  Quek AML, et al. Effects of age and sex on aquaporin-4 autoimmunity.
Arch Neurol 2012;69:1039-43.

13.  Tüzün E, et al. Enhanced complement consumption in neuromyelitis
optica and Behcet's disease patients. J Neuroimmunol. 2011;233(1-2):211-215.

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

15.  Jarius S, Wildemann B. The History of Neuromyelitis Optica. J
Neuroinflammation. 2013;10, 797.

16.  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.

17.  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.

18.  ClinicalTrials.gov. An Efficacy and Safety Study of Ravulizumab in Adult
Participants With NMOSD. NCT Identifier: NCT04201262. Available here
(https://classic.clinicaltrials.gov/ct2/show/NCT04201262) . Accessed August
2023.

Adrian Kemp

Company Secretary

AstraZeneca PLC

 

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