Ultomiris showed zero relapses in adults with neuromyelitis optica spectrum disorder (NMOSD) with median treatment duration of 73 weeks

Results from CHAMPION-NMOSD trial demonstrated Ultomiris reduced the risk of relapse in AQP4 Ab+ NMOSD by 98.6% compared to placebo.
Ultomiris also showed a lower proportion of patients experiencing clinically important worsening in Hauser Ambulatory Index score, a measure of patient mobility.
Strong results across several subgroup analyses add to growing body of evidence supporting C5 inhibition in NMOSD.

Detailed positive results from the Phase III CHAMPION-NMOSD trial showed that Ultomiris (ravulizumab) significantly reduced relapse risk in adults with anti-aquaporin-4 (AQP4) antibody-positive (Ab+) neuromyelitis optica spectrum disorder (NMOSD), compared to the external placebo arm from the pivotal Soliris PREVENT clinical trial. Data were presented today at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress.

NMOSD is a rare and debilitating autoimmune disease that affects the central nervous system (CNS), including the spine and optic nerves.^1-3 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.^4-6

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: “The CHAMPION-NMOSD trial showed zero relapses with a median treatment duration of 73 weeks, providing evidence that ravulizumab may offer patients sustained reduction in the risk of relapse with dosing every eight weeks and underscoring the efficacy of C5 inhibition in managing NMOSD.”

Michael Yeaman, PhD, Professor of Medicine at the UCLA School of Medicine, Director of the Institute for Infection and Immunity, Lundquist Institute at Harbor–UCLA and Chair Medical Advisor to the Guthy-Jackson Charitable Foundation for NMOSD, said: “In recent years, we have seen meaningful progress in bringing safe and effective treatments to patients with AQP4 Ab+ NMOSD, a rare disease that can disrupt many aspects of daily life, including mobility, vision, strength and balance. Based on insights from working with patients and their families every day, continued innovative research and clinical trials help empower people living with NMOSD by advancing new treatment options that may be more compatible with their individual needs and lifestyles.”

Gianluca Pirozzi, MD, PhD, Senior Vice President, Head of Development and Safety, Alexion, said: “CHAMPION-NMOSD is a remarkable example of the innovation required to design and execute rare disease clinical trials that are both scientifically rigorous and clinically meaningful. By seeking input from patients and coordinating with health authorities, this Phase III trial put the needs of patients first and evaluated measures that mattered most to them. We are excited by the significance of the results and the potential of Ultomiris to advance care for the NMOSD community.”

CHAMPION-NMOSD is a global Phase III, open-label, multicentre trial evaluating the safety and efficacy of Ultomiris in adults (n=58). 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. Ultomiris, the active treatment, was compared to the external placebo arm from the pivotal Soliris PREVENT clinical trial.⁷

Data showed zero adjudicated 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). Additionally, 100% of patients receiving Ultomiris remained relapse-free at 48 weeks, compared to 63% of patients in the external placebo arm.⁷

The CHAMPION-NMOSD trial also met key secondary efficacy endpoints, including adjudicated on-trial annualised relapse rate (total number of relapses in the study divided by total number of patient years) and clinically important change from baseline in mobility (ability to walk) as measured by Hauser Ambulation Index (a scale to assess mobility).⁷

Summary of efficacy results from primary treatment period^i,ii

Ultomiris reduced the risk of relapse by 98.6% compared with placebo

1. Results analysed comparing Ultomiris treatment arm to the external placebo group from the PREVENT trial
2. ARR, annualised relapse rate; CI, confidence limit; EDSS, Expanded Disability Status Scale; EQ-5D, EuroQol 5-Dimensions; HAI, Hauser Ambulation Index; N/A, not applicable; SD, standard deviation; VAS, visual analogue scale
3. Because statistical significance for clinically important change from baseline in EQ-5D score was not met, p values for the subsequent lower-ranking secondary efficacy endpoints are not significant; therefore, nominal p values are presented.

Overall, the safety and tolerability of Ultomiris was consistent with previous clinical studies and real-world use and no new safety signals were observed. The most common adverse events (AEs) (greater than or equal to 10% of patients) were COVID-19 (24%), headache (24%), back pain (12%), arthralgia (10%) and urinary tract infection (10%). All cases of COVID-19 were non-serious and considered to be unrelated to Ultomiris. There were two meningococcal infections reported; both patients recovered fully with no sequelae and one continued in the trial. Fifty-six patients are continuing to receive treatment in an ongoing long-term extension period.⁷

CHAMPION-NMOSD subgroup and sensitivity analyses
Additional results from the CHAMPION-NMOSD trial were also presented at ECTRIMS in two posters, detailing subgroup and sensitivity analyses.

In the subgroup analysis, based on time to first adjudicated on-trial relapse, Ultomiris was superior to the external placebo arm in patients receiving monotherapy (n=30; hazard ratio [HR]: 0.021; 95% confidence interval [CI]: 0.000–0.176; relapse risk reduction [RRR]: 97.9%; p<0.0001) and in patients receiving concomitant therapy (n=28; HR: 0.031; 95% CI: 0.000–0.234; RRR: 96.9%; p<0.0001). Significant differences were observed in patients who had received rituximab in the previous year (n=20; HR: 0.063; 95% CI: 0.000–0.562; RRR: 93.7%; p=0.0078) or had not (n=38; HR: 0.019; 95% CI: 0.000-0.142; RRR 98.1%; p<0.0001) compared to placebo.

The robust treatment effect of Ultomiris was also observed across pre-specified efficacy subgroups, including age (<45 years or ≥45 years: RRR: 95.7–97.9%; p≤0.0012), sex (RRR: 94.3–98.2%; p≤0.0068), Asian and white races (RRR: 95.1–97.8%; p≤0.0027) and geographic region (RRR: 91.5–96.1%; p≤0.025).⁸

Further, pre-specified sensitivity analyses were conducted to account for potential differences in baseline patient characteristics that could impact treatment efficacy. Time to first adjudicated relapse and relapse risk reduction were analysed using a stabilised inverse probability of treatment weighting approach. The results were consistent with the primary analysis, suggesting that any differences in baseline characteristics between the Ultomiris and external placebo groups did not impact the treatment effect.⁹

Regulatory submissions for Ultomiris for the treatment of NMOSD are currently under review with multiple health authorities, including in the United States (US), European Union (EU) and Japan.

Notes 

NMOSD 
NMOSD is a rare disease in which the immune system is inappropriately activated to target healthy tissues and cells in the CNS.^1,2 Approximately three-quarters of people with NMOSD are anti-AQP4 Ab+, meaning they produce antibodies that bind to a specific protein, aquaporin-4 (AQP4).¹⁰ 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.^1,11,12

It most commonly affects women and begins in the mid-30s. Men and children may also develop NMOSD, but it is even more rare.^13,14 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.^3-5,15,16 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.^4-6 NMOSD is a distinct disease from other CNS diseases, including multiple sclerosis. The journey to diagnosis can be long, with the disease sometimes misdiagnosed.^17-19

CHAMPION-NMOSD
CHAMPION-NMOSD is aglobal 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.²⁰

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), 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.

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 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 and follow the Company on Twitter @AstraZeneca.

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Dr. Pittock has provided consulting services to Alexion.